We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. ...We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polycomb Repressive Complex 2 (PRC2) catalyzes histone methylation at H3 Lys27, and plays crucial roles during development and diseases in numerous systems. Its catalytic subunit EZH2 represents a ...key nuclear target for long non-coding RNAs (lncRNAs) that emerging to be a novel class of epigenetic regulator and participate in diverse cellular processes. LncRNAs are characterized by high tissue-specificity; however, little is known about the tissue profile of the EZH2- interacting lncRNAs.
Here we performed a global screening for EZH2-binding lncRNAs in tissues including brain, lung, heart, liver, kidney, intestine, spleen, testis, muscle and blood by combining RNA immuno- precipitation and RNA sequencing. We identified 1328 EZH2-binding lncRNAs, among which 470 were shared in at least two tissues while 858 were only detected in single tissue. An RNA motif with specific secondary structure was identified in a number of lncRNAs, albeit not in all EZH2-binding lncRNAs. The EZH2-binding lncRNAs fell into four categories including intergenic lncRNA, antisense lncRNA, intron-related lncRNA and promoter-related lncRNA, suggesting diverse regulations of both cis and trans-mechanisms. A promoter-related lncRNA Hnf1aos1 bound to EZH2 specifically in the liver, a feature same as its paired coding gene Hnf1a, further confirming the validity of our study. In addition to the well known EZH2-binding lncRNAs like Kcnq1ot1, Gas5, Meg3, Hotair and Malat1, majority of the lncRNAs were firstly reported to be associated with EZH2.
Our findings provide a profiling view of the EZH2-interacting lncRNAs across different tissues, and suggest critical roles of lncRNAs during cell differentiation and maturation.
We evaluated the effects of the benzylic leaving group and core structure of arylboronates on H2O2-induced formation of bisquinone methides for DNA interstrand cross-linking. The mechanism of DNA ...cross-linking induced by these arylboronates involves generation of phenol intermediates followed by departure of benzylic leaving groups leading to QMs which directly cross-link DNA via alkylation. The QM formation is the rate-determining step for DNA cross-linking. A better leaving group (Br) and stepwise bisquinone methide formation increased interstrand cross-linking efficiency. These findings provide essential guidelines for designing novel anticancer prodrugs.
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IJS, KILJ, NUK, PNG, UL, UM
Following the “green revolution,”
indica
and
japonica
hybrid breeding has been recognized as a new breakthrough in further improving rice yields. However, heterosis-related grain weight QTLs and the ...basis of yield advantage among subspecies has not been well elucidated. We herein
de novo
assembled the chromosome level genomes of an
indica/xian
rice (Luohui 9) and a
japonica/geng
rice (RPY geng) and found that gene number differences and structural variations between these two genomes contribute to the differences in agronomic traits and also provide two different favorable allele pools to produce better derived recombinant inbred lines (RILs). In addition, we generated a high-generation (> F
15
) population of 272 RILs from the cross between Luohui 9 and RPY geng and two testcross hybrid populations derived from the crosses of RILs and two cytoplasmic male sterile lines (YTA,
indica
and Z7A,
japonica
). Based on three derived populations, we totally identified eight 1,000-grain weight (KGW) QTLs and eight KGW heterosis loci. Of QTLs,
qKGW-6.1
and
qKGW-8.1
were accepted as novel KGW QTLs that have not been reported previously. Interestingly, allele genotyping results revealed that heading date related gene (
Ghd8
) in
qKGW-8.1
and
qLH-KGW-8.1
, can affect grain weight in RILs and rice core accessions and may also play an important role in grain weight heterosis. Our results provided two high-quality genomes and novel gene editing targets for grain weight for future rice yield improvement project.
Intensified charge-coupled device (ICCD) images are captured by ICCD sensors in extremely low-light conditions. They often contains spatially clustered noises and general filtering methods do not ...work well. We find that the scale of the clustered noise in ICCD sensing images is often much smaller than that of the true structural information. Then the clustered noise can be identified by properly down-sampling and then up-sampling the ICCD sensing image and comparing it to the noisy image. Based on this finding, we present a denoising algorithm to remove the randomly clustered noise in ICCD images. First, we over-segment the ICCD image into a set of flat patches, and each patch contains very little structural information. Second, we classify the patches into noisy patches and noise-free patches based on the hypergraph cut method. Then the noise-free patches are easily recovered by the general block-matching and 3D filtering (BM3D) algorithm, since they often do not contain the clustered noise. The noisy patches are recovered by subtracting the identified clustered noise from the noisy patches. After that, we could get the whole recovered ICCD image. Finally, the quality of the recovered ICCD image is further improved by diminishing the remaining sparse noise with robust principal component analysis. Experiments are conducted on a set of ICCD images and compared with four existing denoising algorithms, which shows that the proposed algorithm removes well the randomly clustered noise and preserves the true textural information in the ICCD sensing images.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the mammalian heart, the left ventricle (LV) rapidly becomes more dominant in size and function over the right ventricle (RV) after birth. The molecular regulators responsible for this ...chamber-specific differential growth are largely unknown. We found that cardiomyocytes in the neonatal mouse RV had lower proliferation, more apoptosis, and a smaller average size compared with the LV. This chamber-specific growth pattern was associated with a selective activation of p38 mitogen-activated protein kinase (MAPK) activity in the RV and simultaneous inactivation in the LV. Cardiomyocyte-specific deletion of both the Mapk14 and Mapk11 genes in mice resulted in loss of p38 MAPK expression and activity in the neonatal heart. Inactivation of p38 activity led to a marked increase in cardiomyocyte proliferation and hypertrophy but diminished cardiomyocyte apoptosis, specifically in the RV. Consequently, the p38-inactivated hearts showed RV-specific enlargement postnatally, progressing to pulmonary hypertension and right heart failure at the adult stage. Chamber-specific p38 activity was associated with differential expression of dual-specific phosphatases (DUSPs) in neonatal hearts, including DUSP26. Unbiased transcriptome analysis revealed that IRE1α/XBP1-mediated gene regulation contributed to p38 MAPK-dependent regulation of neonatal cardiomyocyte proliferation and binucleation. These findings establish an obligatory role of DUSP/p38/IRE1α signaling in cardiomyocytes for chamber-specific growth in the postnatal heart.
