DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts.

BACKGROUND: DNA methylation is an important epigenetic modification which has numerous roles in modulating genome function. Its levels are spatially correlated across the genome, typically high in repressed regions but low in transcription factor (TF) binding sites and active regulatory regions. However, the mechanisms establishing genome-wide and TF binding site methylation patterns are still unclear. RESULTS: Here we use a comparative approach to investigate the association of DNA methylation to TF binding evolution in mammals. Specifically, we experimentally profile DNA methylation and combine this with published occupancy profiles of five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1) in the liver of five mammalian species (human, macaque, mouse, rat, dog). TF binding sites are lowly methylated, but they often also have intermediate methylation levels. Furthermore, biding sites are influenced by the methylation status of CpGs in their wider binding regions even when CpGs are absent from the core binding motif. Employing a classification and clustering approach, we extract distinct and species-conserved patterns of DNA methylation levels at TF binding regions. CEBPA, HNF4A, ONECUT1, and FOXA1 share the same methylation patterns, while CTCF's differ. These patterns characterize alternative functions and chromatin landscapes of TF-bound regions. Leveraging our phylogenetic framework, we find DNA methylation gain upon evolutionary loss of TF occupancy, indicating coordinated evolution. Furthermore, each methylation pattern has its own evolutionary trajectory reflecting its genomic contexts. CONCLUSIONS: Our epigenomic analyses indicate a role for DNA methylation in TF binding changes across species including that specific DNA methylation profiles characterize TF binding and are associated with their regulatory activity, chromatin contexts, and evolutionary trajectories.

Observation and all-optical manipulation of replica symmetry breaking dynamics in a multi-Stokes-involved Brillouin random fiber laser photonic system.

In this paper, we propose and demonstrate an all-optical control of RSB transition in a multi-wavelength Brillouin random fiber laser (MWBRFL). Multi-order Stokes light components can be subsequently generated by increasing the power of the Erbium-doped fiber amplifier (EDFA) inside the MWBRFL, providing additional disorder as well as multiple Stokes-involved interplay. It essentially allows diversified laser mode landscapes with adjustable average mode lifetime and random mode density of the 1st order Stokes, which benefits the switching between replica symmetry breaking (RSB) and replica symmetry (RS) states in an optically controlled manner. Results show that the average mode lifetime of the 1st order Stokes component gradually decreases from 250.0 ms to 1.2 ms as high orders from the 2nd to the 5th of Stokes components are activated. Meanwhile, the order parameter q of the 1st order Stokes random lasing emission presents distinct statistical distributions within the selective sub-window under various EDFA optical powers. Consequently, all-optical dynamical control of the 1st Stokes random laser mode landscapes with adjustable average mode lifetime turns out to be attainable, facilitating the RSB transition under an appropriate observation time window. These findings open a new avenue for exploring the underlying physical mechanisms behind the occurrence of the RSB phenomenon in photonic complex systems.

On-chip droplet analysis and cell spheroid screening by capillary wrapping enabled shape-adaptive ferrofluid transporters.

Non-invasive droplet manipulation with no physical damage to the sample is important for the practical value of manipulation tools in multidisciplinary applications from biochemical analysis and diagnostics to cell engineering. It is a challenge to achieve this for most existing photothermal, electric stimuli, and magnetic field-based technologies. Herein, we present a droplet handling toolbox, the ferrofluid transporter, for non-invasive droplet manipulation in an oil environment. It involves the transport of droplets with high robustness and efficiency owing to low interfacial friction. This capability caters to various scenarios including droplets with varying components and solid cargo. Moreover, we fabricated a droplet array by transporter positioning and achieved droplet gating and sorting for complex manipulation in the droplet array. Benefiting from the ease of scale-up and high biocompatibility, the transporter-based droplet array can serve as a digital microfluidic platform for on-chip droplet-based bioanalysis, cell spheroid culture, and downstream drug screening tests.

Mating strategies of Vitex negundo L. var. heterophylla (Franch.) Rehder (Lamiaceae): A mixed mating system with inbreeding depression.

