Mapping of citrullinated fibrinogen B-cell epitopes in rheumatoid arthritis by imaging surface plasmon resonance

Introduction  

Rheumatoid arthritis (RA) frequently involves the loss of tolerance to citrullinated antigens, which may play a role in pathogenicity. Citrullinated fibrinogen is commonly found in inflamed synovial tissue and is a frequent target of autoantibodies in RA patients. To obtain insight into the B-cell response to citrullinated fibrinogen in RA, its autoepitopes were systematically mapped using a new methodology.     

Characterization and In Vivo Pharmacological Rescue of a Wnt2-Gata6 Pathway Required for Cardiac Inflow Tract Development

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Highlights? Wnt2 is required for atrial and inflow tract morphogenesis ? Wnt2 regulates expansion of secondary heart field progenitors ? Defects in Wnt2^?/? mutants can be rescued using Wnt signaling agonists ? Wnt2 cooperates with Gata6 to regulate cardiac inflow tract development     

MAXIMUM SWIM SPEEDS OF CAPTIVE AND FREE-RANGING DELPHINIDS: CRITICAL ANALYSIS OF EXTRAORDINARY PERFORMANCE

Research into dolphin swimming historically was guided by false assumptions pertaining to maximum speed. Accurate measurements on swimming speed and duration of effort of free-ranging dolphins are rare. To examine the variance of maximum swimming speeds, nearly 2,000 speed measurements were obtained for both captive and free-ranging dolphins, including Tursiops truncatus, Pseudorca crassidens, Delphinus capensis , and Delphinus delpbis . Measurements were made from videotapes of dolphins trained to swim fast around a large pool or jumping to a maximum height, videotapes of captured wild dolphins immediately after release, and sequential aerial photographs of a school of free-ranging dolphins startled by a passing airplane. Maximum horizontal speeds for trained animals were 8.2 m/sec for T. truncatus , 8.0 m/sec for D. delphis , and 8.0 m/sec for P. crassidens . Maximum speeds for T. truncatus swimming upwards, prior to vertical leaps ranged from 8.2 to 11.2 m/sec. Wild T. truncatus demonstrated a maximum speed of 5.7 m/sec. Maximum swimming speed of free-ranging D. capensis responding to multiple passes by a low flying airplane was 6.7 m/sec. There was no evidence that the freeranging dolphins have superior swimming capabilities to captive animals. The results of this study imply that realistic maximum swimming speeds for dolphins are lower than previous reports which were based on sparse data and imprecise measurement techniques.     

Kinetics of the interactions between yeast elongation factors 1A and 1Balpha, guanine nucleotides, and aminoacyl-tRNA

The interactions of elongation factor 1A (eEF1A) from Saccharomyces cerevisiae with elongation factor 1Balpha (eEF1Balpha), guanine nucleotides, and aminoacyl-tRNA were studied kinetically by fluorescence stopped-flow. eEF1A has similar affinities for GDP and GTP, 0.4 and 1.1 microm, respectively. Dissociation of nucleotides from eEF1A in the absence of the guanine nucleotide exchange factor is slow (about 0.1 s(-1)) and is accelerated by eEF1Balpha by 320-fold and 250-fold for GDP and GTP, respectively. The rate constant of eEF1Balpha binding to eEF1A (10(7)-10(8) M (-1) s(-1)) is independent of guanine nucleotides. At the concentrations of nucleotides and factors prevailing in the cell, the overall exchange rate is expected to be in the range of 6 s(-1), which is compatible with the rate of protein synthesis in the cell. eEF1A.GTP binds Phe-tRNA(Phe) with a K(d) of 3 nm, whereas eEF1A.GDP shows no significant binding, indicating that eEF1A has similar tRNA binding properties as its prokaryotic homolog, EF-Tu.     

Population Dynamics and Behavior of Bighorn Sheep with Infectious Keratoconjunctivitis

ABSTRACT Introduced disease is a major mortality factor in some populations of bighorn sheep (Ovis canadensis). Epizootics of infectious keratoconjunctivitis (IKC) and contagious ecthyma occurred in bighorn sheep in the Silver Bell Mountains of south-central Arizona, USA, from 1 December 2003 to 31 March 2004. Our objectives were to 1) investigate the influence of the epizootic on abundance and demographics and 2) examine how IKC affected the mortality, behavior, and movements of clinically affected animals. Morbidity was 39%, and all sex and age classes were affected. The population declined 23%, with most mortality in the adult female (1 M, 11 F) segment of the population. Of the diseased animals that were marked (n = 27), 44% recovered and 44% died. Predation (50%) and starvation (33%) were the primary causes of mortality of diseased bighorn sheep. Bighorn sheep that were infected spent less time feeding and moved less than noninfected animals during the epizootic. Managers might be able to minimize losses of infected animals through predator control. To minimize losses to starvation, managers should refrain from any activity that disturbs infected animals (including treatment) because disturbances increase energy expenditures and expose infected animals to injury.     

Survival of Wood Duck Ducklings and Broods in Mississippi and Alabama

ABSTRACT Although North American wood ducks (Aix sponsa) are well-studied throughout their range, researchers know little about demographic and environmental factors influencing survival of ducklings and broods, which is necessary information for population management. We studied radiomarked female and duckling wood ducks that used nest boxes and palustrine wetlands at Noxubee National Wildlife Refuge (NNWR) in Mississippi, USA, in 1996–1999, and riverine wetlands of the Tennessee-Tombigbee Rivers and Waterway (TTRW) system in Alabama in 1998–1999. We estimated survival of ducklings and broods and evaluated potentially important predictors of duckling survival, including age and body mass of brood-rearing females, hatch date of ducklings, duckling mass, brood size at nest departure, inter-day travel distance by ducklings, site and habitat use, and daily minimum air temperature and precipitation. At NNWR, survival of 300 radiomarked ducklings ranged from 0.15 (95% CI = 0.04-0.27) to 0.24 (95% CI = 0.13-0.38) and was 0.21 (95% CI = 0.15-0.28) for 1996–1999. Our overall estimate of brood survival was 0.64 (n = 91; 95% CI = 0.54-0.73). At TTRW, survival of 129 radiomarked ducklings was 0.29 in 1998 (95% CI = 0.20-0.41) and 1999 (95% CI = 0.13-0.45) and was 0.29 (95% CI = 0.20-0.40) for 1998–1999. Our overall estimate of brood survival was 0.71 (n = 38; 95% CI = 0.56-0.85). At NNWR, models that included all predictor variables best explained variation in duckling survival. Akaike weight (w_i) for the best model was 0.81, suggesting it was superior to other models (<0.01 < w_i < 0.18). We detected 4 competing models for duckling survival at TTRW. Inter-day distance traveled by ducklings was important as this variable appeared in all 4 models; duckling survival was positively related to this variable. Patterns of habitat-related survival were similar at both study areas. Ducklings in broods that used scrub-shrub habitats disjunct from wetlands containing aggregations of nest boxes had greater survival probabilities than birds remaining in wetlands with such nest structures. Managers may increase local wood duck recruitment by promoting availability of suitable brood habitats (e.g., scrub-shrub wetlands) without aggregations of nest boxes that may attract predators and by dispersing nest boxes amid or adjacent to these habitats. We did not determine an optimal density of nest boxes relative to local or regional population goals, which remains important research and conservation needs.     

