Analysis of forelimb function in basal ceratopsians

Here, I present the first study of forelimb function in basal ceratopsians [Correction added after publication 28 July 2007: in the preceding sentence 'Here, I present the first study of forelimb function in basal ceratopsians Dinosauria Orthischia ' was corrected to 'Here, I present the first study of forelimb function in basal ceratopsians']. I examined forelimb bones and casts of Psittacosaurus neimongoliensis , Psittacosaurus mongoliensis , Leptoceratops gracilis and Protoceratops andrewsi . For Ps. neimongoliensis and L. gracilis , I used manual manipulations of bones and casts to determine the range of motion at available forelimb joints. I then used range of motion and morphology to test the predictions of several hypotheses of forelimb function. Forelimb morphology and range of motion indicate that Psittacosaurus was an obligate biped and that Leptoceratops and Protoceratops were capable of quadrupedal locomotion. Forelimb mobility was too limited in Psittacosaurus for the hands to reach the mouth. Leptoceratops and Protoceratops are members of an evolutionary radiation in which an extension of the glenoid enabled the forelimbs to sprawl laterally for transverse pivoting, perhaps for display, but quadrupedal locomotion was accomplished with the elbows tucked in. In Protoceratops , the radius crosses over the ulna, causing the palms to face caudally. In Leptoceratops , the radius does not cross over the ulna; the palms face largely medially and the fingers have been reoriented so that flexion produces a caudal, propulsive force, even without caudally facing palms.     

World Antibody Drug Conjugate Summit Europe: February 21–23, 2011; Frankfurt,Germany

The World Antibody Drug Conjugate Summit Europe, organized by Biorbis/Hanson Wade was held in Frankfurt, Germany February 21–23, 2011. Antibody drug conjugates (ADCs), also called immunoconjugates, are becoming an increasingly important class of therapeutics as demonstrated by the attendance of nearly 100 delegates at this highly focused meeting. Updates on three ADCs that are in late-stage clinical development, trastuzumab emtansine (T-DM1), brentuximab vedotin (SGN-35) and inotuzumab ozogamicin (CMC-544), were presented by speakers from ImmunoGen, Genentech, Roche, Seattle Genetics and Pfizer. These ADCs have shown encouraging therapeutic effects against solid tumors (T-DM1) and hematological malignancies (SGN-35, CMC-544). The key feature of the new generation of ADCs is the effective combination of the cytotoxicity of natural or synthetic highly potent antineoplastic agents, tumor selective monoclonal antibodies and blood-stable optimized linkers. Early clinical data for ADCs were showcased by Progenics Pharmaceuticals (PSMA ADC), Celldex (CDX-011) and Biotest (BT-062). Takeda, MedImmune and sanofi-aventis outlined their strategies for process development and analytical characterization. In addition, presentations on duocarmycin based-ADCs, α emitting immunoconjugates and antibody-conjugated nanoparticles were given by representatives from Syntarga, Algeta and the University of Stuttgart, respectively.Key words: antibody drug conjugates, immunoconjugates, trastuzumab emtansine, brentuximab vedotin, inotuzumab ozogamicin, oncology, cancer     

Early Life Stress Interacts with the Diet Deficiency of Omega-3 Fatty Acids during the Life Course Increasing the Metabolic Vulnerability in Adult Rats

Early stress can cause metabolic disorders in adulthood. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) deficiency has also been linked to the development of metabolic disorders. The aim of this study was to assess whether an early stressful event such as maternal separation interacts with the nutritional availability of n-3 PUFAs during the life course on metabolic aspects. Litters were randomized into: maternal separated (MS) and non-handled (NH). The MS group was removed from their dam for 3 hours per day and put in an incubator at 32°C on days 1° to 10° postnatal (PND). On PND 35, males were subdivided into diets that were adequate or deficient in n-3 PUFAs, and this intervention was applied during the subsequent 15 weeks. Animal''s body weight and food consumption were measured weekly, and at the end of the treatment tissues were collected. MS was associated with increased food intake (p = 0.047) and weight gain (p = 0.012), but no differences were found in the NPY hypothalamic content between the groups. MS rats had also increased deposition of abdominal fat (p<0.001) and plasma triglycerides (p = 0.018) when compared to the NH group. Interactions between early life stress and n-3 PUFAs deficiency were found in plasma insulin (p = 0.033), HOMA index (p = 0.049), leptin (p = 0.010) and liver PEPCK expression (p = 0.050), in which the metabolic vulnerability in the MS group was aggravated by the n-3 PUFAs deficient diet exposure. This was associated with specific alterations in the peripheral fatty acid profile. Variations in the neonatal environment interact with nutritional aspects during the life course, such as n-3 PUFAs diet content, and persistently alter the metabolic vulnerability in adulthood.     

The stereochemical course of the reaction catalyzed by soluble bovine lung guanylate cyclase

The stereochemical course of the reaction catalyzed by the soluble form of bovine lung guanylate cyclase has been investigated using [alpha-18O]guanosine 5'-triphosphate (Rp diastereomer) and guanosine 5'-O-(1-thiotriphosphate) (Sp diastereomer) as substrates. The product from the 3-thiomorpholino-1',1'-dioxide sydnonimine-stimulated enzymatic cyclization of [alpha-18O] guanosine 5'-triphosphate was esterified with diazomethane. 31P NMR analysis of the triesters indicated that all of the 18O label was present in the axial position. Guanosine 5'-O-(1-thiotriphosphate) (Sp diastereomer) was cyclized under stimulated and basal enzyme activities and, in both cases, the Rp diastereomer of guanosine 3',5'-cyclic phosphorothioate was formed. This was determined by direct comparison with material synthesized chemically from guanosine 5'-phosphorothioate. The results from these experiments show that the reaction catalyzed by guanylate cyclase proceeds with inversion of configuration at phosphorus and this indicates that the reaction proceeds by way of a single direct displacement reaction.     

A new troodontid theropod dinosaur from the lower Cretaceous of Utah

Background

The theropod dinosaur family Troodontidae is known from the Upper Jurassic, Lower Cretaceous, and Upper Cretaceous of Asia and from the Upper Jurassic and Upper Cretaceous of North America. Before now no undisputed troodontids from North America have been reported from the Early Cretaceous.

Methodology/Principal Findings

Herein we describe a theropod maxilla from the Lower Cretaceous Cedar Mountain Formation of Utah and perform a phylogenetic analysis to determine its phylogenetic position. The specimen is distinctive enough to assign to a new genus and species, Geminiraptor suarezarum. Phylogenetic analysis places G. suarezarum within Troodontidae in an unresolved polytomy with Mei, Byronosaurus, Sinornithoides, Sinusonasus, and Troodon + (Saurornithoides + Zanabazar). Geminiraptor suarezarum uniquely exhibits extreme pneumatic inflation of the maxilla internal to the antorbital fossa such that the anterior maxilla has a triangular cross-section. Unlike troodontids more closely related to Troodon, G. suarezarum exhibits bony septa between the dental alveoli and a promaxillary foramen that is visible in lateral view.

Conclusions/Significance

This is the first report of a North American troodontid from the Lower Cretaceous. It therefore contributes to a fuller understanding of troodontid biogeography through time. It also adds to the known dinosaurian fauna of the Cedar Mountain Formation.     

Plasma Membrane and Chromaffin Granule Characteristics in Digitonin-Treated Chromaffin Cells

