Identification of differentially expressed sense and antisense transcript pairs in breast epithelial tissues

Background: More than 20% of human transcripts have naturally occurring antisense products (or natural antisense transcripts – NATs), some of which may play a key role in a range of human diseases. To date, several databases of in silico defined human sense-antisense (SAS) pairs have appeared, however no study has focused on differential expression of SAS pairs in breast tissue. We therefore investigated the expression levels of sense and antisense transcripts in normal and malignant human breast epithelia using the Affymetrix HG-U133 Plus 2.0 and Almac Diagnostics Breast Cancer DSA microarray technologies as well as massively parallel signature sequencing (MPSS) data. Results: The expression of more than 2500 antisense transcripts were detected in normal breast duct luminal cells and in primary breast tumors substantially enriched for their epithelial cell content by DSA microarray. Expression of 431 NATs were confirmed by either of the other two technologies. A corresponding sense transcript could be identified on DSA for 257 antisense transcripts. Of these SAS pairs, 163 have not been previously reported. A positive correlation of differential expression between normal and malignant breast samples was observed for most SAS pairs. Orientation specific RT-QPCR of selected SAS pairs validated their expression in several breast cancer cell lines and solid breast tumours. Conclusion: Disease-focused and antisense enriched microarray platforms (such as Breast Cancer DSA) confirm the assumption that antisense transcription in the human breast is more prevalent than previously anticipated. Expression of a proportion of these NATs has already been confirmed by other technologies while the true existence of the remaining ones has to be validated. Nevertheless, future studies will reveal whether the relative abundances of antisense and sense transcripts have regulatory influences on the translation of these mRNAs

Production of metal-free diamond nanoparticles

In this paper, the controlled production of high-quality metal-free diamond nanoparticles is demonstrated. Milling with tempered steel is shown to leave behind iron oxide contamination which is difficult to remove. Milling with SiN alleviates this issue but generates more nondiamond carbon. Thus, the choice of milling materials is critically determined by the acceptable contaminants in the ultimate application. The removal of metal impurities, present in all commercially available nanoparticles, will open new possibilities toward the production of customized diamond nanoparticles, covering the most demanding quantum applications

Assessing Human Genetic Variations in Glucose Transporter SLC2A10 and Their Role in Altering Structural and Functional Properties

Purpose: Demand is increasing for clinical genomic sequencing to provide diagnoses for patients presenting phenotypes indicative of genetic diseases, but for whom routine genetic testing failed to yield a diagnosis. DNA-based testing using high-throughput technologies often identifies variants with insufficient evidence to determine whether they are disease-causal or benign, leading to categorization as variants of uncertain significance (VUS).Methods: We used molecular modeling and simulation to generate specific hypotheses for the molecular effects of variants in the human glucose transporter, GLUT10 (SLC2A10). Similar to many disease-relevant membrane proteins, no experimentally derived 3D structure exists. An atomic model was generated and used to evaluate multiple variants, including pathogenic, benign, and VUS.Results: These analyses yielded detailed mechanistic data, not currently predictable from sequence, including altered protein stability, charge distribution of ligand binding surfaces, and shifts toward or away from transport-competent conformations. Consideration of the two major conformations of GLUT10 was important as variants have conformation-specific effects. We generated detailed molecular hypotheses for the functional impact of variants in GLUT10 and propose means to determine their pathogenicity.Conclusion: The type of workflow we present here is valuable for increasing the throughput and resolution with which VUS effects can be assessed and interpreted

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

SeekFusion - A Clinically Validated Fusion Transcript Detection Pipeline for PCR-Based Next-Generation Sequencing of RNA

