How the Devil Ray Got Its Horns: The Evolution and Development of Cephalic Lobes in Myliobatid Stingrays (Batoidea: Myliobatidae)

Manta rays and their relatives of the family Myliobatidae have pectoral fins that have been modified for underwater flight, as well as a pair of fleshy projections at the anterior of the body called cephalic lobes, which are specialized for feeding. As a unique trait with a dedicated function, cephalic lobes offer an excellent opportunity to elucidate the processes by which diverse body plans and features evolve. To shed light on the morphological development and genetic underpinnings of cephalic lobes, we examined paired fin development in cownose rays, which represent the sister taxon to manta rays in the genus Mobula. We find that cephalic lobes develop as anterior pectoral fin domains and lack independent posterior patterning by 5\u27 HoxD genes and Shh, indicating that cephalic lobes are not independent appendages but rather are modified pectoral fin domains. In addition, by leveraging interspecies comparative transcriptomics and domain-specific RNA-sequencing, we identify shared expression of anterior patterning genes, including Alx1, Alx4, Pax9, Hoxa13, Hoxa2, and Hoxd4, in the pectoral fins of cownose ray (Rhinoptera bonasus) and little skate (Leucoraja erinacea), providing evidence supporting homology between the cephalic lobes of myliobatids and the anterior pectoral fins of skates. We also suggest candidate genes that may be involved in development of myliobatid-specific features, including Omd, which is likely associated with development of thick anterior pectoral fin radials of myliobatids, and Dkk1, which may inhibit tissue outgrowth at the posterior boundary of the developing cephalic lobes. Finally, we observe that cephalic lobes share a surprising number of developmental similarities with another paired fin modification: the claspers of male cartilaginous fishes, including enrichment of Hand2, Hoxa13, and androgen receptor. These results suggest that cephalic lobes may have evolved by co-opting developmental pathways that specify novel domains in paired fins. Taken together, these data on morphological development and comparative gene expression patterns illustrate how distinct body plans and seemingly novel features can arise via subtle changes to existing developmental pathways

Behaviour of Solitary Adult Scandinavian Brown Bears (Ursus arctos) when Approached by Humans on Foot

Successful management has brought the Scandinavian brown bear (Ursus arctos L.) back from the brink of extinction, but as the population grows and expands the probability of bear-human encounters increases. More people express concerns about spending time in the forest, because of the possibility of encountering bears, and acceptance for the bear is decreasing. In this context, reliable information about the bear's normal behaviour during bear-human encounters is important. Here we describe the behaviour of brown bears when encountering humans on foot. During 2006–2009, we approached 30 adult (21 females, 9 males) GPS-collared bears 169 times during midday, using 1-minute positioning before, during and after the approach. Observer movements were registered with a handheld GPS. The approaches started 869±348 m from the bears, with the wind towards the bear when passing it at approximately 50 m. The bears were detected in 15% of the approaches, and none of the bears displayed any aggressive behaviour. Most bears (80%) left the initial site during the approach, going away from the observers, whereas some remained at the initial site after being approached (20%). Young bears left more often than older bears, possibly due to differences in experience, but the difference between ages decreased during the berry season compared to the pre-berry season. The flight initiation distance was longer for active bears (115±94 m) than passive bears (69±47 m), and was further affected by horizontal vegetation cover and the bear's age. Our findings show that bears try to avoid confrontations with humans on foot, and support the conclusions of earlier studies that the Scandinavian brown bear is normally not aggressive during encounters with humans

Comparative efficacy of ultrasound-guided and stimulating popliteal-sciatic perineural catheters for postoperative analgesia

