bluuebunny/crossref_metadata_2025 huggingface dataset:
The ACCENT-protocol: a framework for benchmarking and model evaluation
Authors: Grewe V. , Moussiopoulos N. , Builtjes P. , Borrego C. , Isaksen I. S. A. , Volz-Thomas A.
Published: May 2012

Abstract. We summarise results from a workshop on "Model Benchmarking and Quality Assurance" of the EU-Network of Excellence ACCENT, including results from other activities (e.g. COST Action 732) and publications. A formalised evaluation protocol is presented, i.e. a generic formalism describing the procedure of how to perform a model evaluation. This includes eight steps and examples from global model applications which are given for illustration. The first and important step is concerning the purpose of the model application, i.e. the addressed underlying scientific or political question. We give examples to demonstrate that there is no model evaluation per se, i.e. without a focused purpose. Model evaluation is testing, whether a model is fit for its purpose. The following steps are deduced from the purpose and include model requirements, input data, key processes and quantities, benchmark data, quality indicators, sensitivities, as well as benchmarking and grading. We define "benchmarking" as the process of comparing the model output against either observational data or high fidelity model data, i.e. benchmark data. Special focus is given to the uncertainties, e.g. in observational data, which have the potential to lead to wrong conclusions in the model evaluation if not considered carefully.
HESS Opinions "More efforts and scientific rigour are needed to attribute trends in flood time series"
Authors: Merz B. , Vorogushyn S. , Uhlemann S. , Delgado J. , Hundecha Y.
Published: May 2012

Abstract. The question whether the magnitude and frequency of floods have changed due to climate change or other drivers of change is of high interest. The number of flood trend studies is rapidly rising. When changes are detected, many studies link the identified change to the underlying causes, i.e. they attribute the changes in flood behaviour to certain drivers of change. We propose a hypothesis testing framework for trend attribution which consists of essential ingredients for a sound attribution: evidence of consistency, evidence of inconsistency, and provision of confidence statement. Further, we evaluate the current state-of-the-art of flood trend attribution. We assess how selected recent studies approach the attribution problem, and to which extent their attribution statements seem defendable. In our opinion, the current state of flood trend attribution is poor. Attribution statements are mostly based on qualitative reasoning or even speculation. Typically, the focus of flood trend studies is the detection of change, i.e. the statistical analysis of time series, and attribution is regarded as an appendix: (1) flood time series are analysed by means of trend tests, (2) if a significant change is detected, a hypothesis on the cause of change is given, and (3) explanations or published studies are sought which support the hypothesis. We believe that we need a change in perspective and more scientific rigour: detection should be seen as an integral part of the more challenging attribution problem, and detection and attribution should be placed in a sound hypothesis testing framework.
Coupled decadal variability of the North Atlantic Oscillation, regional rainfall and karst spring discharges in the Campania region (southern Italy)
Authors: De Vita P. , Allocca V. , Manna F. , Fabbrocino S.
Published: May 2012

Abstract. Thus far, studies on climate change have focused mainly on the variability of the atmospheric and surface components of the hydrologic cycle, investigating the impact of this variability on the environment, especially with respect to the risks of desertification, droughts and floods. Conversely, the impacts of climate change on the recharge of aquifers and on the variability of groundwater flow have been less investigated, especially in Mediterranean karst areas whose water supply systems depend heavily upon groundwater exploitation. In this paper, long-term climatic variability and its influence on groundwater recharge were analysed by examining decadal patterns of precipitation, air temperature and spring discharges in the Campania region (southern Italy), coupled with the North Atlantic Oscillation (NAO). The time series of precipitation and air temperature were gathered over 90 yr, from 1921 to 2010, using 18 rain gauges and 9 air temperature stations with the most continuous functioning. The time series of the winter NAO index and of the discharges of 3 karst springs, selected from those feeding the major aqueducts systems, were collected for the same period. Regional normalised indexes of the precipitation, air temperature and karst spring discharges were calculated, and different methods were applied to analyse the related time series, including long-term trend analysis using smoothing numerical techniques, cross-correlation and Fourier analysis. The investigation of the normalised indexes highlighted the existence of long-term complex periodicities, from 2 to more than 30 yr, with differences in average values of up to approximately ±30% for precipitation and karst spring discharges, which were both strongly correlated with the winter NAO index. Although the effects of the North Atlantic Oscillation (NAO) had already been demonstrated in the long-term precipitation and streamflow patterns of different European countries and Mediterranean areas, the results of this study allow for the establishment of a link between a large-scale atmospheric cycle and the groundwater recharge of carbonate karst aquifers. Consequently, the winter NAO index could also be considered as a proxy to forecast the decadal variability of groundwater flow in Mediterranean karst areas.
Wet-snow avalanche interaction with a deflecting dam: field observations and numerical simulations in a case study
Authors: Sovilla B. , Sonatore I. , Bühler Y. , Margreth S.
Published: May 2012

