Egg shape changes at the theropod–bird transition, and a morphometric study of amniote eggs

The eggs of amniotes exhibit a remarkable variety of shapes, from spherical to elongate and from symmetrical to asymmetrical. We examine eggshell geometry in a diverse sample of fossil and living amniotes using geometric morphometrics and linear measurements. Our goal is to quantify patterns of morphospace occupation and shape variation in the eggs of recent through to Mesozoic birds (neornithe plus non-neornithe avialans), as well as in eggs attributed to non-avialan theropods. In most amniotes, eggs show significant deviation from sphericity, but departure from symmetry around the equatorial axis is mostly confined to theropods and birds. Mesozoic bird eggs differ significantly from extant bird eggs, but extinct Cenozoic bird eggs do not. This suggests that the range of egg shapes in extant birds had already been attained in the Cenozoic. We conclude with a discussion of possible biological factors imparting variation to egg shapes during their formation in the oviduct

Genotoxic Effects in Swimmers Exposed to Disinfection By-products in Indoor Swimming Pools

37 páginas, 1 figura, 4 tablas.-- PDF con material suplementario.[BACKGROUND]: Exposure to disinfection by-products (DBPs) in drinking water has been associated with cancer risk. A recent study found an increased bladder cancer risk among subjects attending swimming pools relative to those not attending.[OBJECTIVES]: To evaluate whether swimming in pools is associated with biomarkers of genotoxicity.[METHODS]: We collected blood, urine, and exhaled air samples from 49 non-smoking adult volunteers before and after they swam for 40 min in an indoor chlorinated pool. We estimated associations between the concentrations of four trihalomethanes in exhaled breath and changes in the following biomarkers: micronuclei and DNA damage (comet assay) in peripheral blood lymphocytes before and 1 h after swimming, urine mutagenicity (Ames assay) before and 2 h after swimming, and micronuclei in exfoliated urothelial cells before and 2 weeks after swimming. We also estimated associations and interactions with polymorphisms in genes related to DNA repair or DBP metabolism.[RESULTS]: After swimming, the total concentration of the four trihalomethanes in exhaled breath was seven times higher than before swimming. The change in the frequency of micronucleated lymphocytes after swimming increased in association with exhaled concentrations of the brominated trihalomethanes (p = 0.03 for CHCl2Br, p = 0.05 for CHClBr2, p = 0.01 for CHBr3) but not chloroform. Swimming was not associated with DNA damage detectable by the comet assay. Urine mutagenicity increased significantly after swimming in association with the concentration of exhaled CHBr3 (p = 0.004). No significant associations with changes in micronucleated urothelial cells were observed.[CONCLUSIONS]: Our findings support potential genotoxic effects of exposure to DBPs from swimming pools. The positive health effects gained by swimming could be increased by reducing the potential health risks of pool water.Research supported by Plan Nacional Grant SAF2005-07643-C03-01/02/03, Spain and FIS CP06/00341, Spain. CM Villanueva supported by the ISCIII (CP06/00341), Spain, L Font-Ribera by a predoctoral fellowship (FI06/00651), Spain, and D Liviac by a postgraduate fellowship UAB (PIF409-009), Barcelona.Peer reviewe

What’s in the Pool? A Comprehensive Identification of Disinfection By-products and Assessment of Mutagenicity of Chlorinated and Brominated Swimming Pool Water

38 páginas, 2 figuras, 4 tablas.-- PDF con material suplementario.[BACKGROUND]: Swimming pool disinfectants and disinfection by-products (DBPs) have been linked to human health effects, including asthma and bladder cancer, but no studies have provided a comprehensive identification of DBPs in the water and related that to mutagenicity.[OBJECTIVES]: We performed a comprehensive identification of DBPs and disinfectant species in waters from public swimming pools in Barcelona, Catalonia, Spain, that disinfect with either chlorine or bromine, and we determined the mutagenicity of the waters to compare to the analytical results.[METHODS]: We used gas chromatography (GC)/mass spectrometry (MS) to measure THMs in water and GC with electron capture detection (ECD) for air, low and high resolution GC/MS to comprehensively identify DBPs, photometry to measure disinfectant species (free chlorine, monochloroamine, dichloramine, and trichloramine) in the waters, and an ion chromatography method to measure trichloramine in air. We assessed mutagenicity in the Salmonella mutagenicity assay.[RESULTS]: We identified more than 100 DBPs, including many nitrogen-containing DBPs that were likely formed from nitrogen-containing precursors from human inputs, such as urine, sweat, and skin cells. Many DBPs were new and have not been reported previously in either swimming pool or drinking waters. Bromoform levels were greater in the brominated vs. chlorinated pool waters, but many brominated DBPs were also identified in the chlorinated waters. The pool waters were mutagenic at levels similar to that of drinking water (~1200 revertants/L-eq in strain TA100 –S9 mix).[CONCLUSIONS]: This study identified many new DBPs not identified previously in swimming pool or drinking water and found that swimming pool waters are as mutagenic as typical drinking waters.This research was supported by EPA’s intramural research program and the Spanish grants SAF2005-07643-C03-01 (Plan Nacional) and CP06/00341 (Fondo de Investigación Sanitaria). CMV and LFR have, respectively, a contract and a predoctoral fellowship by the Instituto de Salud Carlos III (CP06/00341, FI06/00651). CL acknowledges a grant from the Agreement between Santander-Central Hispano and CSIC.Peer reviewe

