Convergence of the dysregulated regulome in schizophrenia with polygenic risk and evolutionarily constrained enhancers.

Enhancers play an essential role in the etiology of schizophrenia; however, the dysregulation of enhancer activity and its impact on the regulome in schizophrenia remains understudied. To address this gap in our knowledge, we assessed enhancer and gene expression in 1,382 brain samples comprising cases with schizophrenia and unaffected controls. Dysregulation of enhancer expression was concordant with changes in gene expression, and was more closely associated with schizophrenia polygenic risk, suggesting that enhancer dysregulation is proximal to the genetic etiology of the disease. Modeling the shared variance of cis-coordinated genes and enhancers revealed a gene regulatory program that was highly associated with genetic vulnerability to schizophrenia. By integrating coordinated factors with evolutionary constraints, we found that enhancers acquired during human evolution are more likely to regulate genes that are implicated in neuropsychiatric disorders and, thus, hold potential as therapeutic targets. Our analysis provides a systematic view of regulome dysregulation in schizophrenia and highlights its convergence with schizophrenia polygenic risk and human-gained enhancers.

Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome.

The human brain is a complex organ comprised of distinct cell types, and the contribution of the 3D genome to lineage specific gene expression remains poorly understood. To decipher cell type specific genome architecture, and characterize fine scale changes in the chromatin interactome across neural development, we compared the 3D genome of the human fetal cortical plate to that of neurons and glia isolated from the adult prefrontal cortex. We found that neurons have weaker genome compartmentalization compared to glia, but stronger TADs, which emerge during fetal development. Furthermore, relative to glia, the neuronal genome shifts more strongly towards repressive compartments. Neurons have differential TAD boundaries that are proximal to active promoters involved in neurodevelopmental processes. CRISPRi on CNTNAP2 in hIPSC-derived neurons reveals that transcriptional inactivation correlates with loss of insulation at the differential boundary. Finally, re-wiring of chromatin loops during neural development is associated with transcriptional and functional changes. Importantly, differential loops in the fetal cortex are associated with autism GWAS loci, suggesting a neuropsychiatric disease mechanism affecting the chromatin interactome. Furthermore, neural development involves gaining enhancer-promoter loops that upregulate genes that control synaptic activity. Altogether, our study provides multi-scale insights on the 3D genome in the human brain.

Reticular Ratchets for Directing Electrochemiluminescence.

Electrochemiluminescence (ECL) involves charge transfer between electrochemical redox intermediates to produce an excited state for light emission. Ensuring precise control of charge transfer is essential for decoding ECL fundamentals, yet guidelines on how to achieve this for conventional emitters remain unexplored. Molecular ratchets offer a potential solution, as they enable the directional transfer of energy or chemicals while impeding the reverse movement. Herein, we designed 10 pairs of imine-based covalent organic frameworks as reticular ratchets to delicately manipulate the intrareticular charge transfer for directing ECL transduction from electric and chemical energies. Aligning the donor and acceptor (D-A) directions with the imine dipole effectively facilitates charge migration, whereas reversing the D-A direction impedes it. Notably, the ratchet effect of charge transfer directionality intensified with increasing D-A contrast, resulting in a remarkable 680-fold improvement in the ECL efficiency. Furthermore, dipole-controlled exciton binding energy, electron/hole decay kinetics, and femtosecond transient absorption spectra identified the electron transfer tendency from the N-end toward the C-end of reticular ratchets during ECL transduction. An exponential correlation between the ECL efficiency and the dipole difference was discovered. Our work provides a general approach to manipulate charge transfer and design next-generation electrochemical devices.

Low temperature-induced regulatory network rewiring via WRKY regulators during banana peel browning.

Banana (Musa spp.) fruits, as typical tropical fruits, are cold sensitive, and lower temperatures can disrupt cellular compartmentalization and lead to severe browning. How tropical fruits respond to low temperature compared to the cold response mechanisms of model plants remains unknown. Here, we systematically characterized the changes in chromatin accessibility, histone modifications, distal cis-regulatory elements, transcription factor binding, and gene expression levels in banana peels in response to low temperature. Dynamic patterns of cold-induced transcripts were generally accompanied by concordant chromatin accessibility and histone modification changes. These upregulated genes were enriched for WRKY binding sites in their promoters and/or active enhancers. Compared to banana peel at room temperature, large amounts of banana WRKYs were specifically induced by cold and mediated enhancer-promoter interactions regulating critical browning pathways, including phospholipid degradation, oxidation, and cold tolerance. This hypothesis was supported by DNA affinity purification sequencing, luciferase reporter assays, and transient expression assay. Together, our findings highlight widespread transcriptional reprogramming via WRKYs during banana peel browning at low temperature and provide an extensive resource for studying gene regulation in tropical plants in response to cold stress, as well as potential targets for improving cold tolerance and shelf life of tropical fruits.

Schisandrin A can promote the anti-tumor effect of 5-Fu by reversing the immunosuppressive state of the body in rat.

In this study, based on Walker 256 in vitro experiments, CCK-8 assay, clone formation assay, wound healing assay, and flow cytometry were used to detect cell apoptosis and cell cycle. It was found that schisandrin may have significant anti-tumor effects in vitro by inhibiting TGF-ß/Smad signaling pathway. In addition, in vivo experiments, immunohistochemistry was used to observe the expression of HIF-1α, VEGF and VEGFR-2 in tumor tissues. It was found that schisandrin could significantly improve the immunosuppression induced by 5-Fu and enhance the antitumor effect of 5-Fu. The mechanism may be related to the inhibition of Wnt-1/ß-catenin signaling pathway.

Stepwise Protonation of Three-Dimensional Covalent Organic Frameworks for Enhancing Hydrogen Peroxide Photosynthesis.

Three-dimensional covalent organic frameworks (3D COFs), recognized for their tailorable structures and accessible active sites, offer a promising platform for developing advanced photocatalysts. However, the difficulty in the synthesis and functionalization of 3D COFs hinders their further development. In this study, we present a series of 3D-bcu-COFs with 8 connected porphyrin units linked by linear linkers through imine bonds as a versatile platform for photocatalyst design. The photoresponse of 3D-bcu-COFs was initially modulated by functionalizing linear linkers with benzo-thiadiazole or benzo-selenadiazole groups. Furthermore, taking advantage of the well-exposed porphyrin and imine sites in 3D-bcu-COFs, their photocatalytic activity was optimized by stepwise protonation of imine bonds and porphyrin centers. The dual protonated COF with benzo-selenadiazole groups exhibited enhanced charge separation, leading to an increased photocatalytic H2O2 production under visible light. This enhancement demonstrates the combined benefits of linker functionalization and stepwise protonation on photocatalytic efficiency.

Bimodal Oxidation Electrochemiluminescence Mechanism of Coreactant-Embedded Covalent Organic Frameworks via Postsynthetic Modification.

Electrochemiluminescence (ECL) efficiency is determined by charge transfer between coreactants and emitters in coreactant systems, which are usually limited by their slow intermolecular charge transfer. In this study, a covalent organic framework (COF) with aldehyde residue was synthesized, and then coreactants were covalently integrated into the skeleton through the postsynthetic modification strategy, resulting in a crystalline coreactant-embedded COF nanoemitter (C-COF). Compared to the pristine COF with an equivalent external coreactant, C-COF exhibited an extraordinary 1008-fold enhancement of ECL intensity due to the rapid intrareticular charge transfer. Significantly, with the pH increase, C-COF shows protonation-induced ECL enhancement for the first ECL peaked at +1.1 V and an opposite trend for the second ECL at +1.4 V, which were attributed to the antedating oxidation of coreactant in framework and COF self-oxidation, respectively. The resulting bimodal oxidation ECL mechanism was rationalized by spectral characterization and density functional theory calculations. The postsynthetic coreactant-embedded nanoemitters present innovative and universal avenues for advancing ECL systems.

Chromatin and regulatory differentiation between bundle sheath and mesophyll cells in maize.

