bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Side-specific Valve Endothelial Cells on Extracellular Matrix Production by Valve Interstitial Cells
Authors: Mongkoldhumrongkul Napachanok , Yacoub Magdi H. , Chester Adrian H.
Published: July 2012

Valve endothelial cells (VECs) play an important role in regulating the function of the underlying interstitial cells (VICs). However, the regulatory effects VECs from each side of the valve on the production of ECM proteins by VICs have not been studied. This study aims to determine the regulatory effects of VECs isolated from the aortic (aVECs) and ventricular (vVECs) surfaces of the aortic valve on the production of collagen, glycosaminoglycan (GAGs) and elastin by VICs.
Side-specific VECs were co-cultured with VICs using Transwell® inserts and the effects on extracellular matrix production by VICs were investigated by quantifying the amount of secreted collagen and sulphate GAGs by VICs as well as examining gene expressions of collagen, GAGs and elastin components by VICs. Collagen production by VICs was significantly increased by co-culturing with aVEC and vVECs to 154.38 ± 13.71% (p=0.041) and 196.35 ± 16.59% (p=0.008), respectively, of the control (VIC culture without VECs). Furthermore, vVECs significantly enhanced production of sulphate GAGs by VICs to 217.18 ± 32.9% (p=0.008) above control whereas aVECs showed an increase of 150.08 ± 18.0%, which was non-significance. There was no significant difference between sulphate GAGs release in response to vVECs and aVECs. Only fibrillin 1, a component of elastin, gene expression was increased by co-culturing VICs with aVEC, 2.07 ± 0.34 (p=0.008), and vVECs, 2.13 ± 0.31 (p=0.03) fold increase above control. In contrast, media collected over a 48 hour period from aVEC or vVEC cultures and subsequently incubated with VICs (in the absence of VECs) showed no induction on the ECM production by VICs. In conclusion, aVECs and vVECs induce the ECM production and expression by releasing labile molecules which are degradable or lose their activities with time. Further experiments are necessary to identify the mediators that produce these effects and to determine how their release is modulated by the different flow patterns experienced by aVECs and vVECs. This study further highlights the complex interaction and communication between different cell types present in the valve cusps.
Immunological Effects of [alpha]Gal-positive and [alpha]Gal Knockout Biological Heart Valves
Authors: McGregor Christopher G. A. , Kogelberg Heide , Byrne Guerard W.
Published: July 2012

As immune responses likely contribute to degeneration of bioprosthetic heart valves (BHVs), this nonhuman primate study compares the anti-Gal antibody response to BHVs from wild type (WT) pigs (current BHVs) and those from α-galactosyltransferase knockout (GTKO) pigs.
Stented glutaraldehyde fixed BHVs from WT (n=4) and GTKO (n=3) pigs were commercially manufactured and implanted in the mitral position in nonhuman primates using standard surgical techniques. Recipients were treated with Lovenox (1mg/kg BID) for 5 weeks reducing to 1mg/kg daily for one week and then discontinued. Recipients were sensitized to the αGal antigen by immunization to match IgG levels found in humans. Serum antibody responses were monitored by ELISA. WT BHVs were explanted at 3 hours, 1 year, 2 years and the fourth is currently ongoing at 3 years. One GTKO BHV was explanted at 218 days. The remaining two GTKO BHVs are currently ongoing at 3 years. After immunization, circulating anti-Gal IgG levels were comparable in both groups at the time of implantation and were equal or greater than human levels. Anti-Gal antibody levels decreased in both WT and GTKO recipients after implantation. WT recipients, however, retained elevated levels (greater than 20% preimplant values) of anti-Gal IgG for at least the first year post implant. Conversely anti-Gal IgG levels in all GTKO recipients fell within one month and remained at less than 20% preimplant values. Analysis of the area under the curve showed a significant increase of anti-Gal IgG in the WT BHV group compared to GTKO BHV recipients (p<0.01). In this nonhuman primate model, the persistently and significantly (p<0.01) elevated levels of anti-Gal IgG antibody observed in WT but not GTKO BHV recipients, indicate continuing immune stimulation to the αGal antigen. Current commercially available BHVs are similarly known to contain αGal antigen. Anti-Gal antibody has been shown to increase calcification of processed pericardium in the rat implant model. These data support the hypothesis that preformed and induced anti-Gal antibody in BHV recipients may initiate an early immune response, which promotes subsequent calcification. BHVs made from GTKO pigs would eliminate this major xenoreactive antigen and provide a prosthesis with reduced immunogenicity. Such BHVs made from GTKO pigs may have greater durability and be potentially used in younger patients with more active immune systems.
Stress-Fiber Remodeling in 3D: ‘Contact Guidance vs Stretch Avoidance’?
Authors: Foolen Jasper , Baaijens Frank
Published: July 2012

