Optical bi-stability in cubic silicon carbide microring resonators.

We measure the photothermal nonlinear response in suspended cubic silicon carbide (3C-SiC) and 3C-SiC-on-insulator (SiCOI) microring resonators. Bi-stability and thermo-optic hysteresis is observed in both types of resonators, with the suspended resonators showing a stronger response. A photothermal nonlinear index of 4.02×10-15 m2/W is determined for the suspended resonators, while the SiCOI resonators demonstrate one order of magnitude lower photothermal nonlinear index of 4.32×10-16 m2/W. Cavity absorption and temperature analysis suggest that the differences in thermal bi-stability are due to variations in waveguide absorption, likely from crystal defect density differences throughout the epitaxially grown layers. Furthermore, coupled mode theory model shows that the strength of the optical bi-stability, in suspended and SiCOI resonators can be engineered for high power or nonlinear applications.

High-Q suspended optical resonators in 3C silicon carbide obtained by thermal annealing.

We fabricate suspended single-mode optical waveguides and ring resonators in 3C silicon carbide (SiC) that operate at telecommunication wavelength, and leverage post-fabrication thermal annealing to minimize optical propagation losses. Annealed optical resonators yield quality factors of over 41,000, which corresponds to a propagation loss of 7 dB/cm, and is a significant improvement over the 24 dB/cm in the case of the non-annealed chip. This improvement is attributed to the enhancement of SiC crystallinity and a significant reduction of waveguide surface roughness, from 2.4 nm to below 1.7 nm. The latter is attributed to surface layer oxide growth during the annealing step. We confirm that the thermo-optic coefficient, an important parameter governing high-power and temperature-dependent performance of SiC, does not vary with annealing and is comparable to that of bulk SiC. Our annealing-based approach, which is especially suitable for suspended structures, offers a straightforward way to realize high-performance 3C-SiC integrated circuits.

Clinical evaluation of a modified silver fluoride application technique designed to facilitate lesion assessment in outreach programs.

BACKGROUND: An advantage of using silver fluoride treatments for carious primary teeth in outreach programs especially where dental resources are limited is that the treatments can be carried out by dental auxiliaries. One limitation to date is that assessments of lesion status have been based on a tactile test where a sharp probe or explorer is drawn across the surface of a lesion to assess its hardness. This is a technique-sensitive step and has the potential for iatrogenic damage, especially when a lesion is deep. This study was undertaken to determine whether an alternative, non-invasive, visual assessment could be a reliable indicator of lesion status. The approach was based on the retention, or otherwise, of a black surface deliberately created at the time of initial treatment. METHODS: A total of 88 lesions in the primary molars of 45 children, aged 5 to 10 years, were treated with a one-minute application of 40% silver fluoride. The surface of the lesions was then deliberately turned black by the application of 10% stannous fluoride as a reducing agent. All lesions were on an approximal or occlusal surface of a first or second primary molar. The presence or absence of a continuous black surface at 6 months and any changes in radiographic depth that had occurred in that period were determined from digitized photographs and bitewing radiographs. RESULTS: The retention of an uninterrupted black surface was associated with minimal or no caries progression whereas lesions with an incomplete or lost black surface were 4.6 times more likely to have progressed. Use of the Datta and Satten Rank-Sum Test to account for any clustering effect showed that the difference was statistically significant (p < 0.0001). The sensitivity and specificity of the approach were 80% and 81% respectively. CONCLUSION: The retention of a continuous black surface after the application of silver fluoride followed by a reducing agent on carious lesions in primary molars can provide a useful visual indicator of lesion progression and so be relevant for use in dental outreach programs.

Engineering human MEK-1 for structural studies: A case study of combinatorial domain hunting.

Structural biology studies typically require large quantities of pure, soluble protein. Currently the most widely-used method for obtaining such protein involves the use of bioinformatics and experimental methods to design constructs of the target, which are cloned and expressed. Recently an alternative approach has emerged, which involves random fragmentation of the gene of interest and screening for well-expressing fragments. Here we describe the application of one such fragmentation method, combinatorial domain hunting (CDH), to a target which historically was difficult to express, human MEK-1. We show how CDH was used to identify a fragment which covers the kinase domain of MEK-1 and which expresses and crystallizes significantly better than designed expression constructs, and we report the crystal structure of this fragment which explains some of its superior properties. Gene fragmentation methods, such as CDH, thus hold great promise for tackling difficult-to-express target proteins.

Site-specific PEGylation at histidine tags.

