Quantification of HFSHR Signaling to Determine LIPID Raft Residency

Human follicle stimulating hormone (hFSH) is a gonadotropin responsible for regulating reproductive systems by stimulation of Sertoli cells in males and granulosa cells in females. The hFSH receptor (hFSHR) is a seven transmembrane receptor that belongs to the G protein coupled receptor family. The receptor is functionally connected to a G protein on the inside of the cell. Once FSH activates its receptor, a cascade of signaling begins, resulting in the activation of adenylyl cyclase, which increases the intracellular levels of cAMP. In addition, hFSHR stimulation also activates the p44/42 MAP kinase. The spike in cAMP activates the enzyme protein kinase A (PKA), which triggers a series of downstream effectors resulting in follicular stimulation and gametogenesis.Previous work in the Cohen Lab has shown that hFSHR is located in cholesterol-­rich, detergent-­resistant microdomains known as lipid rafts. In an HEK293 cell line stably expressing hFSHR, disruption of lipid rafts by the cholesterol chelator methyl beta-­cyclodextrin (MCD) interferes with PKA activation. Current research is focused on the relevance of hFSHR lipid raft residency in the human granulosa cell line hGrC1; focusing in particular on the activation of signal transduction pathways by hFSHR. The goal was to develop an enzyme-­based, quantitative, non-­radioactive assay for cAMP stimulation that could be used to study the effects of lipid raft disruption by MβCD on hFSHR signaling in hGrC1 cells. The galactosidase assay showed quantitative dose-­dependent responses to hFSH, which indicated that it should be useful for testing MβCD to further determine lipid raft dependence of hFSHR signaling. Studying the regulation of signaling by hFSHR provides more insight into the receptor function and potentially represents new approaches to contraception or treatment of infertility

Weight and Wages: The Effect of Changing BMI Over Time

Obesity in the United States has been growing at an alarming rate, driving up health care costs and also promoting a worsening wage penalty for overweight workers. This study explores the determinants of the wage penalty borne by overweight individuals. To investigate this phenomenon individual BMI history was obtained from the Panel Study of Income Dynamics for 1986-1999. Upon examination of the cross-sectional data from 1986, there was a wage penalty observed for males who were underweight and for females who were overweight. The analysis of panel data from 1986 and 1999 however showed that it is not the BMI in 1986, but rather the change in BMI between 1986 and 1999 that is associated with a wage penalty. Among males, a wage penalty exists for those displayed an increase or decrease in BMI from normal weight compared to those who stayed normal weight. Among females, a wage penalty was seen for all who showed an increase in BMI. These results suggest that the overweight/normal weight wage gap is driven in part by a non-causal explanation rather than a causal explanation such as BMI. For example, individuals with increasing BMI may have lower self-esteem leading to less ambition to climb to higher paying jobs in the work force

Validation of a computational phenotype for finding patients eligible for genetic testing for pathogenic PTEN variants across three centers

BACKGROUND: Computational phenotypes are most often combinations of patient billing codes that are highly predictive of disease using electronic health records (EHR). In the case of rare diseases that can only be diagnosed by genetic testing, computational phenotypes identify patient cohorts for genetic testing and possible diagnosis. This article details the validation of a computational phenotype for PTEN hamartoma tumor syndrome (PHTS) against the EHR of patients at three collaborating clinical research centers: Boston Children\u27s Hospital, Children\u27s National Hospital, and the University of Washington. METHODS: A combination of billing codes from the International Classification of Diseases versions 9 and 10 (ICD-9 and ICD-10) for diagnostic criteria postulated by a research team at Cleveland Clinic was used to identify patient cohorts for genetic testing from the clinical data warehouses at the three research centers. Subsequently, the EHR-including billing codes, clinical notes, and genetic reports-of these patients were reviewed by clinical experts to identify patients with PHTS. RESULTS: The PTEN genetic testing yield of the computational phenotype, the number of patients who needed to be genetically tested for incidence of pathogenic PTEN gene variants, ranged from 82 to 94% at the three centers. CONCLUSIONS: Computational phenotypes have the potential to enable the timely and accurate diagnosis of rare genetic diseases such as PHTS by identifying patient cohorts for genetic sequencing and testing

Analyse systématique des anomalies retrouvées à l'IRM cérébrale chez les patients atteints d'une paraplégie spastique héréditaire associée aux mutations de l'AP4

peer reviewed[en] BACKGROUND AND OBJECTIVES: AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations. METHODS: We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity. RESULTS: We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age. DISCUSSION: Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration

Metabolism of Folates in Plants

International audienceTetrahydrofolate and its derivatives, collectively termed folates or vitamin B9, are essential cofactors for one-carbon metabolism. They transport and donate Cl-units for the synthesis of pantothenate, purines, thymidylate, serine, glycine, methionine and formylmethionyl-tRNA. Also, recent studies indicate that folates can act as electron donors in major cellular processes. Plants and many microorganisms synthesize folates de novo through a complex metabolic route that is now fully elucidated. In contrast, humans and other vertebrates lack a complete biosynthetic pathway and thus need dietary folates, of which plants are major sources. Folate deficiency is widespread in rich and developing countries and is associated with severe health problems. Supplementation of foods with synthetic folic acid and biofortification is an alternative strategy to fight folate deficiency. Encouraging pilot metabolic engineering studies in plants enabled significant enhancement of folate contents. In the next future, increasing our knowledge about the mechanisms controlling folates homeostasis in plants will provide the keys towards efficient biofortification of plant foods