Abstract. In avalanche-prone areas, deflecting dams are widely used to divert avalanches away from endangered objects. In recent years, their effectiveness has been questioned when several large and multiple avalanches have overrun such dams. In 2008, we were able to observe a large wet-snow avalanche, characterized by an high water content, that interacted with a deflecting dam and overflowed it at its lower end. To evaluate the dam's performance, we carried out an airborne laser scanning campaign immediately after the avalanche. This data, together with a video sequence made during the avalanche descent, provided a unique data set to study the dynamics of a wet dense snow avalanche and its flow behavior along a deflecting dam. To evaluate the effect of the complex flow field of the avalanche along the dam and to provide a basis for discussion of the residual risk, we performed numerical simulations using a two-dimensional dense snow avalanche dynamics model with entrainment. In comparison to dry dense snow avalanches, we found that wet-snow avalanches, with high water content, seem to be differently influenced by the local small-scale topography roughness. Rough terrain close to the dam deflected the flow to produce abrupt impacts with the dam. At the impact sites, instability waves were generated and increased the already large flow depths. The complex flow dynamics around the dam may produce large, local snow deposits. Furthermore, the high water content in the snow may decrease the avalanche internal friction angle, inducing wet-snow avalanches to spread further laterally than dry-snow avalanches. Based on our analysis, we made recommendations for designing deflecting dams and for residual risk analysis to take into account the effects of wet-snow avalanche flow.
Insights into declining single‐family residential water demands
Authors: Deoreo William B. , Mayer Peter W.
Published: May 2012

Water use, especially indoor use, in single‐family residences has declined since 1995 and is expected to continue to do so as new technologies enter the market. This conclusion is unavoidable when empirical data from residential end use studies dating back to 1995 are compared. Furthermore, the observed declines in indoor use are not related to economic conditions—the bulk of the data used for the analysis were taken before the 2008 recession. This article presents key data and findings from a 16‐year data collection effort and closely examines changes in water use over that time as well as the potential for additional residential demand reductions in the future. The demand data presented here show patterns in single‐family indoor and outdoor demands and provide a basis for future water supply planning and conservation program design.
USEPA method 415.3: Quantifying TOC, DOC, and SUVA
Authors: Potter Billy B. , Wimsatt John C.
Published: May 2012

The US Environmental Protection Agency has developed a reproducible method that supports the monitoring requirements specified in the Disinfectants/Disinfection Byproducts Rule (D/DBPR). Method 415.3 provides for the quantification of total organic carbon (TOC) and dissolved organic carbon (DOC) in source waters and drinking waters, as well as the determination of specific ultraviolet absorbance (SUVA) at 254 nm, protocols for inorganic carbon interference removal, and DOC filter evaluation and selection. During method development experiments, TOC, DOC, and SUVA were determined for seven source waters using five instrument types. Mean values for DOC, TOC, and SUVA ranged from 0.42 to 3.38 mg/L, 0.42 to 3.64 mg/L, and 1.95 to 3.37 L/mg‐m, respectively, with pooled fortified recoveries of 102.7±1.8%. The data generated using method 415.3 showed improved accuracy and precision over existing methods. The method was ultimately approved as part of the Stage 2 D/DBPR.
Hexavalent chromium review, part 1: Health effects, regulations, and analysis
Authors: McLean Joan E. , McNeill Laurie S. , Edwards Marc A. , Parks Jeffrey L.
Published: May 2012

First of a two‐part review summarizing the current state of the science regarding hexavalent chromium, this article addresses health effects, regulations, and analysis; part 2 will cover occurrence, chemistry, and treatment. Although hexavalent chromium—Cr(VI)—is a known human carcinogen when inhaled, its effects when taken orally (e.g., consumed in drinking water) are still being evaluated. The outcome of the ongoing US Environmental Protection Agency toxicologic review will determine whether a new federal maximum contaminant level will be set specifically for Cr(VI). In California, a public health goal of 0.02 μg/L has been established, and the state is proceeding to set a maximum contaminant level for hexavalent chromium. Analytical methods for hexavalent chromium can reliably quantify Cr(VI) at sub‐parts‐per‐billion levels, whereas methods for measuring total chromium are much less sensitive. A new US Environmental Protection Agency method is available for Cr(VI) analysis, with updated requirements for chromium speciation preservation, holding time, and filtration.
Human Müller Glia with Stem Cell Characteristics Differentiate into Retinal Ganglion Cell (RGC) Precursors In Vitro and Partially Restore RGC Function In Vivo Following Transplantation
Authors: Singhal Shweta , Bhatia Bhairavi , Jayaram Hari , Becker Silke , Jones Megan F. , Cottrill Phillippa B. , Khaw Peng T. , Salt Thomas E. , Limb G. Astrid
Published: May 2012

