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Identity by Descent: Variation in Meiosis, Across Genomes, and in Populations
Gene identity by descent (IBD) is a fundamental concept that underlies genetically mediated similarities among relatives. Gene IBD is traced through ancestral meioses and is defined relative to founders of a pedigree, or to some time point or mutational origin in the coalescent of a set of extant genes in a population. The random process underlying changes in the patterns of IBD across the genome is recombination, so the natural context for defining IBD is the ancestral recombination graph (ARG), which specifies the complete ancestry of a collection of chromosomes. The ARG determines both the sequence of coalescent ancestries across the chromosome and the extant segments of DNA descending unbroken by recombination from their most recent common ancestor (MRCA). DNA segments IBD from a recent common ancestor have high probability of being of the same allelic type. Non-IBD DNA is modeled as of independent allelic type, but the population frame of reference for defining allelic independence can vary. Whether of IBD, allelic similarity, or phenotypic covariance, comparisons may be made to other genomic regions of the same gametes, or to the same genomic regions in other sets of gametes or diploid individuals. In this review, I present IBD as the framework connecting evolutionary and coalescent theory with the analysis of genetic data observed on individuals. I focus on the high variance of the processes that determine IBD, its changes across the genome, and its impact on observable data.
Journal Article
The brain development revolution : science, the media, and public policy
\"Today we perceive children and the influences on them with regard to their developing brains. This book documents how brain development became the dominant lens for understanding children's development, the benefits and missed opportunities for children that resulted, and why brain development compels our attention\"-- Provided by publisher.
Book
MET is required for the recruitment of anti-tumoural neutrophils
Whether neutrophils exert an anti- or pro-tumorigenic function has remained controversial; now, expression of the receptor molecule MET in neutrophils is shown to be required for their ability to restrict tumour growth in several mouse cancer models, with potential implications for human cancer therapy.
Anti-tumour function for MET
Whether neutrophils exert and anti- or pro-tumorigenic function has remained controversial. Massimiliano Mazzone and colleagues now show in several mouse models of cancer that expression of the receptor molecule MET in neutrophils is required for their ability to restrict tumour growth. MET expression in neutrophils is triggered by inflammatory signals, which can also be tumour-derived. MET activity is required for neutrophils to cross an activated endothelium to reach a tumour and to kill cancer cells. MET has been shown to be a therapeutic target in cancer cells which express MET, therefore the findings suggest that any beneficial effect is countered by inhibition of the anti-tumour neutrophil response, and the authors indeed demonstrate this in their mouse model. These findings are of relevance to therapeutic decisions based on anti-MET drugs, where it may be useful to monitor effects of the treatment in tumours showing a neutrophil response.
Mutations or amplification of the
MET
proto-oncogene are involved in the pathogenesis of several tumours
1
,
2
,
3
,
4
, which rely on the constitutive engagement of this pathway for their growth and survival
1
,
5
. However,
MET
is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized
6
,
7
,
8
,
9
,
10
,
11
. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF).
Met
deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly,
Met
is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically,
Met
is induced by tumour-derived tumour necrosis factor (TNF)-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential ‘Achilles’ heel’ of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.
Journal Article
Environmental Chemical Contaminants in Food: Review of a Global Problem
Contamination by chemicals from the environment is a major global food safety issue, posing a serious threat to human health. These chemicals belong to many groups, including metals/metalloids, polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs), perfluorinated compounds (PFCs), pharmaceutical and personal care products (PPCPs), radioactive elements, electronic waste, plastics, and nanoparticles. Some of these occur naturally in the environment, whilst others are produced from anthropogenic sources. They may contaminate our food—crops, livestock, and seafood—and drinking water and exert adverse effects on our health. It is important to perform assessments of the associated potential risks. Monitoring contamination levels, enactment of control measures including remediation, and consideration of sociopolitical implications are vital to provide safer food globally.
Journal Article
CATALISE: A Multinational and Multidisciplinary Delphi Consensus Study. Identifying Language Impairments in Children
Delayed or impaired language development is a common developmental concern, yet there is little agreement about the criteria used to identify and classify language impairments in children. Children's language difficulties are at the interface between education, medicine and the allied professions, who may all adopt different approaches to conceptualising them. Our goal in this study was to use an online Delphi technique to see whether it was possible to achieve consensus among professionals on appropriate criteria for identifying children who might benefit from specialist services. We recruited a panel of 59 experts representing ten disciplines (including education, psychology, speech-language therapy/pathology, paediatrics and child psychiatry) from English-speaking countries (Australia, Canada, Ireland, New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46 statements based on articles and commentaries in a special issue of a journal focusing on this topic. Panel members rated each statement for both relevance and validity on a seven-point scale, and added free text comments. These responses were synthesised by the first two authors, who then removed, combined or modified items with a view to improving consensus. The resulting set of statements was returned to the panel for a second evaluation (round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percent for 24 of 27 round 2 statements, though many respondents qualified their response with written comments. These were again synthesised by the first two authors. The resulting consensus statement is reported here, with additional summary of relevant evidence, and a concluding commentary on residual disagreements and gaps in the evidence base.
Journal Article
Reasoning as memory
\"The chapters in this volume showcase work that demonstrates how advancements in the field of reasoning rely on integrating findings, theories, and paradigms from the field of memory. This timely book offers an overview of this burgeoning area of research and will be of interest to advanced undergraduates on a wide range of cognitive courses, as well as researchers interested in thinking, reasoning, or decision-making\"-- Provided by publisher.
Book
Mediation analysis to identify causes of racial disparity in health outcomes: a comparison of model-based and outcome-based approaches
Background
In United States, there is an urgent need to identify the causes of racial disparity, with infant mortality a prime example. Mediation analysis was designed to evaluate such causal questions. Two main approaches have been promoted. The model-based approach has been adapted to implement counterfactual modeling in which a system of equations is used to partition causal effects and resolve the portion of effects attributable to direct and indirect effects. The outcome-based approach relies on direct Bayesian estimation of the conditional probabilities which are then used to estimate mediation effects. The objective of this study was to compare and evaluate differences between model-based and outcome-based mediation modeling. The motivating example models a binary outcome as a function of a binary cause and a binary mediator.
Methods
The dataset was a random sample of 100,000 births from 2003 that have been made readily available to illustrate mediation modeling. Infant mortality was the outcome of interest. Race was the cause of interest, and the potential mediators were maternal smoking, low birthweight, and teenage maternity. The model-based and outcome-based models were implemented, along with a hybrid or combination model. The hybrid model started as a model-based approach with estimation of regression parameters. From the regression parameters, reverse transformation was used to estimate potential outcomes that were then used in mediational analysis.
Results
The model-based or counterfactual approach performed poorly relative to the Bayesian-implemented outcome-based approach. Evaluating the hybrid model traced the error to the set of equations recommended to estimate the mediation effects.
Conclusions
The Bayesian estimation of potential outcomes provided a simple and intuitive approach to mediation modeling. Bayesian modelers are encouraged to take a lead in identifying causes of racial disparity, along with a myriad of other mediation questions.
Journal Article