GSK2878175, a pan-genotypic non-nucleoside NS5B polymerase inhibitor, in healthy and treatment-naïve chronic hepatitis C subjects.

GSK2878175 is a potent, pan-genotypic, non-nucleoside, nonstructural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics and antiviral activity of GSK2878175 monotherapy in treatment-naïve, noncirrhotic, subjects with hepatitis C virus (HCV) genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study, and treatment was well-tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multilog reduction (P<.001) in plasma HCV RNA log10 IU/mL from Baseline to 24, 48 and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half-life of GSK2878175 that was observed (mean t1/2 range: 60-63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175-based regimens.

Fixed 50:50 mixture of nitrous oxide and oxygen to reduce lumbar-puncture-induced pain: a randomized controlled trial.

BACKGROUND AND PURPOSE: Lumbar puncture (LP) has been frequently performed for more than a century. This procedure is still stressful and often painful. The aim of the study was to evaluate the efficacy of a fixed 50% nitrous oxide-oxygen mixture compared to placebo to reduce immediate procedural pain and anxiety during LP. METHODS: A randomized controlled trial was conducted involving adults who needed a cerebrospinal fluid analysis. Patients were randomly assigned to inhale either a fixed 50% nitrous oxide-oxygen mixture (50% N2 O-O2 ) or medical air (22% O2 -78% N2 ). Cutaneous application of a eutectic mixture of local anaesthetics was systematically done and all LPs were performed with pencil point 25G needles (20G introducer needle). The primary end-point was the maximal pain level felt by the patient during the procedure, the maximal anxiety level being a secondary outcome, both measured using a numerical rating scale (0-10). RESULTS: A total of 66 consecutive patients were randomized. The analysis was intention to treat. The maximal pain was 4.9 ± 2.7 for the 33 patients receiving air and 2.7 ± 2.7 for the 33 receiving 50% N2 O-O2 (P = 0.002). Similarly, the maximal LP-induced anxiety was 4.5 ± 3.1 vs. 2.6 ± 2.6 (P = 0.009), respectively. The number needed to treat to avoid one patient undergoing significant pain (pain score ≥ 4/10) was 2.75. Body mass index >25 kg/m2 was significantly associated with higher pain intensity (P = 0.03). No serious adverse events were attributable to 50% N2 O-O2 inhalation. CONCLUSIONS: Inhalation of a fixed 50% N2 O-O2 mixture is efficient to reduce LP-induced pain and anxiety.

Free energy profiles for two ubiquitous damaging agents: methylation and hydroxylation of guanine in B-DNA.

DNA methylation and hydroxylation are two ubiquitous reactions in DNA damage induction, yet insights are scarce concerning the free energy of activation within B-DNA. We resort to multiscale simulations to investigate the attack of a hydroxyl radical and of the primary diazonium onto a guanine embedded in a solvated dodecamer. Reaction free energy profiles characterize two strongly exergonic processes, yet allow unprecedented quantification of the barrier towards this damage reaction, not higher than 6 kcal mol-1 and sometimes inexistent, and of the exergonicities. In the case of the [G(C8)-OH]˙ intermediate, we challenge the functional dependence of such simulations: recently-proposed functionals, such as M06-2X and LC-BLYP, agree on a ∼4 kcal mol-1 barrier, whereas the hybrid GGA B3LYP functional predicts a barrier-less pathway. In the long term, multiscale approaches can help build up a unified panorama of DNA lesion induction. These results stress the importance of DFT/MM-MD simulations involving new functionals towards the sound modelling of biomolecule damage even in the ground state.

NH3 biofiltration of piggery air.

An aboveground pilot-scale biofilter filled with wood chips was tested to treat ammonia emissions from a piggery located in Brittany (France). Two long-term tests ("summer" and "autumn" experiments) were carried out to improve biofilter applications for agriculture. The influence of climatic conditions on biofilter performance was taken into account. During summer 2012, the biofilter was operated for 74 days at different empty bed residence times (EBRTs) from 6 to 15 s. Inlet NH3 concentrations were relatively constant (around 15 mg m(-3)). Significant NH3 reductions were achieved at EBRT = 12 s (removal efficiencies, RE, ranged between 90 and 100% for loading rates, LR, of around 4 g m(-3) h(-1)). At a lower EBRT (6 s), RE dropped to roughly 30-50%. This was due to the dramatic increase in the loading rate (LR up to 12 g m(-3) h(-1)) but the results showed that the change in atmospheric conditions (temperature and relative humidity) also had a significant influence on biofilter performance. It was evidenced that the use of a humidifier upstream of the biofilter must be taken into account for large-scale biofilter design, but only for specific conditions (the spraying of the biofilter having to be carried out exceptionally). During autumn 2012, the biofilter was operated for 116 days at EBRT = 12 s. RE were around 80% for LR of around 3 g m(-3) h(-1). In such autumnal atmospheric conditions, a demister system should be installed upstream of the biofilter in order to avoid water accumulation in the bed material. Although biofiltration was suitable for NH3 treatment of piggery air, the need to control accurately the medium moisture content implies that biofilters would not be easily managed by a pig farmer.

Addressing the competitive formation of tandem DNA lesions by a nucleobase peroxyl radical: a DFT-D screening.

The presence of two vicinal single-nucleotide oxidative lesions constitutes a pitfall case for DNA repair. Quantum mechanics calculations are performed to elucidate the formation of peroxyl-bridged adducts, where a purine and a pyrimidine base become covalently tethered. A dispersion-corrected density functional theory (DFT-D) screening along the 32 possible adducts built by a combination of the four different nucleobases outlines that guanine is a better tandem partner than adenine, in line with experimental data. In contrast, cytosine and thymine have an overall comparable reactivity as revealed by a highly localized spin density. For a given purine and pyrimidine combination, our computational approach also sketches some differences concerning the syn vs. anti configurations and the orientation strand.

Unraveling the toxicity of tire wear contamination in three freshwater species: From chemical mixture to nanoparticles.

Tire wear particle (TWP) contamination is of growing concern as recent studies show the ubiquity and toxicity of this contaminant in various environmental compartments. The multidimensional aspect of TWPs makes it difficult to assess toxicity and predict impacts on ecosystems, as it combines a complex mixture of chemicals and can release micro- and nanoparticles when suspended in water. Our work aimed to shed light on the toxicity of the different components of TWP leachate, namely, the dissolved chemicals and the nanoparticle fractions, on three freshwater model species of different trophic levels: Chlorella vulgaris, Lemna minor, and Daphnia magna. Acute toxicity was observed for all three fractions in D. magna, and an additive effect was observed between the nanoparticles and dissolved chemicals. L. minor experienced phytotoxicity from the dissolved chemicals only with a decrease up to 50% in photosynthesis efficiency parameters. C. vulgaris showed minor signs of toxicity on apical endpoints in response to each of the fractions. Our study highlights that nanoparticles from TWP leachate that were mostly overlooked in several previous studies are as toxic as dissolved chemicals for the filter-feeder species D. magna, and we also show the toxicity to photosynthesis in aquatic plants.

Design and characterization of a laterally mounted phased-array transducer breast-specific MRgHIFU device with integrated 11-channel receiver array.

PURPOSE: This work presents the design and preliminary evaluation of a new laterally mounted phased-array MRI-guided high-intensity focused ultrasound (MRgHIFU) system with an integrated 11-channel phased-array radio frequency (RF) coil intended for breast cancer treatment. The design goals for the system included the ability to treat the majority of tumor locations, to increase the MR image's signal-to-noise ratio (SNR) throughout the treatment volume and to provide adequate comfort for the patient. METHODS: In order to treat the majority of the breast volume, the device was designed such that the treated breast is suspended in a 17-cm diameter treatment cylinder. A laterally shooting 1-MHz, 256-element phased-array ultrasound transducer with flexible positioning is mounted outside the treatment cylinder. This configuration achieves a reduced water volume to minimize RF coil loading effects, to position the coils closer to the breast for increased signal sensitivity, and to reduce the MR image noise associated with using water as the coupling fluid. This design uses an 11-channel phased-array RF coil that is placed on the outer surface of the cylinder surrounding the breast. Mechanical positioning of the transducer and electronic steering of the focal spot enable placement of the ultrasound focus at arbitrary locations throughout the suspended breast. The treatment platform allows the patient to lie prone in a face-down position. The system was tested for comfort with 18 normal volunteers and SNR capabilities in one normal volunteer and for heating accuracy and stability in homogeneous phantom and inhomogeneous ex vivo porcine tissue. RESULTS: There was a 61% increase in mean relative SNR achieved in a homogeneous phantom using the 11-channel RF coil when compared to using only a single-loop coil around the chest wall. The repeatability of the system's energy delivery in a single location was excellent, with less than 3% variability between repeated temperature measurements at the same location. The execution of a continuously sonicated, predefined 48-point, 8-min trajectory path resulted in an ablation volume of 8.17 cm(3), with one standard deviation of 0.35 cm(3) between inhomogeneous ex vivo tissue samples. Comfort testing resulted in negligible side effects for all volunteers. CONCLUSIONS: The initial results suggest that this new device will potentially be suitable for MRgHIFU treatment in a wide range of breast sizes and tumor locations.

The Behavior Problems Inventory-Short Form for individuals with intellectual disabilities: part II: reliability and validity.

BACKGROUND: The Behavior Problems Inventory-01 (BPI-01) is an informant-based behaviour rating instrument for intellectual disabilities (ID) with 49 items and three sub-scales: Self-injurious Behavior, Stereotyped Behavior and Aggressive/Destructive Behavior. The Behavior Problems Inventory-Short Form (BPI-S) is a BPI-01 spin-off with 30 items. METHODS: The psychometric properties of these two versions of the scale were computed using aggregated archival data from nine different sites in the USA, Wales, England, the Netherlands and Romania with a total of 1122 cases with a BPI-01 total score >0. RESULTS: The internal consistency of the BPI-01 and the BPI-S ranged from fair to excellent with the BPI-01 showing slightly stronger reliability. Construct validity (confirmatory and discriminant) was computed by comparing BPI sub-scale scores with the scores of four other behaviour rating scales (the Aberrant Behavior Checklist, the Diagnostic Assessment for the Severely Handicapped-II, the Nisonger Child Behavior Rating Form and the Inventory for Client and Agency Planning). Strong evidence for confirmatory and discriminant validity was found for both the BPI-01 and the BPI-S. Confirmatory fit indices for the BPI and the BPI-S were comparable and suggesting that the factor structures fit the data well. CONCLUSION: In summary, both BPI versions were found to be equally sound psychometrically and can be endorsed for future use. However, independent future studies are needed to replicate the psychometrics of the BPI-S with new data.

The Behavior Problems Inventory-Short Form for individuals with intellectual disabilities: part I: development and provisional clinical reference data.

BACKGROUND: The Behavior Problems Inventory-01 (BPI-01) is an informant-based behaviour rating instrument that was designed to assess maladaptive behaviours in individuals with intellectual disabilities (ID). Its items fall into one of three sub-scales: Self-injurious Behavior (14 items), Stereotyped Behavior (24 items), and Aggressive/Destructive Behavior (11 items). Each item is rated on a frequency scale (0 = never to 4 = hourly), and a severity scale (0 = no problem to 3 = severe problem). The BPI-01 has been successfully used in several studies and has shown acceptable to very good psychometric properties. One concern raised by some investigators was the large number of items on the BPI-01, which has reduced its user friendliness for certain applications. Furthermore, researchers and clinicians were often uncertain how to interpret their BPI-01 data without norms or a frame of reference. METHODS: The Behavior Problems Inventory-Short Form (BPI-S) was empirically developed, based on an aggregated archival data set of BPI-01 data from individuals with ID from nine locations in the USA, Wales, England, the Netherlands, and Romania (n = 1122). The BPI-S uses the same rating system and the same three sub-scales as the BPI-01, but has fewer items: Self-injurious Behavior (8 items), Stereotyped Behavior (12 items), and Aggressive/Destructive Behavior (10 items). Rating anchors for the severity scales of the Self-injurious Behavior and the Aggressive/Destructive Behavior sub-scales were added in an effort to enhance the objectivity of the ratings. RESULTS: The sensitivity of the BPI-S compared with the BPI-01 was high (0.92 to 0.99), and so were the correlations between the analogous BPI-01 and the BPI-S sub-scales (0.96 to 0.99). Means and standard deviations were generated for both BPI versions in a Sex-by-age matrix, and in a Sex-by-ID Level matrix. Combined sex ranges are also provided by age and level of ID. CONCLUSION: In summary, the BPI-S is a very useful alternative to the BPI-01, especially for research and evaluation purposes involving groups of individuals.

