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| KLHDC8B in Hodgkin lymphoma and possibly twinning.
June 30, 2010 at 7:34 AM
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| | KLHDC8B in Hodgkin lymphoma and possibly twinning. Commun Integr Biol. 2010 Mar;3(2):154-8 Authors: Timms AE, Horwitz MS A key feature of Hodgkin lymphoma is that the malignant cells are binucleated, as a consequence of failed cytokinesis. We recently ascertained a family in which multiple cases of Hodgkin lymphoma had occurred among individuals who inherited a balanced chromosomal translocation. We cloned the translocation breakpoints and found that it disrupted a previously uncharacterized gene, KLHDC8B, encoding a Kelch family protein whose deficiency impairs cytokinesis and leads to binucleated cells. In other families we found a rare single nucleotide polymorphism affecting mitotic translation of KLHDC8B that was associated with and linked to Hodgkin lymphoma. Interestingly, the index family demonstrated an unusual frequency of twins, and there is a previously reported association between Hodgkin lymphoma and twins. Here we review the unusual genetic features of Hodgkin lymphoma, including gender concordance among siblings, and genetically test the hypothesis that KLHDC8B may participate in twinning by disrupting cytokinesis through impediment of polar body separation from oocytes. PMID: 20585509 [PubMed - in process] | | |
| Protective unfolded protein response in human pancreatic Beta cells transplanted into mice.
June 30, 2010 at 7:34 AM
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| | Protective unfolded protein response in human pancreatic Beta cells transplanted into mice. PLoS One. 2010;5(6):e11211 Authors: Kennedy J, Katsuta H, Jung MH, Marselli L, Goldfine AB, Balis UJ, Sgroi D, Bonner-Weir S, Weir GC BACKGROUND: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation. METHODS AND FINDINGS: Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated. CONCLUSIONS: Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins. PMID: 20585452 [PubMed - in process] | | |
| The use of microfiber composites of elastin-like protein matrix reinforced with synthetic collagen in the design of vascular grafts.
June 30, 2010 at 7:34 AM
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| | The use of microfiber composites of elastin-like protein matrix reinforced with synthetic collagen in the design of vascular grafts. Biomaterials. 2010 Jun 26; Authors: Caves JM, Kumar VA, Martinez AW, Kim J, Ripberger CM, Haller CA, Chaikof EL Collagen and elastin networks contribute to highly specialized biomechanical responses in numerous tissues and species. Biomechanical properties such as modulus, elasticity, and strength ultimately affect tissue function and durability, as well as local cellular behavior. In the case of vascular bypass grafts, compliance at physiologic pressures is correlated with increased patency due to a reduction in anastomotic intimal hyerplasia. In this report, we combine extracellular matrix (ECM) protein analogues to yield multilamellar vascular grafts comprised of a recombinant elastin-like protein matrix reinforced with synthetic collagen microfibers. Structural analysis revealed that the fabrication scheme permits a range of fiber orientations and volume fractions, leading to tunable mechanical properties. Burst strengths of 239-2760 mm Hg, compliances of 2.8-8.4%/100 mm Hg, and suture retention strengths of 35-192 gf were observed. The design most closely approximating all target criteria displayed a burst strength of 1483 +/- 143 mm Hg, a compliance of 5.1 +/- 0.8%/100 mm Hg, and a suture retention strength of 173 +/- 4 gf. These results indicate that through incorporation of reinforcing collagen microfibers, recombinant elastomeric protein-based biomaterials can play a significant role in load bearing tissue substitutes. We believe that similar composites can be incorporated into tissue engineering schemes that seek to integrate cells within the structure, prior to or after implantation in vivo. PMID: 20584549 [PubMed - as supplied by publisher] | | |
| Preserved extracellular matrix components and retained biological activity in decellularized porcine mesothelium.
June 30, 2010 at 7:34 AM
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| | Preserved extracellular matrix components and retained biological activity in decellularized porcine mesothelium. Biomaterials. 2010 Jun 26; Authors: Hoganson DM, Owens GE, O'Doherty EM, Bowley CM, Goldman SM, Harilal DO, Neville CM, Kronengold RT, Vacanti JP Mesothelium tissues such as peritoneum and pleura have a thin and strong layer of extracellular matrix that supports mesothelial cells capable of rapid healing. Decellularized porcine mesothelium was characterized for strength, composition of the matrix and biological activity. The tensile strength of the material was 40.65 +/- 21.65 N/cm. Extracellular matrix proteins collagen IV, fibronectin, and laminin as well as glycosaminoglycans were present in the material. Cytokines inherent in the extracellular matrix were preserved. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and transforming growth factor beta (TGF-beta) were retained and the levels of VEGF and TGF-beta in the decellularized mesothelium were higher than those found in decellularized small intestinal submucosa (SIS). The decellularized mesothelium also stimulated human fibroblasts to produce more VEGF than fibroblasts grown on tissue culture plastic. Decellularized mesothelium is a sheet material with a combination of strength and biological activity that may have many potential applications in surgical repair and regenerative medicine. PMID: 20584548 [PubMed - as supplied by publisher] | | |
| A three-dimensional model of the yeast genome.
