Leveraging wall-sized high-resolution displays for comparative genomics analyses of copy number variation

The scale of comparative genomics data frequently overwhelms current data visualization methods on conventional (desktop) displays. This paper describes two types of solution that take advantage of wall-sized high-resolution displays (WHirDs), which have orders of magnitude more display real estate (i.e., pixels) than desktop displays. The first allows users to view detailed graphics of copy number variation (CNV) that were output by existing software. A WHirD's resolution allowed a 10× increase in the granularity of bioinformatics output that was feasible for users to visually analyze, and this revealed a pattern that had previously been smoothed out from the underlying data. The second involved interactive visualization software that was innovative because it uses a music score metaphor to lay out CNV data, overcomes a perceptual distortion caused by amplification/deletion thresholds, uses filtering to reduce graphical data overload, and is the first comparative genomics visualization software that is designed to leverage a WHirD's real estate. In a field evaluation, a clinical user discovered a fundamental error in the way their data had been processed, and established confidence in the software by using it to 'find' known genetic patterns in hepatitis C-driven hepatocellular cancer

Single electron states in polyethylene

We report computer simulations of an excess electron in various structural motifs of polyethylene at room temperature, including lamellar and interfacial regions between amorphous and lamellae, as well as nanometre-sized voids. Electronic properties such as density of states, mobility edges, and mobilities are computed on the different phases using a block Lanczos algorithm. Our results suggest that the electronic density of states for a heterogeneous material can be approximated by summing the single phase density of states weighted by their corresponding volume fractions. Additionally, a quantitative connection between the localized states of the excess electron and the local atomic structure is presented.The US National Science Foundation under grant CHE-0911635 and from his Stokes Professorship in Nano Biophysics from Science Foundation Ireland thanks the Irish Centre for High End Computing (ICHEC) for computer resources and Science Foundation Ireland for support from grant 08-IN.1-I1869

WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis

Bronchiectasis: a model for chronic bacterial infection inducing autoimmunity in rheumatoid arthritis.

ArticleCopyright © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.Objective: Bronchiectasis (BR) is a risk factor for rheumatoid arthritis (RA). Here we examine the potential of BR in generating rheumatoid factors (RFs) and anti-citrullinated peptide antibodies (ACPA) in patients with BR alone and in patients with BR and RA (BRRA). Methods: We studied 122 patients with BR alone, 50 BRRA, 50 RA without lung disease, with 87 asthma and 79 healthy subjects as controls. RFs were measured by an automated analyzer, and ACPA using CCP2. Fine specificities to citrullinated α-enolase (CEP-1), citrullinated vimentin (cVim) and fibrinogen (cFib) with their arginine control peptides (REP-1, Vim and Fib) measured by ELISA. Results: In the BR patients 39% were ever smokers compared to 42% of the controls. Serum samples from BR patients had an increased frequency of RF (25%; p< 0.05) and 5% to CCP2, 7% to CEP-1, 7% to cVIM (all p=ns) and 12% cFib (p <0.05). There was also a corresponding increase in antibodies to the arginine-containing control peptides in the BR patients; REP-1, 19% (p< 0.01) and Vim, 16% (p<0.05), demonstrating that the ACPA response in BR is not citrulline-specific. Lack of citrulline specificity was further confirmed by absorption studies. In BRRA all ACPA specificities were highly citrulline-specific. Conclusion: Bronchiectasis is an unusual but potent model for the induction of autoimmunity in RA by bacterial infection in the lung. Our study suggests that in the early stages of tolerance breakdown, the ACPA response is not citrulline-specific, but becomes more so in those patients with BR that develop BRRA.Arthritis Research UKEuropean UnionIMI project BTCure7th Framework Programme project Gums and Joint

The role of transforming growth factor-beta (TGF-beta) during ovarian follicular development in sheep

BACKGROUND: Recently, several members of the transforming growth factor-beta (TGF-beta) superfamily have been shown to be essential for regulating the growth and differentiation of ovarian follicles and thus fertility. METHODS: Ovaries of neonatal and adult sheep were examined for expression of the TGF-betas 1–3 and their receptors (RI and RII) by in situ hybridization using ovine cDNAs. The effects of TGF-beta 1 and 2 on proliferation and differentiation of ovine granulosa cells in vitro were also studied. RESULTS: The expression patterns of TGF-beta 1 and 2 were similar in that both mRNAs were first observed in thecal cells of type 3 (small pre-antral) follicles. Expression of both mRNAs continued to be observed in the theca of larger follicles and was also present in cells within the stroma and associated with the vascular system of the ovary. There was no evidence for expression in granulosa cells or oocytes. Expression of TGF-beta 3 mRNA was limited to cells associated with the vascular system within the ovary. TGFbetaRI mRNA was observed in oocytes from the type 1 (primordial) to type 5 (antral) stages of follicular growth and granulosa and thecal cells expressed this mRNA at the type 3 (small pre-antral) and subsequent stages of development. The TGFbetaRI signal was also observed in the ovarian stroma and vascular cells. In ovarian follicles, mRNA encoding TGFbetaRII was restricted to thecal cells of type 3 (small pre-antral) and larger follicles. In addition, expression was also observed in some cells of the surface epithelium and in some stromal cells. In granulosa cells cultured for 6 days, both TGF-beta 1 and 2 decreased, in a dose dependent manner, both the amount of DNA and concentration of progesterone. CONCLUSION: In summary, mRNA encoding both TGF-beta 1 and 2 were synthesized by ovarian theca, stroma and cells of the vascular system whereas TGF-beta 3 mRNA was synthesized by vascular cells. Luteinizing granulosa cells also responded to both TGF-beta 1 and beta 2 in vitro. These findings in sheep are consistent with TGF-beta potentially being an important autocrine regulator of thecal cell function and possibly a paracrine regulator of ovarian cell function at various development stages

The design and evaluation of interfaces for navigating gigapixel images in digital pathology

This paper describes the design and evaluation of two generations of an interface for navigating datasets of gigapixel images that pathologists use to diagnose cancer. The interface design is innovative because users panned with an overview:detail view scale difference that was up to 57 times larger than established guidelines, and 1 million pixel ‘thumbnail’ overviews that leveraged the real-estate of high resolution workstation displays. The research involved experts performing real work (pathologists diagnosing cancer), using datasets that were up to 3150 times larger than those used in previous studies that involved navigating images. The evaluation provides evidence about the effectiveness of the interfaces, and characterizes how experts navigate gigapixel images when performing real work. Similar interfaces could be adopted in applications that use other types of high-resolution images (e.g., remote sensing or highthroughput microscopy)

IntAct:intra-operative fluorescence angiography to prevent anastomotic leak in rectal cancer surgery: a randomized controlled trial

Aim Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, the rates of AL have remained static, at around 10–15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (indocyanine green) and near‐infrared laparoscopy can minimize the rate of AL leak compared with conventional white‐light laparoscopy. Two mechanistic sub‐studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. Method IntAct is a prospective, unblinded, parallel‐group, multicentre, European, randomized controlled trial comparing surgery with intra‐operative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end‐point is rate of clinical AL at 90 days following surgery. Secondary end‐points include all AL (clinical and radiological), change in planned anastomosis, complications and re‐interventions, use of stoma, cost‐effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over 3 years, 880 patients from 25 European centres will be recruited and followed up for 90 days. Discussion IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning