An integrated multi-omics analysis reveals osteokines involved in global regulation.

Bone secretory proteins, termed osteokines, regulate bone metabolism and whole-body homeostasis. However, fundamental questions as to what the bona fide osteokines and their cellular sources are and how they are regulated remain unclear. In this study, we analyzed bone and extraskeletal tissues, osteoblast (OB) conditioned media, bone marrow supernatant (BMS), and serum, for basal osteokines and those responsive to aging and mechanical loading/unloading. We identified 375 candidate osteokines and their changes in response to aging and mechanical dynamics by integrating data from RNA-seq, scRNA-seq, and proteomic approaches. Furthermore, we analyzed their cellular sources in the bone and inter-organ communication facilitated by them (bone-brain, liver, and aorta). Notably, we discovered that senescent OBs secrete fatty-acid-binding protein 3 to propagate senescence toward vascular smooth muscle cells (VSMCs). Taken together, we identified previously unknown candidate osteokines and established a dynamic regulatory network among them, thus providing valuable resources to further investigate their systemic roles.

Surface-supported metal-organic frameworks with geometric topological diversity via scanning tunneling microscopy.

Surface-supported metal-organic frameworks (SMOFs) are long-range ordered periodic 2D lattice layers formed by inorganic metal nodes and organic ligands via coordination bonds on substrate surfaces. The atomic resolution STM lays a solid foundation for the conception and construction of SMOFs with large area, stable structure, and special function. In this review, the cutting-edge research of SMOFs from design strategy, preparation process, and how to accurately achieve structural and functional diversity are reviewed. Furthermore, we focus on the design and construction of novel and fascinating periodic and fractal structures, in which some typical honeycomb structures, Kagome lattice, hexagonal geometry, and Sierpinski triangles are summarized, and the related prospects for designing functional nanoscale systems and architectures are prospected. Finally, the challenges faced in the design and synthesis of SMOFs are denoted, and the application prospect and development trend of SMOFs are forecasted based on the current research status.

Symmetry of Pyridine Derivatives Controlled Two-Dimensional Nanostructural Diversity by Co-Assembly with Aromatic Carboxylic Acids.

The self-assembly behaviors of aromatic carboxylic acids are commonly investigated at the liquid/solid interfaces because of their rigid skeletons and both hydrogen-bond donors and receptors. However, self-assemblies of aromatic carboxylic acids with low symmetry and interactions between carboxylic acid and pyridine derivatives are worth exploring. In this work, the self-assembled structural transitions of a kind of low-symmetric aromatic carboxylic acid (H4QDA) are regulated by the coadsorption of two pyridine derivatives (DPE and T4PT) with different symmetry, which are investigated by scanning tunneling microscopy under ambient conditions. For the H4QDA/DPE system, the grid structure appears. For the H4QDA/T4PT system, the coassembled morphologies display an obvious concentration dependence. With the increase of solution concentration of T4PT, three coassembled patterns (network structure, chiral linear structure, and brick-like structure) are observed. Corresponding structural models suggest that the O-H···N hydrogen bonds have great contributions to stabilizing these coassembled structures. Our studies will help to explore the complexity, diversity, and functionality of multiple component systems and are conducive to further understanding the underlying mechanisms in the assembly process.

Study on a Highly Thermostable Dy3+-Activated Borophosphate Phosphor.

Constructing a phosphor with multifunctional applications is an imperative challenge. Especially, highly thermostable luminescence of phosphor is indispensable for stable white-light-emitting diodes (LEDs). Nevertheless, good thermal quenching resistance behavior is unfavorable for a fluorescence intensity ratio (FIR)-based optical temperature sensor. Herein, a highly thermostable Ba3(ZnB5O10)PO4 (BZBP)-based phosphor is successfully achieved via replacing Ba2+ with Dy3+, demonstrating simultaneously promising lighting and thermometry utilizations. Under the excitation of 350 nm, the title phosphor only loses 12% of the initial intensity when the temperature is up to 473 K, ensuring sufficient luminescence thermostability for white-LED lighting. The white-LED device fabricated using the title phosphor emits high-quality white light with a high color rendering index (Ra = 93) and low correlated color temperature (CCT = 3996 K). Meanwhile, the yellow and blue emission intensities demonstrate a downtrend difference with rising temperature. Temperature sensing properties are assessed through FIR technology. The maximal relative sensitivity reaches as high as 0.0379 K-1 at 298 K. These results reveal that the title phosphor has a great potential for indoor lighting and thermometry applications.

ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.

Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.

Surface/interfacial transport through pores control desalination mechanisms in 2D carbon-based membranes.

The shortage of freshwater is a critical concern for contemporary society, and reverse osmosis desalination technology has gathered considerable attention as a potential solution to this problem. It has been recognized that the desalination process involving water flow through angstrom-sized pores has tremendous potential. However, it is challenging to obtain angstrom-sized pore structures with internal mass transfer and surface/interface properties matching the application conditions. Herein, a two-dimensional (2D) zeolite-like carbon structure (Carzeo-ANG) was constructed with unique angstrom-sized pores in the zeolite structure; then, the surface/interfacial transport behavior and percolation effect of the Carzeo-ANG desalination membrane were evaluated by density functional theory (DFT) calculations and classical molecular dynamics. The first-principles calculations in density functional theory were implemented through the Vienna ab initio simulation package (VASP), which is a commercial package for the simulation of carbon-based materials. The results show that Carzeo-ANG is periodically distributed with angstrom-sized pores (effective diameter = 5.4 Å) of dodecacyclic carbon rings, which ensure structural stability while maintaining sufficient mechanical strength. The remarkable salt-ion adsorption properties and mass transfer activity combined with the reasonable density distribution and free energy barrier for water molecules endow the membrane with superior desalination ability. At the pressure of 80 MPa, the rejection efficiency of Cl- and Na+ were 100% and 96.25%, and the membrane could achieve a water flux of 132.71 L cm-2 day-1 MPa-1. Moreover, the interconnected electronic structure of Carzeo-ANG imparts a self-cleaning effect.

In Situ Hydrogel Polymerization to Form a Flexible Polysaccharide Synergetic Binder Network for Stabilizing SiOx/C Anodes.

Today, the commercial application of silicon oxides (SiOx, 1 < x < 2) in lithium-ion batteries (LIBs) still faces the challenge of rapid performance degradation. In this work, by integrating hydrothermal and physicomechanical processes, water-soluble locust bean gum (LBG) and xanthan gum (XG) are utilized to in situ form an LBG@XG binder network to improve the performance of SiOx/C anodes. As a synergy of LBG and XG polysaccharides in hydrogel polymerization, LBG@XG can tightly wrap around SiOx/C particles to prevent plate damage. The flexible SiOx/C anode with the LBG@XG binder exhibits capacity retentions of 74.1% and 76.4% after 1000 cycles at 0.5 A g-1 and 1 A g-1, respectively. The full battery capacity remains stable for 100 cycles at 1 C and the rate performance is excellent (103 mAh g-1 at 3 C). This LBG@XG is demonstrated to be highly electronegative and has a strong attraction to SiOx/C particles, thereby reducing the expansion and increasing the stability of the SiOx/C anodes when coupled with the flexible binder network. In addition to the promising LBG@XG binder, this work also provides a research idea for developing green water-based binders suitable for application in the SiOx/C anodes of LIBs.

Single-cell multi-omics sequencing of human spermatogenesis reveals a DNA demethylation event associated with male meiotic recombination.

Human spermatogenesis is a highly ordered process; however, the roles of DNA methylation and chromatin accessibility in this process remain largely unknown. Here by simultaneously investigating the chromatin accessibility, DNA methylome and transcriptome landscapes using the modified single-cell chromatin overall omic-scale landscape sequencing approach, we revealed that the transcriptional changes throughout human spermatogenesis were correlated with chromatin accessibility changes. In particular, we identified a set of transcription factors and cis elements with potential functions. A round of DNA demethylation was uncovered upon meiosis initiation in human spermatogenesis, which was associated with male meiotic recombination and conserved between human and mouse. Aberrant DNA hypermethylation could be detected in leptotene spermatocytes of certain nonobstructive azoospermia patients. Functionally, the intervention of DNA demethylation affected male meiotic recombination and fertility. Our work provides multi-omics landscapes of human spermatogenesis at single-cell resolution and offers insights into the association between DNA demethylation and male meiotic recombination.

