The human microbial communities are associated with many human diseases such as obesity, diabetes and inflammatory bowel disease. High-throughput sequencing technology has been widely used to ...quantify the microbial composition in order to understand its impacts on human health. Longitudinal measurements of microbial communities are commonly obtained in many microbiome studies. A key question in such microbiome studies is to identify the microbes that are associated with clinical outcomes or environmental factors. However, microbiome compositional data are highly skewed, bounded in 0,1), and often sparse with many zeros. In addition, the observations from repeated measures in longitudinal studies are correlated. A method that takes into account these features is needed for association analysis in longitudinal microbiome data.
In this paper, we propose a two-part zero-inflated Beta regression model with random effects (ZIBR) for testing the association between microbial abundance and clinical covariates for longitudinal microbiome data. The model includes a logistic regression component to model presence/absence of a microbe in the samples and a Beta regression component to model non-zero microbial abundance, where each component includes a random effect to account for the correlations among the repeated measurements on the same subject. Both simulation studies and the application to real microbiome data have shown that ZIBR model outperformed the previously used methods. The method provides a useful tool for identifying the relevant taxa based on longitudinal or repeated measures in microbiome research.
https://github.com/chvlyl/ZIBR CONTACT: hongzhe@upenn.edu.
Abnormal composition of intestinal bacteria—“dysbiosis”—is characteristic of Crohn’s disease. Disease treatments include dietary changes and immunosuppressive anti-TNFα antibodies as well as ...ancillary antibiotic therapy, but their effects on microbiota composition are undetermined. Using shotgun metagenomic sequencing, we analyzed fecal samples from a prospective cohort of pediatric Crohn’s disease patients starting therapy with enteral nutrition or anti-TNFα antibodies and reveal the full complement and dynamics of bacteria, fungi, archaea, and viruses during treatment. Bacterial community membership was associated independently with intestinal inflammation, antibiotic use, and therapy. Antibiotic exposure was associated with increased dysbiosis, whereas dysbiosis decreased with reduced intestinal inflammation. Fungal proportions increased with disease and antibiotic use. Dietary therapy had independent and rapid effects on microbiota composition distinct from other stressor-induced changes and effectively reduced inflammation. These findings reveal that dysbiosis results from independent effects of inflammation, diet, and antibiotics and shed light on Crohn disease treatments.
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•Inflammation, antibiotics, and diet independently affect microbiota in Crohn’s disease•Antibiotics are associated with bacterial dysbiosis and increased fungi•Dysbiosis decreases with reduction in intestinal inflammation•Diet has an independent and rapid effect on gut microbiota composition
Intestinal microbiota dysbiosis is characteristic of Crohn’s disease, but the contributing factors remain unclear. By examining pediatric Crohn’s disease patients, Lewis et al. show that dysbiosis is independently associated with antibiotics, inflammation, and diet and decreases with reduced intestinal inflammation. These results may facilitate biomarker discovery and therapeutic interventions.
Fast and accurate MRI image reconstruction from undersampled data is crucial in clinical practice. Deep learning based reconstruction methods have shown promising advances in recent years. However, ...recovering fine details from undersampled data is still challenging. In this paper, we introduce a novel deep learning based method, Pyramid Convolutional RNN (PC-RNN), to reconstruct images from multiple scales. Based on the formulation of MRI reconstruction as an inverse problem, we design the PC-RNN model with three convolutional RNN (ConvRNN) modules to iteratively learn the features in multiple scales. Each ConvRNN module reconstructs images at different scales and the reconstructed images are combined by a final CNN module in a pyramid fashion. The multi-scale ConvRNN modules learn a coarse-to-fine image reconstruction. Unlike other common reconstruction methods for parallel imaging, PC-RNN does not employ coil sensitive maps for multi-coil data and directly model the multiple coils as multi-channel inputs. The coil compression technique is applied to standardize data with various coil numbers, leading to more efficient training. We evaluate our model on the fastMRI knee and brain datasets and the results show that the proposed model outperforms other methods and can recover more details. The proposed method is one of the winner solutions in the 2019 fastMRI competition.
microRNAs (miRNAs) are non-coding RNAs that regulate gene expression post-transcriptionally, and mounting evidence supports the prevalence and functional significance of their interplay with ...transcription factors (TFs). Here we describe the identification of a regulatory circuit between muscle miRNAs (miR-1, miR-133 and miR-206) and Yin Yang 1 (YY1), an epigenetic repressor of skeletal myogenesis in mouse. Genome-wide identification of potential down-stream targets of YY1 by combining computational prediction with expression profiling data reveals a large number of putative miRNA targets of YY1 during skeletal myoblasts differentiation into myotubes with muscle miRs ranking on top of the list. The subsequent experimental results demonstrate that YY1 indeed represses muscle miRs expression in myoblasts and the repression is mediated through multiple enhancers and recruitment of Polycomb complex to several YY1 binding sites. YY1 regulating miR-1 is functionally important for both C2C12 myogenic differentiation and injury-induced muscle regeneration. Furthermore, we demonstrate that miR-1 in turn targets YY1, thus forming a negative feedback loop. Together, these results identify a novel regulatory circuit required for skeletal myogenesis and reinforce the idea that regulatory circuitries involving miRNAs and TFs are prevalent mechanisms.
Cell-free fetal DNA is present in the plasma of pregnant women. It consists of short DNA fragments among primarily maternally derived DNA fragments. We sequenced a maternal plasma DNA sample at up to ...65-fold genomic coverage. We showed that the entire fetal and maternal genomes were represented in maternal plasma at a constant relative proportion. Plasma DNA molecules showed a predictable fragmentation pattern reminiscent of nuclease-cleaved nucleosomes, with the fetal DNA showing a reduction in a 166-base pair (bp) peak relative to a 143-bp peak, when compared with maternal DNA. We constructed a genome-wide genetic map and determined the mutational status of the fetus from the maternal plasma DNA sequences and from information about the paternal genotype and maternal haplotype. Our study suggests the feasibility of using genome-wide scanning to diagnose fetal genetic disorders prenatally in a noninvasive way.
Gut dysbiosis during inflammatory bowel disease involves alterations in the gut microbiota associated with inflammation of the host gut. We used a combination of shotgun metagenomic sequencing and ...metabolomics to analyze fecal samples from pediatric patients with Crohn's disease and found an association between disease severity, gut dysbiosis, and bacterial production of free amino acids. Nitrogen flux studies using
N in mice showed that activity of bacterial urease, an enzyme that releases ammonia by hydrolysis of host urea, led to the transfer of murine host-derived nitrogen to the gut microbiota where it was used for amino acid synthesis. Inoculation of a conventional murine host (pretreated with antibiotics and polyethylene glycol) with commensal
engineered to express urease led to dysbiosis of the gut microbiota, resulting in a predominance of Proteobacteria species. This was associated with a worsening of immune-mediated colitis in these animals. A potential role for altered urease expression and nitrogen flux in the development of gut dysbiosis suggests that bacterial urease may be a potential therapeutic target for inflammatory bowel diseases.
The consumption of an agrarian diet is associated with a reduced risk for many diseases associated with a 'Westernised' lifestyle. Studies suggest that diet affects the gut microbiota, which ...subsequently influences the metabolome, thereby connecting diet, microbiota and health. However, the degree to which diet influences the composition of the gut microbiota is controversial. Murine models and studies comparing the gut microbiota in humans residing in agrarian versus Western societies suggest that the influence is large. To separate global environmental influences from dietary influences, we characterised the gut microbiota and the host metabolome of individuals consuming an agrarian diet in Western society.
Using 16S rRNA-tagged sequencing as well as plasma and urinary metabolomic platforms, we compared measures of dietary intake, gut microbiota composition and the plasma metabolome between healthy human vegans and omnivores, sampled in an urban USA environment. Plasma metabolome of vegans differed markedly from omnivores but the gut microbiota was surprisingly similar. Unlike prior studies of individuals living in agrarian societies, higher consumption of fermentable substrate in vegans was not associated with higher levels of faecal short chain fatty acids, a finding confirmed in a 10-day controlled feeding experiment. Similarly, the proportion of vegans capable of producing equol, a soy-based gut microbiota metabolite, was less than that was reported in Asian societies despite the high consumption of soy-based products.
Evidently, residence in globally distinct societies helps determine the composition of the gut microbiota that, in turn, influences the production of diet-dependent gut microbial metabolites.
Background
Conventional segmented, retrospectively gated cine (Conv‐cine) is challenged in patients with breath‐hold difficulties. Compressed sensing (CS) has shown values in cine imaging but ...generally requires long reconstruction time. Recent artificial intelligence (AI) has demonstrated potential in fast cine imaging.
Purpose
To compare CS‐cine and AI‐cine with Conv‐cine in quantitative biventricular functions, image quality, and reconstruction time.
Study Type
Prospective human studies.
Subjects
70 patients (age, 39 ± 15 years, 54.3% male).
Field Strength/Sequence
3T; balanced steady state free precession gradient echo sequences.
Assessment
Biventricular functional parameters of CS‐, AI‐, and Conv‐cine were measured by two radiologists independently and compared. The scan and reconstruction time were recorded. Subjective scores of image quality were compared by three radiologists.
Statistical Tests
Paired t‐test and two related‐samples Wilcoxon sign test were used to compare biventricular functional parameters between CS‐, AI‐, and Conv‐cine. Intraclass correlation coefficient (ICC), Bland–Altman analysis, and Kendall's W method were applied to evaluate agreement of biventricular functional parameters and image quality of these three sequences. A P‐value <0.05 was considered statistically significant, and standardized mean difference (SMD) < 0. 100 was considered no significant difference.
Results
Compared to Conv‐cine, no statistically significant differences were identified in CS‐ and AI‐cine function results (all P > 0.05), except for very small differences in left ventricle end‐diastole volumes of 2.5 mL (SMD = 0.082) and 4.1 mL (SMD = 0.096), respectively. Bland–Altman scatter plots revealed that biventricular function results were mostly distributed within the 95% confidence interval. All parameters had acceptable to excellent interobserver agreements (ICC: 0.748–0.989). Compared with Conv‐cine (84 ± 13 sec), both CS (14 ± 2 sec) and AI (15 ± 2 sec) techniques reduced scan time. Compared with CS‐cine (304 ± 17 sec), AI‐cine (24 ± 4 sec) reduced reconstruction time. CS‐cine demonstrated significantly lower quality scores than Conv‐cine, while AI‐cine demonstrated similar scores (P = 0.634).
Conclusion
CS‐ and AI‐cine can achieve whole‐heart cardiac cine imaging in a single breath‐hold. Both CS‐ and AI‐cine have the potential to supplement the gold standard Conv‐cine in studying biventricular functions and benefit patients having difficulties with breath‐holds.
Level of Evidence
1
Technical Efficacy Stage
1
Background and Aims Liver biopsy (LB) traditionally has been performed via a percutaneous (PC), transjugular (TJ), or surgical approach. EUS-guided LB (EUS-LB) is an emerging method that has shown ...promise in terms of tissue yield and procedural safety. Comparison of histologic yield of EUS-LB with other methods of LB has not been done. This study aimed to compare tissue yield of different LB methods. Methods EUS-LB, TJ-LB, and PC-LB were identified retrospectively. EUS-LB was obtained via transgastric and transduodenal biopsy, or via transgastric (left lobe) biopsy alone using a 19-gauge FNA needle (non-Trucut). TJ-LB specimens were obtained with an 18- or 19-gauge needle, and PC–LB specimens with an 18- or 20-gauge needle. Stained slides were digitized on a whole slide scanner, and the total specimen length (TSL) and the count of complete portal triads (CPTs) were determined. Comparisons of TSL and CPT among the 3 groups were done with Wilcoxon rank sum tests. Results Wilcoxon rank sum tests indicated that EUS-LB of both liver regions produced significantly more tissue in terms of both TSL and CPTs compared with a PC-LB ( P = .0000 and .0006). EUS-LB produced significantly longer TSL than TJ-LB ( P = .01) and similar CPTs ( P = .22). Those EUS-LB cases in which the left lobe only was sampled were not statistically different compared with PC-LB and TJ-LB. Conclusion EUS-guided-LB produces specimens at least comparable to, and in some cases better than, PC-LB or TJ-LB. Widely separated liver regions can be easily sampled, which may have some benefit. The role of EUS-LB is likely to increase in the future.
Human mesenchymal stem cells (hMSCs), including human adipose tissue-derived stem cells (hASCs), as well as the secreted extracellular vesicles (EVs), are promising therapeutics in treating ...inflammatory and neural degenerative diseases. However, prolonged expansion can lead to cellular senescence characterized by a gradual loss of self-renewal ability while altering secretome composition and EV generation. Additionally, hMSCs are highly sensitive to biophysical microenvironment in bioreactor systems utilized in scaling production. In this study, hASCs grown on Plastic Plus or Synthemax II microcarriers in a spinner flask bioreactor (SFB) system were compared to traditional 2D culture. The SFB microenvironment was found to increase the expression of genes associated with hASC stemness, nicotinamide adenine dinucleotide (NAD+) metabolism, glycolysis, and the pentose phosphate pathway as well as alter cytokine secretion (e.g., PGE2 and CXCL10). Elevated reactive oxidative species levels in hASCs of SFB culture were observed without increasing rates of cellular senescence. Expression levels of Sirtuins responsible for preventing cellular senescence through anti-oxidant and DNA repair mechanisms were also elevated in SFB cultures. In particular, the EV biogenesis genes were significantly upregulated (3–10 fold) and the EV production increased 40 % per cell in SFB cultures of hASCs. This study provides advanced understanding of hASC sensitivity to the bioreactor microenvironment for EV production and bio-manufacturing towards the applications in treating inflammatory and neural degenerative diseases.
•Human adipose-derived stem cells (hASCs) are sensitive to the bioreactor microenvironment.•The genes associated with hASC stemness, metabolism, and the pentose phosphate pathway show upregulation.•The bioreactor microenvironment alters cytokine secretion.•Bioreactor culture promotes extracellular vesicle biogenesis and secretion.
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