Molecular Effects of Doxycycline Treatment on Pterygium as Revealed by Massive Transcriptome Sequencing

Pterygium is a lesion of the eye surface which involves cell proliferation, migration, angiogenesis, fibrosis, and extracellular matrix remodelling. Surgery is the only approved method to treat this disorder, but high recurrence rates are common. Recently, it has been shown in a mouse model that treatment with doxycycline resulted in reduction of the pterygium lesions. Here we study the mechanism(s) of action by which doxycycline achieves these results, using massive sequencing techniques. Surgically removed pterygia from 10 consecutive patients were set in short term culture and exposed to 0 (control), 50, 200, and 500 µg/ml doxycycline for 24 h, their mRNA was purified, reverse transcribed and sequenced through Illumina’s massive sequencing protocols. Acquired data were subjected to quantile normalization and analyzed using cytoscape plugin software to explore the pathways involved. False discovery rate (FDR) methods were used to identify 332 genes which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors. A high correlation was obtained when comparing ultrasequencing data with qRT-PCR and ELISA results

Aberrant DNA Methylation of Matrix Remodeling and Cell Adhesion Related Genes in Pterygium

10.1371/journal.pone.0014687PLoS ONE62

Influenza Polymerase Activity Correlates with the Strength of Interaction between Nucleoprotein and PB2 through the Host-Specific Residue K/E627

The ribonucleoprotein (RNP) complex is the essential transcription-replication machinery of the influenza virus. It is composed of the trimeric polymerase (PA, PB1 and PB2), nucleoprotein (NP) and RNA. Elucidating the molecular mechanisms of RNP assembly is central to our understanding of the control of viral transcription and replication and the dependence of these processes on the host cell. In this report, we show, by RNP reconstitution assays and co-immunoprecipitation, that the interaction between NP and polymerase is crucial for the function of the RNP. The functional association of NP and polymerase involves the C-terminal ‘627’ domain of PB2 and it requires NP arginine-150 and either lysine-627 or arginine-630 of PB2. Using surface plasmon resonance, we demonstrate that the interaction between NP and PB2 takes place without the involvement of RNA. At 33, 37 and 41°C in mammalian cells, more positive charges at aa. 627 and 630 of PB2 lead to stronger NP-polymerase interaction, which directly correlates with the higher RNP activity. In conclusion, our study provides new information on the NP-PB2 interaction and shows that the strength of NP-polymerase interaction and the resulting RNP activity are promoted by the positive charges at aa. 627 and 630 of PB2

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Seismic assessment of a heavy-timber frame structure with ring-doweled moment-resisting connections

The performance of heavy-timber structures in earthquakes depends strongly on the inelastic behavior of the mechanical connections. Nevertheless, the nonlinear behavior of timber structures is only considered in the design phase indirectly through the use of an R-factor or a q-factor, which reduces the seismic elastic response spectrum. To improve the estimation of this, the seismic performance of a three-story building designed with ring-doweled moment resisting connections is analyzed here. Connections and members were designed to fulfill the seismic detailing requirements present in Eurocode 5 and Eurocode 8 for high ductility class structures. The performance of the structure is evaluated through a probabilistic approach, which accounts for uncertainties in mechanical properties of members and connections. Nonlinear static analyses and multi-record incremental dynamic analyses were performed to characterize the q-factor and develop fragility curves for different damage levels. The results indicate that the detailing requirements of Eurocode 5 and Eurocode 8 are sufficient to achieve the required performance, even though they also indicate that these requirements may be optimized to achieve more cost-effective connections and members. From the obtained fragility curves, it was verified that neglecting modeling uncertainties may lead to overestimation of the collapse capacity

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Hardware Accelerated Wavelet Transformations

. Wavelets and related multiscale representations are important means for edge detection and processing as well as for segmentation and registration. Due to the computational complexity of these approaches no interactive visualization of the extraction process is possible nowadays. By using the hardware of modern graphics workstations for accelerating wavelet decomposition and reconstruction we realize a first important step for removing lags in the visualization cycle. 1 Introduction Feature extraction has been proven to be a useful utility for segmentation and registration in volume visualization [7, 13]. Many edge detection algorithms used in this step employ wavelets or related basis functions for the internal representation of the volume. Additionally, wavelets can be used for fast volume visualization [5] using the Fourier rendering approach [8, 12]. Wavelet analysis is a mainly memory bound problem. Graphics hardware on the other hand regularly has memory systems that can be ad..

Wavelet-Based Progressive Transmission and Security Filtering for Medical Image Distribution

With the rapid expansion of computer networks, communication and storage of medical information has entered a new era. Teleclinical practice and computer digital storage are two important medical information technologies that have made the issue of data compression of crucial importance. Efficiently compressing data is the key to making teleclinical practice feasible, since the bandwidth provided by computer media is too limited for the huge amount of medical data that must be transmitted. Because of the high compressibility of the medical images, data compression is also desirable for digital storage despite the availability of inexpensive hardware for mass storage. This chapter addresses the family of progressive image compression algorithms. The progressive property is preferred because it allows users to gradually recover images from low to high quality images and to stop at any desired bit rate, including lossless recovery. A progressive transmission algorithm with automatic security filtering features for on-line medical image distribution using Daubechies&apos; wavelets has been developed and is discussed in this chapter. The system is practical for real-world applications, processing and coding each 12-bit image of size 512&amp;times;512 within 2 seconds on a Pentium Pro. Besides its exceptional speed, the security filter has demonstrated a remarkable accuracy in detecting sensitive textual information within current or digitized previous medical images