Metazoan genomes are spatially organized at multiple scales, from packaging of DNA around individual nucleosomes to segregation of whole chromosomes into distinct territories. At the intermediate ...scale of kilobases to megabases, which encompasses the sizes of genes, gene clusters and regulatory domains, the three-dimensional (3D) organization of DNA is implicated in multiple gene regulatory mechanisms, but understanding this organization remains a challenge. At this scale, the genome is partitioned into domains of different epigenetic states that are essential for regulating gene expression. Here we investigate the 3D organization of chromatin in different epigenetic states using super-resolution imaging. We classified genomic domains in Drosophila cells into transcriptionally active, inactive or Polycomb-repressed states, and observed distinct chromatin organizations for each state. All three types of chromatin domains exhibit power-law scaling between their physical sizes in 3D and their domain lengths, but each type has a distinct scaling exponent. Polycomb-repressed domains show the densest packing and most intriguing chromatin folding behaviour, in which chromatin packing density increases with domain length. Distinct from the self-similar organization displayed by transcriptionally active and inactive chromatin, the Polycomb-repressed domains are characterized by a high degree of chromatin intermixing within the domain. Moreover, compared to inactive domains, Polycomb-repressed domains spatially exclude neighbouring active chromatin to a much stronger degree. Computational modelling and knockdown experiments suggest that reversible chromatin interactions mediated by Polycomb-group proteins play an important role in these unique packaging properties of the repressed chromatin. Taken together, our super-resolution images reveal distinct chromatin packaging for different epigenetic states at the kilobase-to-megabase scale, a length scale that is directly relevant to genome regulation.
Engineering of genetic networks with artificial signaling pathways (ASPs) can reprogram cellular responses and phenotypes under different circumstances for a variety of diagnostic and therapeutic ...purposes. However, construction of ASPs between originally independent endogenous genes in mammalian cells is highly challenging. Here we report an amplifiable RNA circuit that can theoretically build regulatory connections between any endogenous genes in mammalian cells. We harness the system of catalytic hairpin assembly with combination of controllable CRISPR‐Cas9 function to transduce the signals from distinct messenger RNA expression of trigger genes into manipulation of target genes. Through introduction of these RNA‐based genetic circuits, mammalian cells are endowed with autonomous capabilities to sense the changes of RNA expression either induced by ligand stimuli or from various cell types and control the cellular responses and fates via apoptosis‐related ASPs. Our design provides a generalized platform for construction of ASPs inside the genetic networks of mammalian cells based on differentiated RNA expression.
This study describes an amplifiable RNA circuit based on the system of catalytic hairpin assembly with combination of controllable CRISPR‐Cas9 function, which can directly build regulatory connections between originally independent endogenous genes in mammalian cells. With this design, artificial signaling pathways can be introduced into mammalian cells to control cellular responses and phenotypes through differentiated RNA expression.
This paper presents a stator harmonic currents suppression method for doubly fed induction generators (DFIGs) under distorted grid voltage. In the proposed control strategy, the feed-forward ...regulator instead of the resonant regulator is employed to eliminate the negative impacts on the stator current caused by the distorted grid voltage. The leading phase compensator is applied to compensate the system delay when the sampling frequency is low. This approach can provide both the good dynamic response and strong rejection ability against the stator harmonic voltages. Based on the stator current model of DFIG, the feed-forward regulator is designed in detail. The comparison between the resonant controllers and the feed-forward regulator is also made on the basis of Bode diagram. Then, the robustness against the frequency variations and the parameter deviations is analyzed. Finally, the simulation and experimental results are presented to validate the effectiveness of the proposed control strategy.
We propose a Lax representation of the two-component BKP hierarchy via pseudo-differential operators containing two derivations, and show that it is equivalent to the Lax representation via two types ...of pseudo-differential operators involving only one derivation given by Liu et al. (2011).
•Lax representation of the 2-BKP hierarchy via operators containing two derivations.•Equivalence between Lax equations and bilinear equation of the 2-BKP hierarchy.•Relationship between Baker–Akhiezer functions and tau function.
Oligonucleotide (oligo)-based FISH has emerged as an important tool for the study of chromosome organization and gene expression and has been empowered by the commercial availability of highly ...complex pools of oligos. However, a dedicated bioinformatic design utility has yet to be created specifically for the purpose of identifying optimal oligo FISH probe sequences on the genome-wide scale. Here, we introduce OligoMiner, a rapid and robust computational pipeline for the genome-scale design of oligo FISH probes that affords the scientist exact control over the parameters of each probe. Our streamlined method uses standard bioinformatic file formats, allowing users to seamlessly integrate new and existing utilities into the pipeline as desired, and introduces a method for evaluating the specificity of each probe molecule that connects simulated hybridization energetics to rapidly generated sequence alignments using supervised machine learning. We demonstrate the scalability of our approach by performing genome-scale probe discovery in numerous model organism genomes and showcase the performance of the resulting probes with diffraction-limited and single-molecule superresolution imaging of chromosomal and RNA targets. We anticipate that this pipeline will make the FISH probe design process much more accessible and will more broadly facilitate the design of pools of hybridization probes for a variety of applications.
