15 research outputs found

    PARP1 Associates With R-Loops to Promote Their Resolution and Genome Stability

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    PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA-DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability

    Pro Bono Artium: Understanding the Challenges of Volunteer Lawyers for the Arts

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    This thesis discusses the Volunteer Lawyers for the Arts ("VLA") network and seeks to determine the challenges the network is facing in serving their communities with sufficient pro bono legal assistance. This thesis first asks the broader question of what differentiates one VLA organization from another as well as what is similar between them. It further asks whether the current presidential administration has had any effect on the network and also questions whether a specific regional location is a contributing factor to a VLA's success. From there, it also addresses whether a particular funding structure or marketing strategy works best and also discusses other factors that were not anticipated before research was conducted. Interviews were conducted with the staffs of the three case study organizations and data was collected from their Forms 990, social media, and websites to address all of these questions. This thesis determines that the three case study organizations are facing much of the same challenges and finds that neither a particular regional location nor the current political climate has had too drastic of an influence on their operations. Finally, it provides recommendations as to how they might better serve their communities as well as suggestions for future research.M.S., Arts Administration -- Drexel University, 201

    Estrogens and glucocorticoids in mammary adipose tissue: Relationships with body mass index and breast cancer features

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    CONTEXT: Adipose tissue is an important site for extragonadal steroid hormone biosynthesis through the expression and activity of P450 aromatase, 11β-HSD1 and 17β-HSDs. The contribution of steroid hormones produced by adjacent adipose tissue for the progression and survival of breast tumors is unknown. OBJECTIVE: To quantify estrogens (estradiol, estrone) and glucocorticoids (cortisol, cortisone) in breast adipose tissue from both healthy and diseased women and their relationships with adiposity indices and breast cancer prognostic markers. DESIGN AND SETTING: Breast adipose tissue was collected at time of surgery. PATIENTS: Pre- and post-menopausal women undergoing partial mastectomy for treatment of breast cancer (n=17) or reduction mammoplasty (n=6) were studied. INTERVENTIONS: Estrogen and glucocorticoid relative amounts were determined by liquid chromatography-tandem mass spectrometry. RESULTS: The targeted steroids were reliably detected and quantified in mammary adipose tissues. Women with ER+/PR+ tumor had higher estradiol levels than women with ER-/PR- tumor (P < 0.05). Ratio of estradiol-to-estrone was higher in lean women compared to women with a BMI ≥ 25 kg/m2 (P < 0.05). Mixed-model analyses showed that estradiol, cortisone and cortisol were negatively associated with tumor size (P < 0.05). Relationships between glucocorticoids and tumor size remained significant after adjustment for BMI. The cortisol-to-cortisone ratio was negatively associated with tumor stage (P < 0.05) independently of BMI. CONCLUSIONS: We reliably quantified estrogens and glucocorticoids in breast adipose tissue from healthy women and women suffering from breast cancer. Our findings suggest that smaller breast tumors are associated with higher levels of estradiol and cortisol in adipose tissue

    How do modifiable risk factors affect Alzheimer's disease pathology or mitigate its effect on clinical symptom expression?

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    Epidemiological studies show that modifiable risk factors account for about 40% of the population variability in risk of developing dementia, including sporadic Alzheimer's disease (sAD). Recent findings suggest that these factors might also modify disease trajectories of people with autosomal dominant Alzheimer's disease (ADAD). With positron emission tomography (PET) imaging it is now possible to study the disease many years before its clinical onset. Such studies can provide key knowledge regarding pathways for either the prevention of pathology or the postponement of its clinical expression. The former "resistance pathway" suggests that modifiable risk factors could affect amyloid and tau burden decades before the appearance of cognitive impairment. Alternatively, the "resilience pathway" suggests that modifiable risk factors might mitigate the symptomatic expression of AD pathology on cognition. These pathways are not mutually exclusive and might appear at different disease stages. Here, in a narrative review, we present neuroimaging evidence that supports both pathways in sAD and ADAD. We then propose mechanisms for their protective effect. Among possible mechanisms, we examine neural and vascular mechanisms for the resistance pathway. We also describe brain maintenance and functional compensation as bases for the resilience pathway. Improved mechanistic understanding of both pathways may suggest new interventions

    Positive Effects of Cholinergic Stimulation Favor Young APOE ε4 Carriers

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    The potential of putative cognitive-enhancing compounds to improve mental processing both in healthy and vulnerable populations is an area of growing interest to scientific and clinical communities. The possible influence of individual genetic differences on efficacy of these compounds has yet to be considered. We sought to investigate the profile of young-adult apolipoprotein E (APOE) 4 carriers across cognitive domains given that possession of this gene variant increases risk of developing dementia in later life. We also explored whether APOE genotype interacts with the cognitive enhancer, nicotine. A total of 1 mg of the cholinergic agonist nicotine was administered through nasal spray to healthy non-smoking young adults (aged 18-30) with either 3/3 (N29) or 4 (at least one 4 allele, N27) genotype. Participants were matched on age, sex, and IQ in a placebo-controlled, double-blind 2 (drug: placebo, nicotine) × 2 (genotype: 3, 4) between subjects design. Here, we show that, paradoxically, possession of the 4 allele confers a cognitive advantage on tasks mediated by the frontal lobe, and that young carriers of the 4 allele show larger cognitive benefit from procholinergic nicotinic stimulation. These results are the first to show that genetic differences influence the efficacy of a cognitive enhancer

    Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

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    Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development (MCD), and Charcot-Marie-Tooth disease, type 2O (CMT2O). We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore we analysed our database of 1,024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways