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The homeostasis of hydrogen peroxide (H

Based on computer big data, this paper proposes a new scheme to realize the detection of weak electronic sinusoidal signals using the sensitivity of chaos to parameters in a specific state. This scheme can effectively detect weak sinusoidal signals deep in the background of color noise. The method of chaos detection is given, and the influence of noise on the system state is analyzed. Simulation experiments show that the chaos detection system is very sensitive to small signals, and has a strong ability to suppress any zero-mean color noise.

The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes1,2. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression. N6-methyladenosine RNA and its reader YTHDC1 serve as a bridge to silencing retrotransposons through the RNA derived from these retrotransposons in mouse ES cells.

Construction of high-order difference schemes based on Taylor series expansion has long been a hot topic in computational mathematics, while its application in comprehensive weather models is still very rare. Here, the properties of high-order finite difference schemes are studied based on idealized numerical testing, for the purpose of their application in the Global/Regional Assimilation and Prediction System (GRAPES) model. It is found that the pros and cons due to grid staggering choices diminish with higher-order schemes based on linearized analysis of the one-dimensional gravity wave equation. The improvement of higher-order difference schemes is still obvious for the mesh with smooth varied grid distance. The results of discontinuous square wave testing also exhibits the superiority of high-order schemes. For a model grid with severe non-uniformity and non-orthogonality, the advantage of high-order difference schemes is inapparent, as shown by the results of two-dimensional idealized advection tests under a terrain-following coordinate. In addition, the increase in computational expense caused by high-order schemes can be avoided by the precondition technique used in the GRAPES model. In general, a high-order finite difference scheme is a preferable choice for the tropical regional GRAPES model with a quasi-uniform and quasi-orthogonal grid mesh.

BMP4 regulates a plethora of developmental processes, including the dorsal-ventral axis and neural patterning. Here, we report that BMP4 reconfigures the nuclear architecture during the primed-to-naive transition (PNT). We first established a BMP4-driven PNT and show that BMP4 orchestrates the chromatin accessibility dynamics during PNT. Among the loci opened early by BMP4, we identified Zbtb7a and Zbtb7b (Zbtb7a/b) as targets that drive PNT. ZBTB7A/B in turn facilitate the opening of naive pluripotent chromatin loci and the activation of nearby genes. Mechanistically, ZBTB7A not only binds to chromatin loci near to the genes that are activated, but also strategically occupies those that are silenced, consistent with a role of BMP4 in both activating and suppressing gene expression during PNT at the chromatin level. Our results reveal a previously unknown function of BMP4 in regulating nuclear architecture and link its targets ZBTB7A/B to chromatin remodelling and pluripotent fate control.

BMI-1, a polycomb ring finger oncogene, is highly expressed in multiple cancer cells and is involved in cancer cell proliferation, invasion, and apoptosis. BMI-1 represents a cancer stemness marker that is associated with the regulation of stem cell self-renewal. In this study, pharmacological inhibition (PTC596) or knockdown (siRNA) of BMI-1 reduced cancer stem-like cells and enhanced cancer cell death. Mechanistically, the inhibition of BMI-1 induced the downregulation of Mcl-1 protein, but not Mcl-1 mRNA. PTC596 downregulated Mcl-1 protein expression at the post-translational level through the proteasome-ubiquitin system. PTC596 and BMI-1 siRNA induced downregulation of DUB3 deubiquitinase, which was strongly linked to Mcl-1 destabilization. Furthermore, overexpression of Mcl-1 or DUB3 inhibited apoptosis by PTC596. Taken together, our findings reveal that the inhibition of BMI-1 induces Mcl-1 destabilization through downregulation of DUB3, resulting in the induction of cancer cell death.