When engineering heart valves in vitro, matrix anisotropy is considered important for long-term in vivo functionality. However, it is not fully understood how to guide, maintain and control matrix anisotropy. Experiments suggest that collagen anisotropy is affected by actin-mediated cell traction and associated cellular orientation. Although cellular orientation in 2D can be manipulated via imposed uniaxial cyclic stretch, 3D data are lacking. We questioned how cyclic stretch influences actin and collagen orientation in 3D constructs. A novel micro-tissue platform system was designed, able to dynamically and biochemically load small-scale cell-populated fibrous tissues. Flexible membranes of Bioflex culture plates were provided with a rectangular array silicone posts. These silicone posts constrained a contracting gel mixture of human vena saphena cells (HVSC), collagen type I and matrigel. The constrained tissues were subjected to pure uniaxial cyclic stretch (10%, 0.5Hz, in the presence or absence of agents) on the Flexcell system. F-actin was taken as a measure for the cell traction direction, and the F-actin orientation was quantified throughout the complete tissue thickness (~ 300m) using fiber-tracking software, and was fitted using a bi-model distribution function. Uniaxial cyclic stretching for 3 days (preceded by 3 days of static constraint) resulted in stress-fibers that were oriented perpendicular to the stretching direction only at tissue surfaces, as generally observed in 2D. Strikingly, however, in the tissue core F-actin (and cell) and collagen orientation was biaxial. Immediate cyclic stretching, starting before polymerization of the collagen matrix, resulted in a strong stretch avoidance throughout the tissue, of both F-actin and collagen. We systematically investigated the effect of biochemical treatment, including MMP1 to perturb matrix integrity, MMP-1 + ROCK-inhibitor to counteract the possible MMP1-induced response, as well the effect of a lower and a higher initial collagen density. Experimental data suggests that F-actin stress-fibers avoid cyclic stretch in 3D, unless collagen contact guidance dictates otherwise.
Experimental and Computational Studies of the Aortic Bi-leaflet Mechanical Heart Valve (BMHV) Hemodynamics in an Idealized Left Ventricle
Authors: Bao Le Trung , Chaffin Brandon , Mirabella Lucia , Santhanakrishnan Arvind , Yoganathan Ajit , Sotiropoulos Fotis
Published: July 2012

We aim to validate the performance of our fluid structure interaction (FSI) simulations of a bi-leaflet mechanical heart valve in the aortic position., whose motion is driven by the beating left ventricle. We compare in vitro experiments and computations performed on an idealized model of the left ventricle (LV) with a St. Jude Medical Regent heart valve in the aortic position. The idealized LV consists of a truncated tetrahedron representing a simplified LV chamber with a single deformable surface made of silicone. The silicone surface simulates the lateral wall of the LV. The deformation of the LV is controlled by pressurizing the fluid surrounding the LV chamber via a Vivitro Superpump (Vivitro Systems; British Columbia). The experimental model simulates physiological flow rates and pressures that occur in the LV. The three-dimensional motion of the deformable surface is tracked using high speed cameras and reconstructed using a direct linear transformation. The reconstruction of the motion of the deformable surface has been validated against fluid volume flux of the LV measured using two Transonic Systems Inc. flow probes (Model ME-PXN; Ithaca, NY). The leaflet motion of the SJM is tracked using 2D photogrammetry with a single high speed camera. A two-dimensional DPIV system (LaVision GmbH; Goettingen, Germany) is used to acquire fluid velocity measurements within the ventricle and in the aortic position of the flow field through the cardiac cycle. In the computation, the ventricle kinematics, measured from experiment, is treated as an immersed boundary by the Curvilinear Immersed Boundary (CURVIB) method ( Ge et al., J. Comp. Physics, 2007). The leaflet kinematics of the BMHV are computed from the fluid-structure interaction solver FSI-CURVIB (Borazjani et al., J. Comp. Physics, 2008). The computational domain is a structured mesh of 8 million grid points with a physical timestep of 1 ms. We have previously shown the capability of the FSI solver to resolve the BMHV kinematics and the resulting flow patterns in a stand-alone aorta (Borazjani et al., J. Comp. Physics, 2008). The comparison between the experimental and computational results shows good agreement for the ventricular flow pattern. The details of the validation of coupled LV-BMHV simulations will be discussed in the presentation.
Modulating the Inflammatory Response for In Situ Tissue Engineering – The Role of MCP-1
Authors: Smits Anthal I.P.M. , Driessen-Mol Anita , Bouten Carlijin V.C. , Baaijens Frank P.T.
Published: July 2012

