Marker-assisted selection using ridge regression

In cross between inbred lines, linear regression can be used to estimate the correlation of markers with a trait of interest; these marker effects then allow marker assisted selection (MAS) for quantitative traits. Usually a subset of markers to include in the model must be selected: no completely satisfactory method of doing this exists. We show that replacing this selection of markers by ridge regression can improve the mean response to selection and reduce the variability of selection response.     

Inter- and intra- species differences in plants as hosts to shape Tyria jacobaeae

The effects of sublethal doses of deltamethrin and propoxur, applied topically at LD10, LD30 and LD50 on German cockroaches, were studied by reciprocal crossing. Male and female longevities decreased curvilinearly with increasing sublethal doses of deltamethrin, and decreased linearly with increasing sublethal doses of propoxur. Fecundity of females treated with deltamethrin and propoxur was reduced with increasing sublethal doses of both insecticides. Oothecal production, oothecal hatchability and nymphal production also declined with increasing doses of deltamethrin and propoxur. Preoviposition and incubation periods were not affected by sublethal doses of deltamethrin and propoxur, although some significant differences were observed at certain oothecal numbers. Two-way analysis of variance indicated that only treated females showed an effect on oothecal production while oothecal hatch and nymphal production were governed by both treated females and males. Insecticide susceptibility tests on the progeny of parents treated with sublethal doses demonstrated that these doses did not increase insecticidal tolerance in the F1 generation.     

NMR detection of slow conformational dynamics in an endonuclease toxin

The cytotoxic activity of the secreted bacterial toxin colicin E9 is due to a non-specific DNase housed in the C-terminus of the protein. Double-resonance and triple-resonance NMR studies of the 134-amino acid¹⁵ N- and ¹³C/¹⁵N-labelled DNase domain are presented. Extensive conformational heterogeneity was evident from the presence of far more resonances than expected based on the amino acid sequence of the DNase, and from the appearance of chemical exchange cross-peaks in TOCSY and NOESY spectra. EXSY spectra were recorded to confirm that slow chemical exchange was occurring. Unambiguous sequence-specific resonance assignments are presented for one region of the protein, Pro⁶⁵-Asn⁷², which exists in two slowly exchanging conformers based on the identification of chemical exchange cross-peaks in 3D ¹H-¹H-¹⁵N EXSY-HSQC, NOESY-HSQC and TOCSY-HSQC spectra, together with C and C chemical shifts measured in triple-resonance spectra and sequential NH NOEs. The rates of conformational exchange for backbone amide resonances in this stretch of amino acids, and for the indole NH of either Trp²² or Trp⁵⁸, were determined from the intensity variation of the appropriate diagonal and chemical exchange cross-peaks recorded in 3D¹ H-¹H-¹⁵N NOESY-HSQC spectra. The data fitted a model in which this region of the DNase has two conformers, N_A and N_B, which interchange at 15 °C with a forward rate constant of 1.61 ± 0.5 s^-1 and a backward rate constant of 1.05 ± 0.5 s^-1. Demonstration of this conformational equilibrium has led to a reappraisal of a previously proposed kinetic scheme describing the interaction of E9 DNase with immunity proteins [Wallis et al. (1995) Biochemistry, 34, 13743–13750 and 13751–13759]. The revised scheme is consistent with the specific inhibitor protein for the E9 DNase, Im9, associating with both the N_A and N_B conformers of the DNase and with binding only to the N_B conformer detected because the rate of dissociation of the complex of Im9 and the N_A conformer, N_AI, is extremely rapid. In this model stoichiometric amounts of Im9 convert, the E9 DNase is converted wholly into the N_BI form. The possibility that cis–trans isomerisation of peptide bonds preceding proline residues is the cause of the conformational heterogeneity is discussed. E9 DNase contains 10 prolines, with two bracketing the stretch of amino acids that have allowed the N_A N_B interconversion to be identified, Pro⁶⁵ and Pro⁷³. The model assumes that one or both of these can exist in either the cis or trans form with strong Im9 binding possible to only one form.     