Müller glia with stem cell characteristics have been identified in the adult human eye, and although there is no evidence that they regenerate retina in vivo, they can be induced to grow and differentiate into retinal neurons in vitro. We differentiated human Müller stem cells into retinal ganglion cell (RGC) precursors by stimulation with fibroblast growth factor 2 together with NOTCH inhibition using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). Differentiation into RGC precursors was confirmed by gene and protein expression analysis, changes in cytosolic [Ca2+] in response to neurotransmitters, and green fluorescent protein (GFP) expression by cells transduced with a transcriptional BRN3b-GFP reporter vector. RGC precursors transplanted onto the inner retinal surface of Lister hooded rats depleted of RGCs by N-methyl-d-aspartate aligned onto the host RGC layer at the site of transplantation but did not extend long processes toward the optic nerve. Cells were observed extending processes into the RGC layer and expressing RGC markers in vivo. This migration was observed only when adjuvant anti-inflammatory and matrix degradation therapy was used for transplantation. RGC precursors induced a significant recovery of RGC function in the transplanted eyes as determined by improvement of the negative scotopic threshold response of the electroretinogram (indicative of RGC function). The results suggest that transplanted RGC precursors may be capable of establishing local interneuron synapses and possibly release neurotrophic factors that facilitate recovery of RGC function. These cells constitute a promising source of cells for cell-based therapies to treat retinal degenerative disease caused by RGC dysfunction.
Concise Review: Immunomodulatory Properties of Mesenchymal Stem Cells in Cellular Transplantation: Update, Controversies, and Unknowns
Authors: Atoui Rony , Chiu Ray C.J.
Published: May 2012

Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage, for which the use of autologous donor cells has been preferred to avoid immune rejection. Recently, however, rodent as well as human mesenchymal stem cells have been reported to be uniquely immune-tolerant, in both in vitro and in vivo transplant models. In this review, we explore in detail the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as “universal donor cells” with fascinating clinical implications.
Functional Impairment of Human Resident Cardiac Stem Cells by the Cardiotoxic Antineoplastic Agent Trastuzumab
Authors: Barth Andreas S. , Zhang Yiqiang , Li Taosheng , Smith Rachel R. , Chimenti Isotta , Terrovitis Ioannis , Davis Darryl R. , Kizana Eddy , Ho Alice S. , O'Rourke Brian , Wolff Antonio C. , Gerstenblith Gary , Marbán Eduardo
Published: May 2012

Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes. To test this idea, we exposed human cardiosphere-derived cells (hCDCs), a natural mixture of cardiac stem cells and supporting cells that has been shown to exert potent regenerative effects, to TZM and tested the effects in vitro and in vivo. We found that ERBB2 mRNA and protein are expressed in hCDCs at levels comparable to those in human myocardium. Although clinically relevant concentrations of TZM had no effect on proliferation, apoptosis, or size of the c-kit-positive hCDC subpopulation, in vitro assays demonstrated diminished potential for cardiogenic differentiation and impaired ability to form microvascular networks in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM + hCDCs had a lower ejection fraction, thinner infarct scar, and reduced capillary density in the infarct border zone compared with animals that received hCDCs alone (n = 12 per group). Collectively, these results indicate that TZM inhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, TZM impairs the function of human resident cardiac stem cells, potentially contributing to TZM cardiotoxicity.
Concise Review: Mesenchymal Stem Cells and Translational Medicine: Emerging Issues
Authors: Ren Guangwen , Chen Xiaodong , Dong Fengping , Li Wenzhao , Ren Xiaohui , Zhang Yanyun , Shi Yufang
Published: May 2012

Mesenchymal stem cells (MSCs) are emerging as a promising therapeutic approach of cell-based therapy for a wide range of autoimmune disorders and degenerative diseases. In preclinical and clinical studies, MSCs have been shown to be highly efficient in treating graft-versus-host disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, myocardial infarction, liver cirrhosis, inflammatory bowel disease, and other disorders. The underlying therapeutic mechanisms of MSCs include their homing efficiency to the tissue injury sites, their differentiation potential, their capability to produce a large amount of trophic factors, and their immunomodulatory effect. Because tissue damage sites are complicated milieus with distinct types of inflammatory cells and factors, available data have demonstrated that the properties of MSCs could be fundamentally influenced by the inflammatory elements. Thus, an understanding of the interaction between MSCs and the inflammatory microenvironment will provide critical information in revealing the precise in vivo mechanisms of MSC-mediated therapeutic effects and designing more practical protocols for clinical use of these cells.
Small Molecule Mesengenic Induction of Human Induced Pluripotent Stem Cells to Generate Mesenchymal Stem/Stromal Cells
Authors: Chen Yen Shun , Pelekanos Rebecca A. , Ellis Rebecca L. , Horne Rachel , Wolvetang Ernst J. , Fisk Nicholas M.
Published: May 2012

The translational potential of mesenchymal stem/stromal cells (MSCs) is limited by their rarity in somatic organs, heterogeneity, and need for harvest by invasive procedures. Induced pluripotent stem cells (iPSCs) could be an advantageous source of MSCs, but attempts to derive MSCs from pluripotent cells have required cumbersome or untranslatable techniques, such as coculture, physical manipulation, sorting, or viral transduction. We devised a single-step method to direct mesengenic differentiation of human embryonic stem cells (ESCs) and iPSCs using a small molecule inhibitor. First, epithelial-like monolayer cells were generated by culturing ESCs/iPSCs in serum-free medium containing the transforming growth factor-β pathway inhibitor SB431542. After 10 days, iPSCs showed upregulation of mesodermal genes (MSX2, NCAM, HOXA2) and downregulation of pluripotency genes (OCT4, LEFTY1/2). Differentiation was then completed by transferring cells into conventional MSC medium. The resultant development of MSC-like morphology was associated with increased expression of genes, reflecting epithelial-to-mesenchymal transition. Both ESC- and iPSC-derived MSCs exhibited a typical MSC immunophenotype, expressed high levels of vimentin and N-cadherin, and lacked expression of pluripotency markers at the protein level. Robust osteogenic and chondrogenic differentiation was induced in vitro in ES-MSCs and iPS-MSCs, whereas adipogenic differentiation was limited, as reported for primitive fetal MSCs and ES-MSCs derived by other methods. We conclude that treatment with SB431542 in two-dimensional cultures followed by culture-induced epithelial-to-mesenchymal transition leads to rapid and uniform MSC conversion of human pluripotent cells without the need for embryoid body formation or feeder cell coculture, providing a robust, clinically applicable, and efficient system for generating MSCs from human iPSCs.
Development of Serum-Free Quality and Quantity Control Culture of Colony-Forming Endothelial Progenitor Cell for Vasculogenesis
Authors: Masuda Haruchika , Iwasaki Hiroto , Kawamoto Atsuhiko , Akimaru Hiroshi , Ishikawa Masakazu , Ii Masaaki , Shizuno Tomoko , Sato Atsuko , Ito Rie , Horii Miki , Ishida Hideyuki , Kato Shunichi , Asahara Takayuki
Published: May 2012

Quantitative and qualitative impairment of endothelial progenitor cells (EPCs) limits the efficacy of autologous cell therapy in patients with cardiovascular diseases. Here, we developed a serum-free quality and quantity control culture system for colony-forming EPCs to enhance their regenerative potential. A culture with serum-free medium containing stem cell factor, thrombopoietin, vascular endothelial growth factor, interleukin-6, and Flt-3 ligand was determined as optimal quality and quantity culture (QQc) in terms of the most vasculogenic colony-forming EPC expansion, evaluated by the newly established EPC colony formation assay. The QQc of umbilical cord blood-CD133+ cells for 7 days produced a 52.9-fold increase in total cell number and 3.28-fold frequency in definitive EPC colony development, resulting in a 203.9-fold increase in estimated total definitive EPC colony number in vitro. Pre- or post-QQc cells were intramyocardially transplanted into nude rats with myocardial infarction (MI). Echocardiographic and micromanometer-tipped conductance catheter examinations 28 days post-MI revealed significant preservation of left ventricular (LV) function in rats receiving pre- or post-QQc cells compared with those receiving phosphate-buffered saline. Assessments of global LV contractility indicated a dose-dependent effect of pre- or post-QQc cells and the superior potency of post-QQc cells over pre-QQc cells. Furthermore, immunohistochemistry showed more abundant formation of both human and rat endothelial cells and cardiomyocytes in the infarcted myocardium following transplantation of post-QQc cells compared with pre-QQc cells. Our optimal serum-free quality and quantity culture may enhance the therapeutic potential of EPCs in both quantitative and qualitative aspects for cardiovascular regeneration.
Steering a New Course for Stem Cell Research: NIH's Intramural Center for Regenerative Medicine
Authors: Rao Mahendra S. , Collins Francis S.
Published: May 2012

The phenomenal progress made in stem cell biology in the past few years has infused the field of regenerative medicine with a great deal of scientific enthusiasm. However, along with the excitement of discovery comes a new sense of translational urgency. The prospect of using embryonic and induced pluripotent stem cell tools and technologies to produce cell-based therapies and other treatments is no longer a distant dream; it is a very real opportunity that demands our attention today. As with most new fields, regenerative medicine has experienced some significant growing pains, and we have identified a number of key obstacles to progress. Given our role as the lead U.S. biomedical research agency and the world's largest supporter of medical research, the National Institutes of Health (NIH) has a responsibility to find ways to reduce or remove many of these obstacles and, consequently, has—and continues—to respond to these challenges in a variety of ways. In this brief essay, we will review our progress and highlight a new development: the founding of a Center for Regenerative Medicine on the NIH campus.
Wnt Signaling Orchestration with a Small Molecule DYRK Inhibitor Provides Long-Term Xeno-Free Human Pluripotent Cell Expansion
Authors: Hasegawa Kouichi , Yasuda Shin-ya , Teo Jia-Ling , Nguyen Cu , McMillan Michael , Hsieh Chih-Lin , Suemori Hirofumi , Nakatsuji Norio , Yamamoto Masashi , Miyabayashi Tomoyuki , Lutzko Carolyn , Pera Martin F. , Kahn Michael
Published: May 2012

