451 research outputs found

    Synthetic chromosome fusion: Effects on mitotic and meiotic genome structure and function

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    We designed and synthesized synI, which is ~21.6% shorter than native chrI, the smallest chromosome in Saccharomyces cerevisiae. SynI was designed for attachment to another synthetic chromosome due to concerns surrounding potential instability and karyotype imbalance and is now attached to synIII, yielding the first synthetic yeast fusion chromosome. Additional fusion chromosomes were constructed to study nuclear function. ChrIII-I and chrIX-III-I fusion chromosomes have twisted structures, which depend on silencing protein Sir3. As a smaller chromosome, chrI also faces special challenges in assuring meiotic crossovers required for efficient homolog disjunction. Centromere deletions into fusion chromosomes revealed opposing effects of core centromeres and pericentromeres in modulating deposition of the crossover-promoting protein Red1. These effects extend over 100 kb and promote disproportionate Red1 enrichment, and thus crossover potential, on small chromosomes like chrI. These findings reveal the power of synthetic genomics to uncover new biology and deconvolute complex biological systems Β </p

    Bidirectional Modulation of Alcohol-Associated Memory Reconsolidation through Manipulation of Adrenergic Signaling.

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    Alcohol addiction is a problem of great societal concern, for which there is scope to improve current treatments. One potential new treatment for alcohol addiction is based on disrupting the reconsolidation of the maladaptive Pavlovian memories that can precipitate relapse to drug-seeking behavior. In alcohol self-administering rats, we investigated the effects of bidirectionally modulating adrenergic signaling on the strength of a Pavlovian cue-alcohol memory, using a behavioral procedure that isolates the specific contribution of one maladaptive Pavlovian memory to relapse, the acquisition of a new alcohol-seeking response for an alcohol-associated conditioned reinforcer. The Ξ²-adrenergic receptor antagonist propranolol, administered in conjunction with memory reactivation, persistently disrupted the memory that underlies the capacity of a previously alcohol-associated cue to act as a conditioned reinforcer. By contrast, enhancement of adrenergic signaling by administration of the adrenergic prodrug dipivefrin at reactivation increased the strength of the cue-alcohol memory and potentiated alcohol seeking. These data demonstrate the importance of adrenergic signaling in alcohol-associated memory reconsolidation, and suggest a pharmacological target for treatments aiming to prevent relapse through the disruption of maladaptive memories.This work was supported by a UK Medical Research Council Programme Grant (G1002231) to BJE and ALM and was conducted in the Behavioural and Clinical Neuroscience Institute (BCNI), an initiative jointly funded by the MRC and the Wellcome Trust. MJWS was supported by an MRC Doctoral Training Grant and the James Baird Fund at the Medical School of the University of Cambridge. ALM was partly supported by a BCNI lectureship and the Ferreras-Willetts Fellowship from Downing College, Cambridge.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/npp.2015.24

    Transcriptional regulation of bone formation by the osteoblast-specific transcription factor Osx

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    Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts. Osteoblast differentiation occurs through a multi-step molecular pathway regulated by different transcription factors and signaling proteins. Osx (also known as Sp7) is the only osteoblast-specific transcriptional factor identified so far which is required for osteoblast differentiation and bone formation. Osx knock-out mice lack bone completely and cartilage is normal. This opens a new window to the whole research field of bone formation. Osx inhibits Wnt pathway signaling, a possible mechanism for Osx to inhibit osteoblast proliferation. These reports demonstrate that Osx is the master gene that controls osteoblast lineage commitment and the subsequent osteoblast proliferation and differentiation. This review is to highlight recent progress in understanding the molecular mechanisms of transcriptional regulation of bone formation by Osx

    Carrier Screening for Spinal Muscular Atrophy (SMA) in 107,611 Pregnant Women during the Period 2005–2009: A Prospective Population-Based Cohort Study

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    BACKGROUND: Spinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program. METHODS AND FINDINGS: This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968. CONCLUSION: The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling

    Founder populations and their uses for breast cancer genetics

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    Numerous founder mutations have been reported in BRCA1 and BRCA2. For genetic screening of a population with a founder mutation, testing can be targeted to the mutation, allowing for a more rapid and less expensive test. In addition, more precise estimates of the prior probability of carrying a mutation and of the likelihood of a mutation carrier developing cancer should be possible. For a given founder mutation a large number of carriers are available, so that focused scientific studies of penetrance, expression, and genetic and environmental modifiers of risk can be performed. Finally, founder populations may be a powerful resource to localize additional breast cancer susceptibility loci, because of the reduction in locus heterogeneity

    Changes in the Circadian Rhythm in Patients with Primary Glaucoma

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    Purpose The current study was undertaken to investigate whether glaucoma affects the sleep quality and whether there is any difference between patients with primary glaucoma (primary open angle glaucoma, POAG and primary angle-closure glaucoma, PACG) and healthy subjects, using a validated self-rated questionnaire, the Pittsburgh Sleep Quality Index (PSQI). Methods The sleep quality of patients with POAG and PACG was tested against normal controls. Subjects were divided into three sub-groups according to age. Differences in the frequency of sleep disturbances (PSQI score >7) were assessed. The differences of sleep quality within the three groups and within the POAG group depending on the patientsÒ€ℒ intraocular pressure (IOP) and impairment of visual field (VF) were also studied. Results 92 POAG patients, 48 PACG patients and 199 controls were included. Sleep quality declined with age in control and POAG group (tendency chi-square, P0.05). No significant differences were found in POAG group between patients with a highest IOP in daytime and at nighttime (Ï‑2-test, P>0.05). Conclusions The prevalence of sleep disorders was higher in patients with POAG and PACG than in controls. PACG patients seemed to have a more serious problem of sleep disorders than POAG patients between 61 to 80 years old. No correlation was found between the prevalence of sleep disorders and impairment of VF or the time when POAG patients showed a highest IOP
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