Inflammation is not merely a detrimental response to biomaterials. It can be considered as a natural agent of tissue remodeling, which is pivotal for the approach of in situ cardiovascular tissue engineering. Recently, a biodegradable synthetic scaffold was shown to remodel into a fully functional healthy blood vessel via an inflammation-mediated response. In fact, it was shown that initial infiltration of immune cells (i.e. monocytes) is indispensible for long-term remodeling of scaffolds and functionality of neo-tissues. This remodeling process is orchestrated by potent signaling molecules, of which monocyte chemotactic protein-1 (MCP-1) was identified as a key player. However, the exact mechanism remains unclear. We hypothesize that MCP-1 initiates a desired wound healing cascade by recruiting favorable monocyte and macrophage (M2 type) subpopulations in the implanted scaffold. To investigate the interactions between circulating cells and scaffolds, we have developed and validated a meso-fluidics setup that exposes small-scale 3D scaffolds to a circulating cell suspension in pulsatile flow with pressure and shear stress on the scaffold surface in the physiologic range for aortic valve and small diameter arteries. Electrospun polycaprolactone (PCL) scaffolds were loaded with fibrin gel with and without MCP-1 and placed into the fluidics setup. Human peripheral blood mononuclear cells (hPBMC) were isolated from healthy donors by density gradient centrifuging. The cells were resuspended in culture medium and circulated in the fluidics setup for up to 72 hours at a pulsatile flow (1Hz), with a peak pressure of approximately 100 mmHg and peak shear stress of 1.5 Pa on the scaffold surface. The cell suspensions were characterized at various time points by flow cytometry. The hPBMC suspension at the start consisted of CD45+ lymphocytes and monocytes. After 16 hours in the fluidics setup, the distinct monocyte subpopulation (8-20% of hPBMC) was no longer present in the medium, regardless of MCP-1 presence. This suggests monocyte activation by the scaffold, resulting in cell adhesion and monocyte-to-macrophage differentiation. Moreover, whole-mount immunostaining of the scaffolds demonstrated that addition of MCP-1 resulted in a significant increase in CD163 expression, which indicates the presence of a favorable monocyte subpopulation and macrophage polarization towards a wound healing M2 phenotype. Our results show that the PCL/fibrin scaffold evokes a response from circulating monocytes, resulting in rapid cell adhesion and infiltration. Moreover, this initial response can be modulated using MCP-1 to promote favorable M2 macrophage polarization, initiating the wound healing cascade that is necessary for long term remodeling of the synthetic scaffold.
An Analysis of Tissue-Engineered Pulmonary Valves Implanted in the Elderly Ovine Model
Authors: Theodoridis Karolina , Calistru Alexandru , Meyer Tanja , Tudorache Igor , Cebotari Serghei , Sarikouch Samir , Bara Christoph , Brehm Ralph , Hilfiker Andres , Haverich Axel
Published: July 2012

Bioprosthetic heart valve replacement, recommended for patients older than 65 years of age, increases the quality of life, however grafts exhibit limited functionality due to degradation and calcification. Decellularized and tissue-engineered pulmonary valves (PV) get repopulated by autologous interstitial cells when implanted into juvenile sheep. Thus, in vivo matrix guided regeneration results in restored valve function. In this study, we investigated the regeneration capacity in elderly sheep. Sheep (Ø 7 yrs old, Ø weight of 88.5 kg) received pulmonary valve replacement. Decellularized PV (n=6), decellularized PV coated with proangiogenic CCN1 (n=6), and decellularized, CCN1 coated and reendothelized PV (n=6) were implanted in orthotopic position. For endothelialization PV were seeded with autologous endothelial cells (EC) differentiated from EPC from peripheral blood. Cells were flow adapted in a pulsatile bioreactor system prior implantation. PV functional analysis in vivo was realized by echocardiography, directly after implantation and prior explantation. Allografts were explanted after six and twelve months in vivo and investigated in respect to endothelium coverage, to the integrity of the extracellular matrix, and to the degree and cellular identity of invaded cells by histological and immunochemical stains. All allografts showed good to adequate function, no stenosis, low gradients and only occasional insufficiency without clinical symptoms. No signs of degradation of the extracellular matrix and minimal calcification restricted at the anastomosis of the grafts were found. All grafts were repopulated with cells but to various degree. Only one, explanted after one year, showed complete repopulation including the leaflets. In general, cell-density in the pulmonary artery was higher on the adventitial than on the luminal side and leaflets were better repopulated at the ventricular than at the arterial side. The majority of cells expressed sm-alpha-actin. Endothelial cells located on the luminal side appeared in some grafts as intact complete monolayer. Beside a slight tendency of better repopulation observed in the reendothelialized PV group, no significant difference of cell densities was found among the groups.
Autologous repopulation of decellularized heart valve matrices implanted in the orthotopic position in the elderly sheep demonstrates retained regenerative capacity even in the older organism. This observation combined with the fact that no functional loss must have taken into account, implantation of decellularized heart valves matrices in patients over age 65 remains a therapy option to overcome the drawbacks of current used bioprosthesis.
Marrow Stromal Cell based Stem Cell Based Transcatheter Aortic Valve Implantation: First Experiences in a Preclinical Model
Authors: Emmert Maximilian Y. , Weber Benedikt , Petra Petra , Behr Luc , Sammut Sebastien , Frauenfelder Thomas , Frese Laura , Scherman Jacques , Brokopp Chad E. , Templin Christian , Grünenfelder Jürg , Zünd Gregor , Falk Volkmar , Hoerstrup Simon P.
Published: July 2012

