DNA hydroxymethylation and methylation dynamics during neural differentiation

5’-methylcytosine (5mC) plays a crucial role in the epigenetic regulation of gene expression and, until recently, was the only known epigenetic mark to result from the chemical modification of bases in mammalian deoxyribonucleic acid (DNA). The discovery of 5’-hydroxymethylcytosine (5hmC) at physiologically significant levels in a wide range of tissues, particularly those of the central nervous system, suggests that this novel epigenetic modification may have a similarly important function to 5mC in transcriptional regulation. The highest levels of 5hmC have been consistently found in fully differentiated cell types, whilst stem cells seem to be characterised by very low or insignificant levels of 5hmC. It therefore appears that loss of pluripotency is associated with a substantial increase in global 5hmC levels and this modification may play a crucial role in this switch in cell fate. The central aim of this project was to investigate the potential role of 5hmC by profiling both 5mC and 5hmC in parallel during the differentiation of embryonic stem cells (ESCs) down a neural lineage, allowing for a deeper understanding of the potential function of 5hmC in the genome. Analysis of genome-wide 5mC and 5hmC patterns in ESCs, neural stem cells (NSCs) and astrocytes supported the hypothesis that dynamic changes in the distribution of both modifications contribute to neural specification. Striking differences in 5hmC levels between in vitro- and in vivo-derived samples were observed, suggesting that cell culture models may not successfully recapitulate 5hmC profiles observed during normal development. Finally, a novel method was successfully developed and validated for genome-wide 5hmC profiling (oxBS-450K), allowing sensitive and reproducible detection of 5hmC at single-base resolution

Endothelial Cell Junctional Adhesion Molecules: Role and Regulation of Expression in Inflammation

The authors are funded by the Wellcome Trust (Investigator Award to S. Nourshargh Ref: 098291/Z/12/Z). N. Reglero-Real is additionally supported by funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no [608765]

Magnetotransport properties of a magnetically modulated two-dimensional electron gas with the spin-orbit interaction

We study the electrical transport properties of a two-dimensional electron gas with the Rashba spin-orbit interaction in presence of a constant perpendicular magnetic field $(B_0 \hat z)$ which is weakly modulated by ${\bf B_1} = B_1 \cos (q x) \hat z$, where $B_1 \ll B_0$ and $q = 2 \pi/a$ with $a$ is the modulation period. We obtain the analytical expressions of the diffusive conductivities for spin-up and spin-down electrons. The conductivities for spin-up and spin-down electrons oscillate with different frequencies and produce beating patterns in the amplitude of the Weiss and Shubnikov-de Haas oscillations. We show that the Rashba strength can be determined by analyzing the beating pattern in the Weiss oscillation. We find a simple equation which determines the Rashba spin-orbit interaction strength if the number of Weiss oscillations between any two successive nodes is known from the experiment. We compare our results with the electrically modulated 2DEG with the Rashba interaction. For completeness, we also study the beating pattern formation in the collisional and the Hall conductivities.Comment: 11 pages, 5 figures, re-written with new result

Long-term results of a total knee prosthesis utilising an all polyethylene tibial component

Introduction The aim of this study was to assess the long-term performance of a cemented total knee replacement utilising an All Polyethylene Tibial (APT) component and in addition to perform an engineering analysis of any failures to help refine surgical technique. Materials and methods A total of 26 patients had a total knee replacement performed using a cemented Depuy Press Fit Condylar (PFC) APT component and a cruciate retaining femoral component. At final review all patients were assessed using The Knee Society Score together with radiographs. An engineering analysis simulated loading conditions of the implants that failed and these were compared with the performance of a modular metal-backed Tibial (MBT) component. Results A total of 20 patients were reviewed at mean time of 116 months following surgery. Knee Society Knee Scores and Function Scores in this cohort were 84/100 and 58/100, respectively. Two patients required revision for tibial component failure. Pre-operatively both had valgus deformities and in each case the tibial tray had been lateralised leaving a gap on the medial side where the APT component had no rigid support. The engineering analysis demonstrated that the volume of highly strained cancellous bone was greater in the APT design compared with the MBT design when a model with a 3 mm medial gap was loaded. The stiffer MBT base plate acted more rigidly and shielded the stress applied to the proximal tibial cancellous bone. Conclusion The APT component demonstrated satisfactory clinical and radiographic performance at long-term follow up. Appropriate cortical support of the APT component is important. The implant should be used with a degree of caution in patients with severe deformities and osteoporosis

