The developmental and evolutionary characteristics of transcription factor binding site clustered regions based on an explainable machine learning model.

Gene expression is temporally and spatially regulated by the interaction of transcription factors (TFs) and cis-regulatory elements (CREs). The uneven distribution of TF binding sites across the genome poses challenges in understanding how this distribution evolves to regulate spatio-temporal gene expression and consequent heritable phenotypic variation. In this study, chromatin accessibility profiles and gene expression profiles were collected from several species including mammals (human, mouse, bovine), fish (zebrafish and medaka), and chicken. Transcription factor binding sites clustered regions (TFCRs) at different embryonic stages were characterized to investigate regulatory evolution. The study revealed dynamic changes in TFCR distribution during embryonic development and species evolution. The synchronization between TFCR complexity and gene expression was assessed across species using RegulatoryScore. Additionally, an explainable machine learning model highlighted the importance of the distance between TFCR and promoter in the coordinated regulation of TFCRs on gene expression. Our results revealed the developmental and evolutionary dynamics of TFCRs during embryonic development from fish, chicken to mammals. These data provide valuable resources for exploring the relationship between transcriptional regulation and phenotypic differences during embryonic development.

dbEmbryo multi-omics database for analyses of synergistic regulation in early mammalian embryo development.

During early mammalian embryo development, different epigenetic marks undergo reprogramming and play crucial roles in the mediation of gene expression. Currently, several databases provide multi-omics information on early embryos. However, how interconnected epigenetic markers function together to coordinate the expression of the genetic code in a spatiotemporal manner remains difficult to analyze, markedly limiting scientific and clinical research. Here, we present dbEmbryo, an integrated and interactive multi-omics database for human and mouse early embryos. dbEmbryo integrates data on gene expression, DNA methylation, histone modifications, chromatin accessibility, and higher-order chromatin structure profiles for human and mouse early embryos. It incorporates customized analysis tools, such as "multi-omics visualization," "Gene&Peak annotation," "ZGA gene cluster," "cis-regulation," "synergistic regulation," "promoter signal enrichment," and "3D genome." Users can retrieve gene expression and epigenetic profile patterns to analyze synergistic changes across different early embryo developmental stages. We showed the uniqueness of dbEmbryo among extant databases containing data on early embryo development and provided an overview. Using dbEmbryo, we obtained a phase-separated model of transcriptional control during early embryo development. dbEmbryo offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher molecular regulatory mechanisms of human and mouse early embryo development.

Highly Selective On-Surface Ring-Opening of Aromatic Azulene Moiety.

Controllable ring-opening of polycyclic aromatic hydrocarbons plays a crucial role in various chemical and biological processes. However, breaking down aromatic covalent C-C bonds is exceptionally challenging due to their high stability and strong aromaticity. This study presents a seminal report on the precise and highly selective on-surface ring-opening of the seven-membered ring within the aromatic azulene moieties under mild conditions. The chemical structures of the resulting products were identified using bond-resolved scanning probe microscopy. Furthermore, through density functional theory calculations, we uncovered the mechanism behind the ring-opening process and elucidated its chemical driving force. The key to achieving this ring-opening process lies in manipulating the local aromaticity of the aromatic azulene moiety through strain-induced internal ring rearrangement and cyclodehydrogenation. By precisely controlling these factors, we successfully triggered the desired ring-opening reaction. Our findings not only provide valuable insights into the ring-opening process of polycyclic aromatic hydrocarbons but also open up new possibilities for the manipulation and reconstruction of these important chemical structures.

Learning mapping by curve iteration estimation For real-time underwater image enhancement.

The degradation and attenuation of light in underwater images impose constraints on underwater vision tasks. However, the complexity and the low real-time performance of most current image enhancement algorithms make them challenging in practical applications. To address the above issues, we propose a new lightweight framework for underwater image enhancement. We adopt the curve estimation to learn the mapping between images rather than end-to-end networks, which greatly reduces the requirement for computing resources. Firstly, a designed iterative curve with parameters is used to simulate the mapping from the raw to the enhanced image. Then, the parameters of this curve are learned with a parameter estimation network called CieNet and a set of loss functions. Experimental results demonstrate that our proposed method is superior to existing algorithms in terms of evaluating indexes and visual perception quality. Furthermore, our highly lightweight network enables it to be easily integrated into small devices, making it highly applicable. The extremely short running-time of our method facilitates real-time underwater image enhancement.

