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2.  Structure and Mechanical Response of Protein Hydrogels Reinforced by Block Copolymer Self-Assembly 
Soft matter  2013;9(29):6814-6823.
A strategy for responsively toughening an injectable protein hydrogel has been implemented by incorporating an associative protein as the midblock in triblock copolymers with thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) endblocks, producing materials with a low yield stress necessary for injectability and durability required for load-bearing applications post-injection. Responsive reinforcement triggered by PNIPAM association leads to significant increases in the gel’s elastic modulus as well as its resistance to creep. The performance of these materials is a strong function of molecular design, with certain formulations reaching elastic moduli of up to 130 kPa, effectively reinforced by a factor of 14 over their low temperature moduli, and having stress relaxation times increased by up to a factor of 50. The nanostructural origins of these thermoresponsive enhancements were explored, demonstrating that large micellar cores, high PNIPAM volume fractions, and high densities of associating groups in the protein corona lead to the greatest reinforcement of the gel’s elastic modulus. Gels with the largest micelles and the highest packing fractions also had the longest relaxation times in the reinforced state. These combined structure and mechanics studies reveal that control of both the micellar and protein networks is critical for making high performance gels relevant for biomedical applications.
PMCID: PMC4321950
3.  Myocardial electrotonic response to submaximal exercise in dogs with healed myocardial infarctions: evidence for β-adrenoceptor mediated enhanced coupling during exercise testing 
Introduction: Autonomic neural activation during cardiac stress testing is an established risk-stratification tool in post-myocardial infarction (MI) patients. However, autonomic activation can also modulate myocardial electrotonic coupling, a known factor to contribute to the genesis of arrhythmias. The present study tested the hypothesis that exercise-induced autonomic neural activation modulates electrotonic coupling (as measured by myocardial electrical impedance, MEI) in post-MI animals shown to be susceptible or resistant to ventricular fibrillation (VF).
Methods: Dogs (n = 25) with healed MI instrumented for MEI measurements were trained to run on a treadmill and classified based on their susceptibility to VF (12 susceptible, 9 resistant). MEI and ECGs were recorded during 6-stage exercise tests (18 min/test; peak: 6.4 km/h @ 16%) performed under control conditions, and following complete β-adrenoceptor (β-AR) blockade (propranolol); MEI was also measured at rest during escalating β-AR stimulation (isoproterenol) or overdrive-pacing.
Results: Exercise progressively increased heart rate (HR) and reduced heart rate variability (HRV). In parallel, MEI decreased gradually (enhanced electrotonic coupling) with exercise; at peak exercise, MEI was reduced by 5.3 ± 0.4% (or -23 ± 1.8Ω, P < 0.001). Notably, exercise-mediated electrotonic changes were linearly predicted by the degree of autonomic activation, as indicated by changes in either HR or in HRV (P < 0.001). Indeed, β-AR blockade attenuated the MEI response to exercise while direct β-AR stimulation (at rest) triggered MEI decreases comparable to those observed during exercise; ventricular pacing had no significant effects on MEI. Finally, animals prone to VF had a significantly larger MEI response to exercise.
Conclusions: These data suggest that β-AR activation during exercise can acutely enhance electrotonic coupling in the myocardium, particularly in dogs susceptible to ischemia-induced VF.
PMCID: PMC4318283
electrotonic coupling; β-adrenoceptor stimulation; exercise; arrhythmic risk; myocardial infarction
9.  The Role of pH and Ring-opening Hydrolysis Kinetics on Liposomal Release of Topotecan 
PMCID: PMC4104781  PMID: 24231406
Liposomes; nanotechnology; topotecan; camptothecins; kinetics; membrane binding; permeability
10.  Oxidatively Responsive Chain Extension to Entangle Engineered Protein Hydrogels 
Macromolecules  2014;47(2):791-799.