Design, Development and Validation of a Knee Brace to Standardize the US Imaging Evaluation of Knee Osteoarthritis.

OBJECTIVE: A repeatable and reliable follow-up of knee injuries would be desirable to prevent delayed diagnosis and to monitor the efficacy of the applied treatment over time. Ultrasound (US) techniques are an attractive option to this purpose, since they are safe, low-cost and non-invasive. However, its use in the clinical practice is limited by the high dependency on the operator's experience. Hence, the objective of this study is to provide a standardization of the US image acquisition process for knee osteoarthritis (OA) allowing an extended clinical use of US technologies in this domain. METHODS: Clinical specifications were provided by expert musculoskeletal radiologists thus identifying the subject poses and the US probe positions needed to evaluate the cartilage structure, signs of synovitis and joint effusion. Such considerations were used to derive the technical requirements needed for the development of a wearable brace equipped with specific openings to guide the correct placement of the probe. The feasibility of the developed wearable brace was tested on three healthy volunteers, which were asked to acquire informative US images, similar to the reference images performed by the musculoskeletal radiologist. RESULTS: Thanks to the knee brace, the untrained subjects were able to self-acquire informative B-mode images comparable to the corresponding images acquired by an expert clinician. DISCUSSION/CONCLUSION: The use of a knee brace intended for knee OA US diagnosis demonstrated the possibility to standardize the acquisition protocol and make its application achievable also for untrained subjects, representing a key step toward tele-ultrasonography.

Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction.

BACKGROUND: Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. METHODS AND RESULTS: Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm(2)) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (ΔLVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. CONCLUSION: In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

Real-time imaging of apoptotic cell-membrane changes at the single-cell level in the beating murine heart.

We report a novel real-time imaging model to visualize apoptotic membrane changes of single cardiomyocytes in the injured heart of the living mouse, using fluorescent labeled annexin-V. Annexin-V binds to externalized phosphatidylserine (PS) of cells undergoing programmed cell death. With high-magnification (x100-160) real-time imaging, we visualized the binding of annexin-V to single cardiomyocytes. Kinetic studies at the single-cell level revealed that cardiomyocytes started to bind annexin-V within minutes after reperfusion, following an ischemic period of 30 minutes. The amount of bound annexin-V increased rapidly and reached a maximum within 20-25 minutes. Caspase inhibitors decreased the number of annexin-V-positive cardiomyocytes and slowed down the rate of PS exposure of cardiomyocytes that still bound annexin-V. This technology to study cell biology in the natural environment will enhance knowledge of intracellular signaling pathways relevant for cell-death regulation and strategies to manipulate these pathways for therapeutic effect.

Development and validation of low-intensity pulsed ultrasound systems for highly controlled in vitro cell stimulation.

This work aims to describe the development and validation of two low-intensity pulsed ultrasound stimulation systems able to control the dose delivered to the biological target. Transducer characterization was performed in terms of pressure field shape and intensity, for a high-frequency range (500 kHz to 5 MHz) and for a low-frequency value (38 kHz). This allowed defining the distance, on the beam axis, at which biological samples should be placed during stimulation and to exactly know the intensity at the target. Carefully designed retaining systems were developed, for hosting biological samples. Sealing tests proved their impermeability to external contaminants. The assembly/de-assembly time of the systems resulted ~3 min. Time-domain acoustic simulations allowed to precisely estimate the ultrasound beam within the biological sample chamber, thus enabling the possibility to precisely control the pressure to be transmitted to the biological target, by modulating the transducer's input voltage. Biological in vitro tests were also carried out, demonstrating the sterility of the system and the absence of toxic and inflammatory effects on growing cells after multiple immersions in water, over seven days.