Midbrain FA initiates neuroinflammation and depression onset in both acute and chronic LPS-induced depressive model mice.

Both exogenous gaseous and liquid forms of formaldehyde (FA) can induce depressive-like behaviors in both animals and humans. Stress and neuronal excitation can elicit brain FA generation. However, whether endogenous FA participates in depression occurrence remains largely unknown. In this study, we report that midbrain FA derived from lipopolysaccharide (LPS) is a direct trigger of depression. Using an acute depressive model in mice, we found that one-week intraperitoneal injection (i.p.) of LPS activated semicarbazide-sensitive amine oxidase (SSAO) leading to FA production from the midbrain vascular endothelium. In both in vitro and in vivo experiments, FA stimulated the production of cytokines such as IL-1ß, IL-6, and TNF-α. Strikingly, one-week microinfusion of FA as well as LPS into the midbrain dorsal raphe nucleus (DRN, a 5-HT-nergic nucleus) induced depressive-like behaviors and concurrent neuroinflammation. Conversely, NaHSO3 (a FA scavenger), improved depressive symptoms associated with a reduction in the levels of midbrain FA and cytokines. Moreover, the chronic depressive model of mice injected with four-week i.p. LPS exhibited a marked elevation in the levels of midbrain LPS accompanied by a substantial increase in the levels of FA and cytokines. Notably, four-week i.p. injection of FA as well as LPS elicited cytokine storm in the midbrain and disrupted the blood-brain barrier (BBB) by activating microglia and reducing the expression of claudin 5 (CLDN5, a protein with tight junctions in the BBB). However, the administration of 30 nm nano-packed coenzyme-Q10 (Q10, an endogenous FA scavenger), phototherapy (PT) utilizing 630-nm red light to degrade FA, and the combination of PT and Q10, reduced FA accumulation and neuroinflammation in the midbrain. Moreover, the combined therapy exhibited superior therapeutic efficacy in attenuating depressive symptoms compared to individual treatments. Thus, LPS-derived FA directly initiates depression onset, thereby suggesting that scavenging FA represents a promising strategy for depression treatment.

BN-Embedded Cycloarenes: One-Pot Borylation Synthesis, Photoelectric Properties, and Application in Perovskite Solar Cells.

Incorporating heteroatoms, such as nitrogen, oxygen, and/or sulfur atoms, into cycloarenes can effectively regulate their molecular geometries and (opto)electronic properties. However, the rarity of cycloarenes and heterocycloarenes limits the further exploitation of their applications. Herein, we designed and synthesized the first examples of boron and nitrogen (BN)-doped cycloarenes (BN-C1 and BN-C2) via one-pot intramolecular electrophilic borylation of imine-based macrocycles. BN-C2 adopts a bowl-shaped conformation, while BN-C1 possesses a planar geometry. Accordingly, the solubility of BN-C2 was significantly improved by replacing two hexagons in BN-C1 with two N-pentagons, due to the creation of distortions away from planarity. Various experiments and theoretical calculations were carried out for heterocycloarenes BN-C1 and BN-C2, demonstrating that the incorporated BN bonds diminish the aromaticity of 1,2-azaborine units and their adjacent benzenoid rings but preserve the dominant aromatic properties of pristine kekulene. Importantly, when two additional electron-rich nitrogen atoms were introduced, the highest occupied molecular orbital energy level of BN-C2 was elaborately lifted compared with that of BN-C1. As a result, the energy-level alignment of BN-C2 with the work function of the anode and the perovskite layer was suitable. Therefore, for the first time, heterocycloarene (BN-C2) was explored as a hole-transporting layer in inverted perovskite solar cell devices, in which the power conversion efficiency reached 14.4%.

Computational methods for the prediction of chromatin interaction and organization using sequence and epigenomic profiles.

The exploration of three-dimensional chromatin interaction and organization provides insight into mechanisms underlying gene regulation, cell differentiation and disease development. Advances in chromosome conformation capture technologies, such as high-throughput chromosome conformation capture (Hi-C) and chromatin interaction analysis by paired-end tag (ChIA-PET), have enabled the exploration of chromatin interaction and organization. However, high-resolution Hi-C and ChIA-PET data are only available for a limited number of cell lines, and their acquisition is costly, time consuming, laborious and affected by theoretical limitations. Increasing evidence shows that DNA sequence and epigenomic features are informative predictors of regulatory interaction and chromatin architecture. Based on these features, numerous computational methods have been developed for the prediction of chromatin interaction and organization, whereas they are not extensively applied in biomedical study. A systematical study to summarize and evaluate such methods is still needed to facilitate their application. Here, we summarize 48 computational methods for the prediction of chromatin interaction and organization using sequence and epigenomic profiles, categorize them and compare their performance. Besides, we provide a comprehensive guideline for the selection of suitable methods to predict chromatin interaction and organization based on available data and biological question of interest.

Spatial density of open chromatin: an effective metric for the functional characterization of topologically associated domains.

Topologically associated domains (TADs) are spatial and functional units of metazoan chromatin structure. Interpretation of the interplay between regulatory factors and chromatin structure within TADs is crucial to understand the spatial and temporal regulation of gene expression. However, a computational metric for the sensitive characterization of TAD regulatory landscape is lacking. Here, we present the spatial density of open chromatin (SDOC) metric as a quantitative measurement of intra-TAD chromatin state and structure. SDOC sensitively reflects epigenetic properties and gene transcriptional activity in TADs. During mouse T-cell development, we found that TADs with decreased SDOC are enriched in repressed developmental genes, and the joint effect of SDOC-decreasing and TAD clustering corresponds to the highest level of gene repression. In addition, we revealed a pervasive preference for TADs with similar SDOC to interact with each other, which may reflect the principle of chromatin organization.

UIEOGP: an underwater image enhancement method based on optical geometric properties.

Due to the inconsistent absorption and scattering effects of different wavelengths of light, underwater images often suffer from color casts, blurred details, and low visibility. To address this image degradation problem, we propose a robust and efficient underwater image enhancement method named UIEOGP. It can be divided into the following three steps. First, according to the light attenuation effect presented by Lambert Beer's law, combined with the variance change after attenuation, we estimate the depth of field in the underwater image. Then, we propose a local-based color correction algorithm to address the color cast issue in underwater images, employing the statistical distribution law. Finally, drawing inspiration from the law of light propagation, we propose detail enhancement algorithms, each based on the geometric properties of circles and ellipses, respectively. The enhanced images produced by our method feature vibrant colors, improved contrast, and sharper detail. Extensive experiments show that our method outperforms current state-of-the-art methods. In further experiments, we found that our method is beneficial for downstream tasks of underwater image processing, such as the detection of keypoints and edges in underwater images.

Versatile iodine-doped BiOCl with abundant oxygen vacancies and (110) crystal planes for enhanced pollutant photodegradation.

Crystal plane regulation, defect engineering, and element doping can effectively solve the problems of large band gaps, poor light absorption, and fast recombination of BiOCl. In this work, iodine-doped BiOCl (I/BiOCl) nanowafers with abundant (110) crystal planes and oxygen vacancies (OV) were prepared by a simple hydrothermal method and assessed for pollutant photodegradation. I/BiOCl with a molar ratio of I to Cl of 0.6 (I0.6/BiOCl) degraded under visible light 95.8% of the toxic dye rhodamine B and 85.1% of the persistent antibiotic tetracycline in 5 and 10 min, respectively. In comparison, unmodified BiOCl photodegraded only between 42.0% and 48.2% of these critical water pollutants. Furthermore, I0.6/BiOCl was highly stable with most of its photocatalytic activity remaining after 4 cycles. Three reasons explain the excellent photodegradation properties of I0.6/BiOCl. First, the doped photocatalyst grew abundant (110) crystal planes, which inhibits the recombination of photogenerated electron-hole pairs. Second, the large quantity of OV present in I0.6/BiOCl increased active sites for reactive oxygen species generation, improved photogenerated charge separation, and pollutants adsorption. Lastly, I0.6/BiOCl had a modified electronic band structure enhancing light absorption. Overall, these results describe a promising photocatalyst capable of degrading efficiently major pollutants with different structures.

