Fast direct solution of method of moments applied to multiscale problems

In a recent publication [1], we proposed a new convergence criterion for the Adapted Cross Approximation (ACA) algorithm, based on random sampling of the matrix that represents the residual error at each step of the algorithm. We presented some practical examples involving RCS computations of perfectly conducting benchmark targets exhibiting multiscale features, meaning that the mesh-size of the discrete model of the target is highly variable. These examples demonstrated a considerable improvement in the accuracy of the RCS result without appreciable loss of efficiency. In the presented examples, the solution was obtained by an iterative solver applied to an ACA-compressed Method of Moments impedance matrix. In this paper we apply the new method from [1] to the direct (non-iterative) solution of the MoM matrix. The results demonstrate that in this case, the advantage of the new method is far more important. Compared to ordinary ACA, the same accuracy is obtained in less than a quarter of the computation time

Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor

Recent studies have identified a series of estrogen receptor (ER)interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER alpha-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-angstrom crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the beta-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences. In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER alpha, particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity

Urges to Move and Other Motivation States for Physical Activity in Clinical and Healthy Populations: A Scoping Review Protocol

[EN] Motivation for bodily movement, physical activity and exercise varies from moment to moment. These motivation states may be “affectively-charged,” ranging from instances of lower tension (e.g., desires, wants) to higher tension (e.g., cravings and urges). Currently, it is not known how often these states have been investigated in clinical populations (e.g., eating disorders, exercise dependence/addiction, Restless Legs Syndrome, diabetes, obesity) vs. healthy populations (e.g., in studies of motor control; groove in music psychology). The objective of this scoping review protocol is to quantify the literature on motivation states, to determine what topical areas are represented in investigations of clinical and healthy populations, and to discover pertinent details, such as instrumentation, terminology, theories, and conceptual models, correlates and mechanisms of action. Iterative searches of scholarly databases will take place to determine which combination of search terms (e.g., “motivation states” and “physical activity”; “desire to be physically active,” etc.) captures the greatest number of relevant results. Studies will be included if motivation states for movement (e.g., desires, urges) are specifically measured or addressed. Studies will be excluded if referring to motivation as a trait. A charting data form was developed to scan all relevant documents for later data extraction. The primary outcome is simply the extent of the literature on the topic. Results will be stratified by population/condition. This scoping review will unify a diverse literature, which may result in the creation of unique models or paradigms that can be utilized to better understand motivation for bodily movement and exercise.GA was supported by a fellowship from the Office of Academic Affiliations at the United States Veterans Health Administration, a Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award, Bank of America, N.A., Trustee, and American Heart Association Grant #852679 (GA, 2021–2024).We would like to thank Melissa Eden, Ph.D. (Hanover College, IN) for her valuable assistance in refining aspects of the search strategy. Khristdman Cavalcanti helped with technical aspects of the study. Sunao Akashi Slayton, PharmD BCOP (Smilow Cancer Hospital, Yale – New Haven Hospital, CT) evaluated clinical information and provided nomenclatur

The Immunophilin-Like Protein XAP2 Is a Negative Regulator of Estrogen Signaling through Interaction with Estrogen Receptor α

XAP2 (also known as aryl hydrocarbon receptor interacting protein, AIP) is originally identified as a negative regulator of the hepatitis B virus X-associated protein. Recent studies have expanded the range of XAP2 client proteins to include the nuclear receptor family of transcription factors. In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. Interestingly, we show that XAP2 downregulates the E2-dependent transcriptional activation in an estrogen receptor (ER) isoform-specific manner: XAP2 inhibits ERα but not ERβ-mediated transcription. Thus, knockdown of intracellular XAP2 levels leads to increased ERα activity. XAP2 proteins, carrying mutations in their primary structures, loose the ability of interacting with ERα and can no longer regulate ER target gene transcription. Taken together, this study shows that XAP2 exerts a negative effect on ERα transcriptional activity and may thus prevent ERα-dependent events

Estrogen Receptor-Beta Gene Polymorphism in women with Breast Cancer at the Imam Khomeini Hospital Complex, Iran

ER-alpha and ER-beta genes have been proven to play a significant role in breast cancer. Epidemiologic studies have revealed that age-incidence patterns of breast cancer in Middle East differ from those in the Western countries. Two selected coding regions in the ER-β gene (exons 3 and 7) were scanned in Iranian women with breast cancer (150) and in healthy individuals (147). PCR single-strand conformation polymorphism was performed. A site of silent single nucleotide polymorphism was found only on exon 7. The SNP was found only in breast cancer patients (5.7%) (χ2 = 17.122, P = 0.01). Codon 392 (C1176G) of allele 1 was found to have direct association with the occurrence of lymph node metastasis. Our data suggest that ER-β polymorphism in exon 7 codon 392 (C1176G) is correlated with various aspects of breast cancer and lymph node metastasis in our group of patients

Significant Association of Estrogen Receptor Binding Site Variation with Bipolar Disorder in Females

