Effects and Action Mechanisms of Berberine and Rhizoma coptidis on Gut Microbes and Obesity in High-Fat Diet-Fed C57BL/6J Mice

Gut microbes play important roles in regulating fat storage and metabolism. Rhizoma coptidis (RC) and its main active compound, berberine, have either antimicrobial or anti-obesity activities. In the present study, we hypothesize that RC exerts anti-obesity effects that are likely mediated by mechanisms of regulating gut microbes and berberine may be a key compound of RC. Gut microbes and glucose and lipid metabolism in high-fat diet-fed C57BL/6J (HFD) mice in vivo are investigated after RC and berberine treatments. The results show that RC (200 mg/kg) and berberine (200 mg/kg) significantly lower both body and visceral adipose weights, and reduce blood glucose and lipid levels, and decrease degradation of dietary polysaccharides in HFD mice. Both RC and berberine significantly reduce the proportions of fecal Firmicutes and Bacteroidetes to total bacteria in HFD mice. In the trial ex vivo, both RC and berberine significantly inhibit the growth of gut bacteria under aerobic and anaerobic conditions. In in vitro trials, both RC and berberine significantly inhibit the growth of Lactobacillus (a classical type of Firmicutes) under anaerobic conditions. Furthermore, both RC and berberine significantly increase fasting-induced adipose factor (Fiaf, a key protein negatively regulated by intestinal microbes) expressions in either intestinal or visceral adipose tissues. Both RC and berberine significantly increase mRNA expressions of AMPK, PGC1α, UCP2, CPT1α, and Hadhb related to mitochondrial energy metabolism, which may be driven by increased Fiaf expression. These results firstly suggest that antimicrobial activities of RC and berberine may result in decreasing degradation of dietary polysaccharides, lowering potential calorie intake, and then systemically activating Fiaf protein and related gene expressions of mitochondrial energy metabolism in visceral adipose tissues. Taken together, these action mechanisms may contribute to significant anti-obesity effects. Findings in the present study also indicate that pharmacological regulation on gut microbes can develop an anti-obesity strategy

Hierarchical Classification of Pulmonary Lesions: A Large-Scale Radio-Pathomics Study

Diagnosis of pulmonary lesions from computed tomography (CT) is important but challenging for clinical decision making in lung cancer related diseases. Deep learning has achieved great success in computer aided diagnosis (CADx) area for lung cancer, whereas it suffers from label ambiguity due to the difficulty in the radiological diagnosis. Considering that invasive pathological analysis serves as the clinical golden standard of lung cancer diagnosis, in this study, we solve the label ambiguity issue via a large-scale radio-pathomics dataset containing 5,134 radiological CT images with pathologically confirmed labels, including cancers (e.g., invasive/non-invasive adenocarcinoma, squamous carcinoma) and non-cancer diseases (e.g., tuberculosis, hamartoma). This retrospective dataset, named Pulmonary-RadPath, enables development and validation of accurate deep learning systems to predict invasive pathological labels with a non-invasive procedure, i.e., radiological CT scans. A three-level hierarchical classification system for pulmonary lesions is developed, which covers most diseases in cancer-related diagnosis. We explore several techniques for hierarchical classification on this dataset, and propose a Leaky Dense Hierarchy approach with proven effectiveness in experiments. Our study significantly outperforms prior arts in terms of data scales (6x larger), disease comprehensiveness and hierarchies. The promising results suggest the potentials to facilitate precision medicine.Comment: MICCAI 2020 (Early Accepted

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie

Risk of Stillbirth in the Relation to Water Disinfection By-Products: A Population-Based Case-Control Study in Taiwan

Background: Few epidemiological studies that have assessed the relation between water disinfection by-products (DBPs) and the risk of stillbirth provide inconsistent results. The objective was to assess the relation between exposure to water disinfection by-products and the risk of stillbirth. Methods: We conducted a population-based case-control study of 3,289 cases of stillbirth and a random sample of 32,890 control subjects from 396,049 Taiwanese newborns in 2001–2003 using information from the Birth Registry and Waterworks Registry in Taiwan. We compared the risk of stillbirth in four disinfection by-product exposure categories based on the levels of total trihalomethanes (TTHMs) representing high (TTHMs 20+ mg/L), medium (TTHMs 10–19 mg/L), low exposure (TTHMs 5–9 mg/L), and 0–4 mg/L as the reference category. In addition, we conducted a meta-analysis of the results from the present and 5 previous studies focusing on stillbirth. Findings: In logistic regression analysis adjusting for gender, maternal age, plurality, conception of season and population density of the municipality where the mother lived during pregnancy, the odds ratio (OR) for stillbirth was 1.10 (95 % CI 1.00–1.21) for medium exposure and 1.06 (95 % 0.96–1.17) for high exposure compared to reference category. In the metaanalysis, the summary odds ratio for stillbirth (1.11, 95 % CI: 1.03, 1.19) was consistently elevated. Conclusions: The present study is consistent with the hypothesis that the risk of stillbirth is related to prenatal exposure t

Genomic Regions Identified by Overlapping Clusters of Nominally-Positive SNPs from Genome-Wide Studies of Alcohol and Illegal Substance Dependence

Declaring “replication” from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication is unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally-significant association in each of several independent samples. This approach provides one “nontemplate” approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 M SNP GWA results for dependence on: a) alcohol (including many individuals with dependence on other addictive substances) and b) at least one illegal substance (including many individuals dependent on alcohol). This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally-significant SNPs from samples of the same racial/ethnic background identify the same sets of chromosomal regions. It identifies several genes that are also reported in other independent alcohol-dependence GWA datasets. There is more modest confidence in: a) identification of individual chromosomal regions and genes that are not also identified by data from other independent samples, b) the more modest overlap between results from samples of different racial/ethnic backgrounds and c) the extent to which any gene not identified herein is excluded, since the power of each of these individual samples is modest. Nevertheless, the strong overlap identified among the samples with similar racial/ethnic backgrounds supports contributions to individual differences in vulnerability to addictions that come from newer allelic variants that are common in subsets of current humans

Allocating the fixed cost:an approach based on data envelopment analysis and cooperative game

Allocating the fixed cost among a set of users in a fair way is an important issue both in management and economic research. Recently, Du et al. (Eur J Oper Res 235(1): 206–214, 2014) proposed a novel approach for allocating the fixed cost based on the game cross-efficiency method by taking the game relations among users in efficiency evaluation. This paper proves that the novel approach of Du et al. (Eur J Oper Res 235(1): 206–214, 2014) is equivalent to the efficiency maximization approach of Li et al. (Omega 41(1): 55–60, 2013), and may exist multiple optimal cost allocation plans. Taking into account the game relations in the allocation process, this paper proposes a cooperative game approach, and uses the nucleolus as a solution to the proposed cooperative game. The proposed approach in this paper is illustrated with a dataset from the prior literature and a real dataset of a steel and iron enterprise in China

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined