Because a growing proportion of the beef output in many countries originates from dairy herds, the most critical decisions about the genetic merit of most carcasses harvested are being made by dairy ...producers. Interest in the generation of more valuable calves from dairy females is intensifying, and the most likely vehicle is the use of appropriately selected beef bulls for mating to the dairy females. This is especially true given the growing potential to undertake more beef × dairy matings as herd metrics improve (e.g., reproductive performance) and technological advances are more widely adopted (e.g., sexed semen). Clear breed differences (among beef breeds but also compared with dairy breeds) exist for a whole plethora of performance traits, but considerable within-breed variability has also been demonstrated. Although such variability has implications for the choice of bull to mate to dairy females, the fact that dairy females themselves exhibit such genetic variability implies that “one size fits all” may not be appropriate for bull selection. Although differences in a whole series of key performance indicators have been documented between beef and beef-on-dairy animals, of particular note is the reported lower environmental hoofprint associated with beef-on-dairy production systems if the environmental overhead of the mature cow is attributed to the milk she eventually produces. Despite the known contribution of beef (i.e., both surplus calves and cull cows) to the overall gross output of most dairy herds globally, and the fact that each dairy female contributes half her genetic merit to her progeny, proxies for meat yield (i.e., veal or beef) are not directly considered in the vast majority of dairy cow breeding objectives. Breeding objectives to identify beef bulls suitable for dairy production systems are now being developed and validated, demonstrating the financial benefit of using such breeding objectives over and above a focus on dairy bulls or easy-calving, short-gestation beef bulls. When this approach is complemented by management-based decision-support tools, considerable potential exists to improve the profitability and sustainability of modern dairy production systems by exploiting beef-on-dairy breeding strategies using the most appropriate beef bulls.
The high narrow sense heritability of carcass traits suggests that the underlying additive genetic potential of an individual should be strongly correlated with both animal carcass quality and ...quantity, and therefore, by extension, carcass value. Therefore, the objective of the present study was to detect genomic regions associated with three carcass traits, namely carcass weight, conformation and fat cover, using imputed whole genome sequence in 28,470 dairy and beef sires from six breeds with a total of 2,199,926 phenotyped progeny.
Major genes previously associated with carcass performance were identified, as well as several putative novel candidate genes that likely operate both within and across breeds. The role of MSTN in carcass performance was re-affirmed with the segregating Q204X mutation explaining 1.21, 1.11 and 5.95% of the genetic variance in carcass weight, fat and conformation, respectively in the Charolais population. In addition, a genomic region on BTA6 encompassing the NCAPG/LCORL locus, which is a known candidate locus associated with body size, was associated with carcass weight in Angus, Charolais and Limousin. Novel candidate genes identified included ZFAT in Angus, and SLC40A1 and the olfactory gene cluster on BTA15 in Charolais. Although the majority of associations were breed specific, associations that operated across breeds included SORCS1 on BTA26, MCTP2 on BTA21 and ARL15 on BTA20; these are of particular interest due to their potential informativeness in across-breed genomic evaluations. Genomic regions affecting all three carcass traits were identified in each of the breeds, although these were mainly concentrated on BTA2 and BTA6, surrounding MSTN and NCAPG/LCORL, respectively. This suggests that although major genes may be associated with all three carcass traits, the majority of genes containing significant variants (unadjusted p-value < 10
) may be trait specific associations of small effect.
Although plausible novel candidate genes were identified, the proportion of variance explained by these candidates was minimal thus reaffirming that while carcass performance may be affected by major genes in the form of MSTN and NCAPG/LCORL, the majority of variance is attributed to the additive (and possibly multiplicative) effect of many polymorphisms of small effect.
I‐SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic ...therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I‐SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium.
Clinical Pharmacology & Therapeutics (2009); 86, 1, 97–100 doi:10.1038/clpt.2009.68
A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated ...non-ATG (RAN) translation, producing “c9RAN proteins.” Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.
•(GGGGCC) RNA forms a hairpin structure in equilibrium with a G-quadruplex structure•Neurons directly converted from C9ORF72+ fibroblasts express c9RAN proteins and foci•Small-molecule binders of (GGGGCC)exp RNA ameliorate c9FTD/ALS-associated defects•c9RAN proteins are detected in c9ALS patient cerebrospinal fluid
A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis, presumably via the expression of repeat-containing RNA (r(GGGGCC)exp). Su et al. find that small molecules targeting r(GGGGCC)exp can block c9FTD/ALS-associated defects and reveal a potential biomarker for c9FTD/ALS.
Abstract Background Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this ...relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Objectives This study sought to quantify dose–response associations between LTPA, BMI, and the risk of different HF subtypes. Methods Individual-level data from 3 cohort studies (WHI Women’s Health Initiative, MESA Multi-Ethnic Study of Atherosclerosis, and CHS Cardiovascular Health Study) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction ≥45%), and HFrEF (ejection fraction <45%) were assessed by using multivariable adjusted Cox models and restricted cubic splines. Results The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.97). The dose–response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥25 kg/m2 ) was associated with a greater increase in risk of HFpEF than HFrEF. Conclusions Our study findings show strong, dose–dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF.