Competitive inhibition of a non-natural cofactor dependent formaldehyde dehydrogenase by imidazole.

OBJECTIVES: To better understand the unique inhibitory behavior of a non-natural cofactor preferred formaldehyde dehydrogenase (FalDH) mutant 9B2. RESULTS: We described our serendipitous observation that 9B2 was reversibly inhibited by residual imidazole introduced during protein preparation, while the wild-type enzyme was not sensitive to imidazole. Kinetic analysis showed that imidazole was a competitive inhibitor of formaldehyde with a Ki of 16 µM and an uncompetitive inhibitor of Nicotinamide Cytosine Dinucleotide for 9B2, indicating that formaldehyde and imidazole were combined in the same position. Molecular docking results of 9B2 showed that imidazole could favorably bind very close to the nicotinamide moiety of the cofactor, where formaldehyde was expected to reside for catalysis, which was in line with a competitive inhibition. CONCLUSION: The mutant 9B2 can be competitively inhibited by imidazole, suggesting that cautions should be taken to evaluate activities as protein mutants might attain unexpected sensitivity to a component in buffers for purification or activity assays.

Synthesis of a Dicyclohepta[a,g]heptalene-Containing Polycyclic Conjugated Hydrocarbon and the Impact of Non-Alternant Topologies.

Incorporating non-hexagonal rings into polycyclic conjugated hydrocarbons (PCHs) can significantly affect their electronic and optoelectronic properties and chemical reactivities. Here, we report the first bottom-up synthesis of a dicyclohepta[a,g]heptalene-embedded PCH (1) with four continuous heptagons, which are arranged in a "Z" shape. Compared with its structural isomer bischrysene 1 R with only hexagonal rings, compound 1 presents a distinct antiaromatic character, especially the inner heptalene core, which possesses clear antiaromatic nature. In addition, PCH 1 exhibits a narrower highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap than its benzenoid contrast 1 R, as verified by experimental measurements and theoretical calculations. Our work reported herein not only provides a new way to synthesize novel PCHs with non-alternant topologies but also offers the possibility to tune their electronic and optical properties.

Quantitative proteomic analysis of hepatic tissue in allotetraploid hybridized from red crucian carp and common carp identified crucial proteins and pathways associated with metabolism and growth rate.

Allotetraploid is a new species produced by distant hybridization between red crucian carp (Carassius auratus red var., abbreviated as RCC) and common carp (Cyprinus carpio L., abbreviated as CC). There is a significant difference in growth rate between allotetraploid and its parents. However, the underlying molecular mechanism is largely unknown. In this study, to find direct evidence associated with metabolism and growth rate in protein level, we performed quantitative proteomics analysis on liver tissues between allotetraploid and its parents. A total of 2502 unique proteins were identified and quantified by SWATH-MS in our proteomics profiling. Subsequently, comprehensive bioinformatics analyses including gene ontology enrichment analysis, pathway and network analysis, and protein-protein interaction analysis (PPI) were conducted based on differentially expressed proteins (DEPs) between allotetraploid and its parents. The results revealed several significant DEPs involved in metabolism pathways in liver. More specifically, the integrative analysis highlighted that the DEPs ACSBG1, OAT, and LDHBA play vital roles in metabolism pathways including "pentose phosphate pathway," "TCA cycle," and "glycolysis and gluconeogenesis." These could directly affect the growth rate in fresh water fishes by regulating the metabolism, utilization, and exchange of substance and energy. Since the liver is the central place for metabolism activity in animals, we firstly established the comprehensive and quantitative proteomics knowledge base for liver tissue from freshwater fishes, our study may serve as an irreplaceable reference for further studies regarding fishes' culture and growth.

Engineering Formaldehyde Dehydrogenase from Pseudomonas putida to Favor Nicotinamide Cytosine Dinucleotide.