Dissolution mechanism of Fe3O4 scale by 1-hydroxyethane-1,1-diphosphonic acid: an ab initio molecular metadynamics study.

Using the ab initio molecular metadynamics method, the adsorption of the structure of 1-hydroxyethane-1,1-diphosphonic acid (HEDP) on the Fe3O4 surface and subsequent detachment of Fe atoms from the surface were simulated, and the dissolution mechanism by which HEDP dissolves Fe3O4 scale at room temperature while other organic acids cannot was elucidated. The adsorbed hydroxyl groups, water and HEDP on the Fe3O4 surface play a synergistic role in detaching the Fe ions, which increases the coordination number of the Fe atoms and weakens the original Fe-O bond strength. In addition, the strong coordination ability and flexible molecular structure of HEDP also facilitate dissolution of Fe3O4 scale by breaking down the chemical bonds and forming Fe-HEDP complexes. The free energy surface for the dissolution reaction shows a low barrier, and the descaling reaction is easily accomplished.

Genome Mining and Biosynthetic Reconstitution of Fungal Depsidone Mollicellins Reveal a Dual Functional Cytochrome P450 for Ether Formation.

Depsidones are significant in structural diversity and broad in biological activities; however, their biosynthetic pathways have not been well understood and have attracted considerable attention. Herein, we heterologously reconstituted a depsidone encoding gene cluster from Ovatospora sp. SCSIO SY280D in Aspergillus nidulans A1145, leading to production of mollicellins, a representative family of depsidones, and discovering a bifunctional P450 monooxygenase that catalyzes both ether formation and hydroxylation in the biosynthesis of the mollicellins. The functions of a decarboxylase and an aromatic prenyltransferase are also characterized to understand the tailoring modification steps. This work provides important insights into the biosynthesis of mollicellins.

A fast chemical reprogramming system promotes cell identity transition through a diapause-like state.

Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour intensive, hindering its broad applications and the investigation of underlying molecular mechanisms. Here, through screening of over 21,000 conditions, we develop a fast chemical reprogramming (FCR) system, which significantly improves the kinetics of cell identity rewiring. We find that FCR rapidly goes through an interesting route for pluripotent reprogramming, uniquely transitioning through a developmentally diapause-like state. Furthermore, FCR critically enables comprehensive characterizations using multi-omics technologies, and has revealed unexpected important features including key regulatory factors and epigenetic dynamics. Particularly, activation of pluripotency-related endogenous retroviruses via inhibition of heterochromatin significantly enhances reprogramming. Our studies provide critical insights into how only environmental cues are sufficient to rapidly reinstate pluripotency in somatic cells, and make notable technical and conceptual advances for solving the puzzle of regeneration.

Two tigers cannot live on the same mountain: The impact of the second largest shareholder on controlling shareholder's tunneling behavior.

Under the current corporate governance model, the second largest shareholder (SLS) is a very special, common and important presence, which becomes an important counterweight to the controlling shareholder (CS). Through a game matrix, this paper explains whether the SLS will supervise the CS's tunneling behavior. Based on this, we empirically examine the effect of the SLS on CS's tunneling behavior in Chinese listed firms between 2010 and 2020. The results indicate that the SLS significantly inhibits CS's tunneling behavior. In addition, the heterogeneity analysis reveals that the negative effect of the SLS on CS's tunneling behavior is concentrated in non-state-owned enterprises (NSOEs) and enterprises located in regions with better business environment. This paper provides a reference for resolving the current "conflict of interest" among multiple large shareholders (MLSs), as well as evidence to support the governance role of the SLS in listed firms with MLSs.

Brexpiprazole suppresses cell proliferation and de novo lipogenesis through AMPK/SREBP1 pathway in colorectal cancer.