June 30, 2010 at 7:34 AM
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| | A three-dimensional model of the yeast genome. Nature. 2010 May 20;465(7296):363-7 Authors: Duan Z, Andronescu M, Schutz K, McIlwain S, Kim YJ, Lee C, Shendure J, Fields S, Blau CA, Noble WS Layered on top of information conveyed by DNA sequence and chromatin are higher order structures that encompass portions of chromosomes, entire chromosomes, and even whole genomes. Interphase chromosomes are not positioned randomly within the nucleus, but instead adopt preferred conformations. Disparate DNA elements co-localize into functionally defined aggregates or 'factories' for transcription and DNA replication. In budding yeast, Drosophila and many other eukaryotes, chromosomes adopt a Rabl configuration, with arms extending from centromeres adjacent to the spindle pole body to telomeres that abut the nuclear envelope. Nonetheless, the topologies and spatial relationships of chromosomes remain poorly understood. Here we developed a method to globally capture intra- and inter-chromosomal interactions, and applied it to generate a map at kilobase resolution of the haploid genome of Saccharomyces cerevisiae. The map recapitulates known features of genome organization, thereby validating the method, and identifies new features. Extensive regional and higher order folding of individual chromosomes is observed. Chromosome XII exhibits a striking conformation that implicates the nucleolus as a formidable barrier to interaction between DNA sequences at either end. Inter-chromosomal contacts are anchored by centromeres and include interactions among transfer RNA genes, among origins of early DNA replication and among sites where chromosomal breakpoints occur. Finally, we constructed a three-dimensional model of the yeast genome. Our findings provide a glimpse of the interface between the form and function of a eukaryotic genome. PMID: 20436457 [PubMed - indexed for MEDLINE] | | |
| The Drosophila Fry protein interacts with Trc and is highly mobile in vivo.
June 30, 2010 at 7:34 AM
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| | The Drosophila Fry protein interacts with Trc and is highly mobile in vivo. BMC Dev Biol. 2010;10:40 Authors: Fang X, Lu Q, Emoto K, Adler PN BACKGROUND: Cell polarity is a common feature of eukaryotic cells. The NDR kinases have been found to regulate polarized growth in both animal cells and fungi. Drosophila Tricornered is an NDR kinase that is essential for the normal polarized growth of extensions of epidermal cells and for the tiling and branching of dendrites of da sensory neurons. Tricornered function requires interacting with the large Furry protein (3479 amino acid). RESULTS: We constructed a furry (fry) transgene and established that it rescued the lethality of fry null mutations. The encoded protein was tagged at both its amino and carboxy termini and this allowed us to demonstrate that the protein existed as an uncleaved protein in vivo. We used the C terminal GFP tag to follow the protein in vivo and found it to be highly mobile. Interestingly Fry accumulated at the distal tip of growing bristles. We established that Fry and Trc could be co-immunoprecipitated from wing discs. CONCLUSIONS: The mobility of Fry in both bristles and dendrites suggests that it could function in directing/mediating the intracellular transport needed for polarized growth. Our observations that full length Fry and Trc show only partial co-localization in growing bristles while an amino terminal fragment of Fry shows close to complete co-localization with Trc suggests that the interaction between these proteins is transient and regulated. PMID: 20406475 [PubMed - indexed for MEDLINE] | | |
| Temporal dynamics of myelination in the zebrafish spinal cord.
June 30, 2010 at 7:34 AM
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| | Temporal dynamics of myelination in the zebrafish spinal cord. Glia. 2010 May;58(7):802-12 Authors: Buckley CE, Marguerie A, Alderton WK, Franklin RJ Knowledge of the precise timing of myelination is critical to the success of zebrafish-based in vivo screening strategies for potential remyelination therapies. This study provides a systematic review of the timing of myelination in the zebrafish spinal cord and a critique of techniques by which it may be accurately assessed. The onset of myelination was found to be 3 days postfertilization (d.p.f.); earlier than previously reported. This coincided with the dorsal migration and differentiation of oligodendrocytes and the expression of myelin basic protein (Mbp) transcripts and protein. Our data suggests that immunohistochemistry with zebrafish-specific anti-Mbp from 3 d.p.f. is the optimal histological method for myelin visualization, while quantification of myelination is more reliably achieved by quantitative polymerase chain reaction (qPCR) for mbp from 5 d.p.f.. Transgenic fluorescent lines such as olig2:EGFP can be used to assess oligodendrocyte cell number at 3 d.p.f. and the development of new, more specific lines may enable real time visualization of myelin itself. Quantitative ultrastructural analysis revealed that the myelination of zebrafish axons is regulated according to axonal growth and not absolute axonal size. This study confirms the use of the zebrafish larvae as a versatile and efficient in vivo model of myelination and provides a platform on which future myelination screening studies can be based. PMID: 20140960 [PubMed - indexed for MEDLINE] | | |
| Enhanced chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells in low oxygen environment micropellet cultures.