C4 plants partition photosynthesis enzymes between the bundle sheath (BS) and the mesophyll (M) cells for the better delivery of CO2 to RuBisCO and to reduce photorespiration. To better understand how C4 photosynthesis is regulated at the transcriptional level, we performed RNA-seq, ATAC-seq, ChIP-seq and Bisulfite-seq (BS-seq) on BS and M cells isolated from maize leaves. By integrating differentially expressed genes with chromatin features, we found that chromatin accessibility coordinates with epigenetic features, especially H3K27me3 modification and CHH methylation, to regulate cell type-preferentially enriched gene expression. Not only the chromatin-accessible regions (ACRs) proximal to the genes (pACRs) but also the distal ACRs (dACRs) are determinants of cell type-preferentially enriched expression. We further identified cell type-preferentially enriched motifs, e.g. AAAG for BS cells and TGACC/T for M cells, and determined their corresponding transcription factors: DOFs and WRKYs. The complex interaction between cis and trans factors in the preferential expression of C4 genes was also observed. Interestingly, cell type-preferentially enriched gene expression can be fine-tuned by the coordination of multiple chromatin features. Such coordination may be critical in ensuring the cell type-specific function of key C4 genes. Based on the observed cell type-preferentially enriched expression pattern and coordinated chromatin features, we predicted a set of functionally unknown genes, e.g. Zm00001d042050 and Zm00001d040659, to be potential key C4 genes. Our findings provide deep insight into the architectures associated with C4 gene expression and could serve as a valuable resource to further identify the regulatory mechanisms present in C4 species.

Postsynthetic Annulation of Three-Dimensional Covalent Organic Frameworks for Boosting CO2 Photoreduction.

Three-dimensional covalent organic frameworks (3D COFs), with interconnected pores and exposed functional groups, provide new opportunities for the design of advanced functional materials through postsynthetic modification. Herein, we demonstrate the successful postsynthetic annulation of 3D COFs to construct efficient CO2 reduction photocatalysts. Two 3D COFs, NJU-318 and NJU-319Fe, were initially constructed by connecting hexaphenyl-triphenylene units with pyrene- or Fe-porphyrin-based linkers. Subsequently, the hexaphenyl-triphenylene moieties within the COFs were postsynthetically transformed into π-conjugated hexabenzo-trinaphthylene (pNJU-318 and pNJU-319Fe) to enhance visible light absorption and CO2 photoreduction activity. The optimized photocatalyst, pNJU-319Fe, shows a CO yield of 688 µmol g-1, representing a 2.5-fold increase compared to that of unmodified NJU-319Fe. Notably, the direct synthesis of hexabenzo-trinaphthylene-based COF catalysts was unsuccessful due to the low solubility of conjugated linkers. This study not only provides an effective method to construct photocatalysts but also highlights the unlimited tunability of 3D COFs through structural design and postsynthetic modification.

A Self-Templated Design Approach toward Multivariate Metal-Organic Frameworks for Enhanced Oxygen Evolution.

Multivariate metal-organic framework (MOF) is an ideal electrocatalytic material due to the synergistic effect of multiple metal active sites. In this study, a series of ternary M-NiMOF (M = Co, Cu) through a simple self-templated strategy that the Co/Cu MOF isomorphically grows in situ on the surface of NiMOF is designed. Owing to the electron rearrange of adjacent metals, the ternary CoCu-NiMOFs demonstrate the improved intrinsic electrocatalytic activity. At optimized conditions, the ternary Co3 Cu-Ni2 MOFs nanosheets give the excellent oxygen evolution reaction (OER) performance of current density of 10 mA cm-2 at low overpotential of 288 mV with a Tafel slope of 87 mV dec-1 , which is superior to that of bimetallic nanosheet and ternary microflowers. The low free energy change of potential-determining step identifies that the OER process is favorable at Cu-Co concerted sites along with strong synergistic effect of Ni nodes. Partially oxidized metal sites also reduce the electron density, thus accelerating the OER catalytic rate. The self-templated strategy provides a universal tool to design multivariate MOF electrocatalysts for highly efficient energy transduction.

