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Metalated and free-base A(3)B-type asymmetric phthalocyanines (Pcs) bearing, in the asymmetric quadrant, a flexible alkyl linker of varying chain lengths terminating in a phosphonic acid (PA) group have been synthesized. Two parallel series of asymmetric Pc derivatives bearing aryloxy and arylthio substituents are reported, and their synthesis and characterization through NMR, combustion analysis, and MALDI-MS are described. We also demonstrate the modification of indium tin oxide (ITO) substrates using the PA functionalized asymmetric Pc derivatives and monitoring their electrochemistry. The PA functionalized asymmetric Pcs were anchored to the ITO surface through chemisorption and their electrochemical properties characterized using cyclic voltammetry to investigate the effects of PA structure on the thermodynamics and kinetics of charge transfer. Ionization energies of the modified ITO surfaces were measured using ultraviolet photoemission spectroscopy.

Polymeric endoaortic paving (PEAP) is a process by which a polymer is endovascularly delivered and thermoformed to coat or "pave" the lumen of the aorta. This method may offer an improvement to conventional endoaortic therapy in allowing conformal graft application with reduced risk of endoleak and customization to complex patient geometries. Polycaprolactone (PCL)/polyurethane (PU) blends of various blend ratios were assessed as a potential material for PEAP by characterizing their mechanical, thermoforming and degradation properties. Biaxial tension testing revealed that the blends' stiffness is similar to that of aortic tissue, is higher for blends with more PCL content, and may be affected by thermoforming and degradation. Tubes of blends were able to maintain a higher diameter increase after thermoforming at higher PCL content and higher heating temperatures; 50/50 blend tubes heated to 55 °C were able to maintain 90% of the diameter increase applied. Delamination forces of the blends ranged from 41 to 235 N m⁻². In a Pseudomonas lipase solution, the 50/50 blend had a 94% lower degradation rate than pure PCL, and the 10/90 blend exhibited no degradation. These results indicate that PEAP, consisting of a PCL/PU blend, may be useful in developing the next generation of endoaortic therapy.

During early lung development, airway tubes change shape. Tube length increases more than circumference as a large proportion of lung epithelial cells divide parallel to the airway longitudinal axis. We show that this bias is lost in mutants with increased extracellular signal-regulated kinase 1 (ERK1) and ERK2 activity, revealing a link between the ERK1/2 signaling pathway and the control of mitotic spindle orientation. Using a mathematical model, we demonstrate that change in airway shape can occur as a function of spindle angle distribution determined by ERK1/2 signaling, independent of effects on cell proliferation or cell size and shape. We identify sprouty genes, which encode negative regulators of fibroblast growth factor 10 (FGF10)-mediated RAS-regulated ERK1/2 signaling, as essential for controlling airway shape change during development through an effect on mitotic spindle orientation.

To determine to what extent subjects implanted with the Argus II retinal prosthesis can improve performance compared with residual native vision in a spatial-motor task.

High-contrast square stimuli (5.85 cm sides) were displayed in random locations on a 19″ (48.3 cm) touch screen monitor located 12″ (30.5 cm) in front of the subject. Subjects were instructed to locate and touch the square centre with the system on and then off (40 trials each). The coordinates of the square centre and location touched were recorded.

Ninety-six percent (26/27) of subjects showed a significant improvement in accuracy and 93% (25/27) show a significant improvement in repeatability with the system on compared with off (p<0.05, Student t test). A group of five subjects that had both accuracy and repeatability values <250 pixels (7.4 cm) with the system off (ie, using only their residual vision) was significantly more accurate and repeatable than the remainder of the cohort (p<0.01). Of this group, four subjects showed a significant improvement in both accuracy and repeatability with the system on.

In a study on the largest cohort of visual prosthesis recipients to date, we found that artificial vision augments information from existing vision in a spatial-motor task. Clinical trials registry no NCT00407602.

Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductal calculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cystic fibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local complications, and psychosocial issues associated with the disease are additional therapeutic challenges.

No abstract given.

Acyclovir, a nucleoside analog, is thought to be specific for the human herpesviruses because it requires a virally encoded enzyme to phosphorylate it to acyclovir monophosphate. Recently, acyclovir triphosphate was shown to be a direct inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. Here, we showed that acyclovir is an inhibitor of HIV-1 replication in CD4(+) T cells from cord blood that have undetectable levels of the eight human herpesviruses. Additionally, acyclovir phosphates were detected by reverse-phase-high performance liquid chromatography (RP-HPLC) and quantified in a primer extension assay from cord blood. The data support acyclovir as an inhibitor of HIV-1 replication in herpesvirus-negative cells.

Mesoporous silica-coated hollow manganese oxide (HMnO@mSiO(2)) nanoparticles were developed as a novel T(1) magnetic resonance imaging (MRI) contrast agent. We hypothesized that the mesoporous structure of the nanoparticle shell enables optimal access of water molecules to the magnetic core, and consequently, an effective longitudinal (R(1)) relaxation enhancement of water protons, which value was measured to be 0.99 (mM(-1)s(-1)) at 11.7 T. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, with much shorter T(1) values as compared to direct incubation without electroporation, which was also evidenced by signal enhancement on T(1)-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO(2)-labeled MSCs enabled serial MR monitoring of cell transplants over 14 days. These novel nanoparticles may extend the arsenal of currently available nanoparticle MR contrast agents by providing positive contrast on T(1)-weighted images at high magnetic field strengths.