Engineering artificial protein hydrogels for medical applications requires precise control over their mechanical properties, including stiffness, toughness, extensibility and stability in the physiological environment. Here we demonstrate topological entanglement as an effective strategy to robustly increase the mechanical tunability of a transient hydrogel network based on coiled-coil interactions. Chain extension and entanglement are achieved by coupling the cysteine residues near the N- and C- termini, and the resulting chain distribution is found to agree with the Jacobson-Stockmayer theory. By exploiting the reversible nature of the disulfide bonds, the entanglement effect can be switched on and off by redox stimuli. With the presence of entanglements, hydrogels exhibit a 7.2-fold enhanced creep resistance and a suppressed erosion rate by a factor of 5.8, making the gels more mechanically stable in a physiologically relevant open system. While hardly affecting material stiffness (only resulting in a 1.5-fold increase in the plateau modulus), the entanglements remarkably lead to hydrogels with a toughness of 65,000 J m-3 and extensibility to approximately 3,000% engineering strain, which enables the preparation of tough yet soft tissue simulants. This improvement in mechanical properties resembles that from double-network hydrogels, but is achieved with the use of a single associating network and topological entanglement. Therefore, redox-triggered chain entanglement offers an effective approach for constructing mechanically enhanced and responsive injectable hydrogels.
PMCID: PMC4043348  PMID: 24910474
11.  Paging through history: parchment as a reservoir of ancient DNA for next generation sequencing 
Parchment represents an invaluable cultural reservoir. Retrieving an additional layer of information from these abundant, dated livestock-skins via the use of ancient DNA (aDNA) sequencing has been mooted by a number of researchers. However, prior PCR-based work has indicated that this may be challenged by cross-individual and cross-species contamination, perhaps from the bulk parchment preparation process. Here we apply next generation sequencing to two parchments of seventeenth and eighteenth century northern English provenance. Following alignment to the published sheep, goat, cow and human genomes, it is clear that the only genome displaying substantial unique homology is sheep and this species identification is confirmed by collagen peptide mass spectrometry. Only 4% of sequence reads align preferentially to a different species indicating low contamination across species. Moreover, mitochondrial DNA sequences suggest an upper bound of contamination at 5%. Over 45% of reads aligned to the sheep genome, and even this limited sequencing exercise yield 9 and 7% of each sampled sheep genome post filtering, allowing the mapping of genetic affinity to modern British sheep breeds. We conclude that parchment represents an excellent substrate for genomic analyses of historical livestock.
PMCID: PMC4275887  PMID: 25487331
parchment; next generation sequencing; ancient DNA; ZooMS; sheep
12.  Reinforcement of Shear Thinning Protein Hydrogels by Responsive Block Copolymer Self-Assembly 
Advanced functional materials  2012;23(9):1182-1193.
Shear thinning hydrogels are promising materials that exhibit rapid self-healing following the cessation of shear, making them attractive for a variety of applications including injectable biomaterials. In this work, self-assembly is demonstrated as a strategy to introduce a reinforcing network within shear thinning artificially engineered protein gels, enabling a responsive transition from an injectable state at low temperatures with a low yield stress to a stiffened state at physiological temperatures with resistance to shear thinning, higher toughness, and reduced erosion rates and creep compliance. Protein-polymer triblock copolymers capable of the responsive self-assembly of two orthogonal networks have been synthesized by conjugating poly(N-isopropylacrylamide) to the N- and C- termini of a protein midblock decorated with coiled-coil self-associating domains. Midblock association forms a shear-thinning network, while endblock aggregation at elevated temperatures introduces a second, independent physical network into the protein hydrogel. These new, reversible crosslinks introduce extremely long relaxation times and lead to a five-fold increase in the elastic modulus, significantly larger than is expected from transient network theory. Thermoresponsive reinforcement reduces the high temperature creep compliance by over four orders of magnitude, decreases the erosion rate by at least a factor of five, and increases the yield stress by up to a factor of seven. The reinforced hydrogels also exhibit enhanced resistance to plastic deformation and failure in uniaxial compression. Combined with the demonstrated potential of shear thinning artificial protein hydrogels for various uses, including the minimally-invasive implantation of bioactive scaffolds, this reinforcement mechanism broadens the range of applications that can be addressed with shear-thinning physical gels.