Predicting bite force in mammals: two-dimensional versus three-dimensional lever models.

Bite force is a measure of whole-organism performance that is often used to investigate the relationships between performance, morphology and fitness. When in vivo measurements of bite force are unavailable, researchers often turn to lever models to predict bite forces. This study demonstrates that bite force predictions based on two-dimensional (2-D) lever models can be improved by including three-dimensional (3-D) geometry and realistic physiological cross-sectional areas derived from dissections. Widely used, the 2-D method does a reasonable job of predicting bite force. However, it does so by over predicting physiological cross-sectional areas for the masseter and pterygoid muscles and under predicting physiological cross-sectional areas for the temporalis muscle. We found that lever models that include the three dimensional structure of the skull and mandible and physiological cross-sectional areas calculated from dissected muscles provide the best predictions of bite force. Models that accurately represent the biting mechanics strengthen our understanding of which variables are functionally relevant and how they are relevant to feeding performance.

Raman imaging as a new analytical tool for the quality control of the monitoring of osteogenic differentiation in forming 3D bone tissue.

In this study, adipose-derived stem cells (ASCs) are used to produce 3D bone grafts. The safety and the feasibility of using these bone grafts have been already showed and quality controls are already implemented. However, a cheaper, fast and non-destructive technique is required to monitor the osteogenic differentiation process. Here, the use of Raman imaging to monitor the synthesis of the extracellular matrix and its progressive mineralization occurring during the osteogenic differentiation process is investigated for the first time on a 3D in forming bone tissue. The attention was focused on Raman bands related to this matrix belonging to phosphate, phenylalanine and hydroxyproline, which are very distinctive and intense. The kinetic of the osteogenic differentiation process was first compared between a 2D and a 3D forming bone tissue. It was observed that the kinetics of the osteogenic differentiation process is slower in 3D in forming bone tissue. In a second step, an evaluation of the reliability of the Raman imaging method was performed including a study of the influence of the harvest biopsies position on the forming 3D bone tissue. The repeatability and the specificity of this method were also demonstrated. In a last step, several batches of ASCs were cultured and analyzed in 3D at different time points using Raman imaging. From the mean Raman spectra, mineral to matrix ratios (MTMR) were determined and used to evaluate the formation of mineral deposits accompanying the extracellular matrix synthesis which is indicative of an ongoing osteogenic differentiation process. These ratios peaked between the day 35 and 49. This observation was very interesting since it corresponds to the time at which the 3D bone grafts are used for the patient surgery. To conclude, Raman imaging allowed fast acquisition and time-resolved monitoring in vitro of the mineralization of extracellular matrix during osteogenic differentiation.

Quantitation of active pharmaceutical ingredient through the packaging using Raman handheld spectrophotometers: A comparison study.

Handheld Raman spectroscopy is actually booming. Recent devices improvements aim at addressing the usual Raman spectroscopy issues: fluorescence with shifted-excitation Raman difference spectroscopy (SERDS), poor sensitivity with surface enhanced Raman scattering (SERS) and information only about the sample surface with spatially offset Raman spectroscopy (SORS). While qualitative performances of handheld devices are generally well established, the quantitative analysis of pharmaceutical samples remains challenging. The aim of this study was to compare the quantitative performances of three commercially available handheld Raman spectroscopy devices. Two of them (TruScan and IDRaman mini) are equipped with a 785 nm laser wavelength and operate in a conventional backscattering mode. The IDRaman has the Orbital Raster Scanning (ORS) option to increase the analyzed surface. The third device (Resolve) operates with an 830 nm laser wavelength both in backscattering and in SORS modes. The comparative study was carried out on ibuprofen-mannitol-microcrystalline cellulose ternary mixtures. The concentration of ibuprofen ranged from 24 to 52% (w/w) while the proportions of the two excipients were varied to avoid cross-correlation as much as possible. Analyses were performed either directly through a glass vial or with the glass vial in an opaque polypropylene flask, using a validated FT-NIR spectroscopy method as a reference method. Chemometric analyses were carried out with the Partial Least Squares Regression (PLS-R) algorithm. The quantitative models were validated using the total error approach and the ICH Q2 (R1) guidelines with ±â€¯15% as acceptance limits.