Detecting gene fusions involving driver oncogenes is pivotal in clinical diagnosis and treatment of cancer patients. Recent developments in next-generation sequencing (NGS) technologies have enabled improved assays for bioinformatics-based gene fusions detection. In clinical applications, where a small number of fusions are clinically actionable, targeted polymerase chain reaction (PCR)-based NGS chemistries, such as the QIAseq RNAscan assay, aim to improve accuracy compared to standard RNA sequencing. Existing informatics methods for gene fusion detection in NGS-based RNA sequencing assays traditionally use a transcriptome-based spliced alignment approach or a de-novo assembly approach. Transcriptome-based spliced alignment methods face challenges with short read mapping yielding low quality alignments. De-novo assembly-based methods yield longer contigs from short reads that can be more sensitive for genomic rearrangements, but face performance and scalability challenges. Consequently, there exists a need for a method to efficiently and accurately detect fusions in targeted PCR-based NGS chemistries. We describe SeekFusion, a highly accurate and computationally efficient pipeline enabling identification of gene fusions from PCR-based NGS chemistries. Utilizing biological samples processed with the QIAseq RNAscan assay and in-silico simulated data we demonstrate that SeekFusion gene fusion detection accuracy outperforms popular existing methods such as STAR-Fusion, TOPHAT-Fusion and JAFFA-hybrid. We also present results from 4,484 patient samples tested for neurological tumors and sarcoma, encompassing details on some novel fusions identified

Content Disputes in Wikipedia Reflect Geopolitical Instability

Indicators that rank countries according socioeconomic measurements are important tools for regional development and political reform. Those currently in widespread use are sometimes criticized for a lack of reproducibility or the inability to compare values over time, necessitating simple, fast and systematic measures. Here, we applied the ‘guilt by association’ principle often used in biological networks to the information network within the online encyclopedia Wikipedia to create an indicator quantifying the degree to which pages linked to a country are disputed by contributors. The indicator correlates with metrics of governance, political or economic stability about as well as they correlate with each other, and though faster and simpler, it is remarkably stable over time despite constant changes in the underlying disputes. For some countries, changes over a four year period appear to correlate with world events related to conflicts or economic problems

No straight lines – young women’s perceptions of their mental health and wellbeing during and after pregnancy: a systematic review and meta-ethnography

Background: Young mothers face mental health challenges during and after pregnancy including increased rates of depression compared to older mothers. While the prevention of teenage pregnancy in countries such as the United States and the United Kingdom has been a focus for policy and research in recent decades, the need to understand young women’s own experiences has been highlighted. The aim of this meta-ethnography was to examine young women’s perceptions of their mental health and wellbeing during and after pregnancy to provide new understandings of those experiences. Methods: A systematic review and meta-ethnographic synthesis of qualitative research was conducted. Seven databases were systematically searched and forward and backward searching conducted. Papers were included if they were from Organisation for Economic Co-operation and Development countries and explored mental health and wellbeing experiences of young mothers (age under 20 in pregnancy; under 25 at time of research) as a primary research question – or where evidence about mental health and wellbeing from participants was foregrounded. Nineteen papers were identified and the Critical Appraisal Skills Programme checklist for qualitative research used to appraise the evidence. Following the seven-step process of meta-ethnography, key constructs were examined within each study and then translated into one another. Results: Seven translated themes were identified forming a new line of argument wherein mental health and wellbeing was analysed as relating to individual bodily experiences; tied into past and present relationships; underpinned by economic insecurity and entangled with feelings of societal surveillance. There were ‘no straight lines’ in young women’s experiences, which were more complex than dominant narratives around overcoming adversity suggest. Conclusions: The synthesis concludes that health and social care professionals need to reflect on the operation of power and stigma in young women’s lives and its impact on wellbeing. It adds to understanding of young women’s mental health and wellbeing during and after pregnancy as located in physical and structural factors rather than individual capacities alone

EXIT-chart aided hybrid multiuser detector design for frequency-domain-spread chip-interleaved MC-CDMA

