The winged helix domain of MORF binds CpG islands and the TAZ2 domain of p300.

Acetylation of histones by lysine acetyltransferases (KATs) provides a fundamental mechanism by which chromatin structure and transcriptional programs are regulated. Here, we describe a dual binding activity of the first winged helix domain of human MORF KAT (MORFWH1) that recognizes the TAZ2 domain of p300 KAT (p300TAZ2) and CpG rich DNA sequences. Structural and biochemical studies identified distinct DNA and p300TAZ2 binding sites, allowing MORFWH1 to independently engage either ligand. Genomic data show that MORF/MOZWH1 colocalizes with H3K18ac, a product of enzymatic activity of p300, on CpG rich promoters of target genes. Our findings suggest a functional cooperation of MORF and p300 KATs in transcriptional regulation.

Protection against myocardial ischemia/reperfusion injury in mice by 3-caffeoylquinic acid isomers isolated from Saxifraga tangutica.

The development of ischemic heart disease (IHD) involves a variety of pathophysiological responses, such as mitochondrial dysfunction. Many compounds with antioxidant activity isolated from natural products have been shown to have significant effects on the prevention and treatment of cardiovascular diseases. However, little is known about the palliative effects of 3-caffeoylquinic acid isomers isolated from Saxifraga tangutica (S. tangutica) on myocardial ischemia/reperfusion injury (MIRI). Three isomers of 3-caffeoylquinic acid were isolated from S. tangutica and identified as neochlorogenic acid (Fr2-4-1-1, 18.5 mg), chlorogenic acid (Fr2-5-1-1, 81.7 mg) and cryptochlorogenic acid (Fr2-5-2-1, 15.0 mg) using medium-pressure liquid chromatography-high-pressure two-dimensional liquid chromatography. An in vitro DPPH assay showed that cryptochlorogenic acid (CCGA), neochlorogenic acid (NCGA) and chlorogenic acid (CGA) (in order of activity from strongest to weakest) possessed superior antioxidant activity. Langendorff's in vitro model was utilized to explore the protective effects of 3 caffeoylquinic acid isomers against MIRI. The ex vivo MIRI assay demonstrated that CCGA significantly improved hemodynamic function (P < 0.05), hemodynamic function-related indices (LVDP, RPP, +dP/dt and -dP/dt), and cell morphology in I/R myocardium tissues. In addition, the results of western blot analysis showed that mitochondrial biogenesis was significantly increased in I/R myocardial tissues after treatment with CCGA. In contrast, the activities of CGA and NCGA were lower. This is the first demonstration of efficient preparative isolation of 3-caffeoylquinic acid isomers (CGA, NCGA and CCGA) from S. tangutica. CCGA may be a promising approach for the treatment of cardiac I/R injury, especially for the regulation of mitochondrial biogenesis after MIRI.

Histone H4K16ac Binding Function of the Triple PHD Finger Cassette of MLL4.

The human methyltransferase MLL4 plays a critical role in embryogenesis and development, and aberrant activity of MLL4 is linked to neurodegenerative and developmental disorders and cancer. MLL4 contains the catalytic SET domain that catalyzes mono methylation of lysine 4 of histone H3 (H3K4me1) and seven plant homeodomain (PHD) fingers, six of which have not been structurally and functionally characterized. Here, we demonstrate that the triple PHD finger cassette of MLL4, harboring its fourth, fifth and sixth PHD fingers (MLL4PHD456) forms an integrated module, maintains the binding selectivity of the PHD6 finger toward acetylated lysine 16 of histone H4 (H4K16ac), and is capable of binding to DNA. Our findings highlight functional correlation between H4K16ac and H3K4me1, two major histone modifications that are recognized and written, respectively, by MLL4.

Hotspot Cancer Mutation Impairs KAT8-mediated Nucleosomal Histone Acetylation.

KAT8 is an evolutionarily conserved lysine acetyltransferase that catalyzes histone acetylation at H4K16 or H4K5 and H4K8 through distinct protein complexes. It plays a pivotal role in male X chromosome dosage compensation in Drosophila and is implicated in the regulation of diverse cellular processes in mammals. Mutations and dysregulation of KAT8 have been reported in human neurodevelopmental disorders and various cancers. However, the precise mechanisms by which these mutations disrupt KAT8's normal function, leading to disease pathogenesis, remain largely unknown. In this study, we focus on a hotspot missense cancer mutation, the R98W point mutation within the Tudor-knot domain. Our study reveals that the R98W mutation leads to a reduction in global H4K16ac levels in cells and downregulates the expression of target genes. Mechanistically, we demonstrate that R98 is essential for KAT8-mediated acetylation of nucleosomal histones by modulating substrate accessibility.