Plant reproductive ecology is one of the research hotspots in ecology. With the increasing attention paid to the conservation of plant diversity, the research on reproductive characteristics and flowering biological characteristics of more species has attracted more attention. However, plant reproduction is affected by multiple interacting factors such as pollen limitation and resource availability. Vitex negundo var. heterophylla (Franch.) Rehder (Lamiaceae) is a significant species for water and soil conservation. Previous studies have revealed its mating system by the biological characteristics of flowering and SSR markers, but its reproductive strategies remain to be further studied. We evaluated reproductive success through artificial pollination to explore the reproductive characteristics of V. negundo var. heterophylla for the first time. From the results of fruit set, there is a mixed mating system dominated by outcrossing in V. negundo var. heterophylla accompanied by self-compatibility, and it cannot carry out autonomous selfing. Our data show the pollinator-mediated interaction in the success of reproduction, whereas the effect of anemophily is very weak. And the seed germination rate of inbred line progenies was lower than that of hybrid progenies, which is suspected to be caused by inbreeding depression. The research will provide scientific information for the protection and conservation of V. negundo var. heterophylla from the point of view of reproduction. In sum, the results are necessary to protect animal vectors in the background of insect decline.

Duck Tembusu virus infection activates the MKK3/6-p38 MAPK signaling pathway to promote virus replication.

Duck Tembusu virus (DTMUV) infection poses a serious threat to ducks, chickens, and geese, causing a range of detrimental effects, including reduced egg production, growth retardation, and even death. These consequences lead to substantial economic losses for the Chinese poultry industry. Although it is established that various viral infections can trigger activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway, the precise role and mechanisms underlying p38 MAPK activation in DTMUV infection remain poorly understood. To address this knowledge gap, we conducted a study to investigate whether the replication of DTMUV necessitates the activation of p38 MAPK. We found that DTMUV infection stimulates activation of the MKK3/6-p38 MAPK pathway, and the activation of p38 MAPK increases with viral titer. Subsequently, the use of the small molecule inhibitor SB203580 significantly reduced DTMUV replication by inhibiting p38 MAPK activity. Furthermore, downregulation of p38 MAPK protein expression by siRNA also inhibited DTMUV replication, whereas transient transfection of p38 MAPK protein promoted DTMUV replication. Interestingly, we found that the DTMUV capsid protein activates p38 MAPK, and there is interaction between DTMUV capsid and p38 MAPK. Finally, we found that DTMUV infection induces elevated mRNA expression of IFN-α, IFN-ß, IFN-γ, IL-1ß, IL-6, and IL-12, which is associated with p38 MAPK activity. These results indicated that virus hijacking of p38 activation is a crucial event for DTMUV replication, and that pharmacological blockade of p38 activation represents a potential anti-DTMUV strategy.

Structural insights into gating mechanism and allosteric regulation of NMDA receptors.

N-methyl-d-aspartate receptors (NMDARs) belong to the ionotropic glutamate receptors (iGluRs) superfamily and act as coincidence detectors that are crucial to neuronal development and synaptic plasticity. They typically assemble as heterotetramers of two obligatory GluN1 subunits and two alternative GluN2 (from 2A to 2D) and/or GluN3 (3A and 3B) subunits. These alternative subunits mainly determine the diverse biophysical and pharmacological properties of different NMDAR subtypes. Over the past decade, the unprecedented advances in structure elucidation of these tetrameric NMDARs have provided atomic insights into channel gating, allosteric modulation and the action of therapeutic drugs. A wealth of structural and functional information would accelerate the artificial intelligence-based drug design to exploit more NMDAR subtype-specific molecules for the treatment of neurological and psychiatric disorders.

Isolated Coordination Polyhedron Confinement in ABP2O7:Mn2+ (A = Ba/Sr; B = Mg/Zn).

