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Background Gene interaction networks are graphs in which nodes represent genes and edges represent functional interactions between them. These interactions can be at multiple levels, for instance, gene regulation, protein-protein interaction, or metabolic pathways. To analyse gene interaction networks at a large scale, gene co-expression network analysis is often applied on high-throughput gene expression data such as RNA sequencing data. With the advance in sequencing technology, expression of genes can be measured in individual cells. Single-cell RNA sequencing (scRNAseq) provides insights of cellular development, differentiation and characteristics at the transcriptomic level. High sparsity and high-dimensional data structures pose challenges in scRNAseq data analysis. Results In this study, a sparse inverse covariance matrix estimation framework for scRNAseq data is developed to capture direct functional interactions between genes. Comparative analyses highlight high performance and fast computation of Stein-type shrinkage in high-dimensional data using simulated scRNAseq data. Data transformation approaches also show improvement in performance of shrinkage methods in non-Gaussian distributed data. Zero-inflated modelling of scRNAseq data based on a negative binomial distribution enhances shrinkage performance in zero-inflated data without interference on non zero-inflated count data. Conclusion The proposed framework broadens application of graphical model in scRNAseq analysis with flexibility in sparsity of count data resulting from dropout events, high performance, and fast computational time. Implementation of the framework is in a reproducible Snakemake workflow https://github.com/calathea24/ZINBGraphicalModel and R package ZINBStein https://github.com/calathea24/ZINBStein .

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFNα) and ribavirin. It achieves a sustained viral clearance in only 50-60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFNα. In patients with a rapid virological response to treatment, pegIFNα induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFNα did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.

Background Introduced Wolbachia bacteria can influence the susceptibility of Aedes aegypti mosquitoes to arboviral infections as well as having detrimental effects on host fitness. Previous field trials demonstrated that the w Mel strain of Wolbachia effectively and durably invades Ae. aegypti populations. Here we report on trials of a second strain, w MelPop-PGYP Wolbachia, in field sites in northern Australia (Machans Beach and Babinda) and central Vietnam (Tri Nguyen, Hon Mieu Island), each with contrasting natural Ae. aegypti densities. Methods Mosquitoes were released at the adult or pupal stages for different lengths of time at the sites depending on changes in Wolbachia frequency as assessed through PCR assays of material collected through Biogents-Sentinel (BG-S) traps and ovitraps. Adult numbers were also monitored through BG-S traps. Changes in Wolbachia frequency were compared across hamlets or house blocks. Results Releases of adult w MelPop -Ae. aegypti resulted in the transient invasion of w MelPop in all three field sites. Invasion at the Australian sites was heterogeneous, reflecting a slower rate of invasion in locations where background mosquito numbers were high. In contrast, invasion across Tri Nguyen was relatively uniform. After cessation of releases, the frequency of w MelPop declined in all sites, most rapidly in Babinda and Tri Nguyen. Within Machans Beach the rate of decrease varied among areas, and w MelPop was detected for several months in an area with a relatively low mosquito density. Conclusions These findings highlight challenges associated with releasing Wolbachia - Ae. aegypti combinations with low fitness, albeit strong virus interference properties, as a means of sustainable control of dengue virus transmission.

Phenotypic degeneration in Cordyceps militaris poses a significant concern for producers, yet the mechanisms underlying this phenomenon remain elusive. To address this concern, we isolated two strains that differ in their abilities to form fruiting bodies. Our observations revealed that the degenerated strain lost the capacity to develop fruiting bodies, exhibited limited radial expansion, increased spore density, and elevated intracellular glycerol levels. Transcriptome reanalysis uncovered dysregulation of genes involved in the MAPK signaling pathway in the degenerate strain. Our RT-qPCR results demonstrated reduced expression of sexual development genes, along with upregulation of genes involved in asexual sporulation, glycerol synthesis, and MAPK regulation, when compared to the wild-type strain. Additionally, we discovered that osmotic stress reduced radial growth but increased conidia sporulation and glycerol accumulation in all strains. Furthermore, hyperosmotic stress inhibited fruiting body formation in all neutralized strains. These findings indicate dysregulation of the MAPK signaling pathway, the possibility of the activation of the high-osmolarity glycerol and spore formation modules, as well as the downregulation of the pheromone response and filamentous growth cascades in the degenerate strain. Overall, our study sheds light on the mechanisms underlying Cordyceps militaris degeneration and identifies potential targets for improving cultivation practices.