June 30, 2010 at 7:34 AM
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| | Enhanced chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells in low oxygen environment micropellet cultures. Cell Transplant. 2010;19(1):29-42 Authors: Markway BD, Tan GK, Brooke G, Hudson JE, Cooper-White JJ, Doran MR Chondrogenesis of mesenchymal stem cells (MSCs) is typically induced when they are condensed into a single aggregate and exposed to transforming growth factor-beta (TGF-beta). Hypoxia, like aggregation and TGF-beta delivery, may be crucial for complete chondrogenesis. However, the pellet dimensions and associated self-induced oxygen gradients of current chondrogenic methods may limit the effectiveness of in vitro differentiation and subsequent therapeutic uses. Here we describe the use of embryoid body-forming technology to produce microscopic aggregates of human bone marrow MSCs (BM-MSCs) for chondrogenesis. The use of micropellets reduces the formation of gradients within the aggregates, resulting in a more homogeneous and controlled microenvironment. These micropellet cultures (approximately 170 cells/micropellet) as well as conventional pellet cultures (approximately 2 x 10(5) cells/pellet) were chondrogenically induced under 20% and 2% oxygen environments for 14 days. Compared to conventional pellets under both environments, micropellets differentiated under 2% O(2) showed significantly increased sulfated glycosaminoglycan (sGAG) production and more homogeneous distribution of proteoglycans and collagen II. Aggrecan and collagen II gene expressions were increased in pellet cultures differentiated under 2% O(2) relative to 20% O(2) pellets but 2% O(2) micropellets showed even greater increases in these genes, as well as increased SOX9. These results suggest a more advanced stage of chondrogenesis in the micropellets accompanied by more homogeneous differentiation. Thus, we present a new method for enhancing MSC chondrogenesis that reveals a unique relationship between oxygen tension and aggregate size. The inherent advantages of chondrogenic micropellets over a single macroscopic aggregate should allow for easy integration with a variety of cartilage engineering strategies. PMID: 19878627 [PubMed - indexed for MEDLINE] | | |
| Controlled release of neurotrophin-3 and platelet-derived growth factor from fibrin scaffolds containing neural progenitor cells enhances survival and differentiation into neurons in a subacute model of SCI.
June 30, 2010 at 7:34 AM
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| | Controlled release of neurotrophin-3 and platelet-derived growth factor from fibrin scaffolds containing neural progenitor cells enhances survival and differentiation into neurons in a subacute model of SCI. Cell Transplant. 2010;19(1):89-101 Authors: Johnson PJ, Tatara A, Shiu A, Sakiyama-Elbert SE A consistent problem with stem/neural progenitor cell transplantation following spinal cord injury (SCI) is poor cell survival and uncontrolled differentiation following transplantation. The current study evaluated the feasibility of enhancing embryonic stem cell-derived neural progenitor cell (ESNPC) viability and directing their differentiation into neurons and oligodendrocytes by embedding the ESNPCs in fibrin scaffolds containing growth factors (GF) and a heparin-binding delivery system (HBDS) in a subacute rat model of SCI. Mouse ESNPCs were generated from mouse embryonic stem cells (ESCs) using a 4-/4+ retinoic acid (RA) induction protocol. The ESNPCs were then transplanted as embryoid bodies (EBs, 70% neural progenitor cells) into the subacute model of SCI. ESNPCs (10 EBs per animal) were implanted directly into the SCI lesion, encapsulated in fibrin scaffolds, encapsulated in fibrin scaffolds containing the HBDS, neurotrophin-3 (NT-3), and platelet-derived growth factor (PDGF), or encapsulated in fibrin scaffolds with NT-3 and PDGF with no HBDS. We report here that the combination of the NT-3, PDGF, and fibrin scaffold (with or without HBDS) enhanced the total number of ESNPCs present in the spinal cord lesion 2 weeks after injury. In addition, the inclusion of the HBDS with growth factor resulted in an increase in the number of ESNPC-derived NeuN-positive neurons. These results demonstrate the ability of fibrin scaffolds and the controlled release of growth factors to enhance the survival and differentiation of neural progenitor cells following transplantation into a SCI model. PMID: 19818206 [PubMed - indexed for MEDLINE] | | |
