Cell death caused by single-stranded oligodeoxynucleotide-mediated targeted genomic sequence modification

Targeted gene repair directed by single-stranded oligodeoxynucleotides (ssODNs) offers a promising tool for biotechnology and gene therapy. However, the methodology is currently limited by its low frequency of repair events, variability, and low viability of "corrected" cells. In this study, we showed that during ssODN-mediated gene repair reaction, a significant population of corrected cells failed to divide, and were much more prone to undergo apoptosis, as marked by processing of caspases and PARP-1. In addition, we found that apoptotic cell death triggered by ssODN-mediated gene repair was largely independent of the ATM/ATR kinase. Furthermore, we examined the potential involvement of the mismatch repair (MMR) proteins in this "correction reaction-induced" cell death. Result showed that while defective MMR greatly enhanced the efficiency of gene correction, compromising the MMR system did not yield any viable corrected clone, indicating that the MMR machinery, although plays a critical role in determining ssODN-directed repair, was not involved in the observed cellular genotoxic responses. © 2009. Mary Ann Liebert, Inc.published_or_final_versio

Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease.

Collagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome (AS), are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features

An Efficient Large-Area Grating Coupler for Surface Plasmon Polaritons

We report the design, fabrication and characterization of a periodic grating of shallow rectangular grooves in a metallic film with the goal of maximizing the coupling efficiency of an extended plane wave (PW) of visible or near-infrared light into a single surface plasmon polariton (SPP) mode on a flat metal surface. A PW-to-SPP power conversion factor > 45 % is demonstrated at a wavelength of 780 nm, which exceeds by an order of magnitude the experimental performance of SPP grating couplers reported to date at any wavelength. Conversion efficiency is maximized by matching the dissipative SPP losses along the grating surface to the local coupling strength. This critical coupling condition is experimentally achieved by tailoring the groove depth and width using a focused ion beam.Comment: The final publication is available at http://www.springerlink.com. http://dx.doi.org/10.1007/s11468-011-9303-

The phylogenetically-related pattern recognition receptors EFR and XA21 recruit similar immune signaling components in monocots and dicots

During plant immunity, surface-localized pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs). The transfer of PRRs between plant species is a promising strategy for engineering broad-spectrum disease resistance. Thus, there is a great interest in understanding the mechanisms of PRR-mediated resistance across different plant species. Two well-characterized plant PRRs are the leucine-rich repeat receptor kinases (LRR-RKs) EFR and XA21 from Arabidopsis thaliana (Arabidopsis) and rice, respectively. Interestingly, despite being evolutionary distant, EFR and XA21 are phylogenetically closely related and are both members of the sub-family XII of LRR-RKs that contains numerous potential PRRs. Here, we compared the ability of these related PRRs to engage immune signaling across the monocots-dicots taxonomic divide. Using chimera between Arabidopsis EFR and rice XA21, we show that the kinase domain of the rice XA21 is functional in triggering elf18-induced signaling and quantitative immunity to the bacteria Pseudomonas syringae pv. tomato (Pto) DC3000 and Agrobacterium tumefaciens in Arabidopsis. Furthermore, the EFR:XA21 chimera associates dynamically in a ligand-dependent manner with known components of the EFR complex. Conversely, EFR associates with Arabidopsis orthologues of rice XA21-interacting proteins, which appear to be involved in EFR-mediated signaling and immunity in Arabidopsis. Our work indicates the overall functional conservation of immune components acting downstream of distinct LRR-RK-type PRRs between monocots and dicots

Acupuncture for chronic neck pain: a pilot for a randomised controlled trial

Background: Acupuncture is increasingly being used for many conditions including chronic neck pain. However the evidence remains inconclusive, indicating the need for further well-designed research. The aim of this study was to conduct a pilot randomised controlled parallel arm trial, to establish key features required for the design and implementation of a large-scale trial on acupuncture for chronic neck pain. Methods: Patients whose GPs had diagnosed neck pain were recruited from one general practice, and randomised to receive usual GP care only, or acupuncture ( up to 10 treatments over 3 months) as an adjunctive treatment to usual GP care. The primary outcome measure was the Northwick Park Neck Pain Questionnaire (NPQ) at 3 months. The primary analysis was to determine the sample size for the full scale study. Results: Of the 227 patients with neck pain identified from the GP database, 28 (12.3%) consenting patients were eligible to participate in the pilot and 24 (10.5%) were recruited to the trial. Ten patients were randomised to acupuncture, receiving an average of eight treatments from one of four acupuncturists, and 14 were randomised to usual GP care alone. The sample size for the full scale trial was calculated from a clinically meaningful difference of 5% on the NPQ and, from this pilot, an adjusted standard deviation of 15.3%. Assuming 90% power at the 5% significance level, a sample size of 229 would be required in each arm in a large-scale trial when allowing for a loss to follow-up rate of 14%. In order to achieve this sample, one would need to identify patients from databases of GP practices with a total population of 230,000 patients, or approximately 15 GP practices roughly equal in size to the one involved in this study (i.e. 15,694 patients). Conclusion: This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for neck pain

