bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Myocardial Pericytes: Multipotent Mesodermal Precursors Exhibiting Cardiac Specificity
Authors: Chen William C. W. , Baily James E. , Corselli Mirko , Díaz Mary E. , Sun Bin , Xiang Guosheng , Gray Gillian A. , Huard Johnny , Péault Bruno 
Published: October 2014

Abstract
Perivascular mesenchymal precursor cells (i.e., pericytes) reside in skeletal muscle where they contribute to myofiber regeneration; however, the existence of similar microvessel-associated regenerative precursor cells in cardiac muscle has not yet been documented. We tested whether microvascular pericytes within human myocardium exhibit phenotypes and multipotency similar to their anatomically and developmentally distinct counterparts. Fetal and adult human heart pericytes (hHPs) express canonical pericyte markers in situ, including CD146, NG2, platelet-derived growth factor receptor (PDGFR) β, PDGFRα, alpha-smooth muscle actin, and smooth muscle myosin heavy chain, but not CD117, CD133, and desmin, nor endothelial cell (EC) markers. hHPs were prospectively purified to homogeneity from ventricular myocardium by flow cytometry, based on a combination of positive- (CD146) and negative-selection (CD34, CD45, CD56, and CD117) cell lineage markers. Purified hHPs expanded in vitro were phenotypically similar to human skeletal muscle-derived pericytes (hSkMPs). hHPs express mesenchymal stem/stromal cell markers in situ and exhibited osteo-, chondro-, and adipogenic potentials but, importantly, no ability for skeletal myogenesis, diverging from pericytes of all other origins. hHPs supported network formation with/without ECs in Matrigel cultures; hHPs further stimulated angiogenic responses under hypoxia, markedly different from hSkMPs. The cardiomyogenic potential of hHPs was examined following 5-azacytidine treatment and neonatal cardiomyocyte coculture in vitro, and intramyocardial transplantation in vivo. Results indicated cardiomyocytic differentiation in a small fraction of hHPs. In conclusion, human myocardial pericytes share certain phenotypic and developmental similarities with their skeletal muscle homologs, yet exhibit different antigenic, myogenic, and angiogenic properties. This is the first example of an anatomical restriction in the developmental potential of pericytes as native mesenchymal stem cells. Stem Cells 2015;33:557–573
Regulated Apoptosis of Genetically Modified Hematopoietic Stem and Progenitor Cells Via an Inducible Caspase-9 Suicide Gene in Rhesus Macaques
Authors: Barese Cecilia N. , Felizardo Tania C. , Sellers Stephanie E. , Keyvanfar Keyvan , Di Stasi Antonio , Metzger Mark E. , Krouse Allen E. , Donahue Robert E. , Spencer David M. , Dunbar Cynthia E. 
Published: October 2014

Abstract
The high risk of insertional oncogenesis reported in clinical trials using integrating retroviral vectors to genetically modify hematopoietic stem and progenitor cells (HSPCs) requires the development of safety strategies to minimize risks associated with novel cell and gene therapies. The ability to ablate genetically modified cells in vivo is desirable, should an abnormal clone emerge. Inclusion of “suicide genes” in vectors to facilitate targeted ablation of vector-containing abnormal clones in vivo is one potential safety approach. We tested whether the inclusion of the “inducible Caspase-9” (iCasp9) suicide gene in a gamma-retroviral vector facilitated efficient elimination of vector-containing HSPCs and their hematopoietic progeny in vivo long-term, in an autologous non-human primate transplantation model. Following stable engraftment of iCasp9 expressing hematopoietic cells in rhesus macaques, administration of AP1903, a chemical inducer of dimerization able to activate iCasp9, specifically eliminated vector-containing cells in all hematopoietic lineages long-term, suggesting activity at the HSPC level. Between 75% and 94% of vector-containing cells were eliminated by well-tolerated AP1903 dosing, but lack of complete ablation was linked to lower iCasp9 expression in residual cells. Further investigation of resistance mechanisms demonstrated upregulation of Bcl-2 in hematopoietic cell lines transduced with the vector and resistant to AP1903 ablation. These results demonstrate both the potential and the limitations of safety approaches using iCasp9 to HSPC-targeted gene therapy settings, in a model with great relevance to clinical development. Stem Cells 2015;33:91–100
Interrogation of a Context-Specific Transcription Factor Network Identifies Novel Regulators of Pluripotency
Authors: Kushwaha Ritu , Jagadish Nirmala , Kustagi Manjunath , Tomishima Mark J. , Mendiratta Geetu , Bansal Mukesh , Kim Hyunjae R. , Sumazin Pavel , Alvarez Mariano J. , Lefebvre Celine , Villagrasa-Gonzalez Patricia , Viale Agnes , Korkola James E. , Houldsworth Jane , Feldman Darren R. , Bosl George J. , Califano Andrea , Chaganti R. S. K. 
Published: October 2014