Connecting Aortic Stiffness to Vascular Contraction: Does Sex Matter?

This study was designed to connect aortic stiffness to vascular contraction in young male and female Wistar rats. We hypothesized that female animals display reduced intrinsic media-layer stiffness, which associates with improved vascular function. Atomic force microscopy (AFM)-based nanoindentation analysis was used to derive stiffness (Young's modulus) in biaxially (i.e., longitudinal and circumferential) unloaded aortic rings. Reactivity studies compatible with uniaxial loading (i.e., circumferential) were used to assess vascular responses to a selective α1 adrenergic receptor agonist in the presence or absence of extracellular calcium. Elastin and collagen levels were indirectly evaluated with fluorescence microscopy and a picrosirius red staining kit, respectively. We report that male and female Wistar rats display similar AFM-derived aortic media-layer stiffness, even though female animals withstand higher aortic intima-media thickness-to-diameter ratio than males. Female animals also present reduced phenylephrine-induced aortic force development in concentration-response and time-force curves. Specifically, we observed impaired force displacement in both parts of the contraction curve (Aphasic and Atonic) in experiments conducted with and without extracellular calcium. Additionally, collagen levels were lower in female animals without significant elastin content and fragmentation changes. In summary, sex-related functional differences in isolated aortas appear to be related to dissimilarities in the dynamics of vascular reactivity and extracellular matrix composition rather than a direct response to a shift in intrinsic media-layer stiffness.

A stepwise recognition strategy for the detection of telomerase activity via direct electrochemical analysis of metal-organic frameworks.

The detection of telomerase is of great significance for monitoring cell canceration. The conventional methods depend on the extension of telomerase towards its primer to conduct signal transduction. Herein, a specific and reliable detection strategy based on stepwise recognition was developed for tandem detection of metal ions and enzymes. We first synthesized an electrically active metal-organic framework (MIL-101(Fe)), which can act directly as a signal reporter in phosphate buffered saline after being modified with capture DNA (cDNA). When the zinc ion is added as a coenzyme factor, the modified hairpin DNA on the electrode is cleaved by DNAzyme to yield the activated primer. After the addition of telomerase, the cleaved DNA strand would be extended, and the resulting sequence will be hybridized with the signal label of MIL-101(Fe)-cDNA. Therefore, a signal-on strategy for the detection of telomerase was achieved based on the direct electrochemical analysis of MIL-101(Fe). Moreover, this electrochemical biosensor can discriminate telomerase activity among different cell lines. The stepwise recognition ensured the advantages of an electrochemical biosensor such as high sensitivity and specificity during the detection process, providing a novel method for monitoring and diagnosis of diseases.

Plant and animal chromatin three-dimensional organization: similar structures but different functions.

Chromatin is the main carrier of genetic information and is non-randomly distributed within the nucleus. Next-generation sequence-based chromatin conformation capture technologies have enabled us to directly examine its three-dimensional organization at an unprecedented scale and resolution. In the best-studied mammalian models, chromatin folding can be broken down into three hierarchical levels, compartment, domains, and loops, which play important roles in transcriptional regulation. Although similar structures have now been identified in plants, they might not possess exactly the same functions as the mammalian ones. Here, we review recent Hi-C studies in plants, compare plant chromatin structures with their mammalian counterparts, and discuss the differences between plants with different genome sizes.

Comparative study of tapered versus conventional cylindrical balloon for stent implantation in stenotic tapered artery.