Perineural catheter insertion using ultrasound guidance alone is a relatively new approach. Previous studies have shown that ultrasound-guided catheters take less time to place with high placement success rates, but the analgesic efficacy compared with the established stimulating catheter technique remains unknown. We tested the hypothesis that popliteal-sciatic perineural catheter insertion relying exclusively on ultrasound guidance results in superior postoperative analgesia compared with stimulating catheters. Preoperatively, subjects receiving a popliteal-sciatic perineural catheter for foot or ankle surgery were assigned randomly to either ultrasound guidance (bolus via needle with non-stimulating catheter insertion) or electrical stimulation (bolus via catheter). We used 1.5% mepivacaine 40 mL for the primary surgical nerve block and 0.2% ropivacaine (basal 8 mL·hr−1; bolus 4 mL; 30 min lockout) was infused postoperatively. The primary outcome was average surgical pain on postoperative day one. Forty of the 80 subjects enrolled were randomized to each treatment group. One of 40 subjects (2.5%) in the ultrasound group failed catheter placement per protocol vs nine of 40 (22.5%) in the stimulating catheter group (P = 0.014). The difference in procedural duration (mean [95% confidence interval (CI)]) was −6.48 (−9.90 - −3.05) min, with ultrasound requiring 7.0 (4.0-14.1) min vs stimulation requiring 11.0 (5.0-30.0) min (P < 0.001). The average pain scores of subjects who provided data on postoperative day one were somewhat higher for the 33 ultrasound subjects than for the 26 stimulation subjects (5.0 [1.0-7.8] vs 3.0 [0.0-6.5], respectively; P = 0.032), a difference (mean [95%CI]) of 1.37 (0.03-2.71). For popliteal-sciatic perineural catheters, ultrasound guidance takes less time and results in fewer placement failures compared with stimulating catheters. However, analgesia may be mildly improved with successfully placed stimulating catheters. Clinical trial registration number NCT00876681

The effect of initial local anesthetic dose with continuous interscalene analgesia on postoperative pain and diaphragmatic function in patients undergoing arthroscopic shoulder surgery: a double-blind, randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Interscalene block (ISB) is commonly performed using 20-40 mL of local anesthetic. Spread to adjacent structures and consequent adverse effects including paralysis of the ipsilateral hemidiaphragm are frequent. Pain ratings, analgesic requirements, adverse events, satisfaction, function and diaphragmatic excursion were compared following interscalene block (ISB) with reduced initial bolus volumes.</p> <p>Methods</p> <p>Subjects undergoing arthroscopic rotator cuff repair were randomized to receive 5, 10, or 20 mL ropivacaine 0.75% for ISB in a double-blind fashion (N = 36). Continuous infusion with ropivacaine 0.2% was maintained for 48 h. Pain and diaphragmatic excursion were assessed before block and in the recovery unit.</p> <p>Results</p> <p>Pain ratings in the recovery room were generally less than 4 (0-10 NRS) for all treatment groups, but a statistically significant difference was noted between the 5 and 20 mL groups (NRS: 2.67 vs. 0.62 respectively; p = 0.04). Pain ratings and supplemental analgesic use were similar among the groups at 24 h, 48 h and 12 weeks. There were no differences in the quality of block for surgical anesthesia. Dyspnea was significantly greater in the 20 mL group (p = 0.041). Subjects with dyspnea had significant diaphragmatic impairment more frequently (Relative risk: 2.5; 95%CI: 1.3-4.8; p = 0.042). Increased contralateral diaphragmatic motion was measured in 29 of the 36 subjects. Physical shoulder function at 12 weeks improved over baseline in all groups (baseline mean SST: 6.3, SEM: 0.6; 95%CI: 5.1-7.5; 12 week mean SST: 8.2, SEM: 0.46; 95%CI: 7.3-9.2; p = 0.0035).</p> <p>Conclusions</p> <p>ISB provided reliable surgical analgesia with 5 mL, 10 mL or 20 mL ropivacaine (0.75%). The 20 mL volume was associated with increased complaints of dyspnea. The 5 mL volume was associated with statistically higher pain scores in the immediate postoperative period. Lower volumes resulted in a reduced incidence of dyspnea compared to 20 mL, however diaphragmatic impairment was not eliminated. Compensatory increases in contralateral diaphragmatic movement may explain tolerance for ipsilateral paresis.</p> <p>Trial Registration</p> <p>clinicaltrials.gov. identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00672100">NCT00672100</a></p

Very Low Tidal Volume Ventilation with Associated Hypercapnia - Effects on Lung Injury in a Model for Acute Respiratory Distress Syndrome

BACKGROUND: Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome. METHODOLOGY/PRINCIPAL FINDINGS: In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8-10 ml/kg/PaCO(2) = 40 mm Hg; Group 2: tidal volume = 4-5 ml/kg/PaCO(2) = 80 mm Hg; Group 3: tidal volume = 3-4 ml/kg/PaCO(2) = 120 mm Hg; Group 4: tidal volume = 2-3 ml/kg/PaCO(2) = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO(2) were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4-5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy. CONCLUSION: Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4-5 ml/kg/PaCO(2) 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier–Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system’s components taken in isolation

