Extensive Gene-Specific Translational Reprogramming in a Model of B Cell Differentiation and Abl-Dependent Transformation

To what extent might the regulation of translation contribute to differentiation programs, or to the molecular pathogenesis of cancer? Pre-B cells transformed with the viral oncogene v-Abl are suspended in an immortalized, cycling state that mimics leukemias with a BCR-ABL1 translocation, such as Chronic Myelogenous Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL). Inhibition of the oncogenic Abl kinase with imatinib reverses transformation, allowing progression to the next stage of B cell development. We employed a genome-wide polysome profiling assay called Gradient Encoding to investigate the extent and potential contribution of translational regulation to transformation and differentiation in v-Abl-transformed pre-B cells. Over half of the significantly translationally regulated genes did not change significantly at the level of mRNA abundance, revealing biology that might have been missed by measuring changes in transcript abundance alone. We found extensive, gene-specific changes in translation affecting genes with known roles in B cell signaling and differentiation, cancerous transformation, and cytoskeletal reorganization potentially affecting adhesion. These results highlight a major role for gene-specific translational regulation in remodeling the gene expression program in differentiation and malignant transformation

Vibration-based Bayesian model updating of civil engineering structures applying Gaussian process metamodel

Structural health monitoring plays a significant role in providing information regarding the performance of structures throughout their life spans. However, information that is directly extracted from monitored data is usually susceptible to uncertainties and not reliable enough to be used for structural investigations. Finite element model updating is an accredited framework that reliably identifies structural behavior. Recently, the modular Bayesian approach has emerged as a probabilistic technique in calibrating the finite element model of structures and comprehensively addressing uncertainties. However, few studies have investigated its performance on real structures. In this article, modular Bayesian approach is applied to calibrate the finite element model of a lab-scaled concrete box girder bridge. This study is the first to use the modular Bayesian approach to update the initial finite element model of a real structure for two states—undamaged and damaged conditions—in which the damaged state represents changes in structural parameters as a result of aging or overloading. The application of the modular Bayesian approach in the two states provides an opportunity to examine the performance of the approach with observed evidence. A discrepancy function is used to identify the deviation between the outputs of the experimental and numerical models. To alleviate computational burden, the numerical model and the model discrepancy function are replaced by Gaussian processes. Results indicate a significant reduction in the stiffness of concrete in the damaged state, which is identical to cracks observed on the body of the structure. The discrepancy function reaches satisfying ranges in both states, which implies that the properties of the structure are predicted accurately. Consequently, the proposed methodology contributes to a more reliable judgment about structural safety.</p

Computation-effective structural performance assessment using Gaussian process-based finite element model updating and reliability analysis

Structural health monitoring data has been widely acknowledged as a significant source for evaluating the performance and health conditions of structures. However, a holistic framework that efficiently incorporates monitored data into structural identification and, in turn, provides a realistic life-cycle performance assessment of structures is yet to be established. There are different sources of uncertainty, such as structural parameters, computer model bias and measurement errors. Neglecting to account for these factors results in unreliable structural identifications, consequent financial losses, and a threat to the safety of structures and human lives. This paper proposes a new framework for structural performance assessment that integrates a comprehensive probabilistic finite element model updating approach, which deals with various structural identification uncertainties and structural reliability analysis. In this framework, Gaussian process surrogate models are replaced with a finite element model and its associate discrepancy function to provide a computationally efficient and all-round uncertainty quantification. Herein, the structural parameters that are most sensitive to measured structural dynamic characteristics are investigated and used to update the numerical model. Sequentially, the updated model is applied to compute the structural capacity with respect to loading demand to evaluate its as-is performance. The proposed framework’s feasibility is investigated and validated on a large lab-scale box girder bridge in two different health states, undamaged and damaged, with the latter state representing changes in structural parameters resulted from overloading actions. The results from the box girder bridge indicate a reduced structural performance evidenced by a significant drop in the structural reliability index and an increased probability of failure in the damaged state. The results also demonstrate that the proposed methodology contributes to more reliable judgment about structural safety, which in turn enables more informed maintenance decisions to be made