OBJECTIVE: In the present study, we investigated the role of brexpiprazole on cell proliferation and lipogenesis in colorectal cancer (CRC) and its molecular mechanism. METHODS: The effect of brexpiprazole on CRC cell proliferation was determined by CCK-8, EdU assay, cell clone formation. The flow cytometry was evaluated cell cycle. Differential expression genes (DEGs) were identified by RNA-seq assay after treating HCT116 cells with or without 20 µM brexpiprazole for 24 h. Then, the top 120 DEGs were analyzed by GO and KEGG enrichment analysis. After that, Oil red O staining and the levels of total cholestenone and triglyceride were measured to assess lipogenesis capacity in CRC cells. The related molecules of cell proliferation, lipogenic and AMPK/SREBP1 signal pathways were measured by q-PCR, western blot and immunohistochemical staining. RESULTS: Brexpiprazole remarkably suppressed cell proliferation, lipogenesis, and induced cell cycle arrest in CRC. The underlying mechanisms probably involved the suppression of SREBP1 and the stimulation of AMPK. CONCLUSION: Brexpiprazole inhibited cell proliferation and de novo lipogenesis through AMPK/SREBP1 pathway in CRC.

Molecular structures of 1-hydroxyethane-1,1-diphosphonic acid for removing calcium sulfate scale under different pH conditions.

As an important descaling agent, 1-hydroxyethane-1,1-diphosphonic acid (HEDP) is capable of dissolving calcium sulfate scale when the pH of HEDP solution is adjusted from acidic to weakly alkaline. The molecular structures of Ca-HEDP complexes were determined to understand the impact of pH on the dissolution of calcium sulfate scale. The structures of the complexes revealed that the two phosphonic acid groups and the hydroxyl group of HEDP each provide one O atom to coordinate with the Ca ion to form a stable three-coordinate configuration under alkaline conditions. The electronic structures were investigated by interaction region indicator analysis, atoms in molecules analysis, electron localization function and natural population analysis. The deprotonation of the phosphonic acid group enhances the binding of coordinated O atoms and Ca ions as the pH increases, and weak alkalinity is the optimal process condition as strong alkaline conditions result in the precipitation of hydroxide and Ca ions.

Engineered circular guide RNAs boost CRISPR/Cas12a- and CRISPR/Cas13d-based DNA and RNA editing.

BACKGROUND: The CRISPR/Cas12a and CRISPR/Cas13d systems are widely used for fundamental research and hold great potential for future clinical applications. However, the short half-life of guide RNAs (gRNAs), particularly free gRNAs without Cas nuclease binding, limits their editing efficiency and durability. RESULTS: Here, we engineer circular free gRNAs (cgRNAs) to increase their stability, and thus availability for Cas12a and Cas13d processing and loading, to boost editing. cgRNAs increases the efficiency of Cas12a-based transcription activators and genomic DNA cleavage by approximately 2.1- to 40.2-fold for single gene editing and 1.7- to 2.1-fold for multiplexed gene editing than their linear counterparts, without compromising specificity, across multiple sites and cell lines. Similarly, the RNA interference efficiency of Cas13d is increased by around 1.8-fold. In in vivo mouse liver, cgRNAs are more potent in activating gene expression and cleaving genomic DNA. CONCLUSIONS: CgRNAs enable more efficient programmable DNA and RNA editing for Cas12a and Cas13d with broad applicability for fundamental research and gene therapy.

Association of menstrual blood volume and reproductive outcomes in patients with caesarean scar pregnancy managed using uterine artery embolization and curettage.

This study aimed to assess the association of menstrual blood volumes (MBV) and reproductive outcomes in patients after uterine artery embolization (UAE) combined with curettage for caesarean scar pregnancy (CSP). This retrospective observational study enrolled women who underwent UAE plus curettage for CSP at the Interventional Department of Henan Provincial People's Hospital between December 2012 and December 2017. The primary outcome was pregnancy rate and the secondary outcomes were live birth rate (LBR) and interpregnancy interval. This study finally included 37 women (16 women with normal MBV and 21 women with decreased MBV) with pregnancy intention after UAE plus curettage for CSP. The pregnancy rate in women with normal MBV was higher than those with decreased MBV (81.3% vs. 47.6%; P = 0.048). There were no differences between the two groups regarding the interpregnancy interval (18.4 ± 8.7 vs. 22.2 ± 10.0 months, P = 0.233), and LBR (63% vs. 38%, P = 0.191). In conclusion, Women with normal MBV after UAE combined with curettage for CSP management might have a higher pregnancy rate compared with patients with decreased MBV, but there were no differences in LBR between the two groups.