We investigate the combination of transcatheter aortic-valve implantation (TAVI) and a novel concept of stem cell-based, tissue-engineered heart-valves (TEHV) comprising minimally-invasive techniques for both, cell-harvest and valve-delivery. TAVI represents an emerging technology for the treatment of aortic-valve disease. The utilized bioprostheses are inherently prone to calcific-degeneration and recent evidence suggests even accelerated degeneration resulting from structural-damage due to the crimping-procedures. Autologous, living heart-valve prosthesis with regeneration and repair capacities would overcome such limitations.
Methods: Within a one-step intervention, tri-leaflet TEHV, generated from biodegradable synthetic-scaffolds, were integrated into self-expanding nitinol-stents, seeded with autologous bone-marrow mononuclear cells, crimped and transapically delivered into adult sheep (n=12). The animals were followed up for up to 2 weeks. TEHV-functionality was assessed by fluoroscopy, echocardiography and computed-tomography. Post-mortem analysis was performed using histology, extracellular-matrix analysis and electron-microscopy. Transapical aortic implantation of TEHV was successful in all animals (n=12) and the entire procedure-time from cell-harvest to TEHV-delivery was 109±14min. Fluoroscopy and echocardiography displayed TEHV-functionality demonstrating an adequate leaflet-mobility and co-aptation. Explanted TEHV showed intact leaflet-structures with well defined cusps without signs of thrombus-formation or structural-damage. Histology and ECM analysis displayed a high cellularity indicative for an early cellular-remodelling and in-growth after 2weeks. For the first time, we demonstrate the principal feasibility of a transcatheter, stem cell-based TEHV implantation into the aortic-valve position within a one-step intervention. Its long term functionality proven, a stem cell-based TEHV approach may represent a next generation heart-valve concept extending the clinical indication of transcatheter valves beyond elderly high-risk patients.
Mechanism of Cardiovascular Tissue Immunogenicity Reduction by Ice-free Cryopreservation
Authors: Brockbank Kelvin G.M. , Bayrak Alexandra , Seifert Martina , Stock Ulrich A.
Published: July 2012

A variety of reasons for allograft heart valve failure have been discussed in the past and most investigators have emphasized immunological issues. Standard quantitative and qualitative cellular and matrix evaluations have not helped to solve the discussion of whether remaining allogeneic cells or potentially altered extracellular matrix contributed to the observed degeneration. Preliminary data on patients treated with decellularized allografts has recently demonstrated that decellularization did not significantly improve outcome in terms of pressure gradients and structural deterioration compared to non-decellularized allografts. These early clinical results question the validity of theories suggesting that an immune reaction to the remaining donor cells in allogeneic heart valves is the sole cause of structural deterioration.Porcine and ovine pulmonary and aortic heart valves were cryopreserved using traditional cryopreservation by freezing with 10% dimethylsulfoxide or ice-free cryopreservation in an 83% cryoprotectant formulation consisting of 4.65 mol/L dimethylsulfoxide, 4.65 mol/L formamide and 3.31 mol/L 1,2-propanediol. Cell viability was assessed using a water soluble fluorometric viability oxidation-reduction (REDOX) indicator which detects metabolic activity by both fluorescing and changing color in response to chemical reduction of the growth medium. Statistical analyses were performed using a t-test or one-way analysis of variance, p values<0.05 were considered statistically significant. Viability assessment revealed that heart valve tissues were significantly less viable in ice-free cryopreserved valves compared with frozen valves, p<0.05, due to cryoprotectant cytotoxicity. Juvenile sheep studies demonstrated that ice-free cryopreserved heart valves had minimal T-cell mediated inflammation in the valve leaflet stroma compared with frozen controls. Severe valvular stenosis with right heart failure was observed in recipients of frozen valves, the echo data revealed increased velocity and pressure gradients compared to ice-free valve recipients (p=0.0403, p=0.0591). In vitro studies have demonstrated retention of hemocompatibility, biocompatibility and reduction of ice-free cryopreserved heart valve tissue immunogenicity. Based upon these observations, it is hypothesized that preservation of extracellular matrix structure due to the absence of ice and minimal cell viability due to cryoprotectant cytotoxicity combine to decrease tissue repair activity and reduced immunogenicity. Work in progress is extending ice-free cryopreservation to other cardiovascular and orthopedic tissue engineering applications including in vitro and in vivo cell repopulation.
Scaffolds and Stem Cells for Patient-Tailored Aortic Heart Valve Tissue Engineering
Authors: Simionescu Dan , Jaeggli Michael , Liao Jun , Simionescu Agneta
Published: July 2012

Valve reconstruction or regeneration with living tissue is a daunting project for biomedical engineers and surgeons alike. Our translational approach to development of living valve replacements embraces three main principles: a) the accurate replication of each patient’s 3D aortic valve architecture for optimal functionality, b) layered scaffolds that mimic the aortic valve fibrosa, ventricularis and spongiosa to prevent buckling and enhance mechanical durability and c) the presence of autologous, valvular interstitial cells (VICs) to maintain matrix homeostasis. To create anatomically correct constructs, we used digital image processing of patient chest CT images and generated solid aortic valve root 3D structures using a stereo-lithography printer. Collagenous scaffolds to be used as the fibrosa and ventricularis layers were prepared from acellular porcine pericardium and collagen/GAG hydrogels to be used as the spongiosa layer. Layered scaffolds were attached to the molds, dried, stabilized with a non-toxic polyphenolic agent, rehydrated, the spongiosa seeded with human mesenchymal stem cells and valves subjected to functionality tests in a physiological heart valve bioreactor in sterile culture medium. Engineered valves exhibited excellent functional characteristics; most cells were alive, elongated significantly and stained positive for vimentin and actin, among other markers, suggestive of mechanical stimuli-induced stem cell differentiation into VICs. Ongoing studies are focused on endothelialization of the novel valve surfaces using stem cell-derived endothelial cells and rotational 3D seeding devices. In conclusion, autologous stem cell-seeded tri-layered collagenous scaffolds shaped to recapitulate the aortic heart valve shape and mechanics may provide future foundations for patient-tailored heart valve tissue engineering.
Adipose Fat Derived Tissue-Engineered Heart Valves
Authors: Frese Laura , Sanders Bart , Dijkman Petra E. , Weber Benedikt , Emmert Maximilian Y. , Brokopp Chad , Beer G. , Driessen-Mol Anita , Baaijens Frank P.T. , Hoerstrup Simon P.
Published: July 2012