Multi-energy load forecasting (MELF) is the premise of regional integrated energy systems (RIES) production planning and energy dispatch. The key of MELF is the consideration of multi-energy coupling and the improvement of prediction accuracy. Therefore, a MELF method considering the multi-energy coupling of variation characteristic curves (MELF_MECVCC) for RIES is proposed. The novelty of MELF_MECVCC lies in the following three aspects: (1) For the trend stripping and volatility extraction of multi-energy load time series, the extreme-point symmetric mode decomposition-sample entropy (ESMD-SE) method is introduced to decompose and reconstruct the variation characteristic curves of multi-energy, including trend curve and fluctuation curve. (2) The multi-energy coupling of the variation characteristic curves is considered to reflect the variation characteristics of the multi-energy loads. (3) Different methods are applied according to different variation characteristics, i.e., the combined method based on multi-task learning and long short-term memory network (MTL-LSTM) is applied to predict the trend curve with strong correlation and the least square support vector regression (LSSVR) method is applied to predict the fluctuation curve with strong volatility and high complexity. Based on the actual data set of the University of Texas in Austin, the MELF_MECVCC model is simulated and verified, which shows that the MELF_MECVCC model reduces the mean absolute percentage error (MAPE) and the root mean square error (RMSE) , and fits better with the original load, and has higher prediction accuracy, compared with current advanced algorithms.

A novel compact planar conical beam antenna with high gain, low side lobe level (SLL), enhanced bandwidth, and stable beam pointing angle within the working bandwidth is proposed. With a low profile of 0.11 λ 0 , it consists of a multiport radiator formed by three annular radiation elements and a feeding network. To facilitate the multiport array radiator design, a method to quickly get its overall reflection coefficient is developed, and an element-level pattern diversity (ELPD) technique is applied in the design. The proposed antenna with a feeding network has achieved an impedance bandwidth of 13.2% (4.67 ~ 5.33 GHz), a peak gain of 14.1 dBi, and a SLL of -21 dB at the center frequency of 5 GHz.

The research can be used to generate animal models of severe disease based on the hACE2 mice for development of treatment against severe COVID-19 and also quickly establish specific mouse models in response to other emergency situations in the future.

Lysine-specific histone demethylase 1 (LSD1), also known as KDM1A, can remove the methyl group from lysine 4 and 9 at histone H3, which regulates transcriptional suppression and activation. Recently, high expression of LSD1 in tumors has been shown to be involved in cancer cell proliferation, metastasis, and poor prognosis. We found that SP2509, a potent and reversible inhibitor of LSD1, induced apoptosis in human renal carcinoma (Caki and ACHN) and glioma (U87MG) cells. Pharmacological inhibition and siRNA-mediated silencing of LSD1 expression effectively downregulated anti-apoptotic proteins such as Bcl-2 and Mcl-1. Ectopic expression of these proteins markedly attenuated SP2509-induced apoptosis. At a mechanistic level, we found that inhibition of LSD1 downregulated Bcl-2 at a transcriptional level. Interestingly, protein expression of Mcl-1 was modulated at a post-translation level. Our results reveal that LSD1 could induce apoptotic cell death in renal carcinoma cells through downregulation of Bcl-2 and Mcl-1.

Background Fungicides are often applied to pears before they are kept in storage facilities. The scientific application of pesticides can reduce unnecessary exposure, which in turn could benefit both humans and the environment. Results We investigated dissipation behavior and residue distribution, and conducted risk assessments for prochloraz, pyraclostrobin, and tebuconazole in pears stored under different conditions using ultra-performance liquid chromatography (UPLC). The recoveries of the three fungicides ranged from 76.5% to 114.5%, and the coefficients of variation were 1.0%-8.5%. The half-life (t1/2 ) ranges for degradation of the three fungicides in Dangshan Su pear peel were 8.8-13.9 days after storage at 25 °C and 99.0-346.6 days after storage at 2 °C. Among the three fungicides, tebuconazole had the lowest residue concentration in pear pulp (maximum of 0.226 mg·kg-1 ) and the longest half-life (≥ 231.0 days). Accordingly, among these fungicides, tebuconazole is the most suitable for the preservation of Dangshan Su pears during storage. Finally, we analyzed samples of six pear varieties from markets in China and found that the residue concentrations of the three fungicides in pear pulp and fruit met Chinese standards. Conclusion The results provide a scientific basis for rationalizing the use of prochloraz, pyraclostrobin, and tebuconazole, and improving the safety of pears for eating. © 2019 Society of Chemical Industry.