| [Effect of platelet rich plasma on vascularization of tissue-engineered bone]
June 30, 2010 at 7:34 AM
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| | [Effect of platelet rich plasma on vascularization of tissue-engineered bone] Zhonghua Kou Qiang Yi Xue Za Zhi. 2007 Jul;42(7):436-7 Authors: Li NY, Chen LQ, Chen T, Jin XM, Yuan RT OBJECTIVE: To study the effects of platelet rich plasma (PRP) on vascularization of tissue-engineered bone. METHODS: Bone marrow stromal cell (BMSC) were isolated from iliac bone of dogs. PRP was obtained from the same dog and demineralized bone matrix (DBM) was prepared from homologous bone. Twelve dogs were divided into three groups and the back of each dog was divided into four areas. The DBM- BMSC- PRP was implanted in the area A and B; the DBM-BMSC without PRP was implanted in the area C and D. The implants in the areas A and C were wrapped using myo-fascia with blood vessel of latissimus dorsi. The implants in the area B and D were wrapped using superficial fascia of the back without blood vessel. The implants were taken out 4, 8 and 12 weeks later for examination. RESULTS: The degree of calcification and blood vessel formation of the implants was A > B > C > D. CONCLUSIONS: Both PRP and vessels of latissimus dorsi muscle could promote calcification and vascularization in tissue-engineered bone, when used separately or in combination. PMID: 17961368 [PubMed - indexed for MEDLINE] | | |
| Connective Tissue Growth Factor in Regulation of RhoA Mediated Cytoskeletal Tension Associated Osteogenesis of Mouse Adipose-Derived Stromal Cells.
June 30, 2010 at 7:34 AM
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| | Connective Tissue Growth Factor in Regulation of RhoA Mediated Cytoskeletal Tension Associated Osteogenesis of Mouse Adipose-Derived Stromal Cells. PLoS One. 2010;5(6):e11279 Authors: Xu Y, Wagner DR, Bekerman E, Chiou M, James AW, Carter D, Longaker MT BACKGROUND: Cytoskeletal tension is an intracellular mechanism through which cells convert a mechanical signal into a biochemical response, including production of cytokines and activation of various signaling pathways. METHODS/PRINCIPAL FINDINGS: Adipose-derived stromal cells (ASCs) were allowed to spread into large cells by seeding them at a low-density (1,250 cells/cm(2)), which was observed to induce osteogenesis. Conversely, ASCs seeded at a high-density (25,000 cells/cm(2)) featured small cells that promoted adipogenesis. RhoA and actin filaments were altered by changes in cell size. Blocking actin polymerization by Cytochalasin D influenced cytoskeletal tension and differentiation of ASCs. To understand the potential regulatory mechanisms leading to actin cytoskeletal tension, cDNA microarray was performed on large and small ASCs. Connective tissue growth factor (CTGF) was identified as a major regulator of osteogenesis associated with RhoA mediated cytoskeletal tension. Subsequently, knock-down of CTGF by siRNA in ASCs inhibited this osteogenesis. CONCLUSIONS/SIGNIFICANCE: We conclude that CTGF is important in the regulation of cytoskeletal tension mediated ASC osteogenic differentiation. PMID: 20585662 [PubMed - in process] | | |
| A protocol describing the genetic correction of somatic human cells and subsequent generation of iPS cells.
June 30, 2010 at 2:34 AM
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| | A protocol describing the genetic correction of somatic human cells and subsequent generation of iPS cells. Nat Protoc. 2010 Apr;5(4):647-60 Authors: Raya A, RodrÃguez-Pizà I, Navarro S, Richaud-Patin Y, Guenechea G, Sánchez-Danés A, Consiglio A, Bueren J, Izpisúa Belmonte JC The generation of patient-specific induced pluripotent stem cells (iPSCs) offers unprecedented opportunities for modeling and treating human disease. In combination with gene therapy, the iPSC technology can be used to generate disease-free progenitor cells of potential interest for autologous cell therapy. We explain a protocol for the reproducible generation of genetically corrected iPSCs starting from the skin biopsies of Fanconi anemia patients using retroviral transduction with OCT4, SOX2 and KLF4. Before reprogramming, the fibroblasts and/or keratinocytes of the patients are genetically corrected with lentiviruses expressing FANCA. The same approach may be used for other diseases susceptible to gene therapy correction. Genetically corrected, characterized lines of patient-specific iPSCs can be obtained in 4-5 months. PMID: 20224565 [PubMed - indexed for MEDLINE] | | | | 
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