Klebsiella pneumoniae has been the predominant pathogen of liver abscess, but ST11-K47 carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has rarely been studied as the causative ...organism. We identified an ST11-K47 CR-hvKP (HvKp-su1) from the drainage fluid of a liver abscess in a Chinese man who was diagnosed with liver abscess combined with diabetes, pneumonia, pleural infection, abdominal abscess, and splenic abscess. HvKp-su1 was non-hypermucoviscous and lacked the magA and rmpA genes and pLVPK plasmid but exhibited high virulence, with a high mortality rate (90%) to wax moth larvae (G. mellonella), similar to the hypervirulent Klebsiella pneumoniae ATCC43816 (91.67%). Whole-genome sequencing and bioinformatics analysis indicated that HvKp-su1 possesses a plasmid similar to a type of pLVPK-like plasmid (JX-CR-hvKP-2-P2), which is an uncommon plasmid in CR-hvKP. HvKp-su1 carried multiple resistance genes, including blaKPC-2. blaTEM-1, blaSHV-55, and blaCTX-M-65; hypervirulence genes such as aerobactin (iutA), salmochelin (iroEN), and yersiniabactin (ybtAEPQSTUX); and the type 3 fimbriae-encoding system (mrkACDF). Moreover, v_5377 and v_5429 (cofT, CFA/III (CS8)) located on plasmid 1 were simultaneously predicted to be virulence genes. After the long-term combination use of antibiotics, the patient successfully recovered. In summary, our study clarified the clinical and molecular characteristics of a rare ST11-K47 CR-hvKP (HvKp-su1), raising great concerns about the emergence of ST11-K47 CR-hvKP with multidrug resistance and hypervirulence, and providing insights into the control and treatment of liver abscess caused by ST11-K47 CR-hvKP.
Reinforcement-related cognitive processes, such as reward processing, inhibitory control and social-emotional regulation are critical components of externalising and internalising behaviours. It is ...unclear to what extent the deficit in each of these processes contributes to individual behavioural symptoms, how their neural substrates give rise to distinct behavioural outcomes and whether neural activation profiles across different reinforcement-related processes might differentiate individual behaviours. We created a statistical framework that enabled us to directly compare functional brain activation during reward anticipation, motor inhibition and viewing emotional faces in the European IMAGEN cohort of 2,000 14-year-old adolescents. We observe significant correlations and modulation of reward anticipation and motor inhibition networks in hyperactivity, impulsivity, inattentive behaviour and conduct symptoms, and we describe neural signatures across cognitive tasks that differentiate these behaviours. We thus characterise shared and distinct functional brain activation patterns underling different externalising symptoms and identify neural stratification markers, while accounting for clinically observed comorbidity.
Background The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of ...reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 ( RASGRF2 ) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2−/− mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Methods Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2−/− mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking ( n = 905) and ventral striatal activation during an fMRI reward task ( n = 608). Results The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 ( p < 0.001) and M6 ( p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly ( p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 ( EHD4 ) gene ( p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task ( pempirical < 0.001). Limitations It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2−/− mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Conclusion Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2−/− mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.
Affymetrix high density oligonucleotide expression arrays are widely used across all fields of biological research for measuring genome-wide gene expression. An important step in processing ...oligonucleotide microarray data is to produce a single value for the gene expression level of an RNA transcript using one of a growing number of statistical methods. The challenge for the researcher is to decide on the most appropriate method to use to address a specific biological question with a given dataset. Although several research efforts have focused on assessing performance of a few methods in evaluating gene expression from RNA hybridization experiments with different datasets, the relative merits of the methods currently available in the literature for evaluating genome-wide gene expression from Affymetrix microarray data collected from real biological experiments remain actively debated.
The present study reports a comprehensive survey of the performance of all seven commonly used methods in evaluating genome-wide gene expression from a well-designed experiment using Affymetrix microarrays. The experiment profiled eight genetically divergent barley cultivars each with three biological replicates. The dataset so obtained confers a balanced and idealized structure for the present analysis. The methods were evaluated on their sensitivity for detecting differentially expressed genes, reproducibility of expression values across replicates, and consistency in calling differentially expressed genes. The number of genes detected as differentially expressed among methods differed by a factor of two or more at a given false discovery rate (FDR) level. Moreover, we propose the use of genes containing single feature polymorphisms (SFPs) as an empirical test for comparison among methods for the ability to detect true differential gene expression on the basis that SFPs largely correspond to cis-acting expression regulators. The PDNN method demonstrated superiority over all other methods in every comparison, whilst the default Affymetrix MAS5.0 method was clearly inferior.
A comprehensive assessment of seven commonly used data extraction methods based on an extensive barley Affymetrix gene expression dataset has shown that the PDNN method has superior performance for the detection of differentially expressed genes.