Digitonin permeabilizes the plasma membranes of bovine chromaffin cells to Ca2+, ATP, and proteins and allows micromolar Ca2+ in the medium to stimulate directly catecholamine secretion. In the present study the effects of digitonin (20 microM) on the plasma membrane and on intracellular chromaffin granules were further characterized. Cells with surface membrane labeled with [3H]galactosyl moieties retained label during incubation with digitonin. The inability of digitonin-treated cells to shrink in hyperosmotic solutions of various compositions indicated that tetrasaccharides and smaller molecules freely entered the cells. ATP stimulated [3H]norepinephrine uptake into digitonin-treated chromaffin cells fivefold. The stimulated [3H]norepinephrine uptake was inhibited by 1 microM reserpine, 30 microM NH4+, or 1 microM carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). The data indicate that [3H]norepinephrine was taken up into the intracellular storage granules by the ATP-induced H+ electrochemical gradient across the granule membrane. Reduction of the medium osmolality from 310 mOs to 100 mOs was required to release approximately 50% of the catecholamine from chromaffin granules with digitonin-treated chromaffin cells which indicates a similar osmotic stability to that in intact cells. Chromaffin granules in vitro lost catecholamine when the digitonin concentration was 3 microM or greater. Catecholamine released into the medium by micromolar Ca2+ from digitonin-treated chromaffin cells that had subsequently been washed free of digitonin could not be pelleted in the centrifuge and was not accompanied by release of membrane-bound dopamine-beta-hydroxylase. The studies demonstrate that 20 microM of digitonin caused profound changes in the chromaffin cell plasma membrane permeability but had little effect on intracellular chromaffin granule stability and function. It is likely that the intracellular chromaffin granules were not directly exposed to significant concentrations of digitonin. Furthermore, the data indicate that during catecholamine release induced by micromolar Ca2+, the granule membrane was retained by the cells and that catecholamine release did not result from release of intact granules into the extracellular medium.     

MgATP-independent and MgATP-dependent exocytosis. Evidence that MgATP primes adrenal chromaffin cells to undergo exocytosis

The MgATP dependency of secretion was investigated in digitonin-permeabilized adrenal chromaffin cells. Shortly after permeabilization there is a component of Ca2+-dependent secretion that occurs in the absence of MgATP in the medium. This secretion occurs from cells which are permeable to Ca2+/[ethylene-bis(oxyethylenenitrilo)]tetraacetic acid buffers, to nucleotides, and to proteins. It is prevented by treatment of cells with metabolic inhibitors to reduce cellular ATP prior to permeabilization. The rate of MgATP-independent secretion is rapid and terminates by approximately 2 min after introduction of Ca2+. MgATP-independent secretion is labile and is lost unless Ca2+ is introduced within 8 min of permeabilization. MgATP-dependent secretion occurs at a slower rate than MgATP-independent secretion and continues at a constant rate for 12 min. Preincubation of permeabilized cells with MgATP enhances Ca2+-dependent secretion during a subsequent incubation in the absence of MgATP. Similar MgATP sensitivities are observed when MgATP is present only prior to or only during stimulation with Ca2+ with half-maximal stimulation occurring at 0.4-0.5 and 0.6 mM MgATP, respectively. The data indicate that intact cells are primed by intracellular ATP so that immediately upon permeabilization, there is a component of secretion which is independent of medium MgATP. MgATP partially maintains the primed state after permeabilization by acting before Ca2+ in the secretory pathway.     

Vestigial skeletal structures in dinosaurs

The existence of vestigial structures is one of the main lines of evidence for macroevolution. Here I introduce a phylogenetic bracketing approach to the identification of vestigial structures and apply it to Dinosauria. According to this approach, a structure is considered vestigial if, in comparison with its homolog in at least three successive outgroups, it is reduced to one-third or less its size relative to adjacent structures and if at least distally it has lost the specialized morphology present in the three outgroups. This approach identifies fingers IV and V as vestigial in dinosaurs in general, II–V in sauropods, III in Tyrannosauridae and Caudipteryx , II and III in Shuvuuia and I and III in modern birds. The entire forelimb distal to the elbow is vestigial in Abelisauridae. Vestigial parts of the pelvic girdle and hindlimb include the pubic shaft in Iguanodontia and Ceratopsia, the entire pubis in Ankylosauria, the first metatarsal in derived Iguanodontia, the first metatarsal shaft in Theropoda and the fifth toe in dinosaurs in general. Derived Centrosaurinae and some Chasmosaurus exhibit vestigial supraorbital horns. Some centrosaurines have a vestigial nasal horn. The antorbital cavity is vestigial in Thyreophora, Iguanodontia and Ceratopsidae. I recommend that this information be exploited to increase public awareness of the evidence for macroevolution.