An optimal culture system for human pluripotent stem cells should be fully defined and free of animal components. To date, most xeno-free culture systems require human feeder cells and/or highly complicated culture media that contain activators of the fibroblast growth factor (FGF) and transforming growth factor-β (TGFβ) signaling pathways, and none provide for replacement of FGF/TGFβ ligands with chemical compounds. The Wnt/β-catenin signaling pathway plays an important role in mouse embryonic stem cells in leukemia inhibitory factor-independent culture; however, the role of Wnt/β-catenin signaling in human pluripotent stem cell is still poorly understood and controversial because of the dual role of Wnts in proliferation and differentiation. Building on our previous investigations of small molecules modulating Wnt/β-catenin signaling in mouse embryonic stem cells, we identified a compound, ID-8, that could support Wnt-induced human embryonic stem cell proliferation and survival without differentiation. Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) is the target of the small molecule ID-8. Its role in human pluripotent cell renewal was confirmed by DYRK knockdown in human embryonic stem cells. Using Wnt and the DYRK inhibitor ID-8, we have developed a novel and simple chemically defined xeno-free culture system that allows for long-term expansion of human pluripotent stem cells without FGF or TGFβ activation. These culture conditions do not include xenobiotic supplements, serum, serum replacement, or albumin. Using this culture system, we have shown that several human pluripotent cell lines maintained pluripotency (>20 passages) and a normal karyotype and still retained the ability to differentiate into derivatives of all three germ layers. This Wnt-dependent culture system should provide a platform for complete replacement of growth factors with chemical compounds.
Oncolytic Herpes Simplex Virus Counteracts the Hypoxia-Induced Modulation of Glioblastoma Stem-Like Cells
Authors: Sgubin Donatella , Wakimoto Hiroaki , Kanai Ryuichi , Rabkin Samuel D. , Martuza Robert L.
Published: May 2012

Glioblastoma (GBM), a fatal malignant brain tumor, contains abundant hypoxic regions that provide a “niche” to promote both the maintenance and enrichment of glioblastoma stem-like cells (GSCs) and confer resistance to chemo- and radiotherapy. Since GSCs, with an ability to resist conventional therapies, may be responsible for tumor recurrence, targeting GSCs located in such a hypoxic environment may be critical to improving the therapeutic outcome for GBM patients. Oncolytic viral therapies have been tested in the clinic as a promising therapeutic approach for GBM. In this study, we analyzed and compared the therapeutic effects of oncolytic herpes simplex virus (oHSV) type 1 G47Δ (γ34.5−ICP6−LacZ+α47−) in patient-derived GSCs under normoxia (21% oxygen) and hypoxia (1% oxygen). GSCs cultured in hypoxia showed an increased ability to form neurospheres and expressed higher levels of the putative stem cell marker CD133 compared with GSCs cultured in normoxia. G47Δ exhibited a comparable ability to infect, replicate, and kill GSCs in normoxia and hypoxia in vitro. Importantly, G47Δ could counteract hypoxia-mediated enhancement of the stem-like properties of GSCs, inhibiting their self-renewal and stem cell marker expression. Using orthotopic human GSC xenografts in mice, we demonstrated that intratumoral injection of G47ΔUs11fluc, a newly developed G47Δ derivative that expresses firefly luciferase driven by a true late viral promoter, led to an equivalent frequency of viral infection and replication in hypoxic and nonhypoxic tumor areas. These findings suggest that oHSV G47Δ represents a promising therapeutic strategy to target and kill GSCs, not only in normoxic areas of GBM but also within the hypoxic niche.
Concise Review: The Clinical Application of Mesenchymal Stem Cells for Musculoskeletal Regeneration: Current Status and Perspectives
Authors: Steinert Andre F. , Rackwitz Lars , Gilbert Fabian , Nöth Ulrich , Tuan Rocky S.
Published: May 2012

Regenerative therapies in the musculoskeletal system are based on the suitable application of cells, biomaterials, and/or factors. For an effective approach, numerous aspects have to be taken into consideration, including age, disease, target tissue, and several environmental factors. Significant research efforts have been undertaken in the last decade to develop specific cell-based therapies, and in particular adult multipotent mesenchymal stem cells hold great promise for such regenerative strategies. Clinical translation of such therapies, however, remains a work in progress. In the clinical arena, autologous cells have been harvested, processed, and readministered according to protocols distinct for the target application. As outlined in this review, such applications range from simple single-step approaches, such as direct injection of unprocessed or concentrated blood or bone marrow aspirates, to fabrication of engineered constructs by seeding of natural or synthetic scaffolds with cells, which were released from autologous tissues and propagated under good manufacturing practice conditions (for example, autologous chondrocyte implantation). However, only relatively few of these cell-based approaches have entered the clinic, and none of these treatments has become a “standard of care” treatment for an orthopaedic disease to date. The multifaceted reasons for the current status from the medical, research, and regulatory perspectives are discussed here. In summary, this review presents the scientific background, current state, and implications of clinical mesenchymal stem cell application in the musculoskeletal system and provides perspectives for future developments.
Human Neural Crest Stem Cells Derived from Human ESCs and Induced Pluripotent Stem Cells: Induction, Maintenance, and Differentiation into Functional Schwann Cells
Authors: Liu Qiuyue , Spusta Steven C. , Mi Ruifa , Lassiter Rhonda N.T. , Stark Michael R. , Höke Ahmet , Rao Mahendra S. , Zeng Xianmin
Published: May 2012

The neural crest (NC) is a transient, multipotent, migratory cell population unique to vertebrates that gives rise to diverse cell lineages. Much of our knowledge of NC development comes from studies of organisms such as chicken and zebrafish because human NC is difficult to obtain because of its transient nature and the limited availability of human fetal cells. Here we examined the process of NC induction from human pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). We showed that NC cells could be efficiently induced from hESCs by a combination of growth factors in medium conditioned on stromal cells and that NC stem cells (NCSCs) could be purified by p75 using fluorescence-activated cell sorting (FACS). FACS-isolated NCSCs could be propagated in vitro in five passages and cryopreserved while maintaining NCSC identity characterized by the expression of a panel of NC markers such as p75, Sox9, Sox10, CD44, and HNK1. In vitro-expanded NCSCs were able to differentiate into neurons and glia (Schwann cells) of the peripheral nervous system, as well as mesenchymal derivatives. hESC-derived NCSCs appeared to behave similarly to endogenous embryonic NC cells when injected in chicken embryos. Using a defined medium, we were able to generate and propagate a nearly pure population of Schwann cells that uniformly expressed glial fibrillary acidic protein, S100, and p75. Schwann cells generated by our protocol myelinated rat dorsal root ganglia neurons in vitro. To our knowledge, this is the first report on myelination by hESC- or iPSC-derived Schwann cells.
Platelet-Rich Plasma Greatly Potentiates Insulin-Induced Adipogenic Differentiation of Human Adipose-Derived Stem Cells Through a Serine/Threonine Kinase Akt-Dependent Mechanism and Promotes Clinical Fat Graft Maintenance
Authors: Cervelli Valerio , Scioli Maria G. , Gentile Pietro , Doldo Elena , Bonanno Elena , Spagnoli Luigi G. , Orlandi Augusto
Published: May 2012

The potential plasticity and therapeutic utility in tissue regeneration of human adipose-derived stem cells (ASCs) isolated from adult adipose tissue have recently been highlighted. The use of autologous platelet-rich plasma (PRP) represents an alternative strategy in regenerative medicine for the local release of multiple endogenous growth factors. Here we investigated the signaling pathways and effects of PRP and human recombinant insulin on proliferation and adipogenic differentiation of ASCs in vitro. PRP stimulated proliferation (EC50 = 15.3 ± 1.3% vol/vol), whereas insulin's effect was the opposite (IC50 = 3.0 ± 0.5 μM). Although PRP alone did not increase adipogenesis, in association with insulin it prevented ASC proliferative arrest, greatly enhanced intracytoplasmic lipid accumulation, strongly increased serine/threonine kinase Akt phosphorylation and mouse monoclonal anti-sterol regulatory element binding protein-1 accumulation, and downregulated Erk-1 activity; adipogenic effects were markedly prevented by the Akt inhibitor wortmannin. PRP with insulin synergistically upregulated fibroblast growth factor receptor (FGFR) and downregulated epidermal growth factor receptor (ErbB) expression; moreover, PRP in association prevented insulin-induced insulin-like growth factor-1 receptor and insulin receptor downregulation. The inhibition of FGFR-1, epidermal growth factor receptor (EGFR), and epidermal growth factor receptor-2 (ErbB2) activity reduced ASC proliferation, but only that of FGFR-1 reduced adipogenesis and Akt phosphorylation, whereas the ErbB2 inhibition effects were the opposite. However, EGFR activity was needed for ErbB2-mediated inhibition of ASC adipogenesis. Clinically, the injection of insulin further ameliorated patients' 1-year PRP-induced fat graft volume maintenance and contour restoring. Our results ascertain that PRP in association with insulin greatly potentiates adipogenesis in human ASCs through a FGFR-1 and ErbB2-regulated Akt mechanism. The ameliorated clinical fat graft maintenance suggests additional useful translational applications of combined PRP-insulin treatment in regenerative medicine.
Muscular Dystrophy Campaign: Putting Some Financial Muscle Behind Finding a Cure
Authors: Pohlschmidt Marita
Published: May 2012

The Muscular Dystrophy Campaign, a London-based charitable organization, funds research on muscle function and muscle disease, including the study of muscle stem cells. Dr. Marita Pohlschmidt, the Muscular Dystrophy Campaign's director of research, describes its vision and goals.
Os(II) Based Green to Red Phosphors: A Great Prospect for Solution‐Processed, Highly Efficient Organic Light‐Emitting Diodes
Authors: Du Bo‐Sian , Liao Jia‐Ling , Huang Ming‐Hong , Lin Cheng‐Huei , Lin Hao‐Wu , Chi Yun , Pan Hsiao‐An , Fan Gang‐Lun , Wong Ken‐Tsung , Lee Gene‐Hsiang , Chou Pi‐Tai
Published: May 2012

Preparation and characterization of a new class of emissive Os(II) complexes (1–5) have been achieved using 3‐(thiazol‐2‐yl), 3‐(benzothiazol‐2‐yl), 3‐(imidazol‐2‐yl) and 3‐(benzimidazol‐2‐yl) azole chelates, together with the incorporation of one diphosphine ancillary for satisfying the octahedral coordination arrangement. The resulting Os(II) complexes, except for 5, all show bright emission spanning visible region from green to saturated red, and their structural versus spectroscopic properties have been comprehended by absorption/emission together with computational approaches. Subsequently, a series of solution‐processed OLEDs using 1–4 as the dopant were successfully fabricated, demonstrating excellent device performances with external quantum efficiency (EQE) of 15%, current efficiency exceeding 48 cd/A, and power conversion efficiency up to 50 lm/W. Complex 4 is the only Os(II) based phosphor so far suitable for the fabrication of highly efficient green‐emitting OLEDs.
Oxide Semiconductor Thin‐Film Transistors: A Review of Recent Advances
Authors: Fortunato E. , Barquinha P. , Martins R.
Published: May 2012