The Tudor-knot Domain of KAT5 Regulates Nucleosomal Substrate Acetylation.

The lysine acetyltransferase KAT5 is a pivotal enzyme responsible for catalyzing histone H4 acetylation in cells. In addition to its indispensable HAT domain, KAT5 also encompasses a conserved Tudor-knot domain at its N-terminus. However, the function of this domain remains elusive, with conflicting findings regarding its role as a histone reader. In our study, we have employed a CRISPR tiling array approach and unveiled the Tudor-knot motif as an essential domain for cell survival. The Tudor-knot domain does not bind to histone tails and is not required for KAT5's chromatin occupancy. However, its absence leads to a global reduction in histone acetylation, accompanied with genome-wide alterations in gene expression that consequently result in diminished cell viability. Mechanistically, we find that the Tudor-knot domain regulates KAT5's HAT activity on nucleosomes by fine-tuning substrate accessibility. In summary, our study uncovers the Tudor-knot motif as an essential domain for cell survival and reveals its critical role in modulating KAT5's catalytic efficiency on nucleosome and KAT5-dependent transcriptional programs critical for cell viability.

Histone Readers and Their Roles in Cancer.

Histone proteins in eukaryotic cells are subjected to a wide variety of post-translational modifications, which are known to play an important role in the partitioning of the genome into distinctive compartments and domains. One of the major functions of histone modifications is to recruit reader proteins, which recognize the epigenetic marks and transduce the molecular signals in chromatin to downstream effects. Histone readers are defined protein domains with well-organized three-dimensional structures. In this Chapter, we will outline major histone readers, delineate their biochemical and structural features in histone recognition, and describe how dysregulation of histone readout leads to human cancer.

Polymerization Induced Microphase Separation of ABC Triblock Copolymers for 3D Printing Nanostructured Materials.

Polymerization-induced microphase separation (PIMS) is a versatile technique for producing nanostructured materials. In previous PIMS studies, the predominant approach involved employing homopolymers as macromolecular chain transfer agents (macroCTAs) to mediate the formation of nanostructured materials. In this article, the use of AB diblock copolymers as macroCTAs to design PIMS systems for 3D printing of nanostructured materials is investigated. Specifically, the influence of diblock copolymer composition and block sequence on the resulting nanostructures, and their subsequent impact on bulk properties is systematically investigated. Through careful manipulation of the A/B block ratios, the morphology and size of the nanodomains are successfully controlled. Remarkably, the sequence of A and B blocks significantly affects the microphase separation process, resulting in distinct morphologies. The effect can be attributed to changes in the interaction parameters (χAB , χBC , χAC ) between the different block segments. Furthermore, the block sequence and composition exert profound influence on the thermomechanical, tensile, and swelling properties of 3D printed nanostructured materials. By leveraging this knowledge, it becomes possible to design advanced 3D printable materials with tailored properties, opening new avenues for material engineering.

Dual-Path Information Fusion and Twin Attention-Driven Global Modeling for Solar Irradiance Prediction.

Accurate prediction of solar irradiance holds significant value for renewable energy usage and power grid management. However, traditional forecasting methods often overlook the time dependence of solar irradiance sequences and the varying importance of different influencing factors. To address this issue, this study proposes a dual-path information fusion and twin attention-driven solar irradiance forecasting model. The proposed framework comprises three components: a residual attention temporal convolution block (RACB), a dual-path information fusion module (DIFM), and a twin self-attention module (TSAM). These components collectively enhance the performance of multi-step solar irradiance forecasting. First, the RACB is designed to enable the network to adaptively learn important features while suppressing irrelevant ones. Second, the DIFM is implemented to reinforce the model's robustness against input data variations and integrate multi-scale features. Lastly, the TSAM is introduced to extract long-term temporal dependencies from the sequence and facilitate multi-step prediction. In the solar irradiance forecasting experiments, the proposed model is compared with six benchmark models across four datasets. In the one-step predictions, the average performance metrics RMSE, MAE, and MAPE of the four datasets decreased within the ranges of 0.463-2.390 W/m2, 0.439-2.005 W/m2, and 1.3-9.2%, respectively. Additionally, the average R2 value across the four datasets increased by 0.008 to 0.059. The experimental results indicate that the model proposed in this study exhibits enhanced accuracy and robustness in predictive performance, making it a reliable alternative for solar irradiance forecasting.

TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition.

The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that lead to p300/CBP TAZ2 truncations are found in human cancers, and cells with TAZ2 truncations are vulnerable to histone deacetylase inhibitors. Our study reveals a function of the TAZ2 domain in HAT autoinhibitory regulation and provides a potential therapeutic strategy for the treatment of cancers harboring p300/CBP TAZ2 truncations.

Molecular basis for nuclear accumulation and targeting of the inhibitor of apoptosis BIRC2.

The inhibitor of apoptosis protein BIRC2 regulates fundamental cell death and survival signaling pathways. Here we show that BIRC2 accumulates in the nucleus via binding of its second and third BIR domains, BIRC2BIR2 and BIRC2BIR3, to the histone H3 tail and report the structure of the BIRC2BIR3-H3 complex. RNA-seq analysis reveals that the genes involved in interferon and defense response signaling and cell-cycle regulation are most affected by depletion of BIRC2. Overexpression of BIRC2 delays DNA damage repair and recovery of the cell-cycle progression. We describe the structural mechanism for targeting of BIRC2BIR3 by a potent but biochemically uncharacterized small molecule inhibitor LCL161 and demonstrate that LCL161 disrupts the association of endogenous BIRC2 with H3 and stimulates cell death in cancer cells. We further show that LCL161 mediates degradation of BIRC2 in human immunodeficiency virus type 1-infected human CD4+ T cells. Our findings provide mechanistic insights into the nuclear accumulation of and blocking BIRC2.

Fault Diagnosis of Wind Turbine Generators Based on Stacking Integration Algorithm and Adaptive Threshold.

Fault alarm time lag is one of the difficulties in fault diagnosis of wind turbine generators (WTGs), and the existing methods are insufficient to achieve accurate and rapid fault diagnosis of WTGs, and the operation and maintenance costs of WTGs are too high. To invent a new method for fast and accurate fault diagnosis of WTGs, this study constructs a stacking integration model based on the machine learning algorithms light gradient boosting machine (LightGBM), extreme gradient boosting (XGBoost), and stochastic gradient descent regressor (SGDRegressor) using publicly available datasets from Energias De Portugal (EDP). This model is automatically tuned for hyperparameters during training using Bayesian tuning, and the coefficient of determination (R2) and root mean square error (RMSE) were used to evaluate the model to determine its applicability and accuracy. The fitted residuals of the test set were calculated, the Pauta criterion (3σ) and the temporal sliding window were applied, and a final adaptive threshold method for accurate fault diagnosis and alarming was created. The model validation results show that the adaptive threshold method proposed in this study is better than the fixed threshold for diagnosis, and the alarm times for the GENERATOR fault type, GENERATOR_BEARING fault type, and TRANSFORMER fault type are 1.5 h, 5.8 h, and 3 h earlier, respectively.

LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.

Spodoptera litura larvae are attracted by HvAV-3h-infected S. litura larvae-damaged pepper leaves.

BACKGROUND: Herbivore-induced plant volatiles (HIPVs) are important self-defense outputs of pepper plants to resist insect pests. Ascoviruses are pathogenic to the larvae of most lepidopteran vegetable pests. However, whether Heliothis virescens ascovirus 3h (HvAV-3h)-infected Spodoptera litura larvae can change pepper leaf HIPVs is not well understood. RESULTS: Spodoptera litura larvae preferred S. litura-infested leaves, and this preference was stronger with longer duration of S. litura infestation. In addition, S. litura larvae significantly chose pepper leaves damaged by HvAV-3h-infected S. litura over the healthy pepper leaves. Results also showed that S. litura larvae preferred leaves mechanically damaged and treated with oral secretions from HvAV-3h infected-S. litura larvae in a simulation test. We captured the volatiles emitted by leaves under six treatments. Results showed that the volatile profile changed with the different treatments. Testing of volatile blends, prepared to the proportion released showed that the blend from simulated HvAV-3h-infected S. litura larvae-damaged plants was the most attractive to S. litura larvae. Further, we also found that some of the compounds significantly attracted S. litura larvae at specific concentrations. CONCLUSION: HvAV-3h-infected S. litura can alter the release of HIPVs in pepper plants and thus become more attractive to S. litura larvae. We speculate that this may be due to alterations in the concentration of some compounds (such as geranylacetone and prohydrojasmon) affecting the behavior of S. litura larvae. © 2023 Society of Chemical Industry.

