White adipose tissue (WAT) is an essential regulator of energy storage and systemic metabolic homeostasis. Regulatory networks consisting of immune and structural cells are necessary to maintain WAT ...metabolism, which can become impaired during obesity in mammals. Using single-cell transcriptomics and flow cytometry, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of healthy lean and obese human WAT. We report new subsets and developmental trajectories of adipose-resident innate lymphoid cells, dendritic cells and monocyte-derived macrophage populations that accumulate in obese WAT. Analysis of cell-cell ligand-receptor interactions and obesity-enriched signaling pathways revealed a switch from immunoregulatory mechanisms in lean WAT to inflammatory networks in obese WAT. These results provide a detailed and unbiased cellular landscape of homeostatic and inflammatory circuits in healthy human WAT.
Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound ...cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others.
Pioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helix DBD ...that resembles linker histone and thereby binds its target sites on nucleosomes and in compacted chromatin. Herein, we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD), Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somatic cells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to the ability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motif recognition can occur by coordinate binding between factors. Our findings provide insight into how pioneer factors can target naive chromatin sites.
Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme ...best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.
PurposeWhile the disruptive potential of artificial intelligence (AI) has been receiving growing consensus with regards to its positive influence on entrepreneurship, there is a clear lack of ...systematization in academic literature pertaining to this correlation. The current research seeks to explore the impact of AI on entrepreneurship as an enabler for entrepreneurs, taking into account the crucial application of AI within all Industry 4.0 technological paradigms, such as smart factory, the Internet of things (IoT), augmented reality (AR) and blockchain.Design/methodology/approachA systematic literature review was used to analyze all relevant studies forging connections between AI and entrepreneurship. The cluster interpretation follows a structure that we called the “AI-enabled entrepreneurial process.”FindingsThis study proves that AI has profound implications when it comes to entrepreneurship and, in particular, positively impacts entrepreneurs in four ways: through opportunity, decision-making, performance, and education and research.Practical implicationsThe framework's practical value is linked to its applications for researchers, entrepreneurs and aspiring entrepreneurs (as well as those acting entrepreneurially within established organizations) who want to unleash the power of AI in an entrepreneurial setting.Originality/valueThis research offers a model through which to interpret the impact of AI on entrepreneurship, systematizing disconnected studies on the topic and arranging contributions into paradigms of entrepreneurial and managerial literature.
Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High ...circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
The genus Quercus, which emerged ∼55 million years ago during globally warm temperatures, diversified into ∼450 extant species. We present a high-quality de novo genome assembly of a California ...endemic oak, Quercus lobata, revealing features consistent with oak evolutionary success. Effective population size remained large throughout history despite declining since early Miocene. Analysis of 39,373 mapped protein-coding genes outlined copious duplications consistent with genetic and phenotypic diversity, both by retention of genes created during the ancient γ whole genome hexaploid duplication event and by tandem duplication within families, including numerous resistance genes and a very large block of duplicated DUF247 genes, which have been found to be associated with self-incompatibility in grasses. An additional surprising finding is that subcontext-specific patterns of DNA methylation associated with transposable elements reveal broadly-distributed heterochromatin in intergenic regions, similar to grasses. Collectively, these features promote genetic and phenotypic variation that would facilitate adaptability to changing environments.
ABSTRACT
The innate immune system of patients with Alzheimer's disease and mild cognitive impairment (MCI) is deregulated with highly increased or decreased transcription of inflammatory genes and ...consistently depressed phagocytosis of amyloid‐β1–42 (Aβ) by monocytes and macrophages. Current immune therapies target single mechanisms in the adaptive immune system but not innate immunity. Here, we summarize recent advances in therapy by v‐3, v‐6, and epoxy fatty acids; specialized proresolving mediators; and vitamin D3 that have proven immune effects and emerging cognitive effects in patients with MCI. The hypothesis of this approach is that macrophages of normal participants, but not those of patients with Alzheimer's disease and MCI, possess effective phagocytosis for Aβ and protect homeostasis of the brain and, furthermore, that defective MCI macrophages recover phagocytic function via v‐3. Recent studies of fish‐derived v‐3 supplementation in patients with MCI have shown polarization of Apo«3/«3 patients’ macrophages to an intermediate M1‐M2 phenotype that is optimal for Aβ phagocytosis and the stabilization of cognitive decline. Therefore, accumulating preclinical and preliminary clinical evidence indicates that v‐3 supplementation should be tested in a randomized controlled clinical trial and that the analysis should involve the apolipoprotein E genotype and intervening conditions during trial.—Fiala, M., Kooij, G., Wagner, K., Hammock, B., Pellegrini, M. Modulation of innate immunity of patients with Alzheimer's disease by omega‐3 fatty acids. FASEB J. 31, 3229–3239 (2017). www.fasebj.org
Abstract
Motivation
DNA methylation is important for gene silencing and imprinting in both plants and animals. Recent advances in bisulfite sequencing allow detection of single nucleotide variations ...(SNVs) achieving high sensitivity, but accurately identifying heterozygous SNVs from partially C-to-T converted sequences remains challenging.
Results
We designed two methods, BayesWC and BinomWC, that substantially improved the precision of heterozygous SNV calls from ∼80% to 99% while retaining comparable recalls. With these SNV calls, we provided functions for allele-specific DNA methylation (ASM) analysis and visualizing the methylation status on reads. Applying ASM analysis to a previous dataset, we found that an average of 1.5% of investigated regions showed allelic methylation, which were significantly enriched in transposon elements and likely to be shared by the same cell-type. A dynamic fragment strategy was utilized for DMR analysis in low-coverage data and was able to find differentially methylated regions (DMRs) related to key genes involved in tumorigenesis using a public cancer dataset. Finally, we integrated 40 applications into the software package CGmapTools to analyze DNA methylomes. This package uses CGmap as the format interface, and designs binary formats to reduce the file size and support fast data retrieval, and can be applied for context-wise, gene-wise, bin-wise, region-wise and sample-wise analyses and visualizations.
Availability and implementation
The CGmapTools software is freely available at https://cgmaptools.github.io/.
Supplementary information
Supplementary data are available at Bioinformatics online.
Bisulfite sequencing using next generation sequencers yields genome-wide measurements of DNA methylation at single nucleotide resolution. Traditional aligners are not designed for mapping ...bisulfite-treated reads, where the unmethylated Cs are converted to Ts. We have developed BS Seeker, an approach that converts the genome to a three-letter alphabet and uses Bowtie to align bisulfite-treated reads to a reference genome. It uses sequence tags to reduce mapping ambiguity. Post-processing of the alignments removes non-unique and low-quality mappings.
We tested our aligner on synthetic data, a bisulfite-converted Arabidopsis library, and human libraries generated from two different experimental protocols. We evaluated the performance of our approach and compared it to other bisulfite aligners. The results demonstrate that among the aligners tested, BS Seeker is more versatile and faster. When mapping to the human genome, BS Seeker generates alignments significantly faster than RMAP and BSMAP. Furthermore, BS Seeker is the only alignment tool that can explicitly account for tags which are generated by certain library construction protocols.
BS Seeker provides fast and accurate mapping of bisulfite-converted reads. It can work with BS reads generated from the two different experimental protocols, and is able to efficiently map reads to large mammalian genomes. The Python program is freely available at http://pellegrini.mcdb.ucla.edu/BS_Seeker/BS_Seeker.html.
PDF