Antimicrobial resistance in neonates with suspected sepsis

SettingNobel Medical College and Teaching Hospital, Biratnagar, Nepal.ObjectiveTo determine the pattern of antimicrobial resistance and hospital exit outcomes in neonates with suspected sepsis in a tertiary neonatal intensive care unit (NICU).DesignThis hospital-based cohort study was conducted to follow patients from January to December 2019. All identified cases of suspected sepsis were enlisted from hospital records.ResultsSepsis was suspected in 177 (88%) of the 200 cases admitted in the NICU; 52 (29%) were culture-positive. Pseudomonas was the predominant organism isolated (n = 40; 78%), followed by coagulase negative staphylococcus (n = 12, 23%). Nine (17%) of the 52 isolates were resistant to the Access and Watch group of antibiotics, including some resistance to Reserve group drugs such as imipenem and linezolid. Most treated cases (n = 170, 96%) improved, although 7 (4%) left against medical advice.ConclusionMost of the pathogens were resistant to WHO Access and Watch antibiotics and occasional resistance was observed to Reserve group drugs. Most sepsis was caused by Gram-negative bacilli. Improving turnaround times for antibiotic sensitivity testing using point-of-care testing, and a greater yield of culture-positive results are needed to enhance the management of neonatal sepsis

GPU implementation of Krylov solvers for block-tridiagonal eigenvalue problems

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-319-32149-3_18In an eigenvalue problem defined by one or two matrices with block-tridiagonal structure, if only a few eigenpairs are required it is interesting to consider iterative methods based on Krylov subspaces, even if matrix blocks are dense. In this context, using the GPU for the associated dense linear algebra may provide high performance. We analyze this in an implementation done in the context of SLEPc, the Scalable Library for Eigenvalue Problem Computations. In the case of a generalized eigenproblem or when interior eigenvalues are computed with shift-and-invert, the main computational kernel is the solution of linear systems with a block-tridiagonal matrix. We explore possible implementations of this operation on the GPU, including a block cyclic reduction algorithm.This work was partially supported by the Spanish Ministry of Economy and Competitiveness under grant TIN2013-41049-P. Alejandro Lamas was supported by the Spanish Ministry of Education, Culture and Sport through grant FPU13-06655.Lamas Daviña, A.; Román Moltó, JE. (2016). GPU implementation of Krylov solvers for block-tridiagonal eigenvalue problems. En Parallel Processing and Applied Mathematics. Springer. 182-191. https://doi.org/10.1007%2F978-3-319-32149-3_18S182191Baghapour, B., Esfahanian, V., Torabzadeh, M., Darian, H.M.: A discontinuous Galerkin method with block cyclic reduction solver for simulating compressible flows on GPUs. Int. J. Comput. Math. 92(1), 110–131 (2014)Bientinesi, P., Igual, F.D., Kressner, D., Petschow, M., Quintana-Ortí, E.S.: Condensed forms for the symmetric eigenvalue problem on multi-threaded architectures. Concur. Comput. Pract. Exp. 23, 694–707 (2011)Haidar, A., Ltaief, H., Dongarra, J.: Toward a high performance tile divide and conquer algorithm for the dense symmetric eigenvalue problem. SIAM J. Sci. Comput. 34(6), C249–C274 (2012)Heller, D.: Some aspects of the cyclic reduction algorithm for block tridiagonal linear systems. SIAM J. Numer. Anal. 13(4), 484–496 (1976)Hernandez, V., Roman, J.E., Vidal, V.: SLEPc: a scalable and flexible toolkit for the solution of eigenvalue problems. ACM Trans. Math. Softw. 31(3), 351–362 (2005)Hirshman, S.P., Perumalla, K.S., Lynch, V.E., Sanchez, R.: BCYCLIC: a parallel block tridiagonal matrix cyclic solver. J. Comput. Phys. 229(18), 6392–6404 (2010)Minden, V., Smith, B., Knepley, M.G.: Preliminary implementation of PETSc using GPUs. In: Yuen, D.A., Wang, L., Chi, X., Johnsson, L., Ge, W., Shi, Y. (eds.) GPU Solutions to Multi-scale Problems in Science and Engineering. Lecture Notes in Earth System Sciences, pp. 131–140. Springer, Heidelberg (2013)NVIDIA: CUBLAS Library V7.0. Technical report, DU-06702-001 $$\_$$ v7.0, NVIDIA Corporation (2015)Park, A.J., Perumalla, K.S.: Efficient heterogeneous execution on large multicore and accelerator platforms: case study using a block tridiagonal solver. J. Parallel and Distrib. Comput. 73(12), 1578–1591 (2013)Reguly, I., Giles, M.: Efficient sparse matrix-vector multiplication on cache-based GPUs. In: Innovative Parallel Computing (InPar), pp. 1–12 (2012)Roman, J.E., Vasconcelos, P.B.: Harnessing GPU power from high-level libraries: eigenvalues of integral operators with SLEPc. In: International Conference on Computational Science. Procedia Computer Science, vol. 18, pp. 2591–2594. Elsevier (2013)Seal, S.K., Perumalla, K.S., Hirshman, S.P.: Revisiting parallel cyclic reduction and parallel prefix-based algorithms for block tridiagonal systems of equations. J. Parallel Distrib. Comput. 73(2), 273–280 (2013)Stewart, G.W.: A Krylov-Schur algorithm for large eigenproblems. SIAM J. Matrix Anal. Appl. 23(3), 601–614 (2001)Tomov, S., Nath, R., Dongarra, J.: Accelerating the reduction to upper Hessenberg, tridiagonal, and bidiagonal forms through hybrid GPU-based computing. Parallel Comput. 36(12), 645–654 (2010)Vomel, C., Tomov, S., Dongarra, J.: Divide and conquer on hybrid GPU-accelerated multicore systems. SIAM J. Sci. Comput. 34(2), C70–C82 (2012)Zhang, Y., Cohen, J., Owens, J.D.: Fast tridiagonal solvers on the GPU. In: Proceedings of the 15th ACM SIGPLAN Symposium on Principles and Practice of Parallel Programming. PPopp 2010, pp. 127–136 (2010

