Chromodomain proteins in development: lessons from CHARGE syndrome

Layman WS, Hurd EA, Martin DM. Chromodomain proteins in development: lessons from CHARGE syndrome.In humans, heterozygous mutations in the adenosine triphosphate-dependent chromatin remodeling gene CHD7 cause CHARGE syndrome, a common cause of deaf–blindness, balance disorders, congenital heart malformations, and olfactory dysfunction with an estimated incidence of approximately 1 in 10,000 newborns. The clinical features of CHARGE in humans and mice are highly variable and incompletely penetrant, and most mutations appear to result in haploinsufficiency of functional CHD7 protein. Mice with heterozygous loss of function mutations in Chd7 are a good model for CHARGE syndrome, and analyses of mouse mutant phenotypes have begun to clarify a role for CHD7 during development and into adulthood. Chd7 heterozygous mutant mice have postnatal delayed growth, inner ear malformations, anosmia/hyposmia, and craniofacial defects, and Chd7 homozygous mutants are embryonic lethal. A central question in developmental biology is how chromodomain proteins like CHD7 regulate important developmental processes, and whether they directly activate or repress downstream gene transcription or act more globally to alter chromatin structure and/or function. CHD7 is expressed in a wide variety of tissues during development, suggesting that it has tissue-specific and developmental stage-specific roles. Here, we review recent and ongoing analyses of CHD7 function in mouse models and cell-based systems. These studies explore tissue-specific effects of CHD7 deficiency, known CHD7 interacting proteins, and downstream target sites for CHD7 binding. CHD7 is emerging as a critical regulator of important developmental processes in organs affected by human CHARGE syndrome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79089/1/j.1399-0004.2010.01446.x.pd

The Case for Dynamic Models of Learners' Ontologies in Physics

In a series of well-known papers, Chi and Slotta (Chi, 1992; Chi & Slotta, 1993; Chi, Slotta & de Leeuw, 1994; Slotta, Chi & Joram, 1995; Chi, 2005; Slotta & Chi, 2006) have contended that a reason for students' difficulties in learning physics is that they think about concepts as things rather than as processes, and that there is a significant barrier between these two ontological categories. We contest this view, arguing that expert and novice reasoning often and productively traverses ontological categories. We cite examples from everyday, classroom, and professional contexts to illustrate this. We agree with Chi and Slotta that instruction should attend to learners' ontologies; but we find these ontologies are better understood as dynamic and context-dependent, rather than as static constraints. To promote one ontological description in physics instruction, as suggested by Slotta and Chi, could undermine novices' access to productive cognitive resources they bring to their studies and inhibit their transition to the dynamic ontological flexibility required of experts.Comment: The Journal of the Learning Sciences (In Press

Implementing The Prison Rape Elimination Act: A Toolkit for Jails

Minor edits. “The goal of this Toolkit is to provide jails of all sizes, political divisions, and geographic locations with a step-by-step guide for preventing, detecting, and eliminating sexual abuse of inmates in their custody – and for responding effectively to abuse when it occurs. Prison rape includes all forms of inmate sexual abuse within a correctional facility, including state and federal prisons, county and municipal jails, police lock-ups, holding facilities, inmate transportation vehicles, juvenile detention facilities, and community corrections facilities. Protecting arrestees, detainees, and inmates from sexual violence is part of a jail’s core mission. This toolkit will help assess your jail’s operations with an eye to improvements.” The Toolkit is divided into folders holding materials related to: introductory information about PREA [Prison Rape Elimination Act] and it Standards; a Self-Assessment Checklist with supporting forms “to provide a step-by-step process for jails to review and assess policies, procedures, and practices in light of the PREA Standards and accepted best practices”; and additional resources to assist you in PREA-readiness

How Contemporary Human Reproductive Behaviors Influence the Role of Fertility-Related Genes: The Example of the P53 Gene

Studies on human fertility genes have identified numerous risk/protective alleles involved in the occurrence of reproductive system diseases causing infertility or subfertility. Investigations we carried out in populations at natural fertility seem to suggest that the clinical relevance that some fertility genes are now acquiring depends on their interaction with contemporary reproductive behaviors (birth control, delayed childbearing, and spacing birth order, among others). In recent years, a new physiological role in human fertility regulation has emerged for the tumor- suppressor p53 gene (P53), and the P53 Arg72Pro polymorphism has been associated with recurrent implantation failure in humans. To lend support to our previous observations, we examined the impact of Arg72Pro polymorphism on fertility in two samples of Italian women not selected for impaired fertility but collected from populations with different (premodern and modern) reproductive behaviors. Among the women at near-natural fertility (n = 98), the P53 genotypes were not associated with different reproductive efficiency, whereas among those with modern reproductive behaviors (n = 68), the P53 genotypes were associated with different mean numbers of children [Pro/Pro = 0.75<Pro/Arg = 1.7<Arg/Arg = 2, (p = 0.056)] and a significant negative relationship between the number of children and P53 Pro allele frequencies (p = 0.028) was observed. These results are consistent with those of clinical studies reporting an association between the P53 Pro allele and recurrent implantation failure. By combining these findings with previous ones, we suggest here that some common variants of fertility genes may have become “detrimental” following exposure to modern reproductive patterns and might therefore be associated with reduced reproductive success. Set within an evolutionary framework, this change could lead to the selection of a set of gene variants fitter to current reproductive behaviors as the shift to later child-bearing age in developed countries

NEUROPSYCHOPHARMACOLOGIC STUDIES OF MARIJUANA: SOME SYNTHETIC AND NATURAL THC DERIVATIVES IN ANIMALS AND MAN *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74859/1/j.1749-6632.1971.tb13996.x.pd

Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women

Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = −0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery