Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete
. Here we present EpiMap, a ...compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits
, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.
Finding a causal gene is a fundamental problem in genomic medicine. We present a causal inference framework, CoCoA-diff, that prioritizes disease genes by adjusting confounders without prior ...knowledge of control variables in single-cell RNA-seq data. We demonstrate that our method substantially improves statistical power in simulations and real-world data analysis of 70k brain cells collected for dissecting Alzheimer's disease. We identify 215 differentially regulated causal genes in various cell types, including highly relevant genes with a proper cell type context. Genes found in different types enrich distinctive pathways, implicating the importance of cell types in understanding multifaceted disease mechanisms.
We investigate the manner in which a desire to emulate the rich influences individuals' allocation of time between labour and leisure, greater inequality inducing longer work hours as a result. Data ...on work hours in ten countries over the period 1963-98 show that greater inequality is indeed associated longer work hours. These 'Veblen effects' are large and the estimates are robust using country fixed effects and other specifications. Because consumption inequality is a public bad, a social welfare optimum cannot be implemented by a flat tax on consumption but may be accomplished by more complicated (progressive) consumption taxes.
Deformable organic light-emitting diode (OLED) based optoelectronic devices hold promise for various wearable applications including biomedical systems and displays, but current OLED technologies ...require high voltage and lack the power needed for wearable photodynamic therapy (PDT) applications and wearable displays. This paper presents a parallel-stacked OLED (PAOLED) with high power, more than 100 mW/cm
, at low voltage (<8 V). The current dispersion ratio can be tuned by optimizing the structure of the individual OLEDs stacked to create the PAOLED, allowing control of the PAOLED's wavelength shapes, current efficiency, and power. In this study, a fabricated PAOLED operated reliably for 100 h at a high power of 35 mW/cm
. Confirming its potential application to PDT, the measured singlet oxygen generation ratio of the PAOLED was found to be 3.8 times higher than the reference OLED. The high-power PAOLED achieved a 24% reduction in melanoma cancer cell viability after a short (0.5 h) irradiation. In addition, a white light PAOLED with color tuning was realized through OLED color combination, and a high brightness of over 30 000 cd/m
was realized, below 8.5 V. In conclusion, the PAOLED was demonstrated to be suitable for a variety of low-voltage, high-power wearable optoelectronic applications.
Background
In this study, a hydrogel comprising poly (vinyl alcohol)/pectin (PVA/PET) was prepared by the addition of
Melia azedarach
extract for epithelial restoration.
M
.
azedarach
extract (MAE) ...contains volatile organic plant-derived compounds with antimicrobial properties. MAE has a variety of physiological properties, including antimicrobial, insecticidal, and anti-inflammatory activity. This study aimed to investigate whether MAE-loaded PVA/PET hydrogels have protective effects against burn wound healing.
Methods and findings
To mix
M
.
azedarach
with the gel, nanoparticles containing
M
.
azedarach
were prepared using chitosan/maltodextrin as the wall material. A PVA/PET hydrogel containing
M
.
azedarach
was developed and its applicability as a wound dressing was evaluated. In the in vitro scratch assay, MAE treatment showed a scratch recovery-promoting effect comparable to that of the positive control TGF-β1. The MAE-PVA/PET hydrogel was found to be non-toxic, and the antibacterial activity of the hydrogel was excellent against both gram-positive and gram-negative bacteria. Furthermore, as the formulated hydrogel demonstrated strong antimicrobial activity, its wound-healing efficacy was investigated in vivo using a rat model.
Conclusion
MAE was found to be effective against burn wounds and to have antimicrobial activity in vitro and in vivo.
Recent work has identified dozens of non-coding loci for Alzheimer’s disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile ...epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.
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•Brain regulome from 850,000 RNA and ATAC cells in 92 individuals with and without AD•Methodology to jointly integrate snRNA and snATAC cells and link peaks to genes•AD risk loci prioritization and interpretation with regulatory links and ATAC-QTLs•Late-stage AD shows global epigenomic erosion accompanied by cell identity loss
A large-scale single-cell transcriptomic and epigenomic atlas of Alzheimer’s disease (AD) dissects regulatory programs during AD progression. This study highlights key genetic risk loci and ATAC-QTLs and also reveals epigenomic erosion and cell identity loss during late-stage AD.
Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across ...443 human subjects and diverse Alzheimer’s disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.
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•Single-nucleus transcriptomes and epigenomes of human microglia•Microglia state-specific and disease-stage-specific profile in Alzheimer’s disease•Chromatin accessibility poorly captured microglia transcriptional state diversity•Transcription factor networks regulate microglial states and their transitions
Microglia states showing Alzheimer’s disease (AD)-risk-gene expression and AD-progression-associated expression differences were identified from the microglial transcriptome and epigenomes from the 443 human subjects spanning brain regions and diverse clinical and pathological states. Computational framework and functional studies using iPSC-derived microglia defined the diversity of microglial states across disease, the disease-stage changes of gene expression, and the regulatory network that governs microglial state transitions during the progression of AD.
Triptolide is a natural compound in herbal remedies with anti-inflammatory and anti-proliferative properties. We studied its effects on critical signaling processes within the cell, including Notch1 ...and STAT3 signaling. Our research showed that triptolide reduces cancer cell proliferation by decreasing the expression of downstream targets of these signals. The levels of each signal-related protein and mRNA were analyzed using Western blot and qPCR methods. Interestingly, inhibiting one signal with a single inhibitor alone did not significantly reduce cancer cell proliferation. Instead, MTT assays showed that the simultaneous inhibition of Notch1 and STAT3 signaling reduced cell proliferation. The effect of triptolide was similar to a combination treatment with inhibitors for both signals. When we conducted a study on the impact of triptolide on zebrafish larvae, we found that it inhibited muscle development and interfered with muscle cell proliferation, as evidenced by differences in the staining of myosin heavy chain and F-actin proteins in confocal fluorescence microscopy. Additionally, we noticed that inhibiting a single type of signaling did not lead to any significant muscle defects. This implies that triptolide obstructs multiple signals simultaneously, including Notch1 and STAT3, during muscle development. Chemotherapy is commonly used to treat cancer, but it may cause muscle loss due to drug-related adverse reactions or other complex mechanisms. Our study suggests that anticancer agents like triptolide, inhibiting essential signaling pathways including Notch1 and STAT3 signaling, may cause muscle atrophy through anti-proliferative activity.
Large microbial gene clusters encode useful functions, including energy utilization and natural product biosynthesis, but genetic manipulation of such systems is slow, difficult and complicated by ...complex regulation. We exploit the modularity of a refactored Klebsiella oxytoca nitrogen fixation (nif) gene cluster (16 genes, 103 parts) to build genetic permutations that could not be achieved by starting from the wild-type cluster. Constraint-based combinatorial design and DNA assembly are used to build libraries of radically different cluster architectures by varying part choice, gene order, gene orientation and operon occupancy. We construct 84 variants of the nifUSVWZM operon, 145 variants of the nifHDKY operon, 155 variants of the nifHDKYENJ operon and 122 variants of the complete 16-gene pathway. The performance and behavior of these variants are characterized by nitrogenase assay and strand-specific RNA sequencing (RNA-seq), and the results are incorporated into subsequent design cycles. We have produced a fully synthetic cluster that recovers 57% of wild-type activity. Our approach allows the performance of genetic parts to be quantified simultaneously in hundreds of genetic contexts. This parallelized design-build-test-learn cycle, which can access previously unattainable regions of genetic space, should provide a useful, fast tool for genetic optimization and hypothesis testing.
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