Regulation of transcription factor Nrf2 (NF-E2-related factor 2) involves redox-sensitive proteasomal degradation via the E3 ubiquitin ligase Keap1/Cul3. However, Nrf2 is controlled by other mechanisms that have not yet been elucidated. We now show that glycogen synthase kinase 3 (GSK-3) phosphorylates a group of Ser residues in the Neh6 domain of mouse Nrf2 that overlap with an SCF/β-TrCP destruction motif (DSGIS, residues 334 to 338) and promotes its degradation in a Keap1-independent manner. Nrf2 was stabilized by GSK-3 inhibitors in Keap1-null mouse embryo fibroblasts. Similarly, an Nrf2(ΔETGE) mutant, which cannot be degraded via Keap1, accumulated when GSK-3 activity was blocked. Phosphorylation of a Ser cluster in the Neh6 domain of Nrf2 stimulated its degradation because a mutant Nrf2(ΔETGE 6S/6A) protein, lacking these Ser residues, exhibited a longer half-life than Nrf2(ΔETGE). Moreover, Nrf2(ΔETGE 6S/6A) was insensitive to β-TrCP regulation and exhibited lower levels of ubiquitination than Nrf2(ΔETGE). GSK-3β enhanced ubiquitination of Nrf2(ΔETGE) but not that of Nrf2(ΔETGE 6S/6A). The Nrf2(ΔETGE) protein but not Nrf2(ΔETGE 6S/6A) coimmunoprecipitated with β-TrCP, and this association was enhanced by GSK-3β. Our results show for the first time that Nrf2 is targeted by GSK-3 for SCF/β-TrCP-dependent degradation. We propose a "dual degradation" model to describe the regulation of Nrf2 under different pathophysiological conditions.

The cells responsible for the second phase decay of HIV-1 viremia following the initiation of antiretroviral therapy have yet to be identified. A dynamic model that considers where drugs act in the virus life cycle places constraints on candidate cell types. In this regard, the rapid drop in viremia in patients starting regimens containing the integrase inhibitor raltegravir is of particular interest. We show here that the time delay between reverse transcription and integration is short in differentiated macrophages, making these cells poor candidates for the second phase compartment under the assumptions of standard models of viral dynamics.

This study aimed to evaluate the role of the Obesity Surgery Mortality Risk Score (OS-MRS) to predict the risk of post-operative adverse events, in addition to death, from any laparoscopic bariatric procedure.

The OS-MRS was applied to consecutive patients at a single hospital during October 2008-September 2009. The composite end point comprised one or more of the following adverse events: mortality, re-intervention, re-admission to hospital, venous thromboemobolism, or blood transfusion.

There were 381 patients (men, 19%). The median age was 43 years (range, 19-67 years), with 42% patients aged ≥45 years. The median weight was 126 kg (75-295 kg) and median BMI 46 kg/m(2) (30-84 kg/m(2)); 37% had BMI ≥50 kg/m(2). Twenty-seven percent of patients had hypertension and 3% had a past history of venous thromboembolism. The OS-MRS classes were A (60.1%), B (35.9%), or C (4.0%). Operations comprised adjustable gastric band (37%), Roux-en-Y gastric bypass (54%), sleeve gastrectomy (8%), or biliopancreatic diversion (1%). Of the operations, 1.6% were revisional procedures. An adverse outcome occurred in 19 patients, with distribution in 3.5% of class A patients, 5.8% of class B, and 20.0% of class C (A vs. B, P = 0.451; A vs. C, P = 0.002; B vs. C, P = 0.025). There was one death: OS-MRS class C. On multivariate analysis, OS-MRS (class C vs. A or B; Odds Ratio [OR], 4; P = 0.050) and type of operation (band vs. bypass or sleeve; OR, 9.2; P = 0.033) were independently predictive of the composite end point.

OS-MRS and type of the bariatric operation are independently predictive of the risk of post-operative adverse events.

The potential of poly(propylene fumarate) (PPF) scaffolds as drug carriers was investigated and the kinetics of the drug release quantified using magnetic resonance imaging (MRI) and optical imaging. Three different MR contrast agents were used for coating PPF scaffolds. Initially, iron oxide (IONP) or manganese oxide nanoparticles (MONP) carrying the anti-cancer drug doxorubicin were absorbed or mixed with the scaffold and their release into solution at physiological conditions was measured with MRI and optical imaging. A slow (hours to days) and functional release of the drug molecules into the surrounding solution was observed. In order to examine the release properties of proteins and polypeptides, protamine sulfate, a chemical exchange saturation transfer (CEST) MR contrast agent, was attached to the scaffold. Protamine sulfate showed a steady release rate for the first 24h. Due to its biocompatibility, versatile drug-loading capability and constant release rate, the porous PPF scaffold has potential in various biomedical applications, including MR-guided implantation of drug-dispensing materials, development of drug carrying vehicles, and drug delivery for tumor treatment.