Transparent electronics is today one of the most advanced topics for a wide range of device applications. The key components are wide bandgap semiconductors, where oxides of different origins play an important role, not only as passive component but also as active component, similar to what is observed in conventional semiconductors like silicon. Transparent electronics has gained special attention during the last few years and is today established as one of the most promising technologies for leading the next generation of flat panel display due to its excellent electronic performance. In this paper the recent progress in n‐ and p‐type oxide based thin‐film transistors (TFT) is reviewed, with special emphasis on solution‐processed and p‐type, and the major milestones already achieved with this emerging and very promising technology are summarizeed. After a short introduction where the main advantages of these semiconductors are presented, as well as the industry expectations, the beautiful history of TFTs is revisited, including the main landmarks in the last 80 years, finishing by referring to some papers that have played an important role in shaping transparent electronics. Then, an overview is presented of state of the art n‐type TFTs processed by physical vapour deposition methods, and finally one of the most exciting, promising, and low cost but powerful technologies is discussed: solution‐processed oxide TFTs. Moreover, a more detailed focus analysis will be given concerning p‐type oxide TFTs, mainly centred on two of the most promising semiconductor candidates: copper oxide and tin oxide. The most recent data related to the production of complementary metal oxide semiconductor (CMOS) devices based on n‐ and p‐type oxide TFT is also be presented. The last topic of this review is devoted to some emerging applications, finalizing with the main conclusions. Related work that originated at CENIMAT|I3N during the last six years is included in more detail, which has led to the fabrication of high performance n‐ and p‐type oxide transistors as well as the fabrication of CMOS devices with and on paper.
Close Encounters of the 3D Kind – Exploiting High Dimensionality in Molecular Semiconductors
Authors: Skabara Peter J. , Arlin Jean‐Baptiste , Geerts Yves H.
Published: May 2012

In this Research News article we discuss the significance of dimensionality on the charge‐transport properties of organic semiconductors. Dimensionality is defined in two ways: as a function of (i) the π‐conjugated framework within the molecular structure, and (ii) the degree and direction of intermolecular close‐contacts between molecules in the bulk. In terms of dimensionality, silicon is a good role model for organic semiconductors, since it demonstrates 3D architecture in the bulk through covalent bonding. Achieving this for organics is challenging and requires not only a 3D molecular structure, but also a network of intermolecular short contacts in three dimensions. This review identifies the limitations of low dimensional materials and summarizes the challenges faced in progressing towards fully 3D organic semiconductors.
Biodegradable Composites Reinforced with Kenaf Fibers: Thermal, Mechanical, and Morphological Issues
Authors: Russo Pietro , Carfagna Cosimo , Cimino Francesca , Acierno Domenico , Persico Paola
Published: May 2012

Kenaf fiber reinforced composites were prepared via melt mixing using completely biodegradable poly(3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) (PHBV) and poly(butylenes adipate‐co‐terephthalate) (PBAT). Kenaf fibers were used as received and after chemical treatments aimed to improve fiber–matrix adhesion. The thermal, mechanical, and morphological properties of obtained composites were compared. Thermal measurements have shown no improvement in the thermal stability of PHBV due to reinforcing fibers, whereas detrimental effects have been evidenced for PBAT. Flexural and impact tests have emphasized benefits of chemical modifications depending on the polymer matrix nature as a consequence of an increased interaction at the fiber–matrix interface, also highlighted by scanning electron microscopy observations. © 2012 Wiley Periodicals, Inc. Adv Polym Techn 32: E313–E322, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/adv.21282
Aberrant methylation of H19‐DMR acquired after implantation was dissimilar in soma versus placenta of patients with Beckwith–Wiedemann syndrome
Authors: Higashimoto Ken , Nakabayashi Kazuhiko , Yatsuki Hitomi , Yoshinaga Hokuto , Jozaki Kosuke , Okada Junichiro , Watanabe Yoriko , Aoki Aiko , Shiozaki Arihiro , Saito Shigeru , Koide Kayoko , Mukai Tsunehiro , Hata Kenichiro , Soejima Hidenobu
Published: May 2012

Gain of methylation (GOM) at the H19‐differentially methylated region (H19‐DMR) is one of several causative alterations in Beckwith–Wiedemann syndrome (BWS), an imprinting‐related disorder. In most patients with epigenetic changes at H19‐DMR, the timing of and mechanism mediating GOM is unknown. To clarify this, we analyzed methylation at the imprinting control regions of somatic tissues and the placenta from two unrelated, naturally conceived patients with sporadic BWS. Maternal H19‐DMR was abnormally and variably hypermethylated in both patients, indicating epigenetic mosaicism. Aberrant methylation levels were consistently lower in placenta than in blood and skin. Mosaic and discordant methylation strongly suggested that aberrant hypermethylation occurred after implantation, when genome‐wide de novo methylation normally occurs. We expect aberrant de novo hypermethylation of H19‐DMR happens to a greater extent in embryos than in placentas, as this is normally the case for de novo methylation. In addition, of 16 primary imprinted DMRs analyzed, only H19‐DMR was aberrantly methylated, except for NNAT DMR in the placental chorangioma of Patient 2. To our knowledge, these are the first data suggesting when GOM of H19‐DMR occurs. © 2012 Wiley Periodicals, Inc.
Nucleation effect of surface treated TiO2 on Poly(trimethylene terephthalate) (PTT) nanocomposites
Authors: Ramesh V. , Mohanty S. , Panda B. P. , Nayak S. K.
Published: May 2012