The efficacy of protein-based medicines can be compromised by their rapid clearance from the blood circulatory system. Achieving optimal pharmacokinetics is a key requirement for the successful development of safe protein-based medicines. Protein PEGylation is a clinically proven strategy to increase the circulation half-life of protein-based medicines. One limitation of PEGylation is that there are few strategies that achieve site-specific conjugation of PEG to the protein. Here, we describe the covalent conjugation of PEG site-specifically to a polyhistidine tag (His-tag) on a protein. His-tag site-specific PEGylation was achieved with a domain antibody (dAb) that had a 6-histidine His-tag on the C-terminus (dAb-His(6)) and interferon α-2a (IFN) that had an 8-histidine His-tag on the N-terminus (His(8)-IFN). The site of PEGylation at the His-tag for both dAb-His(6)-PEG and PEG-His(8)-IFN was confirmed by digestion, chromatographic, and mass-spectral studies. A methionine was also inserted directly after the N-terminal His-tag in IFN to give His(8)Met-IFN. Cyanogen bromide digestion studies of PEG-His(8)Met-IFN were also consistent with PEGylation at the His-tag. By using increased stoichiometries of the PEGylation reagent, it was possible to conjugate two separate PEG molecules to the His-tag of both the dAb and IFN proteins. Stability studies followed by in vitro evaluation confirmed that these PEGylated proteins retained their biological activity. In vivo PK studies showed that all of the His-tag PEGylated samples displayed extended circulation half-lives. Together, our results indicate that site-specific, covalent PEG conjugation at a His-tag can be achieved and biological activity maintained with therapeutically relevant proteins.

Serum procalcitonin concentration in the evaluation of febrile infants 2 to 60 days of age.

OBJECTIVE: Febrile infants younger than 60 days are at risk for serious bacterial infections (SBIs) and often undergo extensive laboratory investigation and hospitalization. We aim to determine the diagnostic value of serum procalcitonin (PCT) concentration for identification of febrile infants at low risk for SBI in comparison to the Rochester Criteria (RC). METHODS: Infants 2 to 60 days of age with rectal temperature 38°C were enrolled between May 2004 and March 2007. Blood was obtained from each, and PCT was assessed using BRAHMS PCT LIA method. Information for identification of low-risk infants using RC was obtained. Negative predictive value, sensitivity, specificity, and likelihood ratio of PCT were compared with the RC. In univariate analysis, the components of RC and PCT were considered. Variables holding a significant association with the absence of SBI were included in a backward stepwise logistic regression model with SBI as the dependent variable, creating new low risk criteria. RESULTS: One hundred fifty-five patients were enrolled. Thirteen (8.4%) had an SBI. Procalcitonin concentration at a cutoff value of 0.26 ng/mL is similar in sensitivity (92%) and better in specificity (64%) than RC. A combination of urine white blood cell and PCT was the best model in the regression analysis. CONCLUSIONS: Procalcitonin concentration is a serological marker for identification of or exclusion of SBI in infants aged 2 to 60 days. The predictive value of PCT in combination with urinary white blood cell count may be clinically useful. A validation study is indicated.

Integrated silicon carbide electro-optic modulator.

Owing to its attractive optical and electronic properties, silicon carbide is an emerging platform for integrated photonics. However an integral component of the platform is missing-an electro-optic modulator, a device which encodes electrical signals onto light. As a non-centrosymmetric crystal, silicon carbide exhibits the Pockels effect, yet a modulator has not been realized since the discovery of this effect more than three decades ago. Here we design, fabricate, and demonstrate a Pockels modulator in silicon carbide. Specifically, we realize a waveguide-integrated, small form-factor, gigahertz-bandwidth modulator that operates using complementary metal-oxide-semiconductor (CMOS)-level voltages on a thin film of silicon carbide on insulator. Our device is fabricated using a CMOS foundry compatible fabrication process and features no signal degradation, no presence of photorefractive effects, and stable operation at high optical intensities (913 kW/mm2), allowing for high optical signal-to-noise ratios for modern communications. Our work unites Pockels electro-optics with a CMOS foundry compatible platform in silicon carbide.

Estimating the effects of structural vibration on adaptive optics system performance.

This paper presents analytical tools developed for estimating the effects of structural vibration on closed-loop adaptive optics system image quality. The general equation for the normalized intensity distribution of an image subject to structural vibration is derived. The resulting two-dimensional theoretical point spread function is computed numerically and compared with empirical data obtained on sky at the Multiple Mirror Telescope Observatory. A simplified analytical expression for the normalized intensity distribution is derived for long exposures and used to quantify the effects on Strehl and spot full width at half-maximum as a function of vibration amplitude, telescope diameter, and observation wavelength.