Towards a Model of Contemporary Parenting: The Parenting Behaviours and Dimensions Questionnaire

The assessment of parenting has been problematic due to theoretical disagreement, concerns over generalisability, and problems with the psychometric properties of current parenting measures. The aim of this study was to develop a comprehensive, psychometrically sound self-report parenting measure for use with parents of preadolescent children, and to use this empirical scale development process to identify the core dimensions of contemporary parenting behaviour. Following item generation and parent review, 846 parents completed an online survey comprising 116 parenting items. Exploratory and confirmatory factor analyses supported a six factor parenting model, comprising Emotional Warmth, Punitive Discipline, Anxious Intrusiveness, Autonomy Support, Permissive Discipline and Democratic Discipline. This measure will allow for the comprehensive and consistent assessment of parenting in future research and practice.     

Factors Associated with Clinical Research Recruitment in a Pediatric Academic Medical Center—A Web-Based Survey

Background

One of the most difficult aspects of conducting clinical research is the ability to successfully recruit participants. Pediatric clinical research presents unique recruitment challenges that relate to the need for parental consent on behalf of a minor, child assent, and school attendance. Yet, this has been less well studied. We conducted a survey of investigators performing human subjects research in a single large academic pediatric hospital to better understand characteristics of studies with successful recruitment.

Methods

We conducted a web-based survey from September 2011 to December 2011 of all principal investigators with an Institutional Review Board approved human subjects protocol at Boston Children’s Hospital, a pediatric Academic Medical Center. The survey captured various characteristics of the protocols including study design, staffing, resources, and investigator experience and training as well as respondents’ perceived barriers and facilitators to recruitment. We used chi square tests and Mantel-Haenszel test for linear trend to examine the relationship between selected predictor variables and the binary outcome of successful vs. unsuccessful recruitment and multivariable logistic regression analyses to examine the simultaneous influence of potential predictors on each outcome.

Results

Among the 349 eligible investigators, 52% responded to the survey, and 181 with valid data were included in the analyses. Two-thirds of the 87 protocols closed to enrollment reached 80% or more of their target enrollment, whereas, only one-third of the 94 protocols actively recruiting were meeting 80% of their target. Recruitment method appeared to be the only significant and independent factor associated with achieving 80% or more of target enrollment in closed to enrollment protocols. Closed to enrollment protocols that used recruitment in person were 4.55 times (95% CI 1.30 to 15.93; p = 0.02) more likely to achieve 80% or more of their target enrollment when compared to those that used other recruitment methods. Other potentially modifiable factors such as number of study visits, study duration and investigator experience were suggestive of being meaningfully related to recruitment.

Conclusion

Recruiting in person may promote reaching an acceptable target enrollment in pediatric as well as adult clinical research. Future research is needed on larger and more diverse samples to gain a better understanding of how the characteristics and qualifications of the individuals who conduct recruitment influence participant enrollment as well as how best to approach patient and families for their participation.     

Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure

Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies.     

An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure–activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.     

Recovery of plant species composition and ecosystem function after cessation of grazing in a Mediterranean grassland

Short- and long-term changes in species composition, plant biomass production, and litter decomposition after cessation of grazing were examined in a Mediterranean grassland with high dominance of annual species and strong seasonality in biomass production. Short-term changes were assessed during three consecutive years in plots previously exposed to different grazing pressures and compared to plots in long-term (30–40 years) exclosures. Short-term cessation of grazing led in the short-term to an increase in relative biomass of annual crucifers and tall annual and perennial grasses, while biomass of annual legumes, annual thistles and short annual grasses decreased. Consequently, similarity increased between vegetation recently excluded from grazing and vegetation in long-term protected plots. Our research showed that in systems with high dominance of grasses and annual species, the rapid changes in plant species composition that occur after grazing cessation were associated with a fast recovery of the potential for biomass production to levels found in long-term protected plots, while litter decomposition rate did not change even after long-term cessation of grazing. Moreover, previous history of grazing did not affect plant litter decomposition, despite higher litter quality in grazed treatments. This study provides new insights about the processes involved in the diverse responses of ecosystem functions resulting from shifts in species composition associated with grazing cessation and land use change in Mediterranean grasslands.