Combinatorial RNA Design: Designability and Structure-Approximating Algorithm

In this work, we consider the Combinatorial RNA Design problem, a minimal instance of the RNA design problem which aims at finding a sequence that admits a given target as its unique base pair maximizing structure. We provide complete characterizations for the structures that can be designed using restricted alphabets. Under a classic four-letter alphabet, we provide a complete characterization of designable structures without unpaired bases. When unpaired bases are allowed, we provide partial characterizations for classes of designable/undesignable structures, and show that the class of designable structures is closed under the stutter operation. Membership of a given structure to any of the classes can be tested in linear time and, for positive instances, a solution can be found in linear time. Finally, we consider a structure-approximating version of the problem that allows to extend bands (helices) and, assuming that the input structure avoids two motifs, we provide a linear-time algorithm that produces a designable structure with at most twice more base pairs than the input structure.Comment: CPM - 26th Annual Symposium on Combinatorial Pattern Matching, Jun 2015, Ischia Island, Italy. LNCS, 201

Learning from people with long-term conditions: new insights for governance in primary health care

Internationally, system-wide changes to the structures and systems governing health care aim to improve outcomes for patients, quality of care and access to services. The introduction of top-down centrally driven solutions to governance of health care, at the same time as increasing policy emphasis on greater ‘bottom up’ patient and public involvement in all aspects of health care, has set up complex tensions for policy implementation and health care practice. This paper explores the interplay of these agendas in the context of changes in primary health care services provided by the National Health Service (NHS) in England. Specifically, it looks at an example of service user involvement in a study (the PEGI study) of professional response to changes in the governance and incentives in the care of people with long-term conditions. This qualitative study was conducted in three Primary Care Trust sites in England. Service users influenced and guided the study throughout. In-depth interviews with 56 health and social care professionals engaged in the development of local policies and the delivery of care for people with complex long-term illness drew on vignettes developed by 32 members from three Service User Reference Groups (SURG). Themes generated by the cross case analysis were validated through these SURG groups. The findings presented here focus on four themes about risk and comparison of professionals’/service users’ perspectives of the issues: managing risks/consistent support, the risks of letting go/feeling in control, professionalism/helping people to help themselves, and managing expectations/professionals losing out. Service user involvement added value by: validating understandings of governance, framing debates to focus on what matters at the point of care, and enabling perspective sharing and interaction. We suggest that more collaborative forms of governance in health care, that take account of service user perspectives and enable interaction with professional groups, could help to validate processes of quality assurance and provide motivation for continuous quality improvement. We offer a model for ‘opening up’ collaborative projects to evaluation and appraisal and a process for critical reflection of the interrelationships between the PEGI study context, researcher issues, methods/approach and outcomes/impact of service user involvement

rRNA sequencing in molecular microbiological diagnosis of bacterial infections in the autopsy setting

Diagnosing the aetiology of infectious diseases at autopsy, such as pneumonia, meningitis, sepsis or SUDI, is complicated due to issues including post mortem contamination, difficulty culturing fastidious organisms and subjective interpretation of polymicrobial cultures. Death of organisms may also occur post mortem, especially if antibiotics were given to the patient, but residual DNA from non-viable organisms, amenable to molecular detection, may remain. The 16S rRNA gene is present in all bacteria with conserved and hyper-variable regions along its length, allowing amplification and sequencing of all bacterial 16S sequences present in a sample. 16S sequencing offers potential advantages over culture-based diagnostics and is increasingly used in clinical practice. It has been used to identify bacteria in formalin fixed paraffin embedded (FFPE) surgical pathology specimens but its use has not been reported in autopsy diagnosis. This talk will summarise a study aimed to assess the utility of 16S sequencing as an adjunctive microbiological test in the autopsy. Our preliminary work has used post mortem lung tissue samples from children dying with pneumonia as part of the Pneumonia Etiology Research for Child Health (PERCH) project. The technique has identified known pathogens in some cases and provided additional diagnostic information in others. The presentation will discuss the technical aspects of 16S sequencing from FFPE and autopsy material, and the issues surrounding its application to diagnosis in comparison with standard culture based diagnostics on surgical/autopsy material

OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia

Spermatocytic seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in Adark spermatogonia, SSX2-4 was present in Apale and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from Adark spermatogonia. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Controlling passively-quenched single photon detectors by bright light

Single photon detectors based on passively-quenched avalanche photodiodes can be temporarily blinded by relatively bright light, of intensity less than a nanowatt. I describe a bright-light regime suitable for attacking a quantum key distribution system containing such detectors. In this regime, all single photon detectors in the receiver Bob are uniformly blinded by continuous illumination coming from the eavesdropper Eve. When Eve needs a certain detector in Bob to produce a click, she modifies polarization (or other parameter used to encode quantum states) of the light she sends to Bob such that the target detector stops receiving light while the other detector(s) continue to be illuminated. The target detector regains single photon sensitivity and, when Eve modifies the polarization again, produces a single click. Thus, Eve has full control of Bob and can do a successful intercept-resend attack. To check the feasibility of the attack, 3 different models of passively-quenched detectors have been tested. In the experiment, I have simulated the intensity diagrams the detectors would receive in a real quantum key distribution system under attack. Control parameters and side effects are considered. It appears that the attack could be practically possible.Comment: Experimental results from a third detector model added. Minor corrections and edits made. 11 pages, 10 figure

Coma in fatal adult human malaria is not caused by cerebral oedema

<p>Abstract</p> <p>Background</p> <p>The role of brain oedema in the pathophysiology of cerebral malaria is controversial. Coma associated with severe <it>Plasmodium falciparum </it>malaria is multifactorial, but associated with histological evidence of parasitized erythrocyte sequestration and resultant microvascular congestion in cerebral vessels. To determine whether these changes cause breakdown of the blood-brain barrier and resultant perivascular or parenchymal cerebral oedema, histology, immunohistochemistry and image analysis were used to define the prevalence of histological patterns of oedema and the expression of specific molecular pathways involved in water balance in the brain in adults with fatal falciparum malaria.</p> <p>Methods</p> <p>The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection.</p> <p>Results</p> <p>The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (<it>P </it>= .02).</p> <p>Conclusions</p> <p>Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.</p

<i>Trypanosoma brucei rhodesiense</i> transmitted by a single tsetse fly bite in vervet monkeys as a model of human African trypanosomiasis

Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly was allowed to feed on each host individual, and in all cases infections were successful. The characteristics of infection and disease were similar in all hosts, but the rate of progression varied considerably. Parasites were first detected in the blood 4-10 days after infection, showing that migration of parasites from the site of fly bite was very rapid. Anaemia was a key feature of disease, with a reduction in the numbers and average size of red blood cells and associated decline in numbers of platelets and white blood cells. One to six weeks after infection, parasites were observed in the cerebrospinal fluid (CSF), indicating that they had moved from the blood into the brain; this was associated with a white cell infiltration. This study shows that fly-transmitted infection in vervets accurately mimics human disease and provides a robust model to understand better how sleeping sickness develops

String theoretic QCD axions in the light of PLANCK and BICEP2

The QCD axion solving the strong CP problem may originate from antisymmetric tensor gauge fields in compactified string theory, with a decay constant around the GUT scale. Such possibility appears to be ruled out now by the detection of tensor modes by BICEP2 and the PLANCK constraints on isocurvature density perturbations. A more interesting and still viable possibility is that the string theoretic QCD axion is charged under an anomalous U(1)_A gauge symmetry. In such case, the axion decay constant can be much lower than the GUT scale if moduli are stabilized near the point of vanishing Fayet-Illiopoulos term, and U(1)_A-charged matter fields get a vacuum value far below the GUT scale due to a tachyonic SUSY breaking scalar mass. We examine the symmetry breaking pattern of such models during the inflationary epoch with the Hubble expansion rate 10^{14} GeV, and identify the range of the QCD axion decay constant, as well as the corresponding relic axion abundance, consistent with known cosmological constraints. In addition to the case that the PQ symmetry is restored during inflation, there are other viable scenarios, including that the PQ symmetry is broken during inflation at high scales around 10^{16}-10^{17} GeV due to a large Hubble-induced tachyonic scalar mass from the U(1)_A D-term, while the present axion scale is in the range 10^{9}-5\times 10^{13} GeV, where the present value larger than 10^{12} GeV requires a fine-tuning of the axion misalignment angle. We also discuss the implications of our results for the size of SUSY breaking soft masses.Comment: 29 pages, 1 figure; v3: analysis updated including the full anharmonic effects, references added, version accepted for publication in JHE

Language and social/emotional problems identified at a universal developmental assessment at 30 months

Non peer reviewedPublisher PD

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research