Sustained Oscillations of NF-κB Produce Distinct Genome Scanning and Gene Expression Profiles

NF-κB is a prototypic stress-responsive transcription factor that acts within a complex regulatory network. The signaling dynamics of endogenous NF-κB in single cells remain poorly understood. To examine real time dynamics in living cells, we monitored NF-κB activities at multiple timescales using GFP-p65 knock-in mouse embryonic fibroblasts. Oscillations in NF-κB were sustained in most cells, with several cycles of transient nuclear translocation after TNF-α stimulation. Mathematical modeling suggests that NF-κB oscillations are selected over other non-oscillatory dynamics by fine-tuning the relative strengths of feedback loops like IκBα. The ability of NF-κB to scan and interact with the genome in vivo remained remarkably constant from early to late cycles, as observed by fluorescence recovery after photobleaching (FRAP). Perturbation of long-term NF-κB oscillations interfered with its short-term interaction with chromatin and balanced transcriptional output, as predicted by the mathematical model. We propose that negative feedback loops do not simply terminate signaling, but rather promote oscillations of NF-κB in the nucleus, and these oscillations are functionally advantageous

The Role of Alpha 6 Integrin in Prostate Cancer Migration and Bone Pain in a Novel Xenograft Model

Of the estimated 565,650 people in the U.S. who will die of cancer in 2008, almost all will have metastasis. Breast, prostate, kidney, thyroid and lung cancers metastasize to the bone. Tumor cells reside within the bone using integrin type cell adhesion receptors and elicit incapacitating bone pain and fractures. In particular, metastatic human prostate tumors express and cleave the integrin A6, a receptor for extracellular matrix components of the bone, i.e., laminin 332 and laminin 511. More than 50% of all prostate cancer patients develop severe bone pain during their remaining lifetime. One major goal is to prevent or delay cancer induced bone pain. We used a novel xenograft mouse model to directly determine if bone pain could be prevented by blocking the known cleavage of the A6 integrin adhesion receptor. Human tumor cells expressing either the wildtype or mutated A6 integrin were placed within the living bone matrix and 21 days later, integrin expression was confirmed by RT-PCR, radiographs were collected and behavioral measurements of spontaneous and evoked pain performed. All animals independent of integrin status had indistinguishable tumor burden and developed bone loss 21 days after surgery. A comparison of animals containing the wild type or mutated integrin revealed that tumor cells expressing the mutated integrin resulted in a dramatic decrease in bone loss, unicortical or bicortical fractures and a decrease in the ability of tumor cells to reach the epiphyseal plate of the bone. Further, tumor cells within the bone expressing the integrin mutation prevented cancer induced spontaneous flinching, tactile allodynia, and movement evoked pain. Preventing A6 integrin cleavage on the prostate tumor cell surface decreased the migration of tumor cells within the bone and the onset and degree of bone pain and fractures. These results suggest that strategies for blocking the cleavage of the adhesion receptors on the tumor cell surface can significantly prevent cancer induced bone pain and slow disease progression within the bone. Since integrin cleavage is mediated by Urokinase-type Plasminogen Activator (uPA), further work is warranted to test the efficacy of uPA inhibitors for prevention or delay of cancer induced bone pain

Network deconvolution as a general method to distinguish direct dependencies in networks

Recognizing direct relationships between variables connected in a network is a pervasive problem in biological, social and information sciences as correlation-based networks contain numerous indirect relationships. Here we present a general method for inferring direct effects from an observed correlation matrix containing both direct and indirect effects. We formulate the problem as the inverse of network convolution, and introduce an algorithm that removes the combined effect of all indirect paths of arbitrary length in a closed-form solution by exploiting eigen-decomposition and infinite-series sums. We demonstrate the effectiveness of our approach in several network applications: distinguishing direct targets in gene expression regulatory networks; recognizing directly interacting amino-acid residues for protein structure prediction from sequence alignments; and distinguishing strong collaborations in co-authorship social networks using connectivity information alone. In addition to its theoretical impact as a foundational graph theoretic tool, our results suggest network deconvolution is widely applicable for computing direct dependencies in network science across diverse disciplines.National Institutes of Health (U.S.) (grant R01 HG004037)National Institutes of Health (U.S.) (grant HG005639)Swiss National Science Foundation (Fellowship)National Science Foundation (U.S.) (NSF CAREER Award 0644282

Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2

Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats

Chronic ventricular pacing in children: toward prevention of pacing-induced heart disease

In children with congenital or acquired complete atrioventricular (AV) block, ventricular pacing is indicated to increase heart rate. Ventricular pacing is highly beneficial in these patients, but an important side effect is that it induces abnormal electrical activation patterns. Traditionally, ventricular pacemaker leads are positioned at the right ventricle (RV). The dyssynchronous pattern of ventricular activation due to RV pacing is associated with an acute and chronic impairment of left ventricular (LV) function, structural remodeling of the LV, and increased risk of heart failure. Since the degree of pacing-induced dyssynchrony varies between the different pacing sites, ‘optimal-site pacing’ should aim at the prevention of mechanical dyssynchrony. Especially in children, generally paced from a very early age and having a perspective of life-long pacing, the preservation of cardiac function during chronic ventricular pacing should take high priority. In the perspective of the (patho)physiology of ventricular pacing and the importance of the sequence of activation, this paper provides an overview of the current knowledge regarding possible alternative sites for chronic ventricular pacing. Furthermore, clinical implications and practical concerns of the various pacing sites are discussed. The review concludes with recommendations for optimal-site pacing in children