Genotype-Based Ancestral Background Consistently Predicts Efficacy and Side Effects across Treatments in CATIE and STAR*D

Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient’s unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (n = 765) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (n = 1892). Next, we performed multiple regression analyses to estimate the predictive power of these ancestral dimensions. For 136/89 treatment-outcome combinations tested in CATIE/STAR*D, results indicated 1.67/1.84 times higher median test statistics than expected under the null hypothesis assuming no predictive power (p<0.01, both samples). Thus, ancestry showed robust and pervasive correlations with drug efficacy and side effects in both CATIE and STAR*D. Comparison of the marginal predictive power of MDS ancestral dimensions and self-reported race indicated significant improvements to model fit with the inclusion of MDS dimensions, but mixed evidence for self-reported race. Knowledge of each patient’s unique mosaic of ancestral backgrounds provides a potent immediate starting point for developing algorithms identifying the most effective and safe medication for a wide variety of drug-treatment response combinations. As relatively few new psychiatric drugs are currently under development, such personalized medicine offers a promising approach toward optimizing pharmacotherapy for psychiatric conditions.     

How much do we know about hemolytic capability of pathogenic <Emphasis Type="Italic">Candida</Emphasis> species?

Hemolytic factor production by pathogenic Candida species is considered an important attribute in promoting survival within the mammal host through the ability to assimilate iron from the hemoglobin-heme group. Hemolytic capability has been evaluated for Candida species based on hemolysis zones on plate assay, analysis of hemolytic activity in liquid culture medium, and hemolysis from cell-free culture broth. The production of hemolytic factor is variable among Candida species, where C. parapsilosis is the less hemolytic species. In general, no intraspecies differences in beta-hemolytic activities are found among isolates belonging to C. albicans, C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis. The production of hemolytic factor by Candida species is affected by several factors such as glucose supplementation in the culture medium, blood source, presence of erythrocytes and hemoglobin, and presence of electrolytes. On the basis of existing achievements, more researches are still needed in order to extend our knowledge about the biochemical nature of hemolytic molecules produced by distinct Candida species, the mechanism of hemolysis, and the molecular basis of the hemolytic factor expression.     

Cooperative foraging in neotropical pseudoscorpions: effects of prey changes on behavioral adjustments of colonies

The pseudoscorpion Paratemnoides nidificator is a generalist predator that captures large arthropods that live on tree trunks. Few pseudoscorpions species show some degree of sociality. We investigated how colonies of the pseudoscorpion P. nidificator adjust their cooperative capture behavior under a situation of changing prey types as a simulation of variation in prey availability. We hypothesized that colonies would be more efficient at prey capture under repeated exposure to the same prey, and that the change in the availability of prey would be followed by new behavioral adjustments to adequately exploit the new prey. Eight experimental colonies housed in the laboratory received repetitions of three different ant species as prey. The number of pseudoscorpions attacking the prey, the number of behavioral acts, and the time expended subduing prey were evaluated as measures of prey capture performance, in relation to repetitive exposure to the same prey and also in relation to prey type changes. However, only individuals’ recruitment significantly responded to prey type exposure. Prey capture behavior was heterogeneous among colonies, resulting in highly variable behavioral responses. Colonies showed a tendency toward increasing capture success through repeated prey type exposure. However, 50% of the colonies were unable to capture the new prey type and died of starvation. Although it is a generalist predator, prey capture behavior could depend on different coordination components for subduing and handling large prey. Therefore, changes in prey availability could cause the attenuation of a cooperative relationship in some colonies, making them more prone to failure during capture.     

Establishment and evaluation of detection methods for process-specific residual host cell protein and residual host cell DNA in biological preparation

To establish accurate detection methods of process-specific Escherichia coli residual host cell protein (HCP) and residual host cell DNA (rcDNA) in recombinant biological preparations. Taking the purification process of GLP expressed by E. coli as a specific-process model, the HCP of empty E. coli was intercepted to immunize mice and rabbits. Using IgG from immunized rabbits as the coating antibody and mouse immune serum as the second sandwich antibody, a process-specific enzyme-linked immunosorbent assay (ELISA) for E. coli HCP was established. Targeting the 16S gene of E. coli, ddPCR was used to obtain the absolute copies of rcDNA in samples. Non-process-specific commercial ELISA kit and the process-specific ELISA established in this study were used to detect the HCP in GLP preparation. About 62% of HCPs, which should be process-specific HCPs, could not be detected by the non-process-specific commercial ELISA kit. The sensitivity of established ELISA can reach 338 pg/mL. The rcDNA could be absolutely quantitated by ddPCR, for the copies of rcDNA in three multiple diluted samples showed a reduced gradient. While the copies of rcDNA in three multiple diluted samples could not be distinguished by the qPCR. Process-specific ELISA has high sensitivity in detecting process-specific E. coli HCP. The absolutely quantitative ddPCR has much higher accuracy than the relatively quantitative qPCR, it is a nucleic acid quantitative method that is expected to replace qPCR in the future.     