Summary: Known as a histone H3K9 methyltransferase, SETDB1 is essential for embryonic development and pluripotent inner cell mass (ICM) establishment. However, its function in pluripotency regulation remains elusive. In this study, we find that under the “ground state” of pluripotency with two inhibitors (2i) of the MEK and GSK3 pathways, Setdb1-knockout fails to induce trophectoderm (TE) differentiation as in serum/LIF (SL), indicating that TE fate restriction is not the direct target of SETDB1. In both conditions, Setdb1-knockout activates a group of genes targeted by SETDB1-mediated H3K9 methylation, including Dux. Notably, Dux is indispensable for the reactivation of 2C-like state genes upon Setdb1 deficiency, delineating the mechanistic role of SETDB1 in totipotency restriction. Furthermore, Setdb1-null ESCs maintain pluripotent marker (e.g., Nanog) expression in the 2i condition. This “ground state” Setdb1-null population undergoes rapid cell death by activating Ripk3 and, subsequently, RIPK1/RIPK3-dependent necroptosis. These results reveal the essential role of Setdb1 between totipotency and pluripotency transition. : Wu et al. report the essential role of Setdb1 in the cell fate transition between totipotency and pluripotency. Setdb1-KO ESCs activate a group of genes targeted by SETDB1-mediated H3K9 methylation, including Dux, then initiate 2C-like totipotency transition. Moreover, Setdb1-KO triggers ESC necroptosis in the “ground state” by activating Ripk3. Keywords: Setdb1, H3K9 methylation, 2C-like totipotency, necroptosis

BMP4 regulates a plethora of developmental processes, including the dorsal-ventral axis and neural patterning. Here, we report that BMP4 reconfigures the nuclear architecture during the primed-to-naive transition (PNT). We first established a BMP4-driven PNT and show that BMP4 orchestrates the chromatin accessibility dynamics during PNT. Among the loci opened early by BMP4, we identified Zbtb7a and Zbtb7b (Zbtb7a/b) as targets that drive PNT. ZBTB7A/B in turn facilitate the opening of naive pluripotent chromatin loci and the activation of nearby genes. Mechanistically, ZBTB7A not only binds to chromatin loci near to the genes that are activated, but also strategically occupies those that are silenced, consistent with a role of BMP4 in both activating and suppressing gene expression during PNT at the chromatin level. Our results reveal a previously unknown function of BMP4 in regulating nuclear architecture and link its targets ZBTB7A/B to chromatin remodelling and pluripotent fate control.

The majority of mammalian genomes are devoted to transposable elements (TEs). Whilst TEs are increasingly recognized for their important biological functions, they are a potential danger to genomic stability and are carefully regulated by the epigenetic system. However, the full complexity of this regulatory system is not understood. Here, using mouse embryonic stem cells, we show that TEs are suppressed by heterochromatic marks like H3K9me3, and are also labelled by all major types of chromatin modification in complex patterns, including bivalent activatory and repressive marks. We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE. The loss of Setdb1, Ncor2, Rnf2, Kat5, Prmt5, Uhrf1, and Rrp8 caused widespread changes in TE expression and chromatin accessibility. These effects were context-specific, with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs. Our work reveals the complex patterns of epigenetic regulation of TEs., Transposable elements (TEs) fulfill essential but poorly understood roles in genome organization and gene expression control. Here the authors show that the regulation of TEs occurs through overlapping epigenetic mechanisms that control the expression and chromatin signatures at TEs.

N6-methyladenosine (m6A), the most abundant reversible modification on eukaryote messenger RNA, is recognized by a series of readers, including the YT521-B homology domain family (YTHDF) proteins, which are coupled to perform physiological functions. Here, we report that YTHDF2 and YTHDF3, but not YTHDF1, are required for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Mechanistically, we found that YTHDF3 recruits the PAN2-PAN3 deadenylase complex and conduces to reprogramming by promoting mRNA clearance of somatic genes, including Tead2 and Tgfb1, which parallels the activity of the YTHDF2-CCR4-NOT deadenylase complex. Ythdf2/3 deficiency represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, RNA interference of Tgfb1 or the Hippo signaling effectors Yap1, Taz, and Tead2 rescues Ythdf2/3-defective reprogramming. Overall, YTHDF2/3 couples RNA deadenylation and regulation with the clearance of somatic genes and provides insights into iPSC reprogramming at the posttranscriptional level.