Frailty is associated with major health outcomes. However, the relationships between frailty and frailty symptoms haven't been well studied. This study aims to show the associations between frailty ...and frailty symptoms. The Health and Retirement Study (HRS) is an ongoing longitudinal biannual survey in the United States. Three of the most used frailty diagnoses, defined by the Functional Domains Model, the Burden Model, and the Biologic Syndrome Model, were reproduced according to previous studies. The associations between frailty statuses and input symptoms were assessed using odds ratios and correlation coefficients. The sample sizes, mean ages, and frailty prevalence matched those reported in previous studies. Frailty statuses were weakly correlated with each other (coefficients = 0.19 to 0.38, p 0.05 for all). One to six symptoms defined by the other two models were not significantly correlated with each of the three frailty statuses (p > 0.05 for all). Frailty statuses were significantly correlated with their own bias variables (p < 0.05 for all). Frailty diagnoses lack significant correlations with some of their own frailty symptoms and some of the frailty symptoms defined by the other two models. This finding raises questions like whether the frailty symptoms lacking significant correlations with frailty statuses could be included to diagnose frailty and whether frailty exists and causes frailty symptoms.
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•The intensity map model effectively reveals the complex patterns of land use change.•Urbanization and agriculturalization are the primary manifestations of changes in LULC.•The ...response mechanism of ESV to changes in LULC is analyzed.•Multi scenario simulation of future LULC and ESV based on Markov-PLUS model.•Ecological restoration measures have a curbing effect on the degradation of ESVs.
Changes in land-use patterns are the main driving factors of ecosystem service values (ESVs). The quantitative evaluation of ESVs is significant for the sustainable development of ecologically fragile areas. In this study, the Chishui River Basin (CRB) in China was selected as the study region, and an intensity map (IM) was used to analyze the transformation of land use/land cover (LULC). The modified equivalent coefficient value method was used to evaluate the ESVs based on the 2000, 2010, and 2020 land use datasets. The spatial and temporal distributions of ESV and its response to changes in LULC were analyzed using the Getis-Ord Gi* statistical method and Spearman’s rank correlation analysis. Moreover, spatial and temporal changes in LULC and ESV over the next 30 years in the four development scenarios were simulated using the Markov-PLUS model. The following results were obtained: 1) The farmland and forestland were the dominant LULC categories, and that the LULC pattern dramatically changed in the study area; 2) the total ESV of the CRB decreased significantly from 23.21 billion yuan in 2000 to 22.29 billion yuan in 2020; and 3) the ecological conservation scenario significantly promoted the total ESV, and the town development scenario was more conducive to the urbanization process. Therefore, although the ESV of the CRB showed a decreasing to slowly increasing trend in the context of a series of ecological restoration measures, scientific ecological protection and development policies must be continuously implemented to achieve harmony between ecological service improvement and urbanization development. Our results provide important information for making land-use decisions and facilitating sustainable development in ecologically protected basins.
Liver cirrhosis is a predominant risk factor for hepatocellular carcinoma (HCC). However, the mechanism underlying the progression from cirrhosis to HCC remains unclear. Herein we report the ...concurrent increase of liver progenitor cells (LPCs) and transforming growth factor‐β (TGF‐β) in diethylnitrosamine (DEN)‐induced rat hepatocarcinogenesis and cirrhotic livers of HCC patients. Using several experimental approaches, including 2‐acetylaminofluorene/partial hepatectomy (2‐AAF/PHx) and 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC)‐elicited murine liver regeneration, we found that activation of LPCs in the absence of TGF‐β induction was insufficient to trigger hepatocarcinogenesis. Moreover, a small fraction of LPCs was detected to coexpress tumor initiating cell (T‐IC) markers during rat hepatocarcinogenesis and in human HCCs, and TGF‐β levels were positively correlated with T‐IC marker expression, which indicates a role of TGF‐β in T‐IC generation. Rat pluripotent LPC‐like WB‐F344 cells were exposed to low doses of TGF‐β for 18 weeks imitating the enhanced TGF‐β expression in cirrhotic liver. Interestingly, long‐term treatment of TGF‐β on WB‐F344 cells impaired their LPC potential but granted them T‐IC properties including expression of T‐IC markers, increased self‐renewal capacity, stronger chemoresistance, and tumorigenicity in NOD‐SCID mice. Hyperactivation of Akt but not Notch, signal transducer and activator of transcription 3 (STAT3), or mammalian target of rapamycin (mTOR) was detected in TGF‐β‐treated WB‐F344 cells. Introduction of the dominant‐negative mutant of Akt significantly attenuated T‐IC properties of those transformed WB‐F344 cells, indicating Akt was required in TGF‐β‐mediated‐generation of hepatic T‐ICs. We further demonstrate that TGF‐β‐induced Akt activation and LPC transformation was mediated by microRNA‐216a‐modulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) suppression. Conclusion: Hepatoma‐initiating cells may derive from hepatic progenitor cells exposed to chronic and constant TGF‐β stimulation in cirrhotic liver, and pharmaceutical inhibition of microRNA‐216a/PTEN/Akt signaling could be a novel strategy for HCC prevention and therapy targeting hepatic T‐ICs. (HEPATOLOGY 2012;56:2255–2267)
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