A major challenge in tissue engineering of heart valves is the in vitro creation of mature tissue structures compliant with the native valve function. Concerning the remodeling capacity of the extracellular matrix (ECM), various cell types have been investigated, including prenatal cells, umbilical cord and vascular derived cells. The pluripotency and availability of human mesenchymal stem cells has made them highly attractive for tissue engineering purposes. However, for clinical use, adult bone marrow derived mesenchymal stem cells (MSC) are suboptimal due to the highly invasive donation procedure, and the decline in MSC number and differentiation potential with increasing age of the patient. Adipose derived stem cells (ADSC) represent an interesting alternative of mesodermal origin. The easy and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide a clear advantage. Here, we investigate the suitability of ADSC as a novel cell source for tissue engineered heart valves (TEHV). Tissue Engineered (TE) heart valve leaflets (n=6) were produced, based on PGA/P4HB scaffolds seeded with human ADSC isolated from fat tissue excisions from plastic surgery. To stimulate tissue formation and induce matrix alignment, the TE leaflets were cultivated in dynamic strain bioreactors for 4 weeks. We subsequently reseeded the cultivated valves with ADSC derived endothelial cells. Differentiation into endothelial-like cells was induced by cultivation of ADSC in the presence of vascular endothelial growth factor. To determine the ECM composition of the TE leaflets, biochemical analyses for glycosaminoglycans (GAG), hydroxyproline (HYP) and DNA were performed. To further evaluate the microstructural features, tissue samples of TE leaflets were analyzed by stainings as well as by scanning electron microscopy. The mechanical properties of the ADSC derived TE leaflets were analyzed using a biaxial tensile tester. TE leaflets based on ADSC showed a homogenous vital cell distribution throughout the whole leaflet structure and the formation of a confluent endothelial lining. Furthermore, a mechanically stable matrix with GAG and collagen was demonstrated. These results indicate that ADSC represent an interesting alternative autologous mesenchymal human cell source with clinical relevance due to their easy accessibility and excellent proliferation and tissue formation capacities.
Biotechnology in Argentina: Development and Resources
Authors: Zylberberg Claudia , Oner Asli Ceylan , Zylberberg Ezequiel
Published: July 2012

Biotechnology related developments in Argentina have gained momentum in the past few years. The creation of the Ministry of Science, Technology and Innovative Production in 2007 that focuses on high-tech growth in technology related fields including biotechnology, demonstrates the public sector commitment to a field with a thriving business sector and promising improvements in research and development. By embracing its agricultural advantage and investing in research and innovation, Argentina has seen its stock of biotech companies grow to 120, of which 90 percent are domestic small and medium size. Today, biotechnology researchers in Argentina engage in international collaboration with other scholars and globally recognized institutions and the country has bilateral agreements with other countries to support biotechnology related research and development. There are many governmental and non-profit organizations that are influential in shaping Argentinaâ€™s vision on biotechnology. Although the government places importance in providing support in biotechnology research, innovation and investment, the paper argues that the rapid growth trends in the industry requires biotechnology to become higher on the national agenda. The lack of a royalty collection system, the absence of patent protection, and the inadequate sources of venture capital still remain as important problems. Attracting new forms of foreign capital, higher investment in infrastructure, building on existing regional and global networks in research and development, are all important areas for improvement to advance biotechnology in Argentina. Â
Innovative biotechnology industry strategies in the U.S.â€™ rapidly evolving payer environment
Authors: Collins Sarah Stanton , Collins Will
Published: July 2012

In 2010 healthcare represented 17.9% of GDP; its cost is growing significantly faster (~5%) than economic growth (~ 2%).Â  This growth presents a challenge to all payers, whether they are governments, employers, or individuals.Â  Within healthcare, one of the most rapidly growing areas is â€œspecialty drugsâ€ which are frequently biotechnology agents, or drugs for cancer or orphan conditions.Â  This article starts by discussing the issues of specialty drug cost and the challenges payers face in managing specialty drugs.Â  It then presents market structure and firm strategy theories that provide insight into firm behavior in specialty drug categories.Â  Lastly, it discusses possible events and actions that could dramatically change the biotechnology industry and lead to increased value within the U.S. health care system.
Innovating in the New Austerity
Authors: Burrill G. Steven
Published: July 2012

We are in the midst of dramatic changes in the way life sciences companies are funded. The model of funding a company with venture capital leading to an IPO is now the exception rather than the rule for life sciences companies. Venture investors are no longer willing or able to fund companies with an indefinite exit. Instead, they are waiting later to fund companies, building exits into their investments from the start, and looking to innovative technologies other than therapeutics that can address medical and healthcare system needs, but provide a more predictable path to revenue. The financial pressures of today are leading to creative efforts to forge new business and financing models. They are driving capital efficiency and putting a proper emphasis on value creation. The resulting discipline is welcome. The result is that companies that fail to pursue true innovation and products that create value will find funding difficult to obtain and markets unwilling to pay premiums.Â For those of us who invest in the sector, the good news is that valuations are historically attractive and power at the negotiating table lies with those who have capital. The opportunities before us have never been greater.
Hierarchically Structured Porous Materials for Energy Conversion and Storage
Authors: Li Yu , Fu Zheng‐Yi , Su Bao‐Lian
Published: July 2012

Materials with hierarchical porosity and structures have been heavily involved in newly developed energy storage and conversion systems. Because of meticulous design and ingenious hierarchical structuration of porosities through the mimicking of natural systems, hierarchically structured porous materials can provide large surface areas for reaction, interfacial transport, or dispersion of active sites at different length scales of pores and shorten diffusion paths or reduce diffusion effect. By the incorporation of macroporosity in materials, light harvesting can be enhanced, showing the importance of macrochannels in light related systems such as photocatalysis and photovoltaics. A state‐of‐the‐art review of the applications of hierarchically structured porous materials in energy conversion and storage is presented. Their involvement in energy conversion such as in photosynthesis, photocatalytic H2 production, photocatalysis, or in dye sensitized solar cells (DSSCs) and fuel cells (FCs) is discussed. Energy storage technologies such as Li‐ions batteries, supercapacitors, hydrogen storage, and solar thermal storage developed based on hierarchically porous materials are then discussed. The links between the hierarchically porous structures and their performances in energy conversion and storage presented can promote the design of the novel structures with advanced properties.
Magnetoresistive Memory with Ultralow Critical Current for Magnetization Switching
Authors: Pertsev Nikolay A. , Kohlstedt Hermann
Published: July 2012

The data writing and thermal stability of information storage are studied theoretically for a magnetic random access memory (MRAM) composed of a magnetic tunnel junction or multilayer exhibiting giant magnetoresistance. The theoretical analysis focuses on the magnetization switching in the “free” layer of a MRAM cell, which is induced by a spin‐polarized current imposing a spin‐transfer torque (STT) on the magnetization. It is shown that the writing current in such an STT‐MRAM reduces dramatically near a spin reorientation transition (SRT) driven by lattice strains and/or surface magnetic anisotropy and even tends to zero under certain conditions. In particular, at the size‐driven SRT in the perpendicular‐anisotropy CoFeB‐MgO tunnel junctions, the critical current densities for magnetization reorientations between the parallel and antiparallel states are expected to fall to low values of about 1.3 × 105 and −3.3 × 104 A cm−2. Remarkably, STT‐MRAMs may combine low writing current with very high thermal stability of information storage (retention over 10 years) even at a high density ≈500 Gbit inch−2.
Cooperative Heterogeneous Organocatalysis and Homogeneous Metal Catalysis for the One‐Pot Regioselective Synthesis of 2‐Pyridones
Authors: Allais Christophe , Baslé Olivier , Grassot Jean‐Marie , Fontaine Maxime , Anguille Stéphane , Rodriguez Jean , Constantieux Thierry
Published: July 2012

A direct, one‐pot and regioselective access to N‐alkyl‐ and N‐aryl‐substituted 2‐pyridones is described from readily available β‐keto amides and either primary or secondary propargylic alcohols. This approach involves the combination of two different cooperative homogeneous and heterogeneous catalytic systems based on a transition metal oxide and a supported organocatalyst, respectively.
A qualitative ecological risk assessment of the invasive Nile tilapia, Oreochromis niloticus in a sub‐tropical African river system (Limpopo River, South Africa)
Authors: Zengeya Tsungai A. , Robertson Mark P. , Booth Anthony J. , Chimimba Christian T.
Published: July 2012

This study outlines the development of a qualitative risk assessment method and its application as a screening tool for determining the risk of establishment and spread of the invasive Nile tilapia, Oreochromis niloticus (Linnaeus, 1758), within the central sub‐catchment of the Limpopo River basin in northern South Africa.

The assessment used known physiological tolerance limits of O. niloticus in relation to minimum water temperature, presence or absence of dams, seasonality of river flows, and the presence of indigenous fish species of concern to identify river systems that would be suitable for O. niloticus establishment.

River sections along the Limpopo main river channel and the immediate reaches of its associated tributaries east of the Limpopo/Lephalala river confluence along the Botswana–South Africa–Zimbabwe border were identified as being highly vulnerable to O. niloticus invasion. Rivers in the upper Bushveld catchment (Upper Limpopo, Mogalakwena, Lephalala, Mokolo, Matlabas and Crocodile rivers) were categorized as of medium ecological risk, while headwater streams were considered to be of low ecological risk. The decrease in vulnerability between lowveld and highveld river sections was mainly a function of low water temperatures (8–12°C) associated with increasing altitude.