Abstract
The predominant view of pluripotency regulation proposes a stable ground state with coordinated expression of key transcription factors (TFs) that prohibit differentiation. Another perspective suggests a more complexly regulated state involving competition between multiple lineage-specifying TFs that define pluripotency. These contrasting views were developed from extensive analyses of TFs in pluripotent cells in vitro. An experimentally validated, genome-wide repertoire of the regulatory interactions that control pluripotency within the in vivo cellular contexts is yet to be developed. To address this limitation, we assembled a TF interactome of adult human male germ cell tumors (GCTs) using the Algorithm for the Accurate Reconstruction of Cellular Pathways (ARACNe) to analyze gene expression profiles of 141 tumors comprising pluripotent and differentiated subsets. The network (GCTNet) comprised 1,305 TFs, and its ingenuity pathway analysis identified pluripotency and embryonal development as the top functional pathways. We experimentally validated GCTNet by functional (silencing) and biochemical (ChIP-seq) analysis of the core pluripotency regulatory TFs POU5F1, NANOG, and SOX2 in relation to their targets predicted by ARACNe. To define the extent of the in vivo pluripotency network in this system, we ranked all TFs in the GCTNet according to sharing of ARACNe-predicted targets with those of POU5F1 and NANOG using an odds-ratio analysis method. To validate this network, we silenced the top 10 TFs in the network in H9 embryonic stem cells. Silencing of each led to downregulation of pluripotency and induction of lineage; 7 of the 10 TFs were identified as pluripotency regulators for the first time. Stem Cells 2015;33:367–377
Live Fluorescent RNA-Based Detection of Pluripotency Gene Expression in Embryonic and Induced Pluripotent Stem Cells of Different Species
Authors: Lahm Harald , Doppler Stefanie , Dreßen Martina , Werner Astrid , Adamczyk Klaudia , Schrambke Dominic , Brade Thomas , Laugwitz Karl-Ludwig , Deutsch Marcus-André , Schiemann Matthias , Lange Rüdiger , Moretti Alessandra , Krane Markus 
Published: October 2014

Abstract
The generation of induced pluripotent stem (iPS) cells has successfully been achieved in many species. However, the identification of truly reprogrammed iPS cells still remains laborious and the detection of pluripotency markers requires fixation of cells in most cases. Here, we report an approach with nanoparticles carrying Cy3-labeled sense oligonucleotide reporter strands coupled to gold-particles. These molecules are directly added to cultured cells without any manipulation and gene expression is evaluated microscopically after overnight incubation. To simultaneously detect gene expression in different species, probe sequences were chosen according to interspecies homology. With a common target-specific probe we could successfully demonstrate expression of the GAPDH house-keeping gene in somatic cells and expression of the pluripotency markers NANOG and GDF3 in embryonic stem cells and iPS cells of murine, human, and porcine origin. The population of target gene positive cells could be purified by fluorescence-activated cell sorting. After lentiviral transduction of murine tail-tip fibroblasts Nanog-specific probes identified truly reprogrammed murine iPS cells in situ during development based on their Cy3-fluorescence. The intensity of Nanog-specific fluorescence correlated positively with an increased capacity of individual clones to differentiate into cells of all three germ layers. Our approach offers a universal tool to detect intracellular gene expression directly in live cells of any desired origin without the need for manipulation, thus allowing conservation of the genetic background of the target cell. Furthermore, it represents an easy, scalable method for efficient screening of pluripotency which is highly desirable during high-throughput cell reprogramming and after genomic editing of pluripotent stem cells. Stem Cells 2015;33:392–402
Notch Signaling Regulates Motor Neuron Differentiation of Human Embryonic Stem Cells
Authors: Ben-Shushan Etti , Feldman Eva , Reubinoff Benjamin E. 
Published: October 2014

