Unravelling the allosteric binding mode of αD-VxXXB at nicotinic acetylcholine receptors

αD-conotoxins are 11 kDa homodimers that potently inhibit nicotinic acetylcholine receptors (nAChRs) through a non-competitive (allosteric) mechanism. In this study, we describe the allosteric binding mode of the granulin-like C-terminal (CTD) of VxXXB bound to Lymnea stagnalis acetylcholine binding protein (Ls-AChBP), a soluble homologue of the extracellular ligand-binding domain of nAChRs. This co-crystal complex revealed a novel allosteric binding site for nAChR antagonists outside the C-loop that caps the orthosteric site defined by the nAChR agonist nicotine and the antagonist epibatidine. Mutational and docking studies on Ls-AChBP supported a two-site binding mode for full-length VxXXB, with the first CTD binding site located outside the C-loop as seen in the co-crystal complex, with a second CTD binding site located near the N-terminal end of the adjacent subunit of AChBP. These results provide new structural insight into a novel allosteric mechanism of nAChR inhibition and define the cooperative binding mode of the N-terminal domain linked granulin core domains of αD-conotoxins

Hepatitis E in southern Vietnam: Seroepidemiology in humans and molecular epidemiology in pigs.

Viral pathogens account for a significant proportion of the burden of emerging infectious diseases in humans. The Wellcome Trust-Vietnamese Initiative on Zoonotic Infections (WT-VIZIONS) is aiming to understand the circulation of viral zoonotic pathogens in animals that pose a potential risk to human health. Evidence suggests that human exposure and infections with hepatitis E virus (HEV) genotypes (GT) 3 and 4 results from zoonotic transmission. Hypothesising that HEV GT3 and GT4 are circulating in the Vietnamese pig population and can be transmitted to humans, we aimed to estimate the seroprevalence of HEV exposure in a population of farmers and the general population. We additionally performed sequence analysis of HEV in pig populations in the same region to address knowledge gaps regarding HEV circulation and to evaluate if pigs were a potential source of HEV exposure. We found a high prevalence of HEV GT3 viral RNA in pigs (19.1% in faecal samples and 8.2% in rectal swabs) and a high HEV seroprevalence in pig farmers (16.0%) and a hospital-attending population (31.7%) in southern Vietnam. The hospital population was recruited as a general-population proxy even though this particular population subgroup may introduce bias. The detection of HEV RNA in pigs indicates that HEV may be a zoonotic disease risk in this location, although a larger sample size is required to infer an association between HEV positivity in pigs and seroprevalence in humans

De Novo Transcriptome of Safflower and the Identification of Putative Genes for Oleosin and the Biosynthesis of Flavonoids

Safflower (Carthamus tinctorius L.) is one of the most extensively used oil crops in the world. However, little is known about how its compounds are synthesized at the genetic level. In this study, Solexa-based deep sequencing on seed, leaf and petal of safflower produced a de novo transcriptome consisting of 153,769 unigenes. We annotated 82,916 of the unigenes with gene annotation and assigned functional terms and specific pathways to a subset of them. Metabolic pathway analysis revealed that 23 unigenes were predicted to be responsible for the biosynthesis of flavonoids and 8 were characterized as seed-specific oleosins. In addition, a large number of differentially expressed unigenes, for example, those annotated as participating in anthocyanin and chalcone synthesis, were predicted to be involved in flavonoid biosynthesis pathways. In conclusion, the de novo transcriptome investigation of the unique transcripts provided candidate gene resources for studying oleosin-coding genes and for investigating genes related to flavonoid biosynthesis and metabolism in safflower

Risk Factors of Streptococcus suis Infection in Vietnam. A Case-Control Study

Background: Streptococcus suis infection, an emerging zoonosis, is an increasing public health problem across South East Asia and the most common cause of acute bacterial meningitis in adults in Vietnam. Little is known of the risk factors underlying the disease. Methods and Findings: A case-control study with appropriate hospital and matched community controls for each patient was conducted between May 2006 and June 2009. Potential risk factors were assessed using a standardized questionnaire and investigation of throat and rectal S. suis carriage in cases, controls and their pigs, using real-time PCR and culture of swab samples. We recruited 101 cases of S. suis meningitis, 303 hospital controls and 300 community controls. By multivariate analysis, risk factors identified for S. suis infection as compared to either control group included eating "high risk" dishes, including such dishes as undercooked pig blood and pig intestine (OR1 = 2.22; 95% CI = [1.15-4.28] and OR2 = 4.44; 95% CI = [2.15-9.15]), occupations related to pigs (OR1 = 3.84; 95% CI = [1.32-11.11] and OR2 = 5.52; 95% CI = [1.49-20.39]), and exposures to pigs or pork in the presence of skin injuries (OR1 = 7.48; 95% CI = [1.97-28.44] and OR2 = 15.96; 95% CI = [2.97-85.72]). S. suis specific DNA was detected in rectal and throat swabs of 6 patients and was cultured from 2 rectal samples, but was not detected in such samples of 1522 healthy individuals or patients without S. suis infection. Conclusions: This case control study, the largest prospective epidemiological assessment of this disease, has identified the most important risk factors associated with S. suis bacterial meningitis to be eating 'high risk' dishes popular in parts of Asia, occupational exposure to pigs and pig products, and preparation of pork in the presence of skin lesions. These risk factors can be addressed in public health campaigns aimed at preventing S. suis infectio

A Multi-Center Randomized Trial to Assess the Efficacy of Gatifloxacin versus Ciprofloxacin for the Treatment of Shigellosis in Vietnamese Children

The bacterial genus Shigella is the most common cause of dysentery (diarrhea containing blood and/or mucus) and the disease is common in developing countries with limitations in sanitation. Children are most at risk of infection and frequently require hospitalization and antimicrobial therapy. The WHO currently recommends the fluoroquinolone, ciprofloxacin, for the treatment of childhood Shigella infections. In recent years there has been a sharp increase in the number of organisms that exhibit resistance to nalidixic acid (an antimicrobial related to ciprofloxacin), corresponding with reduced susceptibility to ciprofloxacin. We hypothesized that infections with Shigella strains that demonstrate resistance to nalidixic acid may prevent effective treatment with ciprofloxacin. We performed a randomized controlled trial to compare 3 day ciprofloxacin therapy with 3 days of gatifloxacin, a newer generation fluoroquinolone with greater activity than ciprofloxacin. We measured treatment failure and time to the cessation of individual disease symptoms in 249 children with dysentery treated with gatifloxacin and 245 treated with ciprofloxacin. We could identify no significant differences in treatment failure between the two groups or in time to the cessation of individual symptoms. We conclude that, in Vietnam, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute dysentery

Digital inversion of nonlinear deterministic characteristics of Sigma Delta modulators: a mapping approach

We give a general approach to the problem of digital inversion of non-linear deterministic characteristics in a Sigma Delta modulator, This consists of going back to the elementary definition of a Sigma Delta modulator as a mapping. The difficulty of this approach is that this inversion leads to a whole set of solutions. However, it turns out that the output in an ideal Cb modulator coincides with the geometric center of this set. While this is net longer the case in the presence of non-linear analog imperfections, a general scheme for their digital compensation can be defined by systematically providing as final output the true geometric center of the set. As a preliminary validation, we show the remarquable efficiency of this general correction scheme in the case of static RDC-DAC deviations

Vector quantization analysis of Sigma Delta modulation

When considering a class of finite-dimensional input signals such as bandlimited signals in the discrete Fourier sense within a finite time window [0, T] of observation, we show that a single-loop Sigma Delta modulator behaves like the encoder of a vector quantizer, The intrinsic behavior of the modulator can be studied by analyzing the partition it generates in the input space. We show that this partition yields a particular structure that we call the `'hyperplane wave structure.'' As one consequence to this analysis, it can be proved for the considered class of bandlimited signals that the mean squared error (MSE) of reconstruction cannot asymptotically decrease with the oversampling ratio R faster than O(R(-4)), regardless of the type of reconstruction used. We then generalize this analysis to n-loop Sigma Delta modulators and show that the MSE cannot decrease faster than O(R(-(2n+2)))

Systematic approach to the digital compensation for deterministic nonideal characteristics in Sigma Delta modulation

In this brief we propose a systematic approach to the digital compensation for nonideal deterministic characteristics in a Sigma Delta modulator. It is based on inverting the complete nonlinear deterministic transfer function of the modulator. This operation leads us to a whole set of possible reconstruction estimates from which we systematically pick the geometric center as signal decoding scheme. This approach already proves effective in the particular case of static deviations in the built-in analog-to-digital converter and digital-to-analog converter of the modulator

Implicit coding for very low bit rate image compression

We explore an image compression scheme that does not rely on the usual additive decomposition of an input image into a set of predefined spanning functions. The proposed scheme only encodes implicit properties of the image and reconstructs an estimate by constrained highpass energy minimization. This has particular advantages for very lour bit rate perceptually oriented image compression. We show experimental results in a context where we mainly target the smooth areas and the edges of the image