A study of the nucleation effect of TiO2 in poly(trimethylene terephthalate)/TiO2 nanocomposite has been carried out using different theoretical models. The models were applied and developed with the aim to describe and better understand the influence of the TiO2 dispersion on crystallization characteristics of PTT. The PTT/TiO2 nanocomposites with untreated and surface‐treated TiO2 were prepared by the melt mixing method. The nucleation efficiency of the TiO2 nanoparticles has been analyzed with the use of the Avrami model and Mo's method. It was found that the PTT matrix incorporated with surface‐treated TiO2 particles has a higher crystallization temperature and melting point than that incorporated with untreated TiO2 particles. As per the models, unlike untreated TiO2, surface‐treated TiO2 particles had a lesser effect on the degree of crystallization of the PTT matrix. The TiO2 nanoparticles act as a nucleating agent in the PTT matrix thereby reducing t½ of the crystallization and leading to easier crystallization of the polymer. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Synthesis of bio‐based polyurethanes from epoxidized soybean oil and isopropanolamine
Authors: Miao Shida , Zhang Songping , Su Zhiguo , Wang Ping
Published: May 2012

Epoxidized soybean oil (ESO) and isopropanolamine were used to synthesize a new polyol mixture for preparation of bio‐based polyurethanes. The chemical synthetic route for reaction of ESO with isopropanolamine was analyzed by 1H‐NMR. The results suggested that both ester groups and epoxy groups in ESO had reacted with amino group of isopropanolamine through simultaneous ring‐opening and amidation reactions. Epoxy groups in various situations exhibited different reactivity, and the unreacted epoxy groups were further opened by hydrochloric acid. The synthesized polyol mixture had high hydroxyl number of 317.0 mg KOH/g. A series of polyurethanes were prepared by curing the synthesized polyol mixture with 1,6‐diisocyanatohexance along with different amount of 1,3‐propanediol (PDO) as chain extender. Tensile tests showed that yield strengths of the polyurethanes ranged from 2.74 to 27.76 MPa depending on the content of PDO. Differential scanning calorimetry analysis displayed one glass transition temperature in the range of 24.4–28.7°C for all of the polyurethane samples, and one melt peak at high content of PDO. Thermogravimetric analysis showed that thermal degradations of the polyurethanes started at 240–255°C. In consideration of simple preparation process and renewable property of ESO, the bio‐based polyurethane would have wide range of applications. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Microstructure elucidation of polyflavonoid tannins by MALDI‐TOF‐CID
Authors: Radebe Nonhlanhla , Rode Karsten , Pizzi Antonio , Pasch Harald
Published: May 2012

High molar mass wood tannin extracts are complex mixtures that are distributed in both molar mass and chemical composition. Condensed tannins from quebracho and mimosa woods were analyzed and compared with cacao tannins using matrix‐assisted laser desorption/ionization‐time of flight (MALDI‐TOF) mass spectrometry. Although MALDI‐TOF MS reveals the oligomer structure of the tannins, this method cannot distinguish between isomers with isobaric masses, and therefore, ambiguous structural assignments were made in a number of cases. To determine the actual microstructures present, MALDI‐TOF collision‐induced dissociation (CID) experiments were conducted. MALDI‐TOF‐CID enables monomer sequence determination, and positive assignments of isobaric structures can be made. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Ternary elastomer nanocomposites based on NR/BR/SBR: Effect of nanoclay composition
Authors: Zarei M. , Naderi G. , Bakhshandeh G. R. , Shokoohi S.
Published: May 2012

Elastomer nanocomposites based on natural rubber (NR), butadiene rubber (BR), and styrene butadiene rubber (SBR) containing Cloisite 15A were prepared using a two‐roll mill. Mechanical, morphological, and rheological characterization of the prepared nanocomposites was carried out in order to study the effect of different nanoclay compositions, i.e., 1, 3, 5, 7, and 10 wt %. Intercalation of the elastomer chains into the silicate layers was evidenced by d‐spacing values calculated according to the results of the X‐ray diffraction (XRD) patterns. This was directly confirmed by transmission and scanning electron microscopy (TEM and SEM). The results depict a decreasing trend in the optimum cure time (t90) and scorch time (t5) values of the nanocomposite samples with increasing nanoclay loading; where the elastic modulus (G′) and complex viscosity (η*) of the samples considerably increased. The mechanical properties of the nanocomposites show a considerable increase in the tensile modulus of NR/BR/SBR/Cloisite 15A nanocomposites. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013