Overweight/obesity and depression are both major public health problems among adolescents. However, the question of a link between overweight/obesity and depression remains unresolved in this age group. We examined whether obesity increases risk of depression, or depression increases risk of obesity, or whether there is a reciprocal effect. A two-wave prospective cohort study of adolescents aged 11–17 years at baseline (n=4175) followed up a year later (n=3134) sampled from the Houston metropolitan area. Overweight was defined as 95th percentile >body mass index (BMI) < or = 85th percentile and obese as BMI >95th percentile. Three indicators of depression were examined: any DSM-IV mood disorder, major depression, and symptoms of depression. Data for the two-wave cohort indicated no evidence of reciprocal effects between weight and depression. Weight status predicted neither major depression nor depressive symptoms. However, mood disorders generally and major depression in particular increased risk of future obesity more than twofold. Depressed males had a sixfold increased risk of obesity. Females with depressive symptoms had a marginally increased risk of being overweight but not obese. Our findings, combined with those of recent meta-analyses, suggest that obese youths are not more likely to become depressed but that depressed youths are more likely to become obese.

Refractory black carbon (rBC) mass and number concentrations were quantified by a Single Particle Soot Photometer (SP2) in the CalNex 2010 field study on board the Center for Interdisciplinary Remotely‐Piloted Aircraft Studies (CIRPAS) Twin Otter in the Los Angeles (LA) Basin in May, 2010. The mass concentrations of rBC in the LA Basin ranged from 0.002–0.530μg m−3, with an average of 0.172 μg m−3. Lower concentrations were measured in the Basin outflow regions and above the inversion layer. The SP2 afforded a quantification of the mixing state of rBC aerosols through modeling the scattering cross‐section with a core‐and‐shell Mie model to determine coating thickness. The rBC particles above the inversion layer were more thickly coated by a light‐scattering substance than those below, indicating a more aged aerosol in the free troposphere. Near the surface, as the LA plume is advected from west to east with the sea breeze, a coating of scattering material grows on rBC particles, coincident with a clear growth of ammonium nitrate within the LA Basin and the persistence of water‐soluble organic compounds as the plume travels through the outflow regions. Detailed analysis of the rBC mixing state reveals two modes of coated rBC particles; a mode with smaller rBC core diameters (∼90 nm) but thick (>200 nm) coating diameters and a mode with larger rBC cores (∼145 nm) with a thin (<75 nm) coating. The “weekend effect” in the LA Basin results in more thickly coated rBC particles, coinciding with more secondary formation of aerosol. Key Points Black carbon aerosol levels in the Los Angeles Basin are reported for May, 2010 Coatings on BC aerosol are likely organics and increase with plume age Detailed analysis of the BC mixing state reveal two size modes in the LA Basin

Background and aimsHCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis.MethodsWe assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence.ResultsWe demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV.ConclusionsWe previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD–STAT3 axis potentially driving malignant progression of HCV-associated liver disease.

ObjectiveHepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.DesignLiver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention.ResultsIn patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.ConclusionOur results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.

Previous studies on machine-learning (ML) prediction of axial capacity of composite concrete-filled steel tubular (CFST) columns under axial loading relate mainly to only one cross-section shape, meaning that they are limited to only one given application. In this paper, a ML model—namely support vector machine (SVM)—is proposed for the prediction of CFST columns with different cross-section shapes: circular, elliptical, square and rectangular, because they are the most widely used in engineering structures. A database consisting of 1093 tests was gathered from the available literature and used to train and validate the SVM model. The model’s performance was quantified by various performance indicators: coefficient of determination (R 2 ), root mean squared error, mean absolute error, Willmott’s index of agreement, and mean absolute percentage error. Based on the SVM model, sensitivity analysis, influence of different factors, parametric study and comparison with the literature are presented. A graphic user interface of the proposed model was also implemented. The model could be extended to study the effect of other cross-sectional shapes, making for wider applicability.

This study utilizes large eddy simulation, aircraft measurements, and satellite observations to identify factors that bias the absolute magnitude of metrics of aerosol-cloud-precipitation interactions for warm clouds. The metrics considered are precipitation susceptibility So, which examines rain rate sensitivity to changes in drop number, and a cloud-precipitation metric, χ, which relates changes in rain rate to those in drop size. While wide ranges in rain rate exist at fixed cloud drop concentration for different cloud liquid water amounts, χ and So are shown to be relatively insensitive to the growth phase of the cloud for large datasets that include data representing the full spectrum of cloud lifetime. Spatial resolution of measurements is shown to influence the liquid water path-dependent behavior of So and χ. Other factors of importance are the choice of the minimum rain rate threshold, and how to quantify rain rate, drop size, and the cloud condensation nucleus proxy. Finally, low biases in retrieved aerosol amounts owing to wet scavenging and high biases associated with above-cloud aerosol layers should be accounted for. The paper explores the impact of these effects for model, satellite, and aircraft data.