Oreochromis niloticus is already established in the lower catchment of the Limpopo River basin where indigenous congenerics are at an extinction risk through hybridization and competition exclusion. Oreochromis niloticus, therefore, poses an ecologically unacceptable risk to river systems in the upper catchment where it is yet to establish. The current risk assessment model provides a useful preliminary framework for the identification of river systems that are vulnerable to an O. niloticus invasion where conservation measures should be directed and implemented to prevent its introduction and spread within the Limpopo river system. Copyright © 2012 John Wiley & Sons, Ltd.
Naturally acidic waterways: conceptual food webs for better management and understanding of ecological functioning
Authors: Holland Aleicia , Duivenvoorden Leo J. , Kinnear Susan H. W.
Published: July 2012

Naturally acidic fresh waters have high conservation value, with their habitats supporting a high level of biodiversity as well as providing for rare organisms that are specially adapted to life in low‐pH environments.

Food webs within naturally acidic waterways are heavily reliant on the input of large amounts of organic matter from the surrounding terrestrial environment.

Although these systems are found worldwide, the increasing threats of global climate change and urban developments are placing naturally acidic environments under threat of catastrophic changes to their ecology. Despite this, studies of these unique systems remain in their infancy, especially when compared with systems acidified by anthropogenic means.

This paper aims to explore the varying influences on key food‐web elements in naturally acidic waterways, particularly with regard to allochthonous organic matter (AOM).

A conceptual model for the food webs of naturally acidic environments is presented, with the aim of providing a framework to understand the ecological functioning of these under‐studied systems. This information will be critical in informing management decisions as naturally acidic streams are challenged by increasing environmental pressures.

The possibility that dissolved organic carbon (DOC) can buffer organisms in naturally acidic environments against the toxicity caused by low pH is also explored.

Copyright © 2012 John Wiley & Sons, Ltd.
Controllable Synthesis of Nearly Monodisperse Spherical Aggregates of CeO2 Nanocrystals and Their Catalytic Activity for HCHO Oxidation
Authors: Wang Qin , Jia Wenjing , Liu Baocang , Zhao Wenzhi , Li Changyan , Zhang Jun , Xu Gang
Published: July 2012

Herein, we report a facile surfactant‐assisted solvothermal synthetic method to prepare nearly monodisperse spherical CeO2 nanocrystals. A good control of the size of CeO2 nanocrystals in the range of 100–500 nm was achieved by simply varying the synthetic parameters such as reaction time, volume ratio of ethanol to water (R), molar ratio of PVP, and concentration of Ce(NO3)3⋅6 H2O in solution. A possible mechanism for the growth of spherical CeO2 nanocrystals is proposed. The obtained CeO2 nanocrystals with a surface area of up to 47 m2g−1 were then employed as a catalyst support. By loading Au‐Pd nanoparticles (about 3 wt. %) onto the CeO2 support, an Au‐Pd/CeO2 catalyst was prepared that exhibited high catalytic activity for HCHO oxidation. At the low temperature of 50 °C, the percentage of HCHO conversion was 100 %, suggesting potential applications in preferential oxidation and other catalytic reactions. These Au‐Pd/CeO2 catalysts may also find applications in indoor formaldehyde decontamination and industrial catalysis. The facile solvothermal method can be extended to the preparation of other metal oxide nanocrystals and provides guidance for size‐ and morphology‐controlled synthesis.
Asynchronous Distributed Algorithms for Heading Consensus of Multi‐Agent Systems with Communication Delay
Authors: Li Qin , Jiang Zhong‐Ping
Published: July 2012

In this paper, we propose two asynchronous distributed protocols for the heading consensus of a multi‐agent group which cannot access a global coordinate system and a global time. Both the leaderless and leader‐following cases are addressed, and inter‐agent communication delay is taken into account. It is proved, under some standard connectivity assumptions, that our leaderless algorithm ensures the heading consensus provided the initial headings are not balanced; and the leader‐based algorithm guarantees the global heading consensus.
Hybrid Model Predictive Power Management of A Fuel Cell‐Battery Vehicle
Authors: Meyer Richard T. , DeCarlo Raymond A , Meckl Peter H. , Doktorcik Chris , Pekarek Steve
Published: July 2012

This paper considers optimal power management of a fuel cell‐battery hybrid vehicle (FCHV) powertrain having three distinct modal configurations (modes): electric motor propelling/battery discharging, propelling/charging, and generating/charging. Each mode has a distinct set of dynamics and constraints. Using component dynamical/algebraic models appropriate to power flow management, the paper develops a supervisory‐level switched system model as an interconnection of subsystems. Given the model, the paper sets forth a hybrid model predictive control strategy based on a minimization of a performance index (PI) that trades off tracking and fuel economy in each operational mode. Specifically, the PI trades off velocity tracking error, battery state of charge variance, and electric drive and hydrogen fuel usages while penalizing frictional braking to encourage regenerative braking. The optimization is performed using an embedded system model and collocation with matlab's fmincon to compute mode switches and continuous time controls. The methodology avoids the computational complexity of alternate approaches based on, e.g., mixed integer programming. Projection methods for approximating the switched system solution from the embedded solution are empirically evaluated. To demonstrate the methodology, an example of a FCHV is simulated using three standard velocity driving profiles: a sawtooth profile with a hill climb, the EPA urban dynamic driving schedule, and the New European Driving Cycle. Also, drive cycle fuel usage is compared to that from the Equivalent Consumption Minimization Strategy.
A Quasi‐Sliding Mode Observer‐based Controller forPMSMDrives
Authors: Corradini M.L. , Ippoliti G. , Longhi S. , Marchei D. , Orlando G.
Published: July 2012