The natural tapering of coronary arteries often creates a dilemma for optimal balloon sizing during stenting. The influence of different balloon types, namely, a tapered balloon and a conventional cylindrical balloon, on the mechanical performance of the stent as well as arterial mechanics was investigated via the finite element method. Stent free-expansion and stent deployment in a stenotic tapered artery were investigated numerically. The biomechanical behavior of the two balloon types was compared in terms of stent foreshortening, stent deformation, stent stress distribution, and arterial wall stress distribution. Results indicate that balloon types affect the transient behavior of the stent and the arterial mechanics. Specifically, a tapered balloon could maintain the natural tapering of the coronary artery after stent expansion. In contrast to a cylindrical balloon, tapered balloon also mitigated the foreshortening of the stent (7.69%) as well as the stress concentration in the stent and artery (8.61% and 4.17%, respectively). Hence, tapered balloons should be used in tapered arteries as they may result in low risk of artery injury. This study might provide insights for improved balloon choice and presurgical planning.

Optical Coherence Tomography-Based Modeling of Stent Deployment in Heavily Calcified Coronary Lesion.

In this work, a heavily calcified coronary artery model was reconstructed from optical coherence tomography (OCT) images to investigate the impact of calcification characteristics on stenting outcomes. The calcification was quantified at various cross sections in terms of angle, maximum thickness, and area. The stent deployment procedure, including the crimping, expansion, and recoil, was implemented. The influence of calcification characteristics on stent expansion, malapposition, and lesion mechanics was characterized. Results have shown that the minimal lumen area following stenting occurred at the cross section with the greatest calcification angle. The calcification angle constricted the stretchability of the lesion and thus resulted in a small lumen area. The maximum principal strain and von Mises stress distribution patterns in both the fibrotic tissue and artery were consistent with the calcification profiles. The radially projected region of the calcification tends to have less strain and stress. The peak strain and stress of the fibrotic tissue occurred near the interface with the calcification. It is also the region with a high risk of tissue dissection and strut malapposition. In addition, the superficial calcification with a large angle aggregated the malapposition at the middle of the calcification arc. These detailed mechanistic quantifications could be used to provide a fundamental understanding of the role of calcification in stent expansions, as well as to exploit their potential for enhanced pre- and post-stenting strategies.

Tissue-specific Hi-C analyses of rice, foxtail millet and maize suggest non-canonical function of plant chromatin domains.

Chromatins are not randomly packaged in the nucleus and their organization plays important roles in transcription regulation, which is best studied in the mammalian models. Using in situ Hi-C, we have compared the 3D chromatin architectures of rice mesophyll and endosperm, foxtail millet bundle sheath and mesophyll, and maize bundle sheath, mesophyll and endosperm tissues. We found that their global A/B compartment partitions are stable across tissues, while local A/B compartment has tissue-specific dynamic associated with differential gene expression. Plant domains are largely stable across tissues, while new domain border formations are often associated with transcriptional activation in the region. Genes inside plant domains are not conserved across species, and lack significant co-expression behavior unlike those in mammalian TADs. Although we only observed chromatin loops between gene islands in the large genomes, the maize loop gene pairs' syntenic orthologs have shorter physical distances in small genome monocots, suggesting that loops instead of domains might have conserved biological function. Our study showed that plants' chromatin features might not have conserved biological functions as the mammalian ones.

Impact of Calcium Quantifications on Stent Expansions.

Severely calcified plaque is of great concern when planning and implementing a stenting intervention. In this work, computational models were developed to investigate the influence of calcium characteristics on stenting outcomes. The commonly used clinical measurements of calcium (i.e., the arc angle, maximum thickness, length, and volume) were varied to estimate stenting outcomes in terms of lumen gain, stent underexpansion, strut malapposition, and stress or strain distributions of the stenotic lesion. Results have shown that stenting outcomes were most sensitive to the arc angle of the calcium. A thick calcium with a large arc angle resulted in poor stenting outcomes, such as severe stent underexpansion, D-shaped lumen, increased strut malapposition, and large stresses or strains in the plaque. This was attributed to the circumferential stretch of the tissue. Specifically, the noncalcium component was stretched significantly more than the calcium. The circumferential stretch ratios of calcium and noncalcium component were approximately 1.44 and 2.35, respectively, regardless of calcium characteristics. In addition, the peak stress or strain within the artery and noncalcium component of the plaque occurred at the area adjacent to calcium edges (i.e., the interface between the calcium and the noncalcium component) coincident with the location of peak malapposition. It is worth noting that calcium played a protective role for the artery underneath, which was at the expense of the overstretch and stress concentrations in the other portion of the artery. These detailed mechanistic quantifications could be used to provide a fundamental understanding of the impact of calcium quantifications on stent expansions, as well as to exploit their potential for a better preclinical strategy.

The miRNA-Mediated Post-Transcriptional Regulation of Maize in Response to High Temperature.

High temperature (HT) has recently become one of the most important abiotic stresses restricting crop production worldwide. MicroRNAs (miRNAs) are important regulators in plant development and stress responses. However, knowledge of miRNAs of maize in response to HT is limited. In this study, we simultaneously adopted miRNA sequencing and transcriptome profiling to analyze the differential expression of miRNAs and mRNAs in maize during exposure to HT stress. Our analysis revealed 61 known miRNAs belonging to 26 miRNA families and 42 novel miRNAs showing significant differential expression, with the majority being downregulated. Meanwhile, the expression of 5450 mRNAs was significantly altered in the same stressed tissues. Differentially expressed transcripts were most significantly associated with response to stress, photosynthesis, biosynthesis of secondary metabolites, and signal transduction pathways. In addition, we discovered 129 miRNA­mRNA pairs that were regulated antagonistically, and further depiction of the targeted mRNAs indicated that several transcription factors, protein kinases, and receptor-like-protein-related transmembrane transport and signaling transduction were profoundly affected. This study has identified potential key regulators of HT-stress response in maize and the subset of genes that are likely to be post-transcriptionally regulated by miRNAs under HT stress.

Structural heterogeneity and functional diversity of topologically associating domains in mammalian genomes.

Recent chromosome conformation capture (3C) derived techniques have revealed that topologically associating domain (TAD) is a pervasive element in chromatin three-dimensional (3D) organization. However, there is currently no parameter to quantitatively measure the structural characteristics of TADs, thus obscuring our understanding on the structural and functional differences among TADs. Based on our finding that there exist intrinsic chromatin interaction patterns in TADs, we define a theoretical parameter, called aggregation preference (AP), to characterize TAD structures by capturing the interaction aggregation degree. Applying this defined parameter to 11 Hi-C data sets generated by both traditional and in situ Hi-C experimental pipelines, our analyses reveal that heterogeneous structures exist among TADs, and this structural heterogeneity is significantly correlated to DNA sequences, epigenomic signals and gene expressions. Although TADs can be stable in genomic positions across cell lines, structural comparisons show that a considerable number of stable TADs undergo significantly structural rearrangements during cell changes. Moreover, the structural change of TAD is tightly associated with its transcription remodeling. Altogether, the theoretical parameter defined in this work provides a quantitative method to link structural characteristics and biological functions of TADs, and this linkage implies that chromatin interaction pattern has the potential to mark transcription activity in TADs.

Static Adsorption of an Ethoxylated Nonionic Surfactant on Carbonate Minerals.

The static adsorption of C12-14E22, which is a highly ethoxylated nonionic surfactant, was studied on different minerals using high-performance liquid chromatography (HPLC) combined with an evaporative light scattering detector (ELSD). Of particular interest is the surfactant adsorption in the presence of CO2 because it can be used for foam flooding in enhanced oil recovery applications. The effects of the mineral type, impurities, salinity, and temperature were investigated. The adsorption of C12-14E22 on pure calcite was as low as 0.01 mg/m2 but higher on dolomite depending on the silica and clay content in the mineral. The adsorption remained unchanged when the experiments were performed using a brine solution or 0.101 MPa (1 atm) CO2, which indicates that electrostatic force is not the governing factor that drives the adsorption. The adsorption of C12-14E22 on silica may be due to hydrogen bonding between the oxygen in the ethoxy groups of the surfactant and the hydroxyl groups on the mineral surface. Additionally, thermal decomposition of the surfactant was severe at 80 °C but can be inhibited by operating in a reducing environment. Under reducing conditions, adsorption of C12-14E22 increased at higher temperatures.