Is evolution faster at ecotones? A test using rates and tempo of diet transitions in Neotropical Sigmodontinae (Rodentia,Cricetidae)

We evaluated whether evolution is faster at ecotones as niche shifts may be needed to persist under unstable environment. We mapped diet evolution along the evolutionary history of 350 sigmodontine species. Mapping was used in three new tip‐based metrics of trait evolution – Transition Rates, Stasis Time, and Last Transition Time – which were spatialized at the assemblage level (aTR, aST, aTL). Assemblages were obtained by superimposing range maps on points located at core and ecotone of the 93 South American ecoregions. Using Linear Mixed Models, we tested whether ecotones have species with more changes from the ancestral diet (higher aTR), have maintained the current diet for a shorter time (lower aST), and have more recent transitions to the current diet (lower aLT) than cores. We found lower aTR, and higher aST and aLT at ecotones than at cores. Although ecotones are more heterogeneous, both environmentally and in relation to selection pressures they exert on organisms, ecotone species change little from the ancestral diet as generalist habits are necessary toward feeding in ephemeral environments. The need to incorporate phylogenetic uncertainty in tip‐based metrics was evident from large uncertainty detected. Our study integrates ecology and evolution by analyzing how fast trait evolution is across space.     

Anthropometric Indices and the Incidence of Hypertension: A Comparative Analysis

Objective: To investigate the association between several anthropometric measurements of obesity with the incidence of hypertension. Research Methods and Procedures: Participants were 592 individuals free of hypertension, selected at random from the community. In the baseline evaluation, they were submitted to completed measures of demographics, anthropometrics, blood pressure, and other risk factors for hypertension. Incident hypertension was defined by blood pressure equal or higher than 140/90 mm Hg or use of blood pressure‐lowering drugs. Results: During a mean follow‐up time of 5.6 ± 1.1 years, 127 developed hypertension. The hazard ratios for the development of hypertension, adjusted for age, baseline blood pressure, gender, and alcohol consumption, were 1.042 (p = 0.091) for BMI, 1.023 (p = 0.028) for waist circumference, 1.042 (p = 0.013) for waist‐to‐height ratio, 1.061 (p = 0.014) for waist‐to‐height² index, 1.079 (p = 0.022) for waist‐to‐height³ index, and 1.033 (p = 0.006) for the waist‐to‐hip ratio. Discussion: The correction of the circumference of waist for stature or hip circumference improves its performance in the prediction of the incidence of hypertension.     

Specific phosphopeptide enrichment with immobilized titanium ion affinity chromatography adsorbent for phosphoproteome analysis

The elucidation of protein post-translational modifications, such as phosphorylation, remains a challenging analytical task for proteomic studies. Since many of the proteins targeted for phosphorylation are low in abundance and phosphorylation is typically substoichiometric, a prerequisite for their identification is the specific enrichment of phosphopeptide prior to mass spectrometric analysis. Here, we presented a new method termed as immobilized titanium ion affinity chromatography (Ti (4+)-IMAC) for enriching phosphopeptides. A phosphate polymer, which was prepared by direct polymerization of monomers containing phosphate groups, was applied to immobilize Ti (4+) through the chelating interaction between phosphate groups on the polymer and Ti (4+). The resulting Ti (4+)-IMAC resin specifically isolates phosphopeptides from a digest mixture of standard phosphoproteins and nonphosphoprotein (BSA) in a ratio as low as 1:500. Ti (4+)-IMAC was further applied for phosphoproteome analysis of mouse liver. We also compared Ti (4+)-IMAC to other enrichment methods including Fe (3+)-IMAC, Zr (4+)-IMAC, TiO 2 and ZrO 2, and demonstrate superior selectivity and efficiency of Ti (4+)-IMAC for the isolation and enrichment of phosphopeptides. The high specificity and efficiency of phosphopeptide enrichment by Ti (4+)-IMAC mainly resulted from the flexibility of immobilized titanium ion with spacer arm linked to polymer beads as well as the specific interaction between immobilized titanium ion and phosphate group on phosphopeptides.     

Matrix metalloproteinase 2 activity decreases in human periodontal ligament fibroblast cultures submitted to simulated orthodontic force

Orthodontic force compresses the periodontal ligament promoting the expression of pro-inflammatory mediators and matrix metalloproteinases responsible for tooth movement. The extent in time while periodontal cells are being treated and the increment in the amount of mechanical stress caused by the orthodontic force is thought to regulate the levels of metalloproteinases in the periodontal tissue. To study the possible regulation in the activity of metalloproteinases 2, 3, 7, 9, and 10 by simulated orthodontic force, human periodontal ligament fibroblast cultures were centrifuged (141×g) for 30, 60, 90, and 120 min, simulating the orthodontic force. Cell viability, protein quantification, and activity of metalloproteinases by zymography were evaluated at 24, 48, and 72 h after centrifugation in both cell lysates and growth medium. The activity of the 72-kDa matrix metalloproteinase 2 was decreased at 24 h regardless of the duration of centrifugation and at 48 h in cells centrifuged for 30 min only. Decrease in the amount of total protein in lysates was seen at 48 and 72 h with no change in cell viability. The data seem to indicate that the amount of mechanical stress regulates the levels of secreted matrix metalloproteinase 2. In addition, the centrifugation as a model for simulated orthodontic force may be used as a simple and reliable method to study the role played by matrix metalloproteinases in periodontal ligament when submitted to mechanical force as occurring during tooth movement.