FAPI-Net: A lightweight interpretable network based on feature augmentation and prototype interpretation.

With the increasing application of deep neural networks, their performance requirements in various fields are increasing. Deep neural network models with higher performance generally have a high number of parameters and computation (FLOPs, Floating Point Operations), and have the black-box characteristic. This hinders the deployment of deep neural network models on low-power platforms, as well as sustainable development in high-risk decision-making fields. However, there is little work to ensure the interpretability of the model in the research on the lightweight of the deep neural network model. This paper proposed FAPI-Net (feature augmentation and prototype interpretation), a lightweight interpretable network. It combined feature augmentation convolution blocks and the prototype dictionary interpretability (PDI) module. The feature augmentation convolution block is composed of lightweight feature-map augmentation (FA) modules and a residual connection stack. The FA module could effectively reduce network parameters and computation without losing network accuracy. The PDI module can realize the visualization of model classification reasoning. FAPI-Net is designed regarding MobileNetV3's structure, and our experiments show that the FAPI-Net is more effective than MobileNetV3 and other advanced lightweight CNNs. Params and FLOPs on the ILSVRC2012 dataset are 2 and 20% lower than that on MobileNetV3, respectively, and FAPI-Net with a trainable PDI module has almost no loss of accuracy compared with baseline models. In addition, the ablation experiment on the CIFAR-10 dataset proved the effectiveness of the FA module used in FAPI-Net. The decision reasoning visualization experiments show that FAPI-Net could make the classification decision process of specific test images transparent.

In vitro PCR verification that lysozyme inhibits nucleic acid replication and transcription.

Lysozyme can kill bacteria by its enzymatic activity or through a mechanism involving its cationic nature, which can facilitate electrostatic interactions with the viral capsid, the negatively charged parts of nucleic acids, and polymerase, so binding to nucleic acids may be another biological function of lysozyme. Here, PCR was used as a research tool to detect the effects of lysozyme on the replication and transcription of nucleic acids after treatment in different ways. We found that lysozyme and its hydrolysate can enter cells and inhibit PCR to varying degrees in vitro, and degraded lysozyme inhibited nucleic acid replication more effectively than intact lysozyme. The inhibition of lysozyme may be related to polymerase binding, and the sensitivity of different polymerases to lysozyme is inconsistent. Our findings provide a theoretical basis for further explaining the pharmacological effects of lysozyme, such as antibacterial, antiviral, anticancer, and immune regulatory activities, and directions for the development of new pharmacological effects of lysozyme and its metabolites.

Lovastatin promotes the self-renewal of murine and primate spermatogonial stem cells.

The spermatogonial stem cell (SSC) niche is critical for SSC maintenance and subsequent spermatogenesis. Numerous reproductive hazards impair the SSC niche, thereby resulting in aberrant SSC self-renewal and male infertility. However, promising agents targeting the impaired SSC niche to promote SSC self-renewal are still limited. Here, we screen out and assess the effects of Lovastatin on the self-renewal of mouse SSCs (mSSCs). Mechanistically, Lovastatin promotes the self-renewal of mSSCs and inhibits its inflammation and apoptosis through the regulation of isoprenoid intermediates. Remarkably, treatment by Lovastatin could promote the proliferation of undifferentiated spermatogonia in the male gonadotoxicity model generated by busulfan injection. Of note, we demonstrate that Lovastatin could enhance the proliferation of primate undifferentiated spermatogonia. Collectively, our findings uncover that lovastatin could promote the self-renewal of both murine and primate SSCs and have implications for the treatment of certain types of male infertility using small compounds.