BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells

Women who carry a germline mutation in BRCA1 gene typically develop triple negative breast cancers (TNBC) and high grade serous ovarian cancers (HGSOC). Previously, we reported that wild type BRCA1 proteins, unlike the disease-associated mutant BRCA1 proteins to bind the sole sumo E2-conjugating enzyme Ubc9. In this study, we have used clinically relevant cell lines with known BRCA1 mutations and report the in-vivo association of BRCA1 and Ubc9 in normal mammary epithelial cells but not in BRCA1 mutant HGSOC and TNBC cells by immunofluorescence analysis. BRCA1-mutant HGSOC / TNBC cells and ovarian tumor tissues showed increased expression of Ubc9 compared to BRCA1 reconstituted HGSOC, normal mammary epithelial cells and matched normal ovarian tissues. Knockdown of Ubc9 expression resulted in decreased proliferation and migration of BRCA1 mutant TNBC and HGSOC cells. This is the first study demonstrating the functional link between BRCA1 mutation, high Ubc9 expression and increased migration of HGSOC and TNBC cells. High Ubc9 expression due to BRCA1 mutation may trigger an early growth and transformation advantage to normal breast and ovarian epithelial cells resulting in aggressive cancers. Future work will focus on studying whether Ubc9 expression could show a positive correlation with BRCA1 linked HGSOC and basal like TNBC phenotype

Skin Cancers Among Albinos at a University Teaching Hospital in Northwestern Tanzania: A Retrospective Review of 64 Cases.

Skin cancers are a major risk associated with albinism and are thought to be a major cause of death in African albinos. The challenges associated with the care of these patients are numerous and need to be addressed. The aim of this study was to outline the pattern and treatment outcome of skin cancers among albinos treated at our centre and to highlight challenges associated with the care of these patients and proffer solutions for improved outcome. This was a retrospective study of all albinos with a histopathological diagnosis of skin cancer seen at Bugando Medical Centre from March 2001 to February 2010. Data collected were analyzed using descriptive statistics. A total of 64 patients were studied. The male to female ratio was 1.5:1. The median age of patients was 30 years. The median duration of illness at presentation was 24 months. The commonest reason for late presentation was financial problem. Head and the neck was the most frequent site afflicted in 46(71.8%) patients. Squamous cell carcinoma was the most common histopathological type in 75% of cases. Surgical operation was the commonest modality of treatment in 60 (93.8%) patients. Radiotherapy was given in 24(37.5%) patients. Twenty-seven (42.2%) of the patients did not complete their treatment due to lack of funds. Local recurrence following surgical treatment was recorded in 6 (30.0%) patients. Only thirty-seven (61.7%) patients were available for follow-up at 6-12 months and the remaining patients were lost to follow-up. Skin cancers are the most common cancers among albinos in our environment. Albinism and exposure to ultraviolet light appears to be the most important risk factor in the development of these cancers. Late presentation and failure to complete treatment due to financial difficulties and lack of radiotherapy services at our centre are major challenges in the care of these patients. Early institution of preventive measures, early presentation and treatment, and follow-up should be encouraged in this population for better outcome

Ocean temperature and salinity components of the Madden-Julian oscillation observed by Argo floats

New diagnostics of the Madden-Julian Oscillation (MJO) cycle in ocean temperature and, for the first time, salinity are presented. The MJO composites are based on 4 years of gridded Argo float data from 2003 to 2006, and extend from the surface to 1,400 m depth in the tropical Indian and Pacific Oceans. The MJO surface salinity anomalies are consistent with precipitation minus evaporation fluxes in the Indian Ocean, and with anomalous zonal advection in the Pacific. The Argo sea surface temperature and thermocline depth anomalies are consistent with previous studies using other data sets. The near-surface density changes due to salinity are comparable to, and partially offset, those due to temperature, emphasising the importance of including salinity as well as temperature changes in mixed-layer modelling of tropical intraseasonal processes. The MJO-forced equatorial Kelvin wave that propagates along the thermocline in the Pacific extends down into the deep ocean, to at least 1,400 m. Coherent, statistically significant, MJO temperature and salinity anomalies are also present in the deep Indian Ocean

Video-Based Real Time Analysis of Plankton Particle Size Spectrum

Plankton is one of the most basic components in the marine ecosystem. The community structure and population change of plankton are the important ecological information to reflect the environmental situation. As the fundamental parameter of the plankton community structure, size spectrum is very useful for the evaluation of the marine ecosystem. In this paper, we propose a real-time and adaptive algorithm to calculate the size spectrum of underwater plankton video, which is captured by the high-resolution and high-speed optical camera. First, this algorithm screens the high-resolution plankton images to ensure that every plankton is counted once with the clearest frame. Second, edge detection and morphological methods are performed to get plankton areas. Furthermore, we perform several simplifications that each particle is handled as ellipses shape to calculate the volume to obtain the size spectrum. Moreover, in order to facilitate the biologists to research plankton deeply, we record a region of the clear area containing each plankton to build a plankton database

Towards the glueball spectrum from unquenched lattice QCD

We use a variational technique to study heavy glueballs on gauge configurations generated with 2+1 flavours of ASQTAD improved staggered fermions. The variational technique includes glueball scattering states. The measurements were made using 2150 configurations at 0.092 fm with a pion mass of 360 MeV. We report masses for 10 glueball states. We discuss the prospects for unquenched lattice QCD calculations of the oddballs.Comment: 19 pages, 4 tables and 8 figures. One figure added. Now matches the published versio

An inventory of the Aspergillus niger secretome by combining in silico predictions with shotgun proteomics data

<p>Abstract</p> <p>Background</p> <p>The ecological niche occupied by a fungal species, its pathogenicity and its usefulness as a microbial cell factory to a large degree depends on its secretome. Protein secretion usually requires the presence of a N-terminal signal peptide (SP) and by scanning for this feature using available highly accurate SP-prediction tools, the fraction of potentially secreted proteins can be directly predicted. However, prediction of a SP does not guarantee that the protein is actually secreted and current <it>in silico </it>prediction methods suffer from gene-model errors introduced during genome annotation.</p> <p>Results</p> <p>A majority rule based classifier that also evaluates signal peptide predictions from the best homologs of three neighbouring <it>Aspergillus </it>species was developed to create an improved list of potential signal peptide containing proteins encoded by the <it>Aspergillus niger </it>genome. As a complement to these <it>in silico </it>predictions, the secretome associated with growth and upon carbon source depletion was determined using a shotgun proteomics approach. Overall, some 200 proteins with a predicted signal peptide were identified to be secreted proteins. Concordant changes in the secretome state were observed as a response to changes in growth/culture conditions. Additionally, two proteins secreted via a non-classical route operating in <it>A. niger </it>were identified.</p> <p>Conclusions</p> <p>We were able to improve the <it>in silico </it>inventory of <it>A. niger </it>secretory proteins by combining different gene-model predictions from neighbouring Aspergilli and thereby avoiding prediction conflicts associated with inaccurate gene-models. The expected accuracy of signal peptide prediction for proteins that lack homologous sequences in the proteomes of related species is 85%. An experimental validation of the predicted proteome confirmed <it>in silico </it>predictions.</p

BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that highWNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al