Establishment and Application of a High Throughput Screening System Targeting the Interaction between HCV Internal Ribosome Entry Site and Human Eukaryotic Translation Initiation Factor 3

Viruses are intracellular obligate parasites and the host cellular machinery is usually recruited for their replication. Human eukaryotic translation initiation factor 3 (eIF3) could be directly recruited by the hepatitis C virus (HCV) internal ribosome entry site (IRES) to promote the translation of viral proteins. In this study, we establish a fluorescence polarization (FP) based high throughput screening (HTS) system targeting the interaction between HCV IRES and eIF3. By screening a total of 894 compounds with this HTS system, two compounds (Mucl39526 and NP39) are found to disturb the interaction between HCV IRES and eIF3. And these two compounds are further demonstrated to inhibit the HCV IRES-dependent translation in vitro. Thus, this HTS system is functional to screen the potential HCV replication inhibitors targeting human eIF3, which is helpful to overcome the problem of viral resistance. Surprisingly, one compound HP-3, a kind of oxytocin antagonist, is discovered to significantly enhance the interaction between HCV IRES and eIF3 by this HTS system. HP-3 is demonstrated to directly interact with HCV IRES and promote the HCV IRES-dependent translation both in vitro and in vivo, which strongly suggests that HP-3 has potentials to promote HCV replication. Therefore, this HTS system is also useful to screen the potential HCV replication enhancers, which is meaningful for understanding the viral replication and screening novel antiviral drugs. To our knowledge, this is the first HTS system targeting the interaction between eIF3 and HCV IRES, which could be applied to screen both potential HCV replication inhibitors and enhancers

Biogeography and Virulence of Staphylococcus aureus

Staphylococcus aureus is commonly carried asymptomatically in the human anterior nares and occasionally enters the bloodstream to cause invasive disease. Much of the global diversity of S. aureus remains uncharacterised, and is not clear how disease propensity varies between strains, and between host populations.We compared 147 isolates recovered from five kindergartens in Chengdu, China, with 51 isolates contemporaneously recovered from cases of pediatric infection from the main hospital serving this community. The samples were characterised by MLST, the presence/absence of PVL, and antibiotic resistance profiling.Genotype frequencies within individual kindergartens differ, but the sample recovered from cases of disease shows a general enrichment of certain MLST genotypes and PVL positive isolates. Genotypes under-represented in the disease sample tend to correspond to a single sequence cluster, and this cluster is more common in China than in other parts of the world.Virulence propensity likely reflects a synergy between variation in the core genome (MLST) and accessory genome (PVL). By combining evidence form biogeography and virulence we demonstrate the existence of a "native" clade in West China which has lowered virulence, possibility due to acquired host immunity

Non-monotonic effect of the electronic transport and magnetic properties in a Sm-doped Sr

Sr2IrO4 has been shown to host a novel $J_{\mathrm{eff}}=1/2$ Mott spin-orbit insulating state with antiferromagnetic ordering. Here, the effects of Sm substitution at Sr-site on structural, electrical and magnetic properties are studied in Sr2IrO4. Sm-doped samples still retain the insulating behavior, but with the increase of Sm-doping concentration x, the resistivity firstly decreases for $x \le 0.1$ and then increases. We found that the increment of the Ir-O-Ir bond angle, combined with the modulation of the regularity of IrO6 octahedra, results in the non-monotonic variation of resistivity with x. On the other hand, there are two types of magnetic exchange interactions (i.e., Ir4+-O-Ir4+ and Sm3+-O-Ir4+) in the Sm-doped Sr2−xSmxIrO4 system. The antiferromagnetic component is greatly suppressed in the low concentration x and then an ascension emerges in the high concentration x, which is attributable to the competition between the weakened Ir4+-O-Ir4+ and enhanced Sm3+-O-Ir4+ exchange interactions

Epidemiology and Clinical Characteristics of Pediatric Drug-Resistant Tuberculosis in Chongqing, China.