Tackling climate change by planting trees.

The UK needs to step up its tree-planting efforts to make a dent on climate change. Here, Keith Powell suggests that vets could bring clients together to provide the money and land for such projects.

Big conductance calcium-activated potassium channel openers control spasticity without sedation.

BACKGROUND AND PURPOSE: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity. EXPERIMENTAL APPROACH: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans. KEY RESULTS: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity. CONCLUSIONS AND IMPLICATIONS: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity.

Combinatorial Domain Hunting: An effective approach for the identification of soluble protein domains adaptable to high-throughput applications.

Exploitation of potential new targets for drug and vaccine development has an absolute requirement for multimilligram quantities of soluble protein. While recombinant expression of full-length proteins is frequently problematic, high-yield soluble expression of functional subconstructs is an effective alternative, so long as appropriate termini can be identified. Bioinformatics localizes domains, but doesn't predict boundaries with sufficient accuracy, so that subconstructs are typically found by trial and error. Combinatorial Domain Hunting (CDH) is a technology for discovering soluble, highly expressed constructs of target proteins. CDH combines unbiased, finely sampled gene-fragment libraries, with a screening protocol that provides "holistic" readout of solubility and yield for thousands of protein fragments. CDH is free of the "passenger solubilization" and out-of-frame translational start artifacts of fusion-protein systems, and hits are ready for scale-up expression. As a proof of principle, we applied CDH to p85alpha, successfully identifying soluble and highly expressed constructs encapsulating all the known globular domains, and immediately suitable for downstream applications.

Saccades, salience and attention: the role of the lateral intraparietal area in visual behavior.

Neural activity in the lateral intraparietal area (LIP) has been associated with attention to a location in visual space, and with the intention to make saccadic eye movement. In this study we show that neurons in LIP respond to recently flashed task-irrelevant stimuli and saccade targets brought into the receptive field by a saccade, although they respond much to the same stimuli when they are stable in the environment. LIP neurons respond to the appearance of a flashed distractor even when a monkey is planning a memory-guided delayed saccade elsewhere. We then show that a monkey's attention, as defined by an increase in contrast sensitivity, is pinned to the goal of a memory-guided saccade throughout the delay period, unless a distractor appears, in which case attention transiently moves to the site of the distractor and then returns to the goal of the saccade. LIP neurons respond to both the saccade goal and the distractor, and this activity correlates with the monkey's locus of attention. In particular, the activity of LIP neurons predicts when attention migrates from the distractor back to the saccade goal. We suggest that the activity in LIP provides a salience map that is interpreted by the oculomotor system as a saccade goal when a saccade is appropriate, and simultaneously is used by the visual system to determine the locus of attention.

Ethyl vinyl chloride vapocoolant spray fails to decrease pain associated with intravenous cannulation in children.

The purpose of the study was to determine the effect of ethyl vinyl chloride vapocoolant spray on pain reported by children undergoing intravenous cannulation. A randomized, double-blinded, placebo-controlled trial was conducted on eligible children between the ages of 9 and 18 years seen in a pediatric emergency department and requiring intravenous cannulation. Informed consent was obtained, and children were randomized to receive ethyl vinyl chloride spray, isopropyl alcohol spray, or no spray (control group). Patient demographics and information pertaining to each intravenous cannulation were recorded. Children indicated the degree of pain associated with intravenous cannulation on a 100-mm visual analog scale (VAS) compared to a baseline pain score of "zero." Statistical analysis was performed by using Stata version 7. One hundred twenty-seven subjects were enrolled: 37 received ethyl vinyl chloride vapocoolant spray, 48 received isopropyl alcohol spray (placebo), and 42 received no pretreatment. Mean VAS scores for pain experienced during cannulation were 34, 33, and 31 mL for each group, respectively. Ethyl vinyl chloride vapocoolant spray failed to measurably reduce pain associated with intravenous cannulation when compared to those pretreated with isopropyl alcohol spray or receiving no intervention.

Hypotonic-hyporesponsive episode in a 7-month-old infant after receipt of multiple vaccinations.