In this paper a quasi‐sliding mode control for a permanent magnet synchronous motor (PMSM) is proposed where a cascade control scheme based on a properly designed state observer provides accurate speed tracking performance. The ultimate boundedness of both the observation error and the speed tracking error is proven. The controller performance has been validated using hardware in the loop (HIL) tests on a simulator based on the model of a commercialPMSMdrive. Tests show that the proposed observer‐based controller produces good speed trajectory tracking performance and it is robust in the presence of disturbances affecting the system.
Time Domain Tuning of Fractional Order Controllers Combined With a Smith Predictor for Automation of Water Distribution in Irrigation Main Channel Pools
Authors: Castillo‐Garcia F.J. , Feliu‐Batlle V. , Rivas‐Perez R.
Published: July 2012

This paper proposes a new technique for designing fractional order controllers applied to the automation of main canal pools of a water irrigation system. As large variation of all the plant parameters is present in such systems, a fractional order family of controllers combined with a Smith Predictor is designed using time domain specifications. The designed controllers are compared with the standard combination of a Smith Predictor with a proportional‐integral (PI) controller. All these controllers are tuned to fulfil the same time specifications in the case of canal nominal dynamics. In some canals the plant parameters may experience large changes that deteriorate the time response, and can even unstabilize the closed‐loop system. The fractional controllers are therefore designed to minimize the loss of performance of the system to variations in these parameters. Simulated results show the performance improvements achieved with these controllers compared with a conventional PI controller.
Robust PID‐PSD Controller Design: BMI Approach
Authors: Veselý Vojtech , Rosinová Danica
Published: July 2012

A new robust proportional‐integral‐derivative (PID)–proportional‐sum‐derivative (PSD) controller design method based on linear (bilinear) matrix inequalities (LMI, BMI) is proposed for uncertain affine linear system. The design procedure guarantees the parameter dependent quadratic stability, and guaranteed cost control with a new quadratic cost function (LQRS) including the derivative term for the state vector as a tool to influence the overshoot and response rate. The second approach to the PSD controller design procedure is based on a Lyapunov function with a special term corresponding to the time‐delay part of the control algorithm. The results obtained are illustrated on three examples to show the robust PID, PSD control design procedure and the influence of the choice of matrix S in the extended cost function.
Nonlinear Robust Tracking Control of a Quadrotor UAV on SE(3)
Authors: Lee Taeyoung , Leok Melvin , McClamroch N. Harris
Published: July 2012

This paper provides nonlinear tracking control systems for a quadrotor unmanned aerial vehicle (UAV) that are robust to bounded uncertainties. A mathematical model of a quadrotor UAV is defined on the special Euclidean group, and nonlinear output‐tracking controllers are developed to follow (i) an attitude command, and (ii) a position command for the vehicle center of mass. The controlled system has the desirable properties that the tracking errors are uniformly ultimately bounded, and the size of the ultimate bound can be reduced arbitrarily by control system parameters. Numerical examples illustrating complex maneuvers are provided.
The Effects of Interleukin‐6 Signal Blockade on Fertility, Embryo‐fetal Development, and Immunization In vivo
Authors: Sakurai Takayuki , Takai Ryo , Bürgin Heinrich , Ishihara Kana , Sakamoto Yuichiro , Amano Jun , Higuchi Yoshinobu , Chiba Shuichi , Singer Thomas , Kawamura Akinori , Suzuki Masami , Müller Lutz
Published: July 2012

Possible effects of interleukin‐6 (IL‐6) on reproductive performance, embryonal development, parturition, and postnatal development have been suggested based on protein/mRNAexpression level of IL‐6 in related organs, but less is known about functions of IL‐6 signals in these areas. Following two different approaches have been employed to investigate the role of IL‐6 signals in fertility and pre‐/postnatal development: administration of a rat anti‐mouse IL‐6 receptor antibody, MR16‐1, to mice as a neutralizing antibody system, and B6.129S2‐Il6tm1Kopf/J (IL‐6 knockout [KO]) mice as a KO system. By intravenously dosing 50 mg/kg of MR16‐1 every 3 days, animals in male and female fertility studies and dams in a pre‐/postnatal development study exhibited plasma MR16‐1 concentrations much higher than the effective plasma concentration, indicating that MR16‐1 exposure was sufficient to completely block IL‐6 signals. The concentration of MR16‐1 in the plasma of fetuses exceeded that in the plasma of pregnant animals, and MR16‐1 concentration in milk was about one‐fourth of that in plasma. Both the transient IL‐6 signal blockade by MR16‐1, and the constitutive IL‐6 signal inhibition using IL‐6 KO mice in a combined fertility and pre‐/postnatal development study, revealed no biologically important effects on fertility, early embryonic development to implantation, or pre‐/postnatal development, including IgG/IgM production by keyhole limpet hemocyanin sensitization. These results indicate that IL‐6 signals have no unique, noncompensable roles in reproduction and development in the whole body system, although contributions of IL‐6 in the signaling network appear to exist, as suggested by previously published investigations.