Synergistic photothermal ablative effects of functionalizing carbon nanotubes with a POSS-PCU nanocomposite polymer

10.1186/1477-3155-10-34Journal of Nanobiotechnology10-JNOA

Biochemical engineering nerve conduits using peptide amphiphiles.

Peripheral nerve injury is a debilitating condition. The gold standard for treatment is surgery, requiring an autologous nerve graft. Grafts are harvested from another part of the body (a secondary site) to treat the affected primary area. However, autologous nerve graft harvesting is not without risks, with associated problems including injury to the secondary site. Research into biomaterials has engendered the use of bioartificial nerve conduits as an alternative to autologous nerve grafts. These include synthetic and artificial materials, which can be manufactured into nerve conduits using techniques inspired by nanotechnology. Recent evidence indicates that peptide amphiphiles (PAs) are promising candidates for use as materials for bioengineering nerve conduits. PAs are biocompatible and biodegradable protein-based nanomaterials, capable of self-assembly in aqueous solutions. Their self-assembly system, coupled with their intrinsic capacity for carrying bioactive epitopes for tissue regeneration, form particularly novel attributes for biochemically-engineered materials. Furthermore, PAs can function as biomimetic materials and advanced drug delivery platforms for sustained and controlled release of a plethora of therapeutic agents. Here we review the realm of nerve conduit tissue engineering and the potential for PAs as viable materials in this exciting and rapidly advancing field

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD

Rationally Designed Turn Promoting Mutation in the Amyloid-β Peptide Sequence Stabilizes Oligomers in Solution

Enhanced production of a 42-residue beta amyloid peptide (Aβ42) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs) in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the Aβ42 peptide (Aβ42Nle35p37) that appear to organize Aβ42 into stable oligomers. 2D NMR on the Aβ42Nle35p37 peptide revealed the occurrence of two β-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the Aβ21–43Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD

Multidisciplinary design optimization of film-cooled gas turbine blades

<p>Design optimization of a gas turbine blade geometry for effective film cooling toreduce the blade temperature has been done using a multiobjective optimization formulation. Three optimization formulations have been used. In the first, the average blade temperature is chosen as the objective function to be minimized. An upper bound constraint has been imposed on the maximum blade temperature. In the second, the maximum blade temperature is chosen as the objective function to be minimized with an upper bound constraint on the average blade temperature. In the third formulation, the blade average and maximum temperatures are chosen as objective functions. Shape optimization is performed using geometric parameters associated with film cooling and blade external shape. A quasi-three-dimensional Navier&#8211;Stokes solver for turbomachinery flows is used to solve for the flow field external to the blade with appropriate modifications to incorporate the effect of film cooling. The heat transfer analysis for temperature distribution within the blade is performed by solving the heat diffusion equation using the finite element method. The multiobjective Kreisselmeier&#8211;Steinhauser function approach has been used in conjunction with an approximate analysis technique for optimization. The results obtained using both formulations are compared with reference geometry. All three formulations yield significant reductions in blade temperature with the multiobjective formulation yielding largest reduction in blade temperature.</p

Shape optimization of turbine blades with the integration of aerodynamics and heat transfer

A multidisciplinary optimization procedure, with the integration of aerodynamic and heat transfer criteria, has been developed for the design of gas turbine blades. Two different optimization formulations have been used. In the first formulation, the maximum temperature in the blade section is chosen as the objective function to be minimized. An upper bound constraint is imposed on the blade average temperature and a lower bound constraint is imposed on the blade tangential force coefficient. In the second formulation, the blade average and maximum temperatures are chosen as objective functions. In both formulations, bounds are imposed on the velocity gradients at several points along the surface of the airfoil to eliminate leading edge velocity spikes which deteriorate aerodynamic performance. Shape optimization is performed using the blade external and coolant path geometric parameters as design variables. Aerodynamic analysis is performed using a panel code. Heat transfer analysis is performed using the finite element method. A gradient based procedure in conjunction with an approximate analysis technique is used for optimization. The results obtained using both optimization techniques are compared with a reference geometry. Both techniques yield significant improvements with the multiobjective formulation resulting in slightly superior design

Borreliacidal activity of Borrelia metal transporter A (BmtA) binding small molecules by manganese transport inhibition

Dhananjay Wagh,* Venkata Raveendra Pothineni,* Mohammed Inayathullah, Song Liu, Kwang-Min Kim, Jayakumar Rajadas&nbsp;Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA&nbsp;*These authors contributed equally to this work &nbsp;Abstract: Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn) for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA), a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 &micro;g/mL (250 &micro;M). Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia. &nbsp;Keywords: Lyme disease, BmtA, Borrelia burgdorferi, desloratadine, Bac Titer-Glo assa