It has been well established that theoretical kernel for recently surging genome-wide association study (GWAS) is statistical inference of linkage disequilibrium (LD) between a tested genetic marker ...and a putative locus affecting a disease trait. However, LD analysis is vulnerable to several confounding factors of which population stratification is the most prominent. Whilst many methods have been proposed to correct for the influence either through predicting the structure parameters or correcting inflation in the test statistic due to the stratification, these may not be feasible or may impose further statistical problems in practical implementation.
We propose here a novel statistical method to control spurious LD in GWAS from population structure by incorporating a control marker into testing for significance of genetic association of a polymorphic marker with phenotypic variation of a complex trait. The method avoids the need of structure prediction which may be infeasible or inadequate in practice and accounts properly for a varying effect of population stratification on different regions of the genome under study. Utility and statistical properties of the new method were tested through an intensive computer simulation study and an association-based genome-wide mapping of expression quantitative trait loci in genetically divergent human populations.
The analyses show that the new method confers an improved statistical power for detecting genuine genetic association in subpopulations and an effective control of spurious associations stemmed from population structure when compared with other two popularly implemented methods in the literature of GWAS.
Neuroimaging data have been widely used to understand the neural bases of human behaviors. However, most studies were either based on a few predefined regions of interest or only able to reveal ...limited vital regions, hence not providing an overarching description of the relationship between neuroimaging and behaviors. Here, we proposed a voxel‐based pattern regression that not only could investigate the overall brain‐associated variance (BAV) for a given behavioral measure but could also evaluate the shared neural bases between different behaviors across multiple neuroimaging data. The proposed method demonstrated consistently high reliability and accuracy through comprehensive simulations. We further implemented this approach on real data of adolescents (IMAGEN project, n = 2089) and adults (HCP project, n = 808) to investigate brain‐based variances of multiple behavioral measures, for instance, cognitive behaviors, substance use, and psychiatric disorders. Notably, intelligence‐related scores showed similar high BAVs with the gray matter volume across both datasets. Further, our approach allows us to reveal the latent brain‐based correlation across multiple behavioral measures, which are challenging to obtain otherwise. For instance, we observed a shared brain architecture underlying depression and externalizing problems in adolescents, while the symptom comorbidity may only emerge later in adults. Overall, our approach will provide an important statistical tool for understanding human behaviors using neuroimaging data.
We proposed an MRI‐based strategy that could investigate the overall brain‐associated variance (BAV) for a given behavioral measure and evaluate the shared neural bases (i.e., neuroimaging correlation) between different traits. Using large adolescent and adult neuroimaging datasets, we estimated different levels of BAVs and latent brain‐based correlations across multiple phenotypes.
Coxsackievirus B (CVB) can cause aseptic meningitis, myocarditis and respiratory disease, especially in newborn infants. To compare the susceptibility to CVB infection of fetal and adult mice, we ...prepared primary alveolar epithelial cells (AECs) from lungs of BALB/c mice. In contrast to fetal mouse AECs, those of adults were less susceptible to CVB3 infection, as indicated by decreased cytopathic effects, and reduced levels of viral particles bound at the cell surface. In adult mouse AECs, amplification of the viral genome and virus capsid protein VP1 synthesis were concomitantly reduced. In addition, the cell-surface expression of coxsackievirus and adenovirus receptor (CAR), which plays a key role in the initiation of CVB and pulmonary infection, was downregulated in adult mouse AECs. These findings demonstrate that adult mouse AECs are less susceptible to CVB3 due to decreased CAR levels. Thus, these findings strongly indicate that the level of virus receptors on AECs is one of the crucial determinants for the age-dependence of CVB virulence in the mouse lung.
Linkage disequilibrium (LD) plays a fundamental role in population genetics and in the current surge of studies to screen for subtle genetic variants affecting complex traits. Methods widely ...implemented in LD analyses require samples to be randomly collected, which, however, are usually ignored and thus raise the general question to the LD community of how the non-random sampling affects statistical inference of genetic association. Here we propose a new approach for inferring LD using a sample un-randomly collected from the population of interest.
Simulation study was conducted to mimic generation of samples with various degrees of non-randomness from the simulated populations of interest. The method developed in the paper outperformed its rivals in adequately estimating the disequilibrium parameters in such sampling schemes. In analyzing a 'case and control' sample with beta-thalassemia, the current method presented robustness to non-random sampling in contrast to two commonly used methods.
Through an intensive simulation study and analysis of a real dataset, we demonstrate the robustness of the proposed method to non-randomness in sampling schemes and the significant improvement of the method to provide accurate estimates of the disequilibrium parameter. This method provides a route to improve statistical reliability in association studies.
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect ...cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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