A 7-month-old boy became difficult to arouse, was limp and had blue extremities 8 hours after immunization with intravenous poliovirus, diphtheria-tetanus toxoids-acellular pertussis, Haemophilus influenzae type b-hepatitis B virus and pneumococcal vaccines. The hypotonic-hyporesponsive episode had resolved by the time the infant was seen in an emergency department 1 hour later. The report describes hypotonic-hyporesponsive episode, encourages reporting of vaccine-associated adverse events and discusses prognosis and implications for subsequent immunization.

The role of the lateral intraparietal area of the monkey in the generation of saccades and visuospatial attention.

The brain cannot monitor or react towards the entire world at a given time. Instead, using the process of attention, it selects objects in the world for further analysis. Neuronal activity in the monkey intraparietal area has the properties appropriate for a neuronal substrate of attention: instead of all objects being represented in the parietal cortex, only salient objects are. Such objects can be salient because of their physical properties (recently flashed objects or moving objects) or because they can be made important to the animal by virtue of a task. Although lateral intraparietal area (LIP) neurons respond through the delay period of a memory-guided saccade, they also respond in an enhanced manner to distractors flashed during the delay period of a memory-guided saccade being generated to a position outside the receptive field. This activity parallels the monkey's psychophysical attentional process: attention is ordinarily pinned at the goal of a memory-guided saccade, but it shifts briefly to the locus of a task-irrelevant distractor flashed briefly during the delay period and then returns to the goal. Although neurons in LIP have been implicated as being directly involved in the generation of saccadic eye movements, their activity does not predict where, when, or if a saccade will occur. The ensemble of activity in LIP, however, does accurately describe the locus of attention.

Temporal artery temperature measurements in healthy infants, children, and adolescents.

A noninvasive temporal artery thermometer that uses arterial heat balance technology has been compared to rectal and ear thermometry and is available in the marketplace. This study was undertaken to establish mean temperatures and temperatures 2 standard deviations above the mean for healthy infants, children, and adolescents. Temperatures were measured in healthy patients 0 to 18 years of age using a noninvasive temporal artery thermometer. Temperatures were measured in 2,346 patients. Mean temperatures and temperatures 2 standard deviations above the mean were: 37.1 degrees C (38.1 degrees C) for 383 infants 0 to 2 months; 36.9 degrees C (37.9 degrees C) for 860 children 3 to 47 months; 36.8 degrees C (37.8 degrees C) for 680 children 4 to 9 years; and 36.7 degrees C (37.8 degrees C) for 423 adolescents 10 to 18 years. There were no significant differences in temperatures in white compared to African-American children, children with or without perspiration on their forehead, or between measurements taken on the left compared to the right side of the forehead. This study provides information about temporal artery temperatures in healthy infants and children that can serve as a basis for interpreting temperature measurements in ill children when the same instrument is used.

Factors affecting missed appointment rates for pediatric patients insured by medicaid in a traditional hospital-based resident clinic and hospital-owned practice settings.

Missed appointment rates (MAR) of pediatric patients insured by Medicaid and seen in a traditional hospital-based continuity (teaching) clinic were compared to the rates for the same patients after their care had been transitioned to a community practice. The hypothesis is that when rewarded with shorter waiting times, a less chaotic environment, and more pediatrician continuity, the MAR for patients insured by Medicaid would be lower in the practice setting than it had been in continuity clinic. The MAR decreased from 33% in the continuity clinic in 1999 to 18% in the community practice in 2001 (p<0.01). It was also hypothesized that the MAR for patients insured by Medicaid would be higher in practices with a higher percentage of Medicaid appointments. Among 15 hospital-owned pediatric practices, the MAR for patients insured by Medicaid was positively correlated with the percentage of total appointments that were made by patients insured by Medicaid (correlation coefficient 0.706 [p<0.01]).

Directed Evolution and Biocatalysis.

This review describes the current state of biocatalysis in the chemical industry. Although we recognize the advantages of chemical approaches, we suggest that the use of biological catalysis is about to expand dramatically because of the recent developments in the artificial evolution of genes that code for enzymes. For the first time it is possible to consider the rapid development of an enzyme that is designed for a specific chemical reaction. This technology offers the opportunity to adapt the enzyme to the needs of the process. We describe herein the development of enzyme evolution technology and particularly DNA shuffling. We also consider several classes of enzymes, their current applications, and the limitations that should be addressed. In a review of this length it is impossible to describe all the enzymes with potential for industrial exploitation; there are other classes, which given appropriate activity, selectivity, and robustness, could become useful tools for the industrial chemist. This is an exciting era for biocatalysis and we expect great progress in the future.