Major depression is nearly twice as prevalent in women compared to men. In bipolar disorder, depressive episodes have been reported to be more common amongst female patients. Furthermore, periods of depression often correlate with periods of hormonal fluctuations. A link between hormone signaling and these mood disorders has, therefore, been suggested to exist in many studies. Estrogen, one of the primary female sex hormones, mediates its effect mostly by binding to estrogen receptors (ERs). Nuclear ERs function as transcription factors and regulate gene transcription by binding to specific DNA sequences. A nucleotide change in the binding sequence might alter the binding efficiency, which could affect transcription levels of nearby genes. In order to investigate if variation in ER DNA-binding sequences may be involved in mood disorders, we conducted a genome-wide study of ER DNA-binding in patients diagnosed with major depression or bipolar disorder. Association studies were performed within each gender separately and the results were corrected for multiple testing by the Bonferroni method. In the female bipolar disorder material a significant association result was found for rs6023059 (corrected p-value = 0.023; odds ratio (OR) 0.681, 95% confidence interval (CI) 0.570–0.814), a single nucleotide polymorphism (SNP) placed downstream of the gene coding for transglutaminase 2 (TGM2). Thus, females with a specific genotype at this SNP may be more vulnerable to fluctuating estrogen levels, which may then act as a triggering factor for bipolar disorder

The Role of Oestrogen Receptor Beta (ERβ) in the Aetiology and Treatment of Type 2 Diabetes Mellitus

Introduction: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERβ) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERβ as a therapeutic target. Background: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERβ shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERβ receptor and underscore its therapeutic potential. Conclusion: Studies are needed to further elucidate the exact mechanism underlying the role of ERβ activation as a therapeutic approach in the management of type 2 diabetes

ESR1 and EGF genetic variation in relation to breast cancer risk and survival

The main purposes of this thesis were to analyse common genetic variation in candidate genes and candidate pathways in relation to breast cancer risk, prognosticators and survival, to develop statistical methods for genetic association analysis for evaluating the joint importance of genes, and to investigate the potential impact of adding genetic information to clinical risk factors for projecting individualised risk of developing breast cancer over specific time periods. In Paper I we studied genetic variation in the estrogen receptor α and epidermal growth factor genes in relation to breast cancer risk and survival. We located a region in the estrogen receptor α gene which showed a moderate signal for association with breast cancer risk but were unable to link common variation in the epidermal growth factor gene with breast cancer aetiology or prognosis. In Paper II we investigated whether suspected breast cancer risk SNPs within genes involved in androgen-to-estrogen conversion are associated with breast cancer prognosticators grade, lymph node status and tumour size. The strongest association was observed for a marker within the CYP19A1 gene with histological grade. We also found evidence that a second marker from the same gene is associated with histological grade and tumour size. In Paper III we developed a novel test of association which incorporates multivariate measures of categorical and continuous heterogeneity. In this work we described both a single-SNP and a global multi-SNP test and used simulated data to demonstrate the power of the tests when genetic effects differ across disease subtypes. In Paper IV we assessed the extent to which recently associated genetic risk variants improve breast cancer risk-assessment models. We investigated empirically the performance of eighteen breast cancer risk SNPs together with mammographic density and clinical risk factors in predicting absolute risk of breast cancer. We also examined the usefulness of various prediction models considered at a population level for a variety of individualised breast cancer screening approaches. The goal of a genetic association study is to establish statistical associations between genetic variants and disease states. Each variant linked to a disease can lead the way to a better understanding of the underlying biological mechanisms that govern the development of a disease. Increased knowledge of molecular variation provides the opportunity to stratify populations according to genetic makeup, which in turn has the potential to lead to improved disease prevention programs and improved patient care

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

In order to elucidate the relative importance of oestrogen receptor (ER)α, ERβ and an ERβ variant (ERβ2/βcx) in the response of breast cancers to tamoxifen, tumour levels of each receptor were assessed in 36 patients before and after 3 months of neoadjuvant treatment with tamoxifen (20 mg daily). All patients were postmenopausal women presenting with large ERα-positive breast cancers. Clinical response to treatment was assessed by tumour volume changes as determined from sequential ultrasounds and pathological response by comparison of the tumour morphology before and after treatment. Of 33 cases, 23 (70%) were classified as having a clinical response and 16 (48%) as having a response pathologically. All tumours stained positively for ERα and ERβ and 15 out of 33 (45%) for ERβ2/βcx. There were no significant differences in quantitative expression of any receptor between tumours that subsequently responded and that did not, whether response was assessed clinically or pathologically. Tamoxifen treatment was associated with a decrease in ERα, but an increase was the most frequent change (17 out of 33) in ERβ, and no consistent change was evident in staining of the ERβ2/βcx variant. In summary, ERβ1 and ERβ2/βcx variant protein are detected in ERα-positive breast tumours but their expression is not associated with a response to tamoxifen. Differential changes in ERα and ERβ were seen with treatment