Preclinical pharmacokinetics of MHAA4549A,a human monoclonal antibody to influenza A virus,and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A

MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ～2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.     

Local and Landscape Factors Driving the Structure of Tropical Anuran Communities: Do Ephemeral Ponds have a Nested Pattern?

The sets of species in animal and plant communities often comprise nested subsets of the species in broader communities. Although most mechanisms causing nested patterns are known and have been demonstrated for different environments and taxa, how amphibian communities are structured in ephemeral ponds in tropical disturbed landscapes remains unknown. We investigated if pond size, duration, presence of trees (local factors), and the proportion of forest cover surrounding ponds (landscape factor) affect anuran species richness and composition, and if pond assemblages showed a nested pattern. We sampled 11 ephemeral ponds in a pasture matrix near a large Atlantic Forest remnant in Brazil and measured local and landscape variables inside two buffer zones around each pond (100 and 500 m). We marked 1514 individuals from 23 anuran species, and found that richness in ponds ranged from 3–14 species. Both local and landscape factors explained frog species richness in the sampled ponds, and seemed to affect community composition. Frog communities occurred in a non‐nested pattern, contrary to our expectations: species found in poor subsets were not found in larger, more complex ponds. Local and landscape characteristics create a variety of environments in ephemeral ponds, even in impoverished ones; these characteristics restrict pond occupancy for some species, and result in a non‐nested pattern.     

Selection on an antagonistic behavioral trait can drive rapid genital coevolution in the burying beetle,Nicrophorus vespilloides

Male and female genital morphology varies widely across many taxa, and even among populations. Disentangling potential sources of selection on genital morphology is problematic because each sex is predicted to respond to adaptations in the other due to reproductive conflicts of interest. To test how variation in this sexual conflict trait relates to variation in genital morphology we used our previously developed artificial selection lines for high and low repeated mating rates. We selected for high and low repeated mating rates using monogamous pairings to eliminate contemporaneous female choice and male–male competition. Male and female genital shape responded rapidly to selection on repeated mating rate. High and low mating rate lines diverged from control lines after only 10 generations of selection. We also detected significant patterns of male and female genital shape coevolution among selection regimes. We argue that because our selection lines differ in sexual conflict, these results support the hypothesis that sexually antagonistic coevolution can drive the rapid divergence of genital morphology. The greatest divergence in morphology corresponded with lines in which the resolution of sexual conflict over mating rate was biased in favor of male interests.     

Low metabolic rates in primitive hunters and weaver spiders

The rates of oxygen consumption and carbon dioxide release of primitive hunters and weaver spiders, the Chilean Recluse spider Loxosceles laeta Nicolet (Araneae: Sicariidae) and the Chilean Tiger spider Scytodes globula Nicolet (Araneae: Scytodidae), are analyzed, and their relationship with body mass is studied. The results are compared with the metabolic data available for other spiders. A low metabolic rate is found both for these two species and other primitive hunters and weavers, such as spiders of the families Dysderidae and Plectreuridae. The metabolic rate of this group is lower than in nonprimitive spiders, such as the orb weavers (Araneae: Araneidae). The results reject the proposition of a general relationship for metabolic rate for all land arthropods (related to body mass) and agree with the hypothesis that metabolic rates are affected not only by sex, reproductive and developmental status, but also by ecology and life style, recognizing here, at least in the araneomorph spiders, a group having low metabolism, comprising the primitive hunters and weaver spiders, and another group comprising the higher metabolic rate web building spiders (e.g. orb weavers).     

Brown pigments produced by Yarrowia lipolytica result from extracellular accumulation of homogentisic acid

Yarrowia lipolytica produces brown extracellular pigments that correlate with tyrosine catabolism. During tyrosine depletion, the yeast accumulated homogentisic acid, p-hydroxyphenylethanol, and p-hydroxyphenylacetic acid in the medium. Homogentisic acid accumulated under all aeration conditions tested, but its concentration decreased as aeration decreased. With moderate aeration, equimolar concentrations of alcohol and p-hydroxyphenylacetic acid (1:1) were detected, but with lower aeration the alcohol concentration was twice that of the acid (2:1). p-Hydroxyphenylethanol and p-hydroxyphenylacetic acid may result from the spontaneous disproportionation of the corresponding aldehyde, p-hydroxyphenylacetaldehyde. The catabolic pathway of tyrosine in Y. lipolytica involves the formation of p-hydroxyphenylacetaldehyde, which is oxidized to p-hydroxyphenylacetic acid and then further oxidized to homogentisic acid. Brown pigments are produced when homogentisic acid accumulates in the medium. This acid can spontaneously oxidize and polymerize, leading to the formation of pyomelanins. Mn(2+) accelerated and intensified the oxidative polymerization of homogentisic acid, and lactic acid enhanced the stimulating role of Mn(2+). Alkaline conditions also accelerated pigment formation. The proposed tyrosine catabolism pathway appears to be unique for yeast, and this is the first report of a yeast producing pigments involving homogentisic acid.     