Community Compensatory Trend Prevails from Tropical to Temperate Forest

Community compensatory trend (CCT) is thought to facilitate persistence of rare species and thus stabilize species composition in tropical forests. However, whether CCT acts over broad geographical ranges is still in question. In this study, we tested for the presence of negative density dependence (NDD) and CCT in three forests along a tropical-temperate gradient. Inventory data were collected from forest communities located in three different latitudinal zones in China. Two widely used methods were used to test for NDD at the community level. The first method considered relationships between the relative abundance ratio and adult abundance. The second method emphasized the effect of adult abundance on abundance of established younger trees. Evidence for NDD acting on different growth forms was tested by using the first method, and the presence of CCT was tested by checking whether adult abundance of rare species affected that of established younger trees less than did abundance of common species. Both analyses indicated that NDD existed in seedling, sapling and pole stages in all three plant communities and that this effect increased with latitude. However, the extent of NDD varied among understory, midstory and canopy trees in the three communities along the gradient. Additionally, despite evidence of NDD for almost all common species, only a portion of rare species showed NDD, supporting the action of CCT in all three communities. So, we conclude that NDD and CCT prevail in the three recruitment stages of the tree communities studied; rare species achieve relative advantage through CCT and thus persist in these communities; CCT clearly facilitates newly established species and maintains tree diversity within communities across our latitudinal gradient

Targeting the IL-6 Dependent Phenotype Can Identify Novel Therapies for Cholangiocarcinoma

The need for new therapies for cholangiocarcinoma is highlighted by their poor prognosis and refractoriness to chemotherapy. Increased production of Interleukin-6 promotes cholangiocarcinoma growth and contributes to chemoresistance by activating cell survival mechanisms. We sought to identify biologically active compounds capable of ameliorating the phenotypic effects of IL-6 expression and to explore their potential therapeutic use for cholangiocarcinoma.A genomic signature associated with Interleukin-6 expression in Mz-ChA-1 human malignant cholangiocytes was derived. Computational bioinformatics analysis was performed to identify compounds that induced inverse gene changes to the signature. The effect of these compounds on cholangiocarcinoma growth was then experimentally verified in vitro and in vivo. Interactions with other therapeutic agents were evaluated using median effects analysis.A group of structurally related compounds, nitrendipine, nifedipine and felodipine was identified. All three compounds were cytotoxic to Mz-ChA-1 cells with an IC50 for felodipine of 26 µM, nitrendipine, 44 µM and nifedipine, 15 µM. Similar results were observed in KMCH-1, CC-LP-1 and TFK-1 cholangiocarcinoma cell lines. At a fractional effect of 0.5, all three agents were synergistic with either camptothecin or gemcitabine in Mz-ChA-1 cells in vitro. Co-administration of felodipine and gemcitabine decreased the growth of Mz-ChA-1 cell xenografts in nude athymic mice.Computational bioinformatics analysis of phenotype-based genomic expression can be used to identify therapeutic agents. Using this drug discovery approach based on targeting a defined tumor associated phenotype, we identified compounds with the potential for therapeutic use in cholangiocarcinoma

Evolution of Fruit Traits in Ficus Subgenus Sycomorus (Moraceae): To What Extent Do Frugivores Determine Seed Dispersal Mode?

Fig trees are a ubiquitous component of tropical rain forests and exhibit an enormous diversity of ecologies. Focusing on Ficus subgenus Sycomorus, a phenotypically diverse and ecologically important Old World lineage, we examined the evolution of fruit traits using a molecular phylogeny constructed using 5 kilobases of DNA sequence data from 63 species (50% of global diversity). In particular, we ask whether patterns of trait correlations are consistent with dispersal agents as the primary selective force shaping morphological diversity or if other ecological factors may provide a better explanation? Fig colour, size and placement (axial, cauliflorous, or geocarpic) were all highly evolutionarily liable, and the same fruit traits have evolved in different biogeographic regions with substantially different dispersal agents. After controlling for phylogenetic autocorrelation, we found that fig colour and size were significantly associated with fig placement and plant-life history traits (maximum plant height and leaf area, respectively). However, contrary to prevailing assumptions, fig placement correlated poorly with known dispersal agents and appears more likely determined by other factors, such as flowering phenology, nutrient economy, and habitat preference. Thus, plant life-history, both directly and through its influence on fig placement, appears to have played a prominent role in determining fruit traits in these figs