PMCID: PMC4283780  PMID: 25568642
Hydrogels; Self-Assembly; Stimuli-Responsive Materials; Hybrid Materials; Block Copolymers
13.  Happy New Year from BJR! 
The British Journal of Radiology  2013;87(1033):20130778.
PMCID: PMC3898980
14.  Primary Care Providers’ Initial Treatment Decisions and Antidepressant Prescribing for Adolescent Depression 
Adolescent depression is a serious and undertreated public health problem. Nonetheless, pediatric primary care providers (PCPs) may have low rates of antidepressant prescribing due to structural and training barriers. We examined the impact of symptom severity and provider characteristics on initial depression treatment decisions in a setting with fewer structural barriers, an integrated behavioral health network.
We administered a cross sectional survey to 58 PCPs within a large pediatric practice network. We compared PCP reports of initial treatment decisions in response to two vignettes describing depressed adolescents with either moderate or severe symptoms. We measured PCP depression knowledge, attitudes toward addressing psychosocial concerns, demographics, and practice characteristics.
Few PCPs (25% for moderate, 32% for severe) recommended an antidepressant. Compared with treatment recommendations for moderate depression, severe depression was associated with a greater likelihood of child psychiatry referral (OR 5.50[95% CI 2.47-12.2] p<.001). Depression severity did not affect the likelihood of antidepressant recommendation (OR 1.58[95% CI 0.80-3.11] p=.19). Antidepressants were more likely to be recommended by PCPs with greater depression knowledge (OR 1.72[95% CI 1.14-2.59] p=.009) and access to an on-site mental health provider (OR 5.13[95% CI 1.24-21.2] p=.02) and less likely to be recommended by PCPs who reported higher provider burden when addressing psychosocial concerns (OR 0.85[95% CI 0.75-0.98] p=.02).
PCPs infrequently recommended antidepressants for adolescents, regardless of depression severity. Continued PCP support through experiential training, accounting for provider burden when addressing psychosocial concerns, and co-management with mental health providers may increase PCPs’ antidepressant prescribing.
PMCID: PMC4105359  PMID: 24336091
primary health care; depressive disorder; adolescent; antidepressant agents; physician's practice patterns
15.  GPS-based microenvironment tracker (MicroTrac) model to estimate time–location of individuals for air pollution exposure assessments: Model evaluation in central North Carolina 
A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure to do so can add uncertainty and bias to risk estimates. In this study, a classification model, called MicroTrac, was developed to estimate time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from global positioning system (GPS) data and geocoded building boundaries. Based on a panel study, MicroTrac estimates were compared with 24-h diary data from nine participants, with corresponding GPS data and building boundaries of home, school, and work. MicroTrac correctly classified the ME for 99.5% of the daily time spent by the participants. The capability of MicroTrac could help to reduce the time–location uncertainty in air pollution exposure models and exposure metrics for individuals in health studies.
PMCID: PMC4269558  PMID: 24619294
GPS; time-activity; microenvironment; air pollution; health
16.  Dual Colorimetric and Luminescent Assay for Dipicolinate, a Biomarker of Bacterial Spores 
The Analyst  2013;138(23):10.1039/c3an01658g.
A binary mixture of Tb3+ and pyrocatechol violet (PV) forms a 1:1 Tb3+/PV complex that can be used in a dye displacement assay. Addition of dipicolinate (DPA) to the Tb3+/DPA complex simultaneously produces a PV color change from blue to yellow and luminescence emission from the newly formed Tb3+/DPA complex.
PMCID: PMC3841008  PMID: 24106737
17.  Experimental measurement of coil-rod-coil block copolymer tracer diffusion through entangled coil homopolymers 
Macromolecules  2013;46(4):1651-1658.