The enzyme formaldehyde dehydrogenase (FalDH) from Pseudomonas putida is of particular interest for biotechnological applications as it catalyzes the oxidation of formaldehyde independent of glutathione. However, the consumption of a stoichiometric amount of nicotinamide adenine dinucleotide (NAD) can be challenging at the metabolic level as this may affect many other NAD-linked processes. A potential solution is to engineer FalDH to utilize non-natural cofactors. Here we devised FalDH variants to favor nicotinamide cytosine dinucleotide (NCD) by structure-guided modification of the binding pocket for the adenine moiety of NAD. Several mutants were obtained and the best one FalDH 9B2 had over 150-fold higher preference for NCD than NAD. Molecular docking analysis indicated that the cofactor binding pocket shrunk to better fit NCD, a smaller-sized cofactor. FalDH 9B2 together with other NCD-linked enzymes offer opportunities to assemble orthogonal pathways for biological conversion of C1 molecules.

2D WO3-x Nanosheet with Rich Oxygen Vacancies for Efficient Visible-Light-Driven Photocatalytic Nitrogen Fixation.

Oxygen vacancy modulation holds great promise for enhancing the photocatalytic activity for efficient nitrogen fixation under mild conditions. In this work, the two-dimensional WO3-x nanosheets with rich oxygen vacancies were prepared using solvothermal synthesis. The WO3-x nanosheets (rich oxygen vacancies) display nice photocatalytic activity for N2 reduction to ammonia with a high yield rate of 82.41 µmol·gcat-1·h-1 under irradiation of visible light (420 nm), which is 3.59 times higher than that of the WO3-x nanoparticles (poor oxygen vacancies). Electron spin resonance (ESR), N2 adsorption-desorption isotherms, and transient photocurrent responses in the N2 or Ar atmosphere experiments proved that the rich oxygen vacancies, which are induced by the nanosheet structure, could serve as active sites for the chemisorption of N2 and facilitate the electron transfer from unsaturated sites to activated N2. Moreover, based on the analysis of banding energy, the oxygen vacancies not only boosted the ability of visible light harvesting but also elevated the defect energy level to the Fermi level, further inhibiting the defect relaxation effect. The findings offer an insight into the design of the efficient photocatalysts via structure engineering and defect engineering for photocatalytic N2 fixation.

Facet-Dependent Activation of Oxalic Acid over Magnetic Recyclable Fe3S4 for Efficient Pollutant Removal under Visible Light Irradiation: Enhanced Catalytic Activity, DFT Calculations, and Mechanism Insight.

Photo-Fenton-like reaction based on oxalic acid (OA) activation is a promising method for the fast degradation of pollutants due to the low cost and safety. Hence, the magnetic recyclable greigite (Fe3S4) with the exposed {011} facet (FS-011) was prepared using a facile one-pot hydrothermal method and activated OA under visible light irradiation for pollutant removal, in which the removal efficiency values of FS-011 for metronidazole (MNZ) and hexavalent chromium were 2.02 and 1.88 times higher than that of Fe3S4 with the exposed {112} facet, respectively. Density functional theory calculations revealed that OA was more easily adsorbed by the {011} facet of Fe3S4 than by the {112} facet, and the in situ-generated H2O2 preferred to diffuse away from the active sites of the {011} facet of Fe3S4 than from that of the {112} facet, which was conducive to the continuous adsorption and efficient activation of OA. Moreover, the analyses of Fukui index and dual descriptor confirmed the degradation mechanism that the imidazole ring of MNZ was easy to be attacked by electrophilic species, while the amino group of MNZ was easy to be attacked by nucleophilic species. These findings deeply analyzed the mechanism of enhanced OA activation by facet engineering and consolidated the theoretical basis for practical application of Fenton-like reactions.

Structural Insights into Malic Enzyme Variants Favoring an Unnatural Redox Cofactor.

The use of nicotinamide cytosine dinucleotide (NCD), a biocompatible nicotinamide adenosine dinucleotide (NAD) analogue, is of great scientific and biotechnological interest. Several redox enzymes have been devised to favor NCD, and have been successfully applied in creating NCD-dependent redox systems. However, molecular interactions between cofactor and protein have still to be disclosed in order to guide further engineering efforts. Here we report the structural analysis of an NCD-favoring malic enzyme (ME) variant derived from Escherichia coli. The X-ray crystal structure data revealed that the residues located at position 346 and 401 in ME acted as the "gatekeepers" of the adenine moiety binding cavity. When Arg346 was substituted with either acidic or aromatic residues, the corresponding mutants showed substantially reduced NCD preference. Inspired by these observations, we generated Lactobacillus helveticus derived d-lactate dehydrogenase variants at Ile177, the counterpart to Arg346 in ME, and found a similar trend in terms of cofactor preference changes. As many NAD-dependent oxidoreductases share key structural features, our results provide guidance for protein engineering to obtain more NCD-favoring variants.