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial

Background: Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction (‘optical treatment’) followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching (‘dose’), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. Methods/design: A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. Discussion: This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome

Direct in-situ single-shot measurements of the absolute carrier-envelope phases of ultrashort pulses

Many important physical processes such as nonlinear optics and coherent control are highly sensitive to the absolute carrier-envelope phase (CEP) of driving ultrashort laser pulses. This makes the measurement of CEP immensely important in relevant fields. Even though relative CEPs can be measured with a few existing technologies, the estimate of the absolute CEP is not straightforward and always requires theoretical inputs. Here, we demonstrate a novel in-situ technique based on angular streaking that can achieve such a goal without complicated calibration procedures. Single-shot measurements of the absolute CEP have been achieved with an estimated precision of 0.19 radians

Improving women's knowledge about prenatal screening in the era of non-invasive prenatal testing for Down syndrome - development and acceptability of a low literacy decision aid.

BACKGROUND: Access to information about prenatal screening is important particularly in light of new techniques such as non-invasive prenatal testing (NIPT). This study aimed to develop and examine the acceptability of a low literacy decision aid (DA) about Down syndrome screening among pregnant women with varying education levels and GPs. METHODS: We developed a DA booklet providing information about first-trimester combined testing, maternal serum screening, and NIPT. GPs and women participated in a telephone interview to examine the acceptability of the DA and measure screening knowledge before and after reading the DA. The knowledge measure was designed to assess whether women had understood the gist of the information presented in the decision aid. It comprised conceptual questions (e.g. screening tells you the chance of having a baby with Down syndrome) and numeric questions (e.g. the accuracy of different screening tests). RESULTS: Twenty-nine women and 18 GPs participated. Regardless of education level, most women found the booklet 'very' clearly presented (n = 22, 76%), and 'very' informative (n = 23, 80%). Overall, women's conceptual and numeric knowledge improved after exposure to the DA, from 4% having adequate knowledge to 69%. Women's knowledge of NIPT also improved after receiving the decision aid, irrespective of education. Most GPs found it 'very' clearly presented (n = 13, 72%), and that it would 'very much' facilitate decision-making (n = 16, 89%). CONCLUSIONS: The DA was found to be acceptable to women as well as GPs. A comprehensive evaluation of the efficacy of the decision aid compared to standard information is an important next step. Strategies are needed on how to implement the tool in practice

The effect of mixing entire male pigs prior to transport to slaughter on behaviour, welfare and carcass lesions

peer-reviewedData set for article is also provided.Research is needed to validate lesions recorded at meat inspection as indicators of pig welfare on farm. The aims were to determine the influence of mixing pigs on carcass lesions and to establish whether such lesions correlate with pig behaviour and lesions scored on farm. Aggressive and mounting behaviour of pigs in three single sex pens was recorded on Day −5, −2, and −1 relative to slaughter (Day 0). On Day 0 pigs were randomly allocated to 3 treatments (n = 20/group) over 5 replicates: males mixed with females (MF), males mixed with males (MM), and males unmixed (MUM). Aggressive and mounting behaviours were recorded on Day 0 at holding on farm and lairage. Skin/tail lesions were scored according to severity at the farm (Day −1), lairage, and on the carcass (Day 0). Effect of treatment and time on behaviour and lesions were analysed by mixed models. Spearman rank correlations between behaviour and lesion scores and between scores recorded at different stages were determined. In general, MM performed more aggressive behaviour (50.4 ± 10.72) than MUM (20.3 ± 9.55, P < 0.05) and more mounting (30.9 ± 9.99) than MF (11.4 ± 3.76) and MUM (9.8 ± 3.74, P < 0.05). Skin lesion scores increased between farm (Day −1) and lairage (P < 0.001), but this tended to be significant only for MF and MM (P = 0.08). There was no effect of treatment on carcass lesions and no associations were found with fighting/mounting. Mixing entire males prior to slaughter stimulated mounting and aggressive behaviour but did not influence carcass lesion scores. Carcass skin/tail lesions scores were correlated with scores recorded on farm (rskin = 0.21 and rtail = 0.18, P < 0.01) suggesting that information recorded at meat inspection could be used as indicators of pig welfare on farm.This study was part of the PIGWELFIND project funded by the Department of Agriculture, Food and the Marine (DAFM), Ireland