Quinoxaline-1,4-dioxides (QdNOs) are a class of quinoxaline derivatives that are widely used in humans or animals as drugs or feed additives. However, the metabolic mechanism, especially the involved enzymes, has not been reported in detail. In this study, the N-oxide reduction enzyme, porcine aldehyde oxidase SsAOX1 was identified and characterized. The SsAOX1 gene was cloned from pig liver through reverse-transcription polymerase chain reaction using degenerate primers, which encode a 147-kDa protein with typical aldehyde oxidase motifs, two [2Fe-2S] centers, a flavin adenine dinucleotide (FAD) binding domain, and a molybdenum cofactor domain. After heterologous expression in a prokaryote, purified SsAOX1 formed a functional homodimer under native conditions. Importantly, the SsAOX1 catalyzed the N-oxide reduction at the N1 position of three representative QdNOs (quinocetone, mequindox, and cyadox), which are commonly used as animal feed additives. SsAOX1 has the highest activity toward quinocetone, followed by mequindox and cyadox, with kcat/K(m) values of 1.94 ± 0.04, 1.27 ± 0.15, and 0.43 ± 0.09 minute(-1) μM(-1), respectively. However, SsAOX1 has the lowest substrate affinity for quinocetone, followed by the cyadox and mequindox, with K(m) values of 4.36 ± 0.56, 3.16 ± 0.48, and 2.96 ± 0.51 μM, respectively. In addition, using site-directed mutagenesis, we found that substitution of glycine 1019 with threonine endows SsAOX1 with N-oxide reductive activity at the N4 position. The goal of this study was to identify and characterize the N-oxide reduction enzyme for a class of veterinary drugs, QdNOs, which will aid in the elucidation of the metabolic pathways of QdNOs and will provide a theoretical basis for their administration and new veterinary drug design.

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). We further show that Klf4 contributes to Cd34+/Fxyd5+/Psca+ keratinocyte-like NR fate and that IFN-γ impedes the final transition to chimera-competent pluripotency along the RP cells. We analyze more than 150,000 single cells from both OSK and chemical reprograming and identify additional NR/RP bifurcation points. Our work reveals a generic bifurcation model for cell fate decisions during somatic cell reprogramming that may be applicable to other systems and inspire further improvements for reprogramming.

T-2 toxin is a mycotoxin that is toxic to plants, animals, and humans. However, its molecular mechanism remains unclear, especially in chickens. In this study, using 2D electrophoresis with MALDI-TOF/TOF-MS, 53 proteins were identified as up- or downregulated by T-2 toxin in chicken primary hepatocytes. Functional network analysis by ingenuity pathway analysis showed that the top network altered by T-2 toxin is associated with neurological disease, cancer, organismal injury, and abnormalities. Most of the identified proteins were associated with one of eight functional classes, including cell redox homeostasis, transcriptional or translational regulation, cell cycle or cell proliferation, stress response, lipid metabolism, transport, carbohydrate metabolism, and protein degradation. Subcellular location categorization showed that the identified proteins were predominantly located in the mitochondrion (34%) and interestingly, the expression of all the identified mitochondrial proteins was increased. Further cellular analysis showed that T-2 toxin was able to induce the ROS accumulation and could lead to an increase in mitochondrial mass and adenosine 5'-triphosphate content, which indicated that oxidative stress and mitochondrial enhancement occurred in T-2 toxin-treated cells. Overall, these results characterize the global proteomic response of chicken primary hepatocytes to T-2 toxin, which may lead to a better understanding of the molecular mechanisms underlying its toxicity.

The user equilibrium in traffic network is the result of users' competition and path distance, travel time and reliability are major factors that travelers consider when selecting paths. In the paper, from the point of view of users, the intrinsic cause of the change of path travel time is analyzed, the disutility function expression based on late arrival penalty factor is put forward, a user equilibrium assignment model built on risk preference is set up, and the equivalent of equilibrium conditions: variational inequality and its corresponding algorithm are offered as well. In the end the model is tested in a small-scale network, sensitivity analysis of the parameters is offered and rationality of the model and utility of the algorithm are proved by the outcome of a numerical experiment.