Photo-RAFT Polymerization for Hydrogel Synthesis through Barriers and Development of Light-Regulated Healable Hydrogels under NIR Irradiation.

We report an aqueous and near-infrared (NIR) light mediated photoinduced reversible addition-fragmentation chain transfer (photo-RAFT) polymerization system catalyzed by tetrasulfonated zinc phthalocyanine (ZnPcS4 - ) in the presence of peroxides. Taking advantage of its fast polymerization rates and high oxygen tolerance, this system is successfully applied for the preparation of hydrogels. Exploiting the enhanced penetration of NIR light, photoinduced gelation is effectively performed through non-transparent biological barriers. Notably, the RAFT agents embedded in these hydrogel networks can be reactivated on-demand, enabling the hydrogel healing under NIR light irradiation. In contrast to the minimal healing capability (<15 %) of hydrogels prepared by free radical polymerization (FRP), RAFT-mediated networks display more than 80 % recovery of tensile strength. Although healable polymer networks under UV and blue lights have already been established, this work is the first photochemistry system using NIR light, facilitating photoinduced healing of hydrogels through thick non-transparent barriers.

TRIM28 secures skeletal stem cell fate during skeletogenesis by silencing neural gene expression and repressing GREM1/AKT/mTOR signaling axis.

Long bones are generated by mesoderm-derived skeletal progenitor/stem cells (SSCs) through endochondral ossification, a process of sequential chondrogenic and osteogenic differentiation tightly controlled by the synergy between intrinsic and microenvironment cues. Here, we report that loss of TRIM28, a transcriptional corepressor, in mesoderm-derived cells expands the SSC pool, weakens SSC osteochondrogenic potential, and endows SSCs with properties of ectoderm-derived neural crest cells (NCCs), leading to severe defects of skeletogenesis. TRIM28 preferentially enhances H3K9 trimethylation and DNA methylation on chromatin regions more accessible in NCCs; loss of this silencing upregulates neural gene expression and enhances neurogenic potential. Moreover, TRIM28 loss causes hyperexpression of GREM1, which is an extracellular signaling factor promoting SSC self-renewal and SSC neurogenic potential by activating AKT/mTORC1 signaling. Our results suggest that TRIM28-mediated chromatin silencing establishes a barrier for maintaining the SSC lineage trajectory and preventing a transition to ectodermal fate by regulating both intrinsic and microenvironment cues.

Diblock Copolymer Stabilized Liquid Metal Nanoparticles: Particle Settling Behavior and Application to 3D Printing.

Eutectic gallium indium (EGaIn) is a liquid metal with promising applications due to its favorable thermal and electrical conductivity, low viscosity, and metallic nature. For applications, including imaging, catalysis, and nanomedicine, stable EGaIn particles with submicron diameters are required. However, the low viscosity and high density of EGaIn have typically precluded the formation of stable submicron particles due to rapid EGaIn droplet coalescence. In this work, we show that poly(acrylic acid)-block-poly(N,N'-dimethylacrylamide) copolymers are able to effectively stabilize EGaIn nanodroplets formed upon ultrasonication, where the poly(acrylic acid) block anchors the polymer to the EGaIn surface and the poly(N,N'-dimethylacrylamide) block provides colloidal stability to the particles in solution. Although the high density of EGaIn causes rapid particle settling, the behavior is predictable, which allows the average particle size to be controlled through centrifugation. We demonstrate that stable EGaIn particles with sizes on the order of 50-100 nm and narrow particle size distributions can be easily obtained using this method and further used in photopolymer resins to prepare 3D printed EGaIn-polymer hybrid materials. The predictable sizes and high stability of these EGaIn nanoparticles should allow further applications in soft-electronics, nanomedicine, catalysis, and other nanotechnology.

Histone H3 proline 16 hydroxylation regulates mammalian gene expression.

Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian cells, namely histone H3 with hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding of KDM5A to its substrate, histone H3 with trimethylation at the fourth lysine residue (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and a corresponding decrease of H3K4me3 at target genes. Genome- and transcriptome-wide analyses show that the EGLN2-KDM5A axis regulates target gene expression in mammalian cells. Specifically, our data demonstrate repression of the WNT pathway negative regulator DKK1 through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/ß-catenin signaling in triple-negative breast cancer (TNBC). This study characterizes a regulatory mark in the histone code and reveals a role for H3P16oh in regulating mammalian gene expression.

Unilateral biportal endoscopic lumbar interbody fusion assisted by intraoperative O-arm total navigation for lumbar degenerative disease: A retrospective study.

Background: Recently, unilateral biportal endoscopic lumbar interbody fusion (BE-LIF) has been successfully applied for degenerative diseases of the lumbar spine, with good clinical results reported. However, the drawbacks include radiation exposure, limited field of view, and steep learning curves. Objective: This retrospective study aimed to compare the results between navigation and non-navigation groups and explore the benefits of BE-LIF assisted by intraoperative O-arm total navigation. Methods: A total of 44 patients were retrospectively analyzed from August 2020 to June 2021. Perioperative data were collected, including operative time, estimated intraoperative blood loss, postoperative drainage, postoperative hospital stay, radiation dose, and duration of radiation exposure. In addition, clinical outcomes were evaluated using postoperative data, such as the Oswestry Disability Index (ODI), visual analog scale (VAS), modified MacNab criteria, Postoperative complications and fusion rate. Results: The non-navigation and navigation groups included 23 and 21 patients, respectively. All the patients were followed up for at least 12 months. No significant differences were noted in the estimated intraoperative blood loss, postoperative drainage, postoperative hospital stay, fusion rate, or perioperative complications between the two groups. The radiation dose was significantly lower in the navigation group than in the non-navigation group. The average total operation time in the navigation group was lower than that in the non-navigation group (P < 0.01). All clinical outcomes showed improvement at different time points postoperatively, with no significant difference noted between the two groups (P > 0.05). Conclusions: Compared with the non-navigation approach, O-arm total navigation assistive BE-LIF technology not only has similar clinical results, but also can provide accurate intraoperative guidance and help spinal surgeons achieve accurate decompression. Furthermore, it can reduce radiation exposure to surgeons and operation time, which improve the efficiency and safety of surgery.

Preparation and Application of Decellularized ECM-Based Biological Scaffolds for Articular Cartilage Repair: A Review.

Cartilage regeneration is dependent on cellular-extracellular matrix (ECM) interactions. Natural ECM plays a role in mechanical and chemical cell signaling and promotes stem cell recruitment, differentiation and tissue regeneration in the absence of biological additives, including growth factors and peptides. To date, traditional tissue engineering methods by using natural and synthetic materials have not been able to replicate the physiological structure (biochemical composition and biomechanical properties) of natural cartilage. Techniques facilitating the repair and/or regeneration of articular cartilage pose a significant challenge for orthopedic surgeons. Whereas, little progress has been made in this field. In recent years, with advances in medicine, biochemistry and materials science, to meet the regenerative requirements of the heterogeneous and layered structure of native articular cartilage (AC) tissue, a series of tissue engineering scaffolds based on ECM materials have been developed. These scaffolds mimic the versatility of the native ECM in function, composition and dynamic properties and some of which are designed to improve cartilage regeneration. This review systematically investigates the following: the characteristics of cartilage ECM, repair mechanisms, decellularization method, source of ECM, and various ECM-based cartilage repair methods. In addition, the future development of ECM-based biomaterials is hypothesized.

Designing Nanostructured 3D Printed Materials by Controlling Macromolecular Architecture.

Nanostructured polymeric materials play important roles in many advanced applications, however, controlling the morphologies of polymeric thermosets remains a challenge. This work uses multi-arm macroCTAs to mediate polymerization-induced microphase separation (PIMS) and prepare nanostructured materials via photoinduced 3D printing. The characteristic length scale of microphase-separated domains is determined by the macroCTA arm length, while nanoscale morphologies are controlled by the macroCTA architecture. Specifically, using 2- and 4- arm macroCTAs provides materials with different morphologies compared to analogous monofunctional linear macroCTAs at similar compositions. The mechanical properties of these nanostructured thermosets can also be tuned while maintaining the desired morphologies. Using multi-arm macroCTAs can thus broaden the scope of accessible nanostructures for extended applications, including the fabrication of actuators and potential drug delivery devices.