It is well established that all interactions are symmetric: when the effect of X on Y is conditional on the value of Z, the effect of Z must be conditional on the value of X. Yet the typical practice ...when testing an interactive theory is to (1) view one variable, Z, as the conditioning variable, (2) offer a hypothesis about how the marginal effect of the other variable, X, is conditional on the value of Z, and (3) construct a marginal effect plot for X to test the theory. We show that the failure to make additional predictions about how the effect of Z varies with the value of X, and to evaluate them with a second marginal effect plot, means that scholars often ignore evidence that can be extremely valuable for testing their theory. As a result, they either understate or, more worryingly, overstate the support for their theories.
Designs of clinical trials have changed little since the advent of randomization in the 1940s. Modern innovations in designs are being driven by the increasing recognition in clinical research that ...diseases are heterogeneous and patients who apparently have the same disease require different therapies. This article describes some innovations in clinical trial design across therapeutic areas but with a focus on oncology. No one knows what the future holds for clinical trial design but the status quo of large trials that pretend the patient population is homogeneous is not sustainable, either economically or scientifically/medically. No one knows what the eventual business model and regulatory model will be, but they will be very different from today's.
Excellent reproductive performance in both males and females is fundamental to profitable dairy and beef production systems. In this review we undertook a meta-analysis of genetic parameters for ...female reproductive performance across 55 dairy studies or populations and 12 beef studies or populations as well as across 28 different studies or populations for male reproductive performance. A plethora of reproductive phenotypes exist in dairy and beef cattle and a meta-analysis of the literature suggests that most of the female reproductive traits in dairy and beef cattle tend to be lowly heritable (0.02 to 0.04). Reproductive-related phenotypes in male animals (e.g. semen quality) tend to be more heritable than female reproductive phenotypes with mean heritability estimates of between 0.05 and 0.22 for semen-related traits with the exception of scrotal circumference (0.42) and field non-return rate (0.001). The low heritability of reproductive traits, in females in particular, does not however imply that genetic selection cannot alter phenotypic performance as evidenced by the decline until recently in dairy cow reproductive performance attributable in part to aggressive selection for increased milk production. Moreover, the antagonistic genetic correlations among reproductive traits and both milk (dairy cattle) and meat (beef cattle) yield is not unity thereby implying that simultaneous genetic selection for both increased (milk and meat) yield and reproductive performance is indeed possible. The required emphasis on reproductive traits within a breeding goal to halt deterioration will vary based on the underlying assumptions and is discussed using examples for Ireland, the United Kingdom and Australia as well as quantifying the impact on genetic gain for milk production. Advancements in genomic technologies can aid in increasing the accuracy of selection for especially reproductive traits and thus genetic gain. Elucidation of the underlying genomic mechanisms for reproduction could also aid in resolving genetic antagonisms. Past breeding programmes have contributed to the deterioration in reproductive performance of dairy and beef cattle. The tools now exist, however, to reverse the genetic trends in reproductive performance underlying the observed phenotypic trends.
As the environments in which livestock are reared become more variable, animal robustness becomes an increasingly valuable attribute. Consequently, there is increasing focus on managing and breeding ...for it. However, robustness is a difficult phenotype to properly characterise because it is a complex trait composed of multiple components, including dynamic elements such as the rates of response to, and recovery from, environmental perturbations. In this review, the following definition of robustness is used: the ability, in the face of environmental constraints, to carry on doing the various things that the animal needs to do to favour its future ability to reproduce. The different elements of this definition are discussed to provide a clearer understanding of the components of robustness. The implications for quantifying robustness are that there is no single measure of robustness but rather that it is the combination of multiple and interacting component mechanisms whose relative value is context dependent. This context encompasses both the prevailing environment and the prevailing selection pressure. One key issue for measuring robustness is to be clear on the use to which the robustness measurements will employed. If the purpose is to identify biomarkers that may be useful for molecular phenotyping or genotyping, the measurements should focus on the physiological mechanisms underlying robustness. However, if the purpose of measuring robustness is to quantify the extent to which animals can adapt to limiting conditions then the measurements should focus on the life functions, the trade-offs between them and the animal’s capacity to increase resource acquisition. The time-related aspect of robustness also has important implications. Single time-point measurements are of limited value because they do not permit measurement of responses to (and recovery from) environmental perturbations. The exception being single measurements of the accumulated consequence of a good (or bad) adaptive capacity, such as productive longevity and lifetime efficiency. In contrast, repeated measurements over time have a high potential for quantification of the animal’s ability to cope with environmental challenges. Thus, we should be able to quantify differences in adaptive capacity from the data that are increasingly becoming available with the deployment of automated monitoring technology on farm. The challenge for future management and breeding will be how to combine various proxy measures to obtain reliable estimates of robustness components in large populations. A key aspect for achieving this is to define phenotypes from consideration of their biological properties and not just from available measures.
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