With the advent of EXtrinsic Information Transfer (EXIT) charts, we are capable of analyzing, predicting and visually comparing the convergence behaviours of different turbo Multi-User Detectector (MUD)s. The different MUDs have diverse EXIT characteristics and hence their superposition allows us to create a combined EXIT curve, which closely matches that of the channel decoder. Hence a near-capacity operation is facilitated by combining the benifits of different MUDs and therefore to create a superior MUD. Thus in this contribution, we propose a novel hybrid MUD combining scheme, which combines the advantages of a high performance and low complexity in form of an advanced hybrid MUD solution. The transmitted bits are unknown at the receiver, hence it is not feasible to directly evaluate the mutual information gain of the iterative MUD in consecutive iterations, hence we propose a realistic algorithm for estimating this mutual information gain, which is then used for activating the most appropriate constituent MUD as and when it is necessary. The constituent MUDs are the Matched Filter (MF) based Soft Interference Cancellation (SoIC) and the optimum Bayesian MUDs, which are invoked in the scenario of Frequency-Domain-Spread Chip-Interleaved (FDSCI) Multiple Carrier Code Division Multiple Access (MC-CDMA). The resultant hybrid MUD is capable of outperforming both the MF-SoIC and Bayesian turbo MUDs in the terms of the attainable complexity and Bit-Error-Rate (BER) performance

Plasma-photonic spatiotemporal synchronization of relativistic electron and laser beams

Modern particle accelerators and their applications increasingly rely on precisely coordinated interactions of intense charged particle and laser beams. Femtosecond-scale synchronization alongside micrometre-scale spatial precision are essential e.g. for pump-probe experiments, seeding and diagnostics of advanced light sources and for plasma-based accelerators. State-of-the-art temporal or spatial diagnostics typically operate with low-intensity beams to avoid material damage at high intensity. As such, we present a plasma-based approach, which allows measurement of both temporal and spatial overlap of high-intensity beams directly at their interaction point. It exploits amplification of plasma afterglow arising from the passage of an electron beam through a laser-generated plasma filament. The corresponding photon yield carries the spatiotemporal signature of the femtosecond-scale dynamics, yet can be observed as a visible light signal on microsecond-millimetre scales

Duchamp's Erotic Stereoscopic Exercises

This article explores certain links between medicine and art, with regard to their use of stereoscopy. I highlight a work by the artist Marcel Duchamp (the ready-made Stéréoscopie a la Main) and stereoscopic cards used in ophthalmic medicine. Both instances involve the drawing of graphic marks over previously existing stereoscopic cards. This similarity between Stéréoscopie a la Main and stereoscopic cards is echoed in the form of "stereoscopic exercises." Stereoscopic exercises were prescribed by doctors to be performed with the stereoscope as early as 1864. Stereoscopic cards were widely diffused in the 19th century, often promoted as "stay-at-home travel." It was over such kinds of materials that both Marcel Duchamp and doctors of ophthalmic medicine drew their graphic marks. I explore Duchamp's Stéréoscopie a la Main as a hypothetical basis for stereoscopic exercises of different types, proposing that this rectified ready-made is the locus for erotic stereoscopic exercises.Este artigo busca explorar certos elos entre a medicina e a arte por meio da estereoscopia. Destaca-se uma obra do artista Marcel Duchamp (o ready-made Stéréoscopie a la Main) e cartões estereoscópicos usados na oftalmologia. As duas instâncias envolvem o desenho de marcas gráficas sobre cartões estereoscópicos pré-existentes. A similaridade entre Stéréoscopie a la Main e os ditos cartões ecoa também na forma dos exercícios estereoscópicos. O cartão estereoscópico foi amplamente difundido na segunda metade do séc. XIX, frequentemente na forma da "viagem sem sair de casa." Foi sobre esse tipo de material que tanto médicos quanto Marcel Duchamp desenharam suas marcas. Explora-se a obra Stéréoscopie a la Main como um sítio hipotético para uma espécie de exercício, propondo que tal ready-made retificado seja um lugar para exercícios estereoscópicos eróticos