Recovery of Magnesium from Industrial Effluent and Its Implication on Carbon Capture and Storage

Municipal and industrial wastewater can be a potential source of magnesium. Therefore, the development of magnesium recovery technology can both release the burden of wastewater treatment and help recycle the metal, which is in high-market demand. Also, the recovery of magnesium in the form of magnesium carbonate has an implication on carbon capture and storage (CCS). In this study, fluidized bed homogeneous crystallization (FBHC) was employed for the recovery of magnesium from actual industrial effluent. The optimal conditions for the operation of FBHC were pH, 11.3; [Mg2+]/[CO32-], 1.2; surface loading rate, 1.8 kg/m2 h; and upflow velocity, 15.5 m/h, where the total recovery (TR) and crystallization (CR) efficiencies reached 88.5 and 85.4%, respectively. The recovered products were of high purity (93.5%) and in the form of nesquehonite (MgCO3·3H2O) pellets (size 1.2 mm), which could be further reused easily. From the scanning electron microscopy analysis, it was observed that they possessed a round shape and a smooth surface. In summary, FBHC is a promising recovery technology for magnesium-rich wastewater, where carbon capture and storage can be simultaneously integrated

Whole Genome Sequence Analysis of Salmonella Typhi Isolated in Thailand before and after the Introduction of a National Immunization Program

Vaccines against Salmonella Typhi, the causative agent of typhoid fever, are commonly used by travellers, however, there are few examples of national immunization programs in endemic areas. There is therefore a paucity of data on the impact of typhoid immunization programs on localised populations of S. Typhi. Here we have used whole genome sequencing (WGS) to characterise 44 historical bacterial isolates collected before and after a national typhoid immunization program that was implemented in Thailand in 1977 in response to a large outbreak; the program was highly effective in reducing typhoid case numbers. Thai isolates were highly diverse, including 10 distinct phylogenetic lineages or genotypes. Novel prophage and plasmids were also detected, including examples that were previously only reported in Shigella sonnei and Escherichia coli. The majority of S. Typhi genotypes observed prior to the immunization program were not observed following it. Post-vaccine era isolates were more closely related to S. Typhi isolated from neighbouring countries than to earlier Thai isolates, providing no evidence for the local persistence of endemic S. Typhi following the national immunization program. Rather, later cases of typhoid appeared to be caused by the occasional importation of common genotypes from neighbouring Vietnam, Laos, and Cambodia. These data show the value of WGS in understanding the impacts of vaccination on pathogen populations and provide support for the proposal that large-scale typhoid immunization programs in endemic areas could result in lasting local disease elimination, although larger prospective studies are needed to test this directly

A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure

Vibration-based Bayesian model updating of civil engineering structures applying Gaussian process metamodel

Structural health monitoring plays a significant role in providing information regarding the performance of structures throughout their life spans. However, information that is directly extracted from monitored data is usually susceptible to uncertainties and not reliable enough to be used for structural investigations. Finite element model updating is an accredited framework that reliably identifies structural behavior. Recently, the modular Bayesian approach has emerged as a probabilistic technique in calibrating the finite element model of structures and comprehensively addressing uncertainties. However, few studies have investigated its performance on real structures. In this article, modular Bayesian approach is applied to calibrate the finite element model of a lab-scaled concrete box girder bridge. This study is the first to use the modular Bayesian approach to update the initial finite element model of a real structure for two states—undamaged and damaged conditions—in which the damaged state represents changes in structural parameters as a result of aging or overloading. The application of the modular Bayesian approach in the two states provides an opportunity to examine the performance of the approach with observed evidence. A discrepancy function is used to identify the deviation between the outputs of the experimental and numerical models. To alleviate computational burden, the numerical model and the model discrepancy function are replaced by Gaussian processes. Results indicate a significant reduction in the stiffness of concrete in the damaged state, which is identical to cracks observed on the body of the structure. The discrepancy function reaches satisfying ranges in both states, which implies that the properties of the structure are predicted accurately. Consequently, the proposed methodology contributes to a more reliable judgment about structural safety