Many research efforts have focused on designing new inorganic phosphors to meet different application requirements. The structure-photoluminescence relationship between activator ions and the matrix lattice plays an irreparable role in designing target phosphors. Herein, a series of ABP2O7:Mn2+ (A = Ba/Sr; B = Mg/Zn) phosphors are prepared for a detailed study on the relationship between the luminescence performance and spatial structure and symmetry of the doping site of Mn2+. Due to the weak interaction between nearest B-B pairs, [BO5] is defined as an isolated coordination polyhedron whose structure and symmetry directly influence the photoluminescence of Mn2+. The emission wavelength of Mn2+ is ∼620 nm when it occupies the triangular bipyramid [MgO5] in BaMgP2O7. When Mn2+ occupies the quadrangular pyramid-typed [MgO5] or [ZnO5] in SrMgP2O7, SrZnP2O7, and BaZnP2O7, the emission wavelengths peak at ∼670 nm. We propose a conception of isolated coordination polyhedral confinement to clarify the luminescence performance of Mn2+ in the fivefold coordination configuration with different geometries, which has great theoretical research significance for designing inorganic phosphors.

Populational pan-ethnic screening panel enabled by deep whole genome sequencing.

Birth defect is a global threat to the public health systems. Mitigating neonatal anomalies is hampered by elusive molecular mechanisms of pathogenic mutations and poor subsequent translation into preventative measures. Applying appropriate strategies in China to promote reproductive health is particularly challenging, as the Chinese population compromises complex genomic diversity due to the inclusion of many ethnic groups with distinct genetic backgrounds. To investigate and evaluate the feasibility of implementing a pan-ethnic screening strategy, and guide future reproductive counselling, high-quality variants associated with autosome recessive (AR) diseases derived from the largest publicly available cohort of the Chinese population were re-analysed using a bottom-up approach. The analyses of gene carrier rates (GCRs) across distinct ethnic groups revealed that substantial heterogeneity existed potentially due to diverse evolutionary selection. The sampling population, sequencing coverage and underlying population structure contributed to the differential variants observed between ChinaMAP and the East Asian group in gnomAD. Beyond characteristics of GCR, potential druggable targets were additionally explored according to genomic features and functional roles of investigated genes, demonstrating that phase separation could be a therapeutic target for autosomal recessive diseases. A further examination of estimated GCR across ethnic groups indicated that most genes shared by at least two populations could be utilised to direct the design of a pan-ethnic screening application once sequencing and interpreting costs become negligible. To this end, a list of autosomal recessive disease genes is proposed based on the prioritised rank of GCR to formulate a tiered screening strategy.

Abnormal developmental trajectory and vulnerability to cardiac arrhythmias in tetralogy of Fallot with DiGeorge syndrome.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Ventricular dysfunction and cardiac arrhythmias are well-documented complications in patients with repaired TOF. Whether intrinsic abnormalities exist in TOF cardiomyocytes is unknown. We establish human induced pluripotent stem cells (hiPSCs) from TOF patients with and without DiGeorge (DG) syndrome, the latter being the most commonly associated syndromal association of TOF. TOF-DG hiPSC-derived cardiomyocytes (hiPSC-CMs) show impaired ventricular specification, downregulated cardiac gene expression and upregulated neural gene expression. Transcriptomic profiling of the in vitro cardiac progenitors reveals early bifurcation, as marked by ectopic RGS13 expression, in the trajectory of TOF-DG-hiPSC cardiac differentiation. Functional assessments further reveal increased arrhythmogenicity in TOF-DG-hiPSC-CMs. These findings are found only in the TOF-DG but not TOF-with no DG (ND) patient-derived hiPSC-CMs and cardiac progenitors (CPs), which have implications on the worse clinical outcomes of TOF-DG patients.

A Bio-Inspired Spiking Neural Network with Few-Shot Class-Incremental Learning for Gas Recognition.

The sensitivity and selectivity profiles of gas sensors are always changed by sensor drifting, sensor aging, and the surroundings (e.g., temperature and humidity changes), which lead to a serious decline in gas recognition accuracy or even invalidation. To address this issue, the practical solution is to retrain the network to maintain performance, leveraging its rapid, incremental online learning capacity. In this paper, we develop a bio-inspired spiking neural network (SNN) to recognize nine types of flammable and toxic gases, which supports few-shot class-incremental learning, and can be retrained quickly with a new gas at a low accuracy cost. Compared with gas recognition approaches such as support vector machine (SVM), k-nearest neighbor (KNN), principal component analysis (PCA) +SVM, PCA+KNN, and artificial neural network (ANN), our network achieves the highest accuracy of 98.75% in five-fold cross-validation for identifying nine types of gases, each with five different concentrations. In particular, the proposed network has a 5.09% higher accuracy than that of other gas recognition algorithms, which validates its robustness and effectiveness for real-life fire scenarios.

Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits.

N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits. Here we report full-length cryo-EM structures of the human N1-N2D di-heterotetramer (di-receptor), rat N1-N2C di-receptor and N1-N2A-N2C tri-heterotetramer (tri-receptor) at a best resolution of 3.0 Å. The bilobate N-terminal domain (NTD) in N2D intrinsically adopts a closed conformation, leading to a compact NTD tetramer in the N1-N2D receptor. Additionally, crosslinking the ligand-binding domain (LBD) of two N1 protomers significantly elevated the channel open probability (Po) in N1-N2D di-receptors. Surprisingly, the N1-N2C di-receptor adopted both symmetric (minor) and asymmetric (major) conformations, the latter further locked by an allosteric potentiator, PYD-106, binding to a pocket between the NTD and LBD in only one N2C protomer. Finally, the N2A and N2C subunits in the N1-N2A-N2C tri-receptor display a conformation close to one protomer in the N1-N2A and N1-N2C di-receptors, respectively. These findings provide a comprehensive structural understanding of diverse function in major NMDA receptor subtypes.

Broadband UV-Excitation and Red/Far-Red Emission Materials for Plant Growth: Tunable Spectrum Conversion in Eu3+,Mn4+ Co-doped LaAl0.7Ga0.3O3 Phosphors.

Broadband ultraviolet (UV) excitation and red/far-red emission phosphors can effectively convert solar spectrum to enhance photosynthesis and promote morphogenesis in plants. Based on the above application requirements, Eu3+ single-doped LaAl1-yGayO3 solid solutions and Eu3+,Mn4+ codoped LaAl0.7Ga0.3O3 phosphors were designed and synthesized in this work. The LaAl0.7Ga0.3O3:0.05Eu3+ (LAG:Eu3+) phosphor exhibits a strong charge transfer band (CTB) excitation and characteristic 5D0 → 7F2 transition red emission (619 nm), which is very similar to the luminescence properties of Eu3+-organic ligand compound (EuL3). Rietveld refinement studies further revealed that the cation substitution disturbs the site symmetry. The optimal Eu3+, Mn4+ co-doped LaAl0.7Ga0.3O3 (LAG:Eu,Mn) phosphor possesses a dual-band excitation spectrum in broadband ultraviolet (UVA, UVB) area and a dual-band emission spectrum within red/far-red area. Under the sunlight radiation, the real-time spectrum of luminous laminated glasses fabricated by coating the LAG:Eu,Mn phosphor shows the percentage of radiant intensity in the red/far-red region significantly increases, suggesting that the phosphor can be a promising candidate for solar spectral conversion in plant cultivation. We believe this work provides a new idea for developing novel broadband ultraviolet excitation and red/far-red emission phosphors.

Suppression of Thermal Quenching for CsPbX3 (X = Cl, Br, and I) Quantum Dots via the Hollow Structure of SrTiO3 and Light-Emitting Diode Applications.

All-inorganic perovskite quantum dots (PQDs, CsPbX3, X = Cl, Br, and I) show outstanding application prospects in the field of photoelectric devices. In recent years, the development of PQDs has greatly improved their stability to water, oxygen, and light. However, thermal quenching of PQDs greatly limits their practical application. Herein, we embed PQDs into ATiO3 (A = Ca, Ba, and Sr) of three different mesoporous spherical structures to explore the effect on thermal quenching of PQDs. Because of the unique mesoporous hollow microsphere structure and low thermal conductivity of SrTiO3, it can effectively block the heat transfer and improve the thermal quenching of PQDs. The photoluminescence (PL) intensity of CsPbBr3@SrTiO3 composites is 72.6% of the initial intensity after heating to 120 °C. Moreover, the PL intensity of CsPbBr3@SrTiO3 composites remains about 80% of the initial value even when stored in air for 20 days or irradiated by 365 nm UV light for 48 h. A neutral white light-emitting diode is assembled by a blue chip, CsPbBr3@SrTiO3 composites, and red phosphor of K2SiF6:Mn4+, which has a color temperature of 5389 K and a color gamut covered 133% of National Television Standards Committee (NTSC).

An Anomaly Detection Algorithm Based on Ensemble Learning for 5G Environment.

With the advent of the digital information age, new data services such as virtual reality, industrial Internet, and cloud computing have proliferated in recent years. As a result, it increases operator demand for 5G bearer networks by providing features such as high transmission capacity, ultra-long transmission distance, network slicing, and intelligent management and control. Software-defined networking, as a new network architecture, intends to increase network flexibility and agility and can better satisfy the demands of 5G networks for network slicing. Nevertheless, software-defined networking still faces the challenge of network intrusion. We propose an abnormal traffic detection method based on the stacking method and self-attention mechanism, which makes up for the shortcoming of the inability to track long-term dependencies between data samples in ensemble learning. Our method utilizes a self-attention mechanism and a convolutional network to automatically learn long-term associations between traffic samples and provide them to downstream tasks in sample embedding. In addition, we design a novel stacking ensemble method, which computes the sample embedding and the predicted values of the heterogeneous base learner through the fusion module to obtain the final outlier results. This paper conducts experiments on abnormal traffic datasets in the software-defined network environment, calculates precision, recall and F1-score, and compares and analyzes them with other algorithms. The experimental results show that the method designed in this paper achieves 0.9972, 0.9996, and 0.9984 in multiple indicators of precision, recall, and F1-score, respectively, which are better than the comparison methods.

The highly conserved RNA-binding specificity of nucleocapsid protein facilitates the identification of drugs with broad anti-coronavirus activity.

The binding of SARS-CoV-2 nucleocapsid (N) protein to both the 5'- and 3'-ends of genomic RNA has different implications arising from its binding to the central region during virion assembly. However, the mechanism underlying selective binding remains unknown. Herein, we performed the high-throughput RNA-SELEX (HTR-SELEX) to determine the RNA-binding specificity of the N proteins of various SARS-CoV-2 variants as well as other ß-coronaviruses and showed that N proteins could bind two unrelated sequences, both of which were highly conserved across all variants and species. Interestingly, both sequences are virtually absent from the human transcriptome; however, they exhibit a highly enriched, mutually complementary distribution in the coronavirus genome, highlighting their varied functions in genome packaging. Our results provide mechanistic insights into viral genome packaging, thereby increasing the feasibility of developing drugs with broad-spectrum anti-coronavirus activity by targeting RNA binding by N proteins.

Effect of Ammoniated Fiber Explosion Combined with H2O2 Pretreatment on the Hydrogen Production Capacity of Herbaceous and Woody Waste.

An appropriate pretreatment process is an important part of the preparation of biomass energy from agricultural and forestry waste. Compared to physical and chemical pretreatments alone, the combined ammoniated fiber explosion (AFEX) + hydrogen peroxide (H2O2) pretreatment process can significantly improve the lignin degradation rate and saccharification efficiency, thus improving the hydrogen production capacity during medium-temperature dark fermentation. This study showed that the combined pretreatment increased the saccharification efficiency of herbaceous, hardwood, and softwood biomass by 58.7, 39.5, and 20.6% and the corresponding gas production reached 145.49, 80.75, and 57.52 mL/g, respectively. In addition, X-ray diffraction, scanning electron microscopy, and Fourier-transform infrared spectroscopy showed that AFEX + H2O2 disrupted the structure of the feedstock and was more favorable for lignin removal. Soluble metabolites indicated that AFEX + H2O2 pretreatment enhanced the butyrate metabolic pathway of the substrate and biohydrogen generation and increased the levels of extracellular polymers and microbial community structure.

Effect of Ammonia Fiber Expansion Combined with NaOH Pretreatment on the Resource Efficiency of Herbaceous and Woody Lignocellulosic Biomass.

The most essential issue facing the world today is the provision of energy and sustainable consumption of natural resources. Pretreatment is an essential step to produce biofuels from lignocellulosic biomass. In this study, ammonia fiber explosion (AFEX) combined with NaOH (A-NaOH) pretreatment effects on the characteristics of Pennisetum sinese (herbaceous), oak (hardwood), and camphor wood (softwood) were assessed using enzymatic efficiency analysis, thereby identifying the composition properties of subsequent bio-H2 production. The results show that the lignin removal (84.2%, 59.7%, and 36.7%, respectively) at 5%A-NaOH conditions and enzymatic efficiency (36.2%, 9.7%, and 6.5%, respectively) of Pennisetum sinese (P. sinese), oak, and camphor wood were significantly increased under 4% A-NaOH conditions. Further A-NaOH pretreatment significantly promoted dark fermentation bio-H2 production (152.3, 99.1, and 76.9 mL/g TS, respectively) and volatile acid production (4660.2, 3720.2, and 3496.2 mg/L, respectively) of P. sinese, oak, and camphor wood. These findings show that A-NaOH pretreatment is an effective means of utilization of lignocellulose resources.

Structural Confinement and Energetic Matching Synergistic Effect toward a High-Energy Transfer Efficiency and a Significant Red Emission Enhancement in a Eu2+,Ln3+ Co-doped Sr9LiMn(PO4)7 Whitlockite Phosphor.

Despite an encouraging progress, Mn2+-activated red phosphors suffer from an insufficient emission intensity and a bad color purity. Thus, it is necessary to find a new strategy to realize a bright red emission through highly efficient Mn2+ sensitization. Herein, manipulating Eu2+-sensitized Sr9LiMn(PO4)7 (SLMP) composition by Ln3+ heterovalent substitution is proved to be able to substantially gain a tremendous Mn2+ emission enhancement and result in a dominant red Mn2+ emission. It is found that the emission enhancement ratio is proportional to the order of lanthanide contraction. Notably, Tb3+ doping realizes a 427-fold rise in the integrated emission intensity compared with the SLMP host, which is close to the theoretical maximum of 500. An underlying mechanism for Mn2+ red emission enhancement is proposed, which is attributed to a high-energy transfer probability from Eu2+ to Mn2+ via Ln3+-induced further structural confinement plus an energetic match effect. Meanwhile, homovalent (Ca2+) substitution could precisely tailor Mn2+ emitting color from orange-red to deep red. A warm-white LED device with a low color temperature of 3394 K, a high color-rendering index of 90.2, and suitable CIE coordinates of (0.403, 0.373) is fabricated using optimized phosphor SLMP:Eu2+, Tb3+. These results might reveal a new strategy to develop new red-emitting phosphors with a bright and highly purified red Mn2+ emission.

Self-reduction-induced BaMgP2O7:Eu2+/3+: a multi-stimuli-responsive phosphor for X-ray detection, anti-counterfeiting and optical thermometry.

Mixed-valence Eu2+/3+-activated phosphors have attracted wide attention due to their excellent luminescence tunability. Steady control of the Eu2+/Eu3+ ratio is the key to achieving reproducible Eu2+/3+ co-doped materials. In this work, BaMgP2O7:xEu2+/3+ (BMPO:Eu, x = 0.001-0.20) was successfully prepared by the traditional solid-state method in air. Eu3+ undergoes selective self-reduction at Ba2+ sites surrounded by a [P2O7] framework, leading to quantitive Eu2+/Eu3+. The phosphors exhibit a blue-violet emission band at ∼410 nm due to 5d-4f transitions of Eu2+ and a group of red emission peaks from 5D0-7FJ of Eu3+. Controllable multicolor emissions are realized by regulating the Eu content and excitations. A linear response of overall luminescence intensity to irradiation dose makes the phosphor appropriate for X-ray detection. The combination of UV-blue excitation-dependent color evolution and X-ray luminescence qualifies the phosphors with great potential for multi-level anti-counterfeiting. In addition, Eu3+ presents abnormal anti-thermal quenching, so that the fluorescence intensity ratio (FIR) of Eu2+/Eu3+ changes in the temperature range of 300-520 K, suggesting a promising application in optical thermometry. Therefore, selectively partial self-reduction in a multi-cationic host is an effective strategy to design mixed-valence co-doped materials, providing a multiplicity of applications.