Growth,plant quality and leaf damage patterns in a dioecious tree species: is gender important?

Frequently, female plants allocate more resources to reproductive structures and defense-related secondary compounds in comparison with male plants that invest more resources to growth, reflecting trade-offs between reproduction, growth and defense. Therefore, differences in herbivory can be expected between genders. In this study, over two years, we analyzed the differences in plant chemical defense, nutritional quality, plant size and herbivory between genders in the dioecious tree, Spondias purpurea in a Mexican tropical dry forest. We estimated the total leaf area and the area consumed by folivory using a digital image of each leaf. The nutritional quality was estimated as water content, and the concentration of chlorophyll and total nonstructural carbohydrates. The secondary metabolites analyzed were total content of soluble phenolics, flavonoids, protein precipitation capacity of tannins, gallotannins, soluble proanthocyanidins, hydrolyzable tannins and ellagitannins. Our results differ from most of studies that analyze the differential herbivory patterns in dioecious plants. We found that female trees had higher levels of herbivory than male trees of S. purpurea. In the same way, female trees showed higher size and nutritional quality than males, while chemical defense was higher in male trees. The higher percentage of folivory in female trees of S. purpurea is associated with greater nutritional quality and lower chemical defenses. Our results show that male-biased herbivory might not be universal in dioecious species. Therefore, studies of fitness components affected by herbivory are necessary to understand the evolution of dioecy and the importance of herbivores as selective agents on breeding system features.     

Effect of the commercial extract of the brown alga Ascophyllum nodosum Mont. on Kappaphycus alvarezii (Doty) Doty ex P.C. Silva in situ submitted to lethal temperatures

Kappaphycus alvarezii is being introduced in several countries and in some of them there is a need to adapt this cultivation to periods with lethal temperatures, such as the 16–18 °C that occurs in the winter in southern Brazil. Moreover, there is the need to maintain the seedlings during this lethal temperature period. Considering the promising results obtained with the commercial powder extract of Ascophyllum nodosum (Acadian marine plant extract powder—AMPEP) treatment in the cultivation of K. alvarezii in vitro and in the sea allowing more resistance to epiphytes and increasing the growth rate and carrageenan yield, it was hypothesized that seedlings previously subjected to an AMPEP treatment could be more resilient to lethal temperatures. The daily growth rate and carrageenan yield and gel quality (gel strength and gel viscosity) of K. alvarezii in vitro previously treated with AMPEP were analyzed under temperature stress. The daily growth rates and the gel strengths of the AMPEP-treated samples were increased. In spite of the lower carrageenan yield and lower gel viscosity, the values were within the ones accepted by the carrageenan industry. Thus, the treatment of the seedlings of the K. alvarezii with AMPEP solution can be used as an alternative to lower temperature effects on crops as a preventive action for the cultivation of the seedlings in tanks and in the sea in periods of low temperatures at sea.     

Protease Activated Receptor-2 Contributes to Heart Failure

Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to induce hypertrophic growth in vitro. PAR-2 also contributes to myocardial infarction and heart remodeling after ischemia/reperfusion injury. In this study, we found that PAR-2 induced hypertrophic growth of cultured rat neonatal cardiomyocytes in a MEK1/2 and p38 dependent manner. In addition, PAR-2 activation on mouse cardiomyocytes increased expression of the pro-fibrotic chemokine MCP-1. Furthermore, cardiomyocyte-specific overexpression of PAR-2 in mice induced heart hypertrophy, cardiac fibrosis, inflammation and heart failure. Finally, in a mouse model of myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, PAR-2 deficiency attenuated heart remodeling and improved heart function independently of its contribution to the size of the initial infarct. Taken together, our data indicate that PAR-2 signaling contributes to the pathogenesis of hypertrophy and heart failure.     

Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.