Abstract
In the pMN domain of the spinal cord, Notch signaling regulates the balance between motor neuron differentiation and maintenance of the progenitor state for later oligodendrocyte differentiation. Here, we sought to study the role of Notch signaling in regulation of the switch from the pMN progenitor state to differentiated motor neurons in a human model system. Human embryonic stem cells (hESCs) were directed to differentiate to pMN-like progenitor cells by the inductive action of retinoic acid and a Shh agonist, purmorphamine. We found that the expression of the Notch signaling effector Hes5 was induced in hESC-derived pMN-like progenitors and remained highly expressed when they were cultured under conditions favoring motor neuron differentiation. Inhibition of Notch signaling by a γ-secretase inhibitor in the differentiating pMN-like progenitor cells decreased Hes5 expression and enhanced the differentiation toward motor neurons. Conversely, over-expression of Hes5 in pMN-like progenitor cells during the differentiation interfered with retinoic acid- and purmorphamine-induced motor neuron differentiation and inhibited the emergence of motor neurons. Inhibition of Notch signaling had a permissive rather than an inductive effect on motor neuron differentiation. Our results indicate that Notch signaling has a regulatory role in the switch from the pMN progenitor to the differentiated motor neuron state. Inhibition of Notch signaling can be harnessed to enhance the differentiation of hESCs toward motor neurons. Stem Cells 2015;33:403–415
A Thyroid Hormone Receptor/KLF9 Axis in Human Hepatocytes and Pluripotent Stem Cells
Authors: Cvoro Aleksandra , Devito Liani , Milton Flora A. , Noli Laila , Zhang Aijun , Filippi Celine , Sakai Keiko , Suh Ji Ho , H. Sieglaff Douglas , Dhawan Anil , Sakai Takao , Ilic Dusko , Webb Paul 
Published: October 2014

AbstractBiological processes require close cooperation of multiple transcription factors that integrate different signals. Thyroid hormone receptors (TRs) induce Krüppel-like factor 9 (KLF9) to regulate neurogenesis. Here, we show that triiodothyronine (T3) also works through TR to induce KLF9 in HepG2 liver cells, mouse liver, and mouse and human primary hepatocytes and sought to understand TR/KLF9 network function in the hepatocyte lineage and stem cells. Knockdown experiments reveal that KLF9 regulates hundreds of HepG2 target genes and modulates T3 response. Together, T3 and KLF9 target genes influence pathways implicated in stem cell self-renewal and differentiation, including Notch signaling, and we verify that T3 and KLF9 cooperate to regulate key Notch pathway genes and work independently to regulate others. T3 also induces KLF9 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) and this effect persists during differentiation to definitive endoderm and hiPSC-derived hepatocytes. Microarray analysis reveals that T3 regulates hundreds of hESC and hiPSC target genes that cluster into many of the same pathways implicated in TR and KLF9 regulation in HepG2 cells. KLF9 knockdown confirms that TR and KLF9 cooperate to regulate Notch pathway genes in hESC and hiPSC, albeit in a partly cell-specific manner. Broader analysis of T3 responsive hESC/hiPSC genes suggests that TRs regulate multiple early steps in ESC differentiation. We propose that TRs cooperate with KLF9 to regulate hepatocyte proliferation and differentiation and early stages of organogenesis and that TRs exert widespread and important influences on ESC biology. Stem Cells 2015;33:416–428
Alternative Generation of CNS Neural Stem Cells and PNS Derivatives from Neural Crest-Derived Peripheral Stem Cells
Authors: Weber Marlen , Apostolova Galina , Widera Darius , Mittelbronn Michel , Dechant Georg , Kaltschmidt Barbara , Rohrer Hermann 
Published: October 2014