Past and present distribution, densities and movements of blue whales Balaenoptera musculus in the Southern Hemisphere and northern Indian Ocean

• 1 Blue whale locations in the Southern Hemisphere and northern Indian Ocean were obtained from catches (303 239), sightings (4383 records of ≥8058 whales), strandings (103), Discovery marks (2191) and recoveries (95), and acoustic recordings.
• 2 Sighting surveys included 7 480 450 km of effort plus 14 676 days with unmeasured effort. Groups usually consisted of solitary whales (65.2%) or pairs (24.6%); larger feeding aggregations of unassociated individuals were only rarely observed. Sighting rates (groups per 1000 km from many platform types) varied by four orders of magnitude and were lowest in the waters of Brazil, South Africa, the eastern tropical Pacific, Antarctica and South Georgia; higher in the Subantarctic and Peru; and highest around Indonesia, Sri Lanka, Chile, southern Australia and south of Madagascar.
• 3 Blue whales avoid the oligotrophic central gyres of the Indian, Pacific and Atlantic Oceans, but are more common where phytoplankton densities are high, and where there are dynamic oceanographic processes like upwelling and frontal meandering.
• 4 Compared with historical catches, the Antarctic (‘true’) subspecies is exceedingly rare and usually concentrated closer to the summer pack ice. In summer they are found throughout the Antarctic; in winter they migrate to southern Africa (although recent sightings there are rare) and to other northerly locations (based on acoustics), although some overwinter in the Antarctic.
• 5 Pygmy blue whales are found around the Indian Ocean and from southern Australia to New Zealand. At least four groupings are evident: northern Indian Ocean, from Madagascar to the Subantarctic, Indonesia to western and southern Australia, and from New Zealand northwards to the equator. Sighting rates are typically much higher than for Antarctic blue whales.
• 6 South‐east Pacific blue whales have a discrete distribution and high sighting rates compared with the Antarctic. Further work is needed to clarify their subspecific status given their distinctive genetics, acoustics and length frequencies.
• 7 Antarctic blue whales numbered 1700 (95% Bayesian interval 860–2900) in 1996 (less than 1% of original levels), but are increasing at 7.3% per annum (95% Bayesian interval 1.4–11.6%). The status of other populations in the Southern Hemisphere and northern Indian Ocean is unknown because few abundance estimates are available, but higher recent sighting rates suggest that they are less depleted than Antarctic blue whales.

     

The discovery of highly selective erbB2 (Her2) inhibitors for the treatment of cancer

The synthesis and biological evaluation of potent and selective inhibitors of the erbB2 kinase is presented. Based on the 4-anilinoquinazoline chemotype, the syntheses of several new series of erbB2 inhibitors are described with quinazoline and pyrido[4,3-d]pyrimidine cores. The vast majority of these compounds are found to be >100x selective over the closely related EGFR kinase. Two lead compounds are further shown to have low clearance and moderate bioavailability in rat.     

Roles of the negatively charged N-terminal extension of Saccharomyces cerevisiae ribosomal protein S5 revealed by characterization of a yeast strain containing human ribosomal protein S5

Ribosomal protein (rp) S5 belongs to a family of ribosomal proteins that includes bacterial rpS7. rpS5 forms part of the exit (E) site on the 40S ribosomal subunit and is essential for yeast viability. Human rpS5 is 67% identical and 79% similar to Saccharomyces cerevisiae rpS5 but lacks a negatively charged (pI approximately 3.27) 21 amino acid long N-terminal extension that is present in fungi. Here we report that replacement of yeast rpS5 with its human homolog yielded a viable yeast strain with a 20%-25% decrease in growth rate. This replacement also resulted in a moderate increase in the heavy polyribosomal components in the mutant strain, suggesting either translation elongation or termination defects, and in a reduction in the polyribosomal association of the elongation factors eEF3 and eEF1A. In addition, the mutant strain was characterized by moderate increases in +1 and -1 programmed frameshifting and hyperaccurate recognition of the UAA stop codon. The activities of the cricket paralysis virus (CrPV) IRES and two mammalian cellular IRESs (CAT-1 and SNAT-2) were also increased in the mutant strain. Consistently, the rpS5 replacement led to enhanced direct interaction between the CrPV IRES and the mutant yeast ribosomes. Taken together, these data indicate that rpS5 plays an important role in maintaining the accuracy of translation in eukaryotes and suggest that the negatively charged N-terminal extension of yeast rpS5 might affect the ribosomal recruitment of specific mRNAs.