A key step in assembling the tree of life is the construction of species-rich phylogenies from multilocus--but often incomplete--sequence data sets. We describe previously unknown structure in the landscape of solutions to the tree reconstruction problem, comprising sometimes vast "terraces" of trees with identical quality, arranged on islands of phylogenetically similar trees. Phylogenetic ambiguity within a terrace can be characterized efficiently and then ameliorated by new algorithms for obtaining a terrace's maximum-agreement subtree or by identifying the smallest set of new targets for additional sequencing. Algorithms to find optimal trees or estimate Bayesian posterior tree distributions may need to navigate strategically in the neighborhood of large terraces in tree space.

No abstract given.

To investigate whether the insertion of a gel-based marker at the time of stereotactic breast biopsy allows subsequent preoperative localization to be performed under ultrasound guidance.

One hundred consecutive women who underwent either a 10 G stereotactic vacuum-assisted breast biopsy or 14 G stereotactic core biopsy with marker placement, followed by wire localization and surgical excision were identified. All had mammographic abnormalities not initially visible with ultrasound. The method of preoperative localization was recorded and its success judged with reference to the wire position on the post-procedure films relative to the mammographic abnormality and the marker. Histopathology data were reviewed to ensure the lesion had been adequately excised.

Eighty-three women (83%) had a successful ultrasound-guided wire localization. Successful ultrasound-guided localization was more likely after stereotactic vacuum biopsy (86%) compared to stereotactic core biopsy (68%), although this did not quite reach statistical significance (p=0.06).

The routine placement of a gel-based marker after stereotactic breast biopsy facilitates preoperative ultrasound-guided localization.

No abstract given.

To identify and quantify the health related concepts contained in the most common outcome instruments used in adult burn care, and to compare the content of these instruments based on their linkage to the International Classification of Functioning, Disability and Health (ICF). The ICF has been validated as a reference tool by the World Health Organization and is a framework that incorporates physical, emotional, environmental and social aspects of daily functioning.

Electronic searches of MEDLINE, EMBASE CINAHL, PsychINFO and the Cochrane Library from 2003 onwards were carried out using a predetermined search strategy. Specific characteristics of the included studies and data pertaining to the outcome instruments were extracted. Two reviewers independently categorised the underlying concepts contained in the most commonly used outcome measures and linked them to ICF categories using standardised linkage rules.

Out of a total 132 included studies, 151 outcome instruments were identified. Of these, 14 frequently used generic and burn-specific instruments were selected for linkage to the ICF. From the 381 items contained in the 14 instruments, 356 concepts were extracted and subsequently linked to 99 ICF categories. Nearly 46% of the concepts were linked to body function and 20% to activities and participation, whereas only a few concepts were formally linked to health condition, body structures and personal or environmental factors.

The ICF proved highly useful for the content comparison of frequently used generic and burn-specific instruments. The results may provide clinicians and researchers with new insights when selecting health-status measures for clinical studies in those with burn injury.

Periventricular leukomalacia, PVL, is the leading cause of cerebral palsy in prematurely born infants, and therefore more effective interventions are required. The objective of this study was to develop an ischemic injury model of PVL in mice and to determine the feasibility of in vivo magnetization transfer (MT) magnetic resonance imaging (MRI) as a potential monitoring tool for the evaluation of disease severity and experimental therapeutics. Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal day 5 (P5); at P60, in vivo T2-weighted (T2w) and MT-MRI were performed and correlated with postmortem histopathology. In vivo T2w MRI showed thinning of the right corpus callosum, but no significant changes in hippocampal and hemispheric volumes. Magnetization transfer MRI revealed significant white matter abnormalities in the bilateral corpus callosum and internal capsule. These quantitative MT-MRI changes correlated highly with postmortem findings of reduced myelin basic protein in bilateral white matter tracts. Ventriculomegaly and persistent astrogliosis were observed on the ligated side, along with evidence of axonopathy and fewer oligodendrocytes in the corpus callosum. We present an ischemia-induced mouse model of PVL, which has pathologic abnormalities resembling autopsy reports in infants with PVL. We further validate in vivo MRI techniques as quantitative monitoring tools that highly correlate with postmortem histopathology.

No abstract given.

This paper presents our initial experience using a single cross grasp, four-strand repair with an active mobilization regimen in a general trauma hospital setting. Variably experienced members of the trauma service of a large general hospital used a four-strand single cross grasp tenorrhaphy technique for acute repair of 73 zone one and two flexor digitorum profundus tendon lacerations in 53 patients. Postoperatively, all patients commenced an active mobilization program within 12 hours of the surgical repair. With a minimum 3 months post-repair follow-up of 89% of the repaired flexor digitorum profundus tendons, 71% of fingers achieved a good or excellent outcome. There were three (4.6%) flexor digitorum profundus ruptures post surgery. A four-strand single cross grasp repair using 3-0 braided polyester suture and active post-repair mobilization can achieve satisfactory outcomes in the general trauma service setting; however, patient compliance remains a problem.