AbstractNeural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex-positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC-like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage. Stem Cells 2015;33:574–588
Steady-State Creep Deformations and Stresses in FGM Rotating Thick Cylindrical Pressure Vessels
Authors: Nejad M. Z. , Hoseini Z. , Niknejad A. , Ghannad M. 
Published: October 2014

AbstractIn the present study, a closed-form analytical solution for the steady-state creep stresses of rotating thick cylindrical pressure vessels made of functionally graded materials (FGMs) is carried out. Norton's law governs the creep response of the material. Exact solutions for stresses and strain rate are obtained under the plane strain condition. How different material parameters involved in Norton's law affect radial and circumferential stresses together with the equivalent strain rate in rotating thick-walled cylindrical vessels under internal pressure is investigated. The result obtained shows that the property of FGMs has a significant influence on the equivalent creep strain rate and stresses distributions along the radial direction.
A Micromechanics Model for Effective Coupled Thermo-Electro-Elastic Properties of Macro Fiber Composites with Interdigitated Electrodes
Authors: Lezgy-Nazargah M. 
Published: October 2014

AbstractIn this study, a fully micromechanical model based on iso-field assumptions is developed for computing the effective coupled thermo-electro-elastic material properties of Macro Fiber Composites (MFCs) in the linear regime. The explicit formulations are derived using the thermo-electro-elastic constitutive equations under the iso-field assumptions and multiple loading conditions. The effects of piezoelectric fiber volume fraction and matrix properties on the effective material constants of MFCs are studied through some examples. In order to validate the accuracy of the present micromechanical formulations, comparisons have been made with other results available in the literature.
A Flat Asymptotic Frictionless Contact Subject to Normal Load and Bending Moment
Authors: Shao G.-Q. , Hong J. , Jiang X.-J. , Zhu L.-B. , Chen X. , Zhu Y.-S. 
Published: October 2014

AbstractA calculation model is put forward to analyze the interfacial response of an elastic frictionless punch, pressed normally into a half-plane, and subject to bending moment throughout this paper to observe the important effect that different normal loads and bending moments on the contact pressure distribution and contact deformation. Results for the detailed considerations have been given to the specific different cases of ηc. A characteristic response of the punch to a surplus bending moment has been found. The small differences can be observed between both methods show characteristic features of the FEM model and the theoretical model. The presented numerical results illustrate the influences of the normal load and bending moment on the contact stresses. The results obtained can be used to analyze the crack nucleation in fretting when the punch is acted upon by the normal force and the bending moment.
Cavitation Bubble in Compressible Fluid Near the Rigid Wall Subjected to the Acoustic Wave with Arbitrary Incidence Angle in Three-Dimensional
Authors: Ye X. , Yao X.-L. , Sun L.-Q. , Wang B. 
Published: October 2014

AbstractA balanced cavitation bubble is released near the rigid wall in the sound field generated by the incidence plane wave and its reflecting wave. With the modified boundary integral equation, the dynamics of bubble is solved considering the compressibility of fluid in this paper. Also the Bernoulli equation as the boundary condition for cavitation bubble in sound field is deduced using Euler equation. Since the arbitrary incidence angle of acoustic wave, the three-dimensional model is utilized. The bubble will expand or contract at first according to the initial phase of acting acoustic pressure on bubble surface. And during the contraction phase, the liquid jet with high speed will be generated pointing to rigid wall but be deflected to the incidence direction of acoustic wave. The oblique degree of jet will be affected by the incidence angle and initial distance between bubble center and rigid wall. The oscillation amplitude of bubble will be affected by the incidence amplitude and incidence frequency, but be limited by the rigid wall. Since the compressibility of fluid, the perturbation will propagate to the far-field. Thus the oscillation amplitude of bubble will be reduced.
Lactose inhibits regulatory T-cell-mediated suppression of effector T-cell interferon-γ and IL-17 production
Authors: Paasela Monika , Kolho Kaija-Leena , Vaarala Outi , Honkanen Jarno 
Published: October 2014