A Molecular Transformer: A π-Conjugated Macrocycle as an Adaptable Host.

Here, we report a facile method to synthesize a series of macrocycles with different conformations. The planar macrocycle dimer (1), twisted macrocycle trimer (2) and "figure-eight" tetramer (3) are clearly elucidated by X-ray single-crystal analysis, in which the electron-rich phenanthrene units offer the possibility of supramolecular assembly. As expected, in the solid state, 1 and 3 assemble into a columnar stack and an interlocking dimer, respectively, via π-π interactions between the phenanthrene units. Compared to the rigid conformation of dimer 1, the structure of tetramer 3 is more flexible due to its enlarged ring size. 3 can deform from a figure-eight into a boat-shaped geometry to host a planar electron-deficient guest using its electron-rich phenanthrene units. When assembled with spherical electron-deficient C60 , interestingly, 3 further undergoes a conformational transformation from a figure-eight to a belt shape in order to host C60 . These supramolecular assembly behaviors of 3 demonstrate that it is an adaptable macrocyclic host for both planar molecules and fullerenes.

Upregulation of TDRD1 Promotes the Sexual Maturation in Allotetraploids Hybridized from Red Crucian Carp (Carassius auratus Red var) (♀) and Common Carp (Cyprinus carpio L) (♂).

Allotetraploid hybrids of Red Crucian Carp (Carassius auratus red var, abbreviated as RCC) (♀) and common Carp (Cyprinus carpio L, abbreviated as CC) (♂) is a species produced by distant hybridization. In this study, SWATH mass spectrometry (SWATH-MS) was applied for quantitative proteomics profiling of gonad tissues of allotetraploids and their parents RCC (♀) and CC (♂). A total of 2338 unique proteins were identified in our proteomic profiling by SWATH-MS. Gene enrichment and network analysis based on differentially expressed proteins revealed some metabolic enzymes involved in gonad growth and development of allotetraploids. Especially, the upregulated gene TDRD1 (ratio = 2.59, p = 0.02) in allotetraploids plays a significant role in spermatogenesis, which could speed up the sexual maturation during the process of gonad growth and development. Protein-protein interaction and pathway analysis further suggested that TDRD1 served as a hub protein in metabolic-related pathways and networks. It could regulate gonad development via regulating metabolic pathways in a synergistic way with surrounding regulatory factors including CS, GPIA, PGK1, and IDH2. In addition, TDRD1 could directly regulate spermatogenesis in conjunction with PIWIL1, PIWIL2, and VASA. Quantitative proteomics integrated with network analysis explored the molecular mechanism in that TDRD1 regulated sexual maturation, development, and growth of allotetraploids in a synergetic way with metabolic genes and pathways.

Engineering d-Lactate Dehydrogenase to Favor an Non-natural Cofactor Nicotinamide Cytosine Dinucleotide.

Synthetic nicotinamide adenine dinucleotide (NAD) analogues are of great scientific and biotechnological interest. One such analogue, nicotinamide cytosine dinucleotide (NCD), has been successfully applied to creating bioorthogonal redox systems. Yet, only a few redox enzymes have been devised to favor NCD. We have engineered Lactobacillus helveticus-derived NAD-dependent d-lactate dehydrogenase (LhDLDH) to favor NCD by semirational design. Sequence alignment and structural analysis revealed that amino acid residues I177 and N213 form a "gate" guarding the NAD adenine moiety binding cavity. Saturated mutagenesis libraries were constructed by using the mutant LhDLDH-V152R as the parental sequence. Mutants were obtained with good catalytic efficiency, and NCD preference increased by up to 940-fold. Experiments showed that Escherichia coli cells expressing mutants with higher NCD preference afforded much less d-lactate, thus suggesting the potential to construct NCD-mediated orthogonal metabolism.