Evolution of opinions on social networks in the presence of competing committed groups

Public opinion is often affected by the presence of committed groups of individuals dedicated to competing points of view. Using a model of pairwise social influence, we study how the presence of such groups within social networks affects the outcome and the speed of evolution of the overall opinion on the network. Earlier work indicated that a single committed group within a dense social network can cause the entire network to quickly adopt the group's opinion (in times scaling logarithmically with the network size), so long as the committed group constitutes more than about 10% of the population (with the findings being qualitatively similar for sparse networks as well). Here we study the more general case of opinion evolution when two groups committed to distinct, competing opinions $A$ and $B$, and constituting fractions $p_A$ and $p_B$ of the total population respectively, are present in the network. We show for stylized social networks (including Erd\H{o}s-R\'enyi random graphs and Barab\'asi-Albert scale-free networks) that the phase diagram of this system in parameter space $(p_A,p_B)$ consists of two regions, one where two stable steady-states coexist, and the remaining where only a single stable steady-state exists. These two regions are separated by two fold-bifurcation (spinodal) lines which meet tangentially and terminate at a cusp (critical point). We provide further insights to the phase diagram and to the nature of the underlying phase transitions by investigating the model on infinite (mean-field limit), finite complete graphs and finite sparse networks. For the latter case, we also derive the scaling exponent associated with the exponential growth of switching times as a function of the distance from the critical point.Comment: 23 pages: 15 pages + 7 figures (main text), 8 pages + 1 figure + 1 table (supplementary info

IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages.

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen

The 1983 drought in the West Sahel: a case study

Some drought years over sub-Saharan west Africa (1972, 1977, 1984) have been previously related to a cross-equatorial Atlantic gradient pattern with anomalously warm sea surface temperatures (SSTs) south of 10°N and anomalously cold SSTs north of 10°N. This SST dipole-like pattern was not characteristic of 1983, the third driest summer of the twentieth century in the Sahel. This study presents evidence that the dry conditions that persisted over the west Sahel in 1983 were mainly forced by high Indian Ocean SSTs that were probably remanent from the strong 1982/1983 El Niño event. The synchronous Pacific impact of the 1982/1983 El Niño event on west African rainfall was however, quite weak. Prior studies have mainly suggested that the Indian Ocean SSTs impact the decadal-scale rainfall variability over the west Sahel. This study demonstrates that the Indian Ocean also significantly affects inter-annual rainfall variability over the west Sahel and that it was the main forcing for the drought over the west Sahel in 1983

A Generalization of Otsu's Method and Minimum Error Thresholding

We present Generalized Histogram Thresholding (GHT), a simple, fast, and effective technique for histogram-based image thresholding. GHT works by performing approximate maximum a posteriori estimation of a mixture of Gaussians with appropriate priors. We demonstrate that GHT subsumes three classic thresholding techniques as special cases: Otsu's method, Minimum Error Thresholding (MET), and weighted percentile thresholding. GHT thereby enables the continuous interpolation between those three algorithms, which allows thresholding accuracy to be improved significantly. GHT also provides a clarifying interpretation of the common practice of coarsening a histogram's bin width during thresholding. We show that GHT outperforms or matches the performance of all algorithms on a recent challenge for handwritten document image binarization (including deep neural networks trained to produce per-pixel binarizations), and can be implemented in a dozen lines of code or as a trivial modification to Otsu's method or MET.Comment: ECCV 202

Effect of gas diffusion layer properties on water distribution across air-cooled, open-cathode polymer electrolyte fuel cells: A combined ex-situ X-ray tomography and in-operando neutron imaging study

In-operando diagnostic techniques provide a means of understanding the internal workings of fuel cells under normal operating conditions so that improved designs and operating regimes can be identified. Here, an approach is used which combines ex‐situ characterisation of two anode gas diffusion/microporous layers (GDL-A and GDL-B) with X-ray computed tomography (CT) and in-operando analysis using neutron imaging of operating fuel cells. The combination of TGA, SEM and X-ray CT reveals that GDL-A has a thin microporous layer with ∼26% PTFE covering a thick diffusion layer composed of ‘spaghetti’-shaped fibres. GDL-B is covered by two microporous media (29% and 6.6% PTFE) penetrating deep within the linear fibre network. The neutron imaging reveals two pathways for water transport underneath the cooling channel, either diffusing through the cathode GDL to the active channels, or diffusing through the membrane and towards the anode. The behaviour of water in the GDL is directly affected by the anode gas diffusion, PTFE content and porosity