Our interest in lactose as an immunomodulatory molecule results from studies showing that lactose binds to galectin-9, which has been shown to have various regulatory functions in the immune system including regulation of T-cell responses. Impaired regulation of T helper (Th)1 and Th17 type immune responses and dysfunction of regulatory T cells (Treg) have been implicated in many human immune-mediated diseases. In the present study, we investigated the effects of lactose on immune regulation using co-cultures of human peripheral blood mononuclear cell (PBMC)-derived Tregand effector T cells (Teff) obtained from twenty healthy adults. Treg, i.e. CD4+CD25+CD127−, were isolated from PBMC by immunomagnetic separation. The fraction of CD4+CD127−cells that was depleted of CD25+cells was used as Teff. Tregand Teffat a ratio 1:5 were activated and the effects of lactose on the secretion of interferon-γ (IFN-γ) and IL-17 were analysed using ELISA for protein and quantitative RT-PCR for mRNA. Tregdown-regulated the secretion of both IFN-γ (8·8–3·9 ng/ml,n20,P= 0·003) and IL-17 (0·83–0·64 ng/ml,n15,P= 0·04) in co-cultures, while in the presence of lactose the levels of secreted IFN-γ and IL-17 remained high and no down-regulation was observed (16·4v. 3·99 ng/ml,n20,P< 0·0001, and 0·74v. 0·64 ng/ml,n15,P= 0·005, respectively). We showed that lactose inhibits human Treg-mediated suppression of Th1 and Th17 immune responsesin vitro.
Nasogastric nutrition is efficacious in severe acute pancreatitis: a systematic review and meta-analysis
Authors: Nally Deirdre M. , Kelly Enda G. , Clarke Mary , Ridgway Paul 
Published: October 2014

In patients with severe acute pancreatitis (AP), enteral nutrition is delivered by nasojejunal (NJ) tube to minimise pancreatic stimulation. Nasogastric (NG) feeding represents an alternative route. The primary objective of this systematic review and meta-analysis was to evaluate the efficacy of NG feeding. Secondary objectives were to compare the NG and NJ routes and assess the side effects of the former. The primary endpoint was exclusive NG feeding with delivery of 75 % of nutritional targets. Additional outcomes included change to total parenteral nutrition (TPN), increased pain or disease severity, vomiting, diarrhoea, delivery rate reduction and tube displacement. Among the retrieved studies, six were found to be eligible for the qualitative review and four for the meta-analysis. NG nutrition was received by 147 patients; exclusive NG feeding was achieved in 90 % (133/147). Of the 147 patients, 129 (87 %) received 75 % of the target energy. In studies where all subjects received exclusive NG nutrition, 82 % (seventy-four of the ninety patients) received >75 % of the intended energy. Compared with NJ nutrition, there was no significant difference in the delivery of 75 % of nutritional targets (pooled risk ratio (RR) 1·02; 95 % CI 0·75, 1·38.) or no increased risk of change to TPN (pooled RR 1·05; 95 % CI 0·45, 2·48), diarrhoea (pooled RR 1·28; 95 % CI 0·62, 2·66), exacerbation of pain (pooled RR 1·10; 95 % CI 0·47, 2·61) or tube displacement (pooled RR 0·44; 95 % CI 0·11, 1·73). Vomiting and diarrhoea were the most common side effects of NG feeding (13·3 and 12·9 %, respectively). With respect to the delivery of nutrition, 11·2 % of the patients required delivery rate reduction and 3·4 % dislodged the tube. Other side effects included elevated levels of aspirates (9·1 %), abdominal distension (1·5 %), pain exacerbation (7·5 %) and increased disease severity (1·6 %). In conclusion, NG feeding is efficacious in 90 % of patients. Further research is required to optimise the delivery of NG nutrition and examine ‘gut-rousing’ approaches to nutrition in patients with severe AP.