To gain insight into the epidemiology of childhood drug resistant tuberculosis (DR-TB) in China that has the second largest burden of TB and the largest number of multidrug resistant (MDR) TB cases in the world, we performed the cross-sectional study to investigate drug resistance of four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin and ethambutol) using Mycobacterium tuberculosis isolates from 196 culture-confirmed pediatric TB cases diagnosed in the Children's Hospital of Chongqing Medical University, China during 2008-2013. Univariate and multivariate logistic regression analyses were performed to assess the associations between patient demographic and clinical characteristics and DR-and MDR-TB, respectively. Twenty-eight percent (56/196) of the study patients exhibited resistance to at least one of the four first-line anti-TB drugs tested. MDR was found in 4.6% (9/196) of the study patients. More than half (5/9, 55.6%) of the MDR cases were from a single county of Chongqing. A significant association was found between being acid-fast bacilli-smear negative and DR-TB (adjusted OR, 2.33; 95% CI, 1.13-4.80) and between having concurrent thoracic-extrathoracic involvement and MDR-TB (adjusted OR, 9.49; 95% CI, 1.05-85.92), respectively. The findings of this study indicate that the rate of DR is high among pediatric TB patients in Chongqing and suggest an urgent need for studies to identify MDR transmission hotspots in Chongqing, thereby contributing to the control DR- and MDR-TB epidemics in China. The study also generates new insight into the pathogenesis of DR and MDR M. tuberculosis strains and highlights the importance of studying childhood TB to the goal of global TB control

Efficacy and Safety of Acotiamide for the Treatment of Functional Dyspepsia: Systematic Review and Meta-Analysis

Background. There are no treatments with established efficacy for this disorder so far. Aim. To systematically review the efficacy of acotiamide in the treatment of patients with FD. Methods. We searched main electronic databases through November 2013. RCTs evaluating the efficacy of acotiamide versus placebo in FD patients were included. Pooled risk ratio (RR) with 95% confidential interval (CI) was calculated. Results. Six publications including seven RCTs were eligible for inclusion. The summary RR of overall improvement of FD symptoms in patients receiving acotiamide versus placebo was 1.29 (95% CI, 1.19–1.40, P<0.00001; I2=15%). Acotiamide improved the symptoms of patients with postprandial distress syndrome (PDS) (RR, 1.29; 95% CI, 1.09–1.53, P=0.003; I2=0%), and the summary RR for patients with epigastric pain syndrome (EPS) was 0.92 (95% CI, 0.76–1.11, P=0.39; I2=0%). Acotiamide showed a significantly beneficial effect on the elimination of some individual FD symptoms compared with placebo. Adverse events were not significantly different between acotiamide and placebo groups. Subgroup analyses suggested that acotiamide 100 mg three times daily (tid) showed consistent efficacy not only for the overall improvement but also for the elimination of some individual symptoms in FD patients. Conclusions. Acotiamide has the potential to improve the symptoms of patients with FD, particularly of patients with PDS, without major adverse effects. The dosage of acotiamide 100 mg tid might be the appropriate dose in the treatment of FD

Byzantine Fault Tolerance for Collaborative Editing With Commutative Operations

In this paper, we present a study on how to achieve Byzantine fault tolerance for collaborative editing systems with commutative operations. Recent research suggests that Conflict-free Replicated Data Types (CRDTs) can be used to construct collaborative editing systems where concurrent update operations are commutative. This new approach is shown to avoid the complex issue of conflict resolution for concurrent updates to a shared document. The shared document is often modeled as a linear text buffer where each basic element is assigned a globally unique and totally ordered identifier. The linear text buffer constructed this way would constitute as a CRDT, which would make concurrent update operations issued by different users commutative. State convergence at all users can be achieved automatically as long as the users could receive the same set of operations irrespective of their relative ordering. However, it is not straightforward to guarantee state convergence in the presence of malicious users and external adversaries. In this paper, we carefully analyze the threats towards this type of systems, and propose a lightweight solution to achieve Byzantine fault tolerance with low runtime overhead. We define a set of correctness properties for such systems and prove that the proposed Byzantine fault tolerance mechanisms guarantee these properties