The diffusion of coil-rod-coil triblock copolymers in entangled coil homopolymers is experimentally measured and demonstrated to be significantly slower than rod or coil homopolymers of the same molecular weight. A model coil-rod-coil triblock was prepared by expressing rodlike alanine-rich α-helical polypeptides in E. coli and conjugating coillike poly(ethylene oxide) (PEO) to both ends to form coil-rod-coil triblock copolymers. Tracer diffusion through entangled PEO homopolymer melts was measured using forced Rayleigh scattering at various rod lengths, coil molecular weights, and coil homopolymer concentrations. For rod lengths, L, that are close to the entanglementh length, a, the ratio between triblock diffusivity and coil homopolymer diffusivity decreases monotonically and is only a function of L/a, in quantitative agreement with previous simulation results. For large rod lengths, diffusion follows an arm retraction scaling, which is also consistent with previous theoretical predictions. These experimental results support the key predictions of theory and simulation, suggesting that the mismatch in curvature between rod and coil entanglement tubes leads to the observed diffusional slowing.
PMCID: PMC4256073  PMID: 25484454
18.  Operative Management of Rib Fractures in the Setting of Flail Chest: A Systematic Review and Meta-Analysis 
Annals of surgery  2013;258(6):10.1097/SLA.0b013e3182895bb0.
Flail chest (FC) results in paradoxical chest wall movement, altered respiratory mechanics, and frequently respiratory failure. Despite advances in ventilatory management, FC remains associated with significant morbidity and mortality. Operative fixation of the flail segment has been advocated as an adjunct to supportive care, but no definitive clinical trial exists to delineate the role of surgery.
To perform a systematic review and meta-analysis of studies comparing operative to nonoperative therapy in adult FC patients. Outcomes were duration of mechanical ventilation (DMV), intensive care unit length of stay (ICULOS), hospital length of stay (HLOS), mortality, incidence of pneumonia, and tracheostomy.
A comprehensive search of 5 electronic databases was performed to identify randomized controlled trials and observational studies (cohort or case-control). Pooled effect size (ES) or relative risk (RR) was calculated using a fixed or random effects model, as appropriate.
Nine studies with a total of 538 patients met inclusion criteria. Compared to control treatment, operative management of FC was associated with shorter DMV (pooled ES −4.52; days, 95% confidence interval [CI] −5.54, −3.50), ICULOS (−3.40 days; 95% CI −6.01,−0.79), HLOS (−3.82 days; 95% CI −7.12,−0.54), and decreased mortality (pooled RR 0.44; 95% CI 0.28, 0.69), pneumonia (0.45; 95% CI 0.30, 0.69), and tracheostomy (0.25; 95% CI 0.13, 0.47).
As compared to nonoperative therapy, operative fixation of FC is associated with reductions in DMV, LOS, mortality, and complications associated with prolonged MV. These findings support the need for an adequately powered clinical study to further define the role of this intervention.
PMCID: PMC3694995  PMID: 23511840
19.  An Evidence-based Psychotherapy for Bipolar Disorder in Community Mental Health Settings: Facilitators and Barriers to IPSRT Implementation 
Despite widespread use of individual outpatient psychotherapies in community mental health clinics (CMHCs), few studies have examined implementation of these psychotherapies. This exploratory qualitative study identified key themes associated with the implementation of an empirically supported psychotherapy in CMHCs.
We conducted semi-structured interviews with twelve key informants from four CMHCs trained in interpersonal and social rhythm therapy (IPSRT) and categorized recurring key themes.
Five major themes were identified: pre- training familiarity with IPSRT, administrative and management support, IPSRT “fit” with usual practice and clinic culture, implementation team and plan, and supervision and consultation. Discussion of these themes varied between participants from clinics that had successfully implemented IPSRT and those that had not.
Interviewees identified both key themes and several strategies for facilitating implementation. Our findings suggest that when these key factors are present, outcome-enhancing treatments can be implemented and sustained, even in clinics with limited resources.
PMCID: PMC4138052  PMID: 24292731
20.  In Vivo Imaging Of Bone Using a Deep-Red Fluorescent Molecular Probe Bearing Multiple Iminodiacetate Groups 
Molecular pharmaceutics  2013;10(11):4263-4271.
