The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these ...mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10
), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10
) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
The class of proteins collectively known as periplasmic immunoglobulin‐like chaperones play an essential role in the assembly of a diverse set of adhesive organelles used by pathogenic strains of ...Gram‐negative bacteria. Herein, we present a combination of genetic and structural data that sheds new light on chaperone–subunit and subunit–subunit interactions in the prototypical P pilus system, and provides new insights into how PapD controls pilus biogenesis. New crystallographic data of PapD with the C‐terminal fragment of a subunit suggest a mechanism for how periplasmic chaperones mediate the extraction of pilus subunits from the inner membrane, a prerequisite step for subunit folding. In addition, the conserved N‐ and C‐terminal regions of pilus subunits are shown to participate in the quaternary interactions of the mature pilus following their uncapping by the chaperone. By coupling the folding of subunit proteins to the capping of their nascent assembly surfaces, periplasmic chaperones are thereby able to protect pilus subunits from premature oligomerization until their delivery to the outer membrane assembly site.
PapD is an immunoglobulin-like chaperone that mediates the assembly of P pili in uropathogenic strains of Escherichia coli. It binds and caps interactive surfaces on pilus subunits to prevent their ...premature associations in the periplasm. We elucidated the structural basis of a mechanism whereby PapD also interacts with itself, capping its own subunit binding surface. Crystal structures of dimeric forms of PapD revealed that this self-capping mechanism involves a rearrangement and ordering of the C2-D2 and F1-G1 loops upon dimerization which might ensure that a stable dimer is not formed in solution in spite of a relatively large dimer interface. An analysis of site directed mutations revealed that chaperone dimerization requires the same surface that is otherwise used to bind subunits.
Abstract only Background: The role of antiplatelet agents in the modulation of arterial disease is well described, but a paucity of data exists regarding their role in chronic venous insufficiency ...(CVI). We hypothesize that platelet responses to various antiplatelet agents are altered when comparing platelet function within refluxing and non-refluxing vein segments. Additionally, changes in platelet phenotype may alter vein wall biology. Methods: Isolated platelets were obtained simultaneously from the patient antecubital vein (ACV) and a refluxing greater saphenous vein (GSV) during surgical phlebectomy and compared to platelets from healthy individuals. Non-refluxing GSV was harvested for coronary bypass. Platelet surface receptor activation was assessed through P2Y12 (clopidogrel), PAR1 (vorapaxar), and thromboxane (aspirin) pathways by flow cytometry for p-selectin. Immunoblotting assessed CD41 (platelet) and CD45 (WBC) within the wall of vein samples. Results: Platelets from refluxing GSV showed a significant increase in reactivity via all platelet signaling pathways, especially P2Y12 and thromboxane when compared to platelets from the ACV in the same patient. Conversely, platelets collected from the ACV in CVI patients showed a significant decrease in reactivity to all agonists compared to ACV in healthy individuals without CVI. Most notably, GSV from a patient with CVI had a reduction in CD41 content, but a seven-fold increase in the CD45:CD41 ratio, compared to GSV from healthy people (Figure). Conclusions: Platelet activation by these clinically relevant pathways is enhanced locally in the refluxing GSV, yet systemic, circulating platelets isolated from CVI patients are 2-3-fold less active than systemic platelets from healthy people. Our data suggest that reflux may locally alter the circulating platelet phenotype and in turn also have a role in remodeling the vein wall.
We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.
Meta-analyses included summary estimates based on Cox ...models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).
We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10
. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10
, hazard ratio HR = 0.88, 95% confidence interval CI = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10
, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.
We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Two of the large mission concepts developed for the 2020 Astronomy and Astrophysics Decadal Survey - the Large UV/Optical/Infrared (LUVOIR) Surveyor and the Habitable Exoplanet (HabEx) Observatory - ...aim to perform direct imaging and spectroscopy of exo-Earth candidates with high-contrast coronagraphs. Meeting this ambitious science goal will require architectures with large-area primary mirrors to achieve the high resolution and greater photon flux needed to detect faint objects, as well as instrumentation to suppress light from a host star ~10 billion times brighter than the exoplanet of interest. Achieving contrast of 10 −10 at visible wavelengths using a coronagraph ushers in a new regime where the corresponding wavefront stability is expressed in units of picometers rather than nanometers. The NASA-funded "Ultra-Stable Large Telescope Research and Analysis - Technology Maturation" (ULTRA-TM) program is working to mature critical technologies for ultra-stable optical systems to support these mission concepts and enable ground-breaking science. This paper describes the progress towards demonstrating performance of enabling technologies through component-level hardware testbeds - specifically for picometer-capable edge sensors and actuators with flight-like properties, which are needed for active sensing and control of large, segmented primary mirrors like LUVOIR. Key performance requirements include resolution, range, and operational bandwidth, which are derived from wavefront stability budgets traceable to the top-level coronagraph performance and science goals driving the ultra-stability need. Raising the TRL of these technologies will address some of the most difficult parts of the stability problem with the tightest requirements and longest lead times, as well as provide significant risk reduction for their inclusion in future mission concepts.
Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine ...mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 0.82–0.88) and ER-negative (OR = 0.87 0.82–0.91) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 0.91–0.95 and OR = 1.06 1.03–1.09) and ER-negative (OR = 0.95 0.91–0.98 and OR = 1.08 1.04–1.13) disease. There was weaker evidence for iCHAV4, located 5′ of ADO, associated only with ER-positive breast cancer (OR = 0.93 0.90–0.96). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1–4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
Some of the most visible expressions of human culture are illustrated architecturally. Unfortunately for archaeologists, the architecture being studied is not always visible and must be inferred ...from soil inconsistencies or charred remains. This study deals with research into roughly a millennium of Native American architecture in the Southeast and includes research on the variation of construction techniques employed both above and below ground. Most of the architecture discussed is that of domestic houses with some emphasis on large public buildings and sweat lodges. The authors use an array of methods and techniques in examining native architecture including experimental archaeology, ethnohistory, ethnography, multi-variant analysis, structural engineering, and wood science technology. A major portion of the work, and probably the most important in terms of overall significance, is that it addresses the debate of early Mississippian houses and what they looked like above ground and the changes that occurred both before and after the arrival of Europeans.   Contributors : Dennis B. Blanton Tamira K. Brennan  Ramie A. Gougeon Tom H. Gresham Vernon J. Knight Jr.  Cameron H. Lacquement  Robert H. Lafferty, III Mark A. McConaughy Nelson A. Reed  Robert J. Scott Lynne P. Sullivan
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