Introduction and establishment of fluoroquinolone-resistant Shigella sonnei into Bhutan

Shigella sonnei is a major contributor to the global burden of diarrhoeal disease, generally associated with dysenteric diarrhoea in developed countries but also emerging in developing countries. The reason for the recent success of S. sonnei is unknown, but is likely catalysed by its ability to acquire resistance against multiple antimicrobials. Between 2011 and 2013, S. sonnei exhibiting resistance to fluoroquinolones, the first-line treatment recommended for shigellosis, emerged in Bhutan. Aiming to reconstruct the introduction and establishment of fluoroquinolone-resistant S. sonnei populations in Bhutan, we performed whole-genome sequencing on 71 S. sonnei samples isolated in Bhutan between 2011 and 2013.We found that these strains represented an expansion of a clade within the previously described lineage III, found specifically in Central Asia. Temporal phylogenetic reconstruction demonstrated that all of the sequenced Bhutanese S. sonnei diverged from a single ancestor that was introduced into Bhutan around 2006. Our data additionally predicted that fluoroquinolone resistance, conferred by mutations in gyrA and parC, arose prior to the introduction of the founder strain into Bhutan. Once established in Bhutan, these S. sonnei had access to a broad gene pool, as indicated by the acquisition of extended-spectrum β-lactamase-encoding plasmids and genes encoding type IV pili. The data presented here outline a model for the introduction and maintenance of fluoroquinolone-resistant S. sonnei in a new setting. Given the current circulation of fluoroquinolone-resistant S. sonnei in Asia, we speculate that this pattern of introduction is being recapitulated across the region and beyond

Ventilator-associated respiratory infection in a resource-restricted setting: impact and etiology

Ventilator-associated respiratory infection (VARI) is a significant problem in resource-restricted intensive care units (ICUs), but differences in casemix and etiology means VARI in resource-restricted ICUs may be different from that found in resource-rich units. Data from these settings are vital to plan preventative interventions and assess their cost-effectiveness, but few are available.We conducted a prospective observational study in four Vietnamese ICUs to assess the incidence and impact of VARI. Patients ≥ 16 years old and expected to be mechanically ventilated &gt; 48 h were enrolled in the study and followed daily for 28 days following ICU admission.Four hundred fifty eligible patients were enrolled over 24 months, and after exclusions, 374 patients' data were analyzed. A total of 92/374 cases of VARI (21.7/1000 ventilator days) were diagnosed; 37 (9.9%) of these met ventilator-associated pneumonia (VAP) criteria (8.7/1000 ventilator days). Patients with any VARI, VAP, or VARI without VAP experienced increased hospital and ICU stay, ICU cost, and antibiotic use (p &lt; 0.01 for all). This was also true for all VARI (p &lt; 0.01 for all) with/without tetanus. There was no increased risk of in-hospital death in patients with VARI compared to those without (VAP HR 1.58, 95% CI 0.75-3.33, p = 0.23; VARI without VAP HR 0.40, 95% CI 0.14-1.17, p = 0.09). In patients with positive endotracheal aspirate cultures, most VARI was caused by Gram-negative organisms; the most frequent were Acinetobacter baumannii (32/73, 43.8%) Klebsiella pneumoniae (26/73, 35.6%), and Pseudomonas aeruginosa (24/73, 32.9%). 40/68 (58.8%) patients with positive cultures for these had carbapenem-resistant isolates. Patients with carbapenem-resistant VARI had significantly greater ICU costs than patients with carbapenem-susceptible isolates (6053 USD (IQR 3806-7824) vs 3131 USD (IQR 2108-7551), p = 0.04) and after correction for adequacy of initial antibiotics and APACHE II score, showed a trend towards increased risk of in-hospital death (HR 2.82, 95% CI 0.75-6.75, p = 0.15).VARI in a resource-restricted setting has limited impact on mortality, but shows significant association with increased patient costs, length of stay, and antibiotic use, particularly when caused by carbapenem-resistant bacteria. Evidence-based interventions to reduce VARI in these settings are urgently needed