Deep-red fluorescent molecular probes are described that have dendritic molecular architecture with a squaraine rotaxane core scaffold and multiple peripheral iminodiacetate groups as the bone targeting units. Iminodiacetates have inherently lower bone affinity than bisphosphonates and a major goal of the study was to determine how many appended iminodiacetate groups are required for effective deep-red fluorescence imaging of bone in living rodents. A series of in vitro and in vivo imaging studies showed that a tetra(iminodiacetate) probe stains bones much more strongly than an analogous bis(iminodiacetate) probe. In addition, a control tetra(iminodiapropionate) probe exhibited no bone targeting ability. The tetra(iminodiacetate) probe targeted the same regions of high bone turnover as the near-infrared bisphosphonate probe OsteoSense®750. Longitudinal studies showed that the fluorescence image signal from living mice treated with the tetra(iminodiacetate) probe was much more stable over 19 days than the signal from OsteoSense®750. The narrow emission band of the tetra(iminodiacetate) probe makes it very attractive for inclusion in multiplex imaging protocols that employ a mixture of multiple fluorescent probes in preclinical studies of bone growth or in fluorescence guided surgery. The results also suggest that molecules or nanoparticles bearing multivalent iminodiacetate groups have promise as bone targeting agents with tunable properties for various pharmaceutical applications.
PMCID: PMC3943353  PMID: 24099089
Bone targeting; in vivo imaging; multivalency; iminodiacetate; fluorescence molecular imaging; squaraine rotaxane
21.  Impact of Graft Position on Failure of Single-Stage Bulbar Urethroplasties with Buccal Mucosa Graft 
Urology  2013;82(5):1166-1170.
To determine whether patency rates after bulbar urethroplasty with buccal mucosa graft onlay differ based on whether the graft is placed ventrally or dorsally.
This was a retrospective, single-center study of all single-stage bulbar urethroplasties performed from 2001- 2011 by two surgeons in which buccal mucosa was used as an onlay graft. Failure was defined as the need for endoscopic or open revision of the reconstruction, or placement of a suprapubic catheter for urinary retention.
A total of 103 patients were reviewed; 41 underwent dorsal onlay, and 62 underwent ventral onlay. Mean age was 40.8 years. Most (84%) patients underwent a prior procedure, which consisted of DVIU in 69%, dilation in 53%, and urethroplasty in 14%. Mean stricture length was 3.9cm. At a mean follow-up of 36 months, failure occurred in 19 patients (12 ventral, 7 dorsal). The vast majority of these patients (79%) were successfully treated with a single dilation or DVIU. There was no difference in failure rate or time to failure according to whether graft position was ventral or dorsal. In multivariate analysis, diabetes was predictive of failure (OR 8.7, 95% CI 1.6-46.5, p = 0.01).
Single-stage bulbar urethroplasty with buccal mucosa graft is an effective procedure for patients with a bulbar urethral stricture that is not amenable to primary anastomosis. From our experience, we cannot conclude that dorsal or ventral graft position is inherently superior. Patients with diabetes may be more likely to require additional procedures following bulbar urethroplasty with buccal grafting.
PMCID: PMC4066651  PMID: 24055240
Anterior Urethral Stricture; Urethral Stricture; Anterior; Urethral Stenosis; Buccal Mucosa; Grafting; Skin
22.  Modeling Spatial and Temporal Variability of Residential Air Exchange Rates for the Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS) 
Air pollution health studies often use outdoor concentrations as exposure surrogates. Failure to account for variability of residential infiltration of outdoor pollutants can induce exposure errors and lead to bias and incorrect confidence intervals in health effect estimates. The residential air exchange rate (AER), which is the rate of exchange of indoor air with outdoor air, is an important determinant for house-to-house (spatial) and temporal variations of air pollution infiltration. Our goal was to evaluate and apply mechanistic models to predict AERs for 213 homes in the Near-Road Exposures and Effects of Urban Air Pollutants Study (NEXUS), a cohort study of traffic-related air pollution exposures and respiratory effects in asthmatic children living near major roads in Detroit, Michigan. We used a previously developed model (LBL), which predicts AER from meteorology and questionnaire data on building characteristics related to air leakage, and an extended version of this model (LBLX) that includes natural ventilation from open windows. As a critical and novel aspect of our AER modeling approach, we performed a cross validation, which included both parameter estimation (i.e., model calibration) and model evaluation, based on daily AER measurements from a subset of 24 study homes on five consecutive days during two seasons. The measured AER varied between 0.09 and 3.48 h−1 with a median of 0.64 h−1. For the individual model-predicted and measured AER, the median absolute difference was 29% (0.19 h‑1) for both the LBL and LBLX models. The LBL and LBLX models predicted 59% and 61% of the variance in the AER, respectively. Daily AER predictions for all 213 homes during the three year study (2010–2012) showed considerable house-to-house variations from building leakage differences, and temporal variations from outdoor temperature and wind speed fluctuations. Using this novel approach, NEXUS will be one of the first epidemiology studies to apply calibrated and home-specific AER models, and to include the spatial and temporal variations of AER for over 200 individual homes across multiple years into an exposure assessment in support of improving risk estimates.