Connecting behaviour and performance: the evolution of biting behaviour and bite performance in bats.

Variation in behaviour, performance and ecology are traditionally associated with variation in morphology. A neglected part of this ecomorphological paradigm is the interaction between behaviour and performance, the ability to carry out tasks that impact fitness. Here we investigate the relationship between biting behaviour and performance (bite force) among 20 species of ecologically diverse bats. We studied the patterns of evolution of plasticity in biting behaviour and bite force, and reconstructed ancestral states for behaviour and its plasticity. Both behavioural and performance plasticity exhibited accelerating evolution over time, and periods of rapid evolution coincided with major dietary shifts from insect-feeding to plant-feeding. We found a significant, positive correlation between behavioural plasticity and bite force. Bats modulated their performance by changing their biting behaviour to maximize bite force when feeding on hard foods. The ancestor of phyllostomids was likely a generalist characterized by high behavioural plasticity, a condition that also evolved in specialized frugivores and potentially contributed to their diversification.

Oral contraceptives, lanosterol, and platelet hyperactivity in rat.

Lanosterol, a cholesterol precursor that increases considerably in the platelets of rats treated with oral contraceptives, was incubated with either platelet-rich plasma or washed platelet suspension. After 2 minutes there was a remarkable dose-related increase in platelet activity. This platelet hyperactivity was measured by clotting time and platelet aggregation could not be reproduced by cholesterol or ethinylestradiol.

Requirements for comparing the performance of finite element models of biological structures.

The widespread availability of three-dimensional imaging and computational power has fostered a rapid increase in the number of biologists using finite element analysis (FEA) to investigate the mechanical function of living and extinct organisms. The inevitable rise of studies that compare finite element models brings to the fore two critical questions about how such comparative analyses can and should be conducted: (1) what metrics are appropriate for assessing the performance of biological structures using finite element modeling? and, (2) how can performance be compared such that the effects of size and shape are disentangled? With respect to performance, we argue that energy efficiency is a reasonable optimality criterion for biological structures and we show that the total strain energy (a measure of work expended deforming a structure) is a robust metric for comparing the mechanical efficiency of structures modeled with finite elements. Results of finite element analyses can be interpreted with confidence when model input parameters (muscle forces, detailed material properties) and/or output parameters (reaction forces, strains) are well-documented by studies of living animals. However, many researchers wish to compare species for which these input and validation data are difficult or impossible to acquire. In these cases, researchers can still compare the performance of structures that differ in shape if variation in size is controlled. We offer a theoretical framework and empirical data demonstrating that scaling finite element models to equal force: surface area ratios removes the effects of model size and provides a comparison of stress-strength performance based solely on shape. Further, models scaled to have equal applied force:volume ratios provide the basis for strain energy comparison. Thus, although finite element analyses of biological structures should be validated experimentally whenever possible, this study demonstrates that the relative performance of un-validated models can be compared so long as they are scaled properly.

A novel GPR55-mediated satiety signal in the oval Bed Nucleus of the Stria Terminalis.

Nestled within feeding circuits, the oval (ov) region of the Bed Nucleus of the Stria Terminalis (BNST) may be critical for monitoring energy balance through changes in synaptic strength. Here we report that bidirectional plasticity at ovBNST GABA synapses was tightly linked to the caloric state of male rats, seesawing between long-term potentiation (iLTP, fed) and depression (iLTD, food restricted). L-α-lysophosphatidylinositol (LPI) acting on GPR55 receptors and 2-arachidonoylglycerol (2-AG) through CB1R were respectively responsible for fed (iLTP) and food restricted (iLTD) states. Thus, we have characterized a potential gating mechanism within the ovBNST that may signal metabolic state within the rat brain feeding circuitry.