Dof transcription factors plant-specific and associates with growth and development in plants. We conducted comprehensive and systematic analyses of Dof transcription factors in sugarcane, and ...identified 29 SsDof transcription factors in sugarcane genome. Those SsDof genes were divided into five groups, with similar gene structures and conserved motifs within the same groups. Segmental duplications are predominant in the evolution of Dof in sugarcane. Cis-element analysis suggested that the functions of SsDofs were involved in growth and development, hormones and abiotic stresses responses in sugarcane. Expression patterns indicated that SsDof7, SsDof23 and SsDof24 had a comparatively high expression in all detected tissues, indicating these genes are crucial in sugarcane growth and development. Moreover, we examined the transcription levels of SsDofs under four plant hormone treatments, SsDof7-3 and SsDof7-4 were down-regulated after ABA treatment, while SsDof7-1 and SsDof7-2 were induced after the same treatment, indicating different alleles may play different roles in response to plant hormones. We also analyzed SsDofs' expression profiling under four abiotic stresses, SsDof5 and SsDof28 significantly responded to these four stresses, indicating they are associate with abiotic stresses responses. Collectively, our results yielded allele specific expression of Dof genes responding to hormones and abiotic stresses in sugarcane, and their cis-elements could be crucial for sugarcane improvement.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Topology identification is important to ensure a safe and stable distribution network operation, especially in the case of high proportion of new energy access to the distribution network. It could ...provide structural information for distribution network management and the foundation of distribution network system analysis. In consideration of the influence of different power flow parameters on topology identification results, this paper proposes a topology identification method based on gradient boosting decision tree (GBDT) and attribute weighted naive Bayes (AWNB). Firstly, a gradient boosting decision tree was used to calculate the importance of different power flow parameters to reduce the data dimension and computational complexity. Then each attribute is given a weight based on the result of the importance calculation. Secondly, the weighted set was used as input to train the AWNB classifier to make the model more realistic. Finally, the IEEE 30-node model was used to verify the performance of the proposed method. The results indicate that the proposed method has high accuracy and good robustness, which could maintain a high success rate of topology identification under different noise environments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:Genetic diversity and the heterogeneous nature of cardiac fibroblasts (CFbs) have hindered characterization of the molecular mechanisms that regulate cardiac fibrosis. The Hybrid Mouse ...Diversity Panel offers a valuable tool to examine genetically diverse cardiac fibroblasts and their role in fibrosis.
METHODS:Three strains of mice (C57BL/6J, C3H/HeJ, and KK/HlJ) were selected from the Hybrid Mouse Diversity Panel and treated with either isoproterenol (ISO) or saline by an intraperitoneally implanted osmotic pump. After 21 days, cardiac function and levels of fibrosis were measured by echocardiography and trichrome staining, respectively. Activation and proliferation of CFbs were measured by in vitro and in vivo assays under normal and injury conditions. RNA sequencing was done on isolated CFbs from each strain. Results were analyzed by Ingenuity Pathway Analysis and validated by reverse transcription-qPCR, immunohistochemistry, and ELISA.
RESULTS:ISO treatment in C57BL/6J, C3H/HeJ, and KK/HlJ mice resulted in minimal, moderate, and extensive levels of fibrosis, respectively (n=7–8 hearts per condition). Isolated CFbs treated with ISO exhibited strain-specific increases in the levels of activation but showed comparable levels of proliferation. Similar results were found in vivo, with fibroblast activation, and not proliferation, correlating with the differential levels of cardiac fibrosis after ISO treatment. RNA sequencing revealed that CFbs from each strain exhibit unique gene expression changes in response to ISO. We identified Ltbp2 as a commonly upregulated gene after ISO treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure patients.
CONCLUSIONS:This study highlights the importance of genetic variation in cardiac fibrosis by using multiple inbred mouse strains to characterize CFbs and their response to ISO treatment. Our data suggest that, although fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In addition, by comparing CFbs from multiple strains, we identified pathways as potential therapeutic targets and LTBP2 as a marker for fibrosis, with relevance to patients with underlying myocardial fibrosis.
With the development of materials science and micro-nano fabrication techniques, miniature soft robots at millimeter or submillimeter size can be manufactured and actuated remotely. The small-scaled ...robots have the unique capability to access hard-to-reach regions in the human body in a noninvasive manner. To date, it is still challenging for miniature robots to accurately move in the diverse and dynamic environments in the human body (e.g., in blood flow). To effectively locomote in the vascular system, miniature swimmers with upstream swimming capability are required. Herein, we design and fabricate a miniature robotic swimmer capable of performing ultrafast swimming in a fluidic environment. The maximum velocity of the swimmer in water is 30 cm/s, which is 60 body lengths. Moreover, in a tubular environment, the swimmer can still obtain a swimming velocity of 17 cm/s. The swimmer can also perform upstream swimming in a tubular environment with a velocity of 5 cm/s when the flow speed is 10 cm/s. The ultrasound-guided navigation of the swimmer in a phantom mimicking a blood vessel is also realized. This work gives insight into the design of agile undulatory milliswimmers for future biomedical applications.
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