PMCID: PMC4245625  PMID: 25386953
air exchange rate modeling; air pollution; health; exposure
23.  Impact of Aneurysm Repair on Thoracic Aorta Hemodynamics 
Circulation  2013;128(17):10.1161/CIRCULATIONAHA.112.000850.
PMCID: PMC3886838  PMID: 24146124
magnetic resonance angiography; magnetic resonance imaging; bicuspid aortic valve; aneurysm; aortic surgery
24.  Francisella tularensis Schu S4 Lipopolysaccharide Core Sugar and O-Antigen Mutants Are Attenuated in a Mouse Model of Tularemia 
Infection and Immunity  2014;82(4):1523-1539.
The virulence factors mediating Francisella pathogenesis are being investigated, with an emphasis on understanding how the organism evades innate immunity mechanisms. Francisella tularensis produces a lipopolysaccharide (LPS) that is essentially inert and a polysaccharide capsule that helps the organism to evade detection by components of innate immunity. Using an F. tularensis Schu S4 mutant library, we identified strains that are disrupted for capsule and O-antigen production. These serum-sensitive strains lack both capsule production and O-antigen laddering. Analysis of the predicted protein sequences for the disrupted genes (FTT1236 and FTT1238c) revealed similarity to those for waa (rfa) biosynthetic genes in other bacteria. Mass spectrometry further revealed that these proteins are involved in LPS core sugar biosynthesis and the ligation of O antigen to the LPS core sugars. The 50% lethal dose (LD50) values of these strains are increased 100- to 1,000-fold for mice. Histopathology revealed that the immune response to the F. tularensis mutant strains was significantly different from that observed with wild-type-infected mice. The lung tissue from mutant-infected mice had widespread necrotic debris, but the spleens lacked necrosis and displayed neutrophilia. In contrast, the lungs of wild-type-infected mice had nominal necrosis, but the spleens had widespread necrosis. These data indicate that murine death caused by wild-type strains occurs by a mechanism different from that by which the mutant strains kill mice. Mice immunized with these mutant strains displayed >10-fold protective effects against virulent type A F. tularensis challenge.
PMCID: PMC3993386  PMID: 24452684
25.  Toxoplasma gondii exposure affects neural processing speed as measured by acoustic startle latency in schizophrenia and controls 
Schizophrenia research  2013;150(1):258-261.
The prevalence of Toxoplasma gondii (TOXO) infection in schizophrenia (SCZ) is elevated compared to controls (odds ratio=2.73). TOXO infection is associated with psychomotor slowing in rodents and non-psychiatric humans. Latency of the acoustic startle response, an index of neural processing speed, is the time it takes for a startling stimulus to elicit the reflexive response through a three-synapse subcortical circuit. We report a significant slowing of latency in TOXO seropositive SCZ vs. seronegative SCZ, and in TOXO seropositive controls vs. seronegative controls. Latency was likewise slower in SCZ subjects than in controls. These findings indicate a slowing of neural processing speed with chronic TOXO infection; the slowest startle latency was seen in the TOXO seropositive SCZ group.
PMCID: PMC3786776  PMID: 23953218
schizophrenia; Toxoplasma gondii; acoustic startle; latency

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