Water Catchers within Sub-Nano Channels Promote Step-by-Step Zinc-Ion Dehydration Enable Highly Efficient Aqueous Zinc-Metal Batteries.

Zinc metal suffers from violent and long-lasting water-induced side reactions and uncontrollable dendritic Zn growth, which seriously reduce the coulombic efficiency (CE) and lifespan of aqueous zinc-metal batteries (AZMBs). To suppress the corresponding harmful effects of the highly active water, a stable zirconium-based metal-organic framework with water catchers decorated inside its sub-nano channels is used to protect Zn-metal. Water catchers within narrow channels can constantly trap water molecules from the solvated Zn-ions and facilitate step-by-step desolvation/dehydration, thereby promoting the formation of an aggregative electrolyte configuration, which consequently eliminates water-induced corrosion and side reactions. More importantly, the functionalized sub-nano channels also act as ion rectifiers and promote fast but even Zn-ions transport, thereby leading to a dendrite-free Zn metal. As a result, the protected Zn metal demonstrates an unprecedented cycling stability of more than 10 000 h and an ultra-high average CE of 99.92% during 4000 cycles. More inspiringly, a practical NH4V4O10//Zn pouch-cell is fabricated and delivers a capacity of 98 mAh (under high cathode mass loading of 25.7 mg cm-2) and preserves 86.2% capacity retention after 150 cycles. This new strategy in promoting highly reversible Zn metal anodes would spur the practical utilization of AZMBs.

Conjoint research of WGCNA, single-cell transcriptome and structural biology reveals the potential targets of IDD development and treatment and JAK3 involvement.

OBJECTIVES: This study conducted integrated analysis of bulk RNA sequencing, single-cell RNA sequencing and Weighted Gene Co-expression Network Analysis (WGCNA), to comprehensively decode the most essential genes of intervertebral disc degeneration (IDD); then mainly focused on the JAK3 macromolecule to identify natural compounds to provide more candidate drug options in alleviating IDD. METHODS: In the first part, we performed single-cell transcriptome analysis and WGCNA workflow to delineate the most pivotal genes of IDD. Then series of structural biology approaches and high-throughput virtual screening techniques were performed to discover potential compounds targeting JAK-STAT signaling pathway, such as Libdock, ADMET, precise molecular docking algorithm and in-vivo drug stability assessment. RESULTS: Totally 4 hub genes were determined in the development of IDD, namely VEGFA, MMP3, TNFSF11, and TIMP3, respectively. Then, 3 novel natural materials, ZINC000014952116, ZINC000003938642 and ZINC000072131515, were determined as potential compounds, with less toxicities and moderate ADME characteristics. In-vivo drug stability assessment suggested that these drugs could interact with JAK3, and their ligand-JAK3 complexes maintained the homeostasis in-vivo, which acted as regulatory role to JAK3 protein. Among them, ZINC000072131515, also known as Menaquinone, demonstrated significant protective roles to alleviate the progression of IDD in vitro, which proved the nutritional therapy in alleviating IDD. CONCLUSIONS: This study reported the essential genes in the development of IDD, and also the roles of Menaquinone to ameliorate IDD through inhibiting JAK3 protein. This study also provided more options and resources on JAK3 targeted screening, which may further expand the drug resources in the pharmaceutical market.

Integrated analysis of single-cell transcriptome and structural biology approach reveals the dynamics changes of NP subtypes and roles of Menaquinone in attenuating intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a progressive and chronic disease, the mechanisms have been studied extensively as a whole, while the cellular heterogeneity of cells in nucleus pulposus (NP) tissues remained controversial for a long time. This study conducted integrated analysis through single-cell sequencing analysis, weighted gene co-expression network analysis (WGCNA), and differential expression analysis, to systematically decipher the longitudinal alterations of distinct NP subtypes, and also analyzed the most essential genes in the development of IDD. Then, this study further conducted structural biology method to discover the potential lead compounds through a suite of advanced approaches like high-throughput screening (HTVS), pharmaceutical characteristics assessment, CDOCKER module as well as molecular dynamics simulation, etc., aiming to ameliorate the progression of IDD. Totally 5 NP subpopulations were identified with distinct biological functions based on their unique gene expression patterns. The predominant dynamics changes mainly involved RegNPs and EffNPs, the RegNPs were mainly aggregated in normal NP tissues and drastically decreased in degenerative NP, while EffNPs, as pathogenic subtype, exhibited opposite phenomenon. Importantly, this study further reported the essential roles of Menaquinone in alleviating degenerative NP cells for the first time, which could provide solid evidence for the application of nutritional therapy in the treatment of IDD. This study combined scRNA-seq, bulk-RNA seq and HTVS techniques to systematically decipher the longitudinal changes of NP subtypes during IDD. EffNPs were considered to be 'chief culprit' in IDD progression, while the novel natural drug Menaquinone could reverse this phenomenon.Communicated by Ramaswamy H. Sarma.

Deciphering the sequential changes of monocytes/macrophages in the progression of IDD with longitudinal approach using single-cell transcriptome.

Intervertebral disk degeneration (IDD) is a chronic inflammatory disease with intricate connections between immune infiltration and oxidative stress (OS). Complex cell niches exist in degenerative intervertebral disk (IVD) and interact with each other and regulate the disk homeostasis together. However, few studies have used longitudinal approach to describe the immune response of IDD progression. Here, we conducted conjoint analysis of bulk-RNA sequencing and single-cell sequencing, together with a series of techniques like weighted gene co-expression network analysis (WGCNA), immune infiltration analysis, and differential analysis, to systematically decipher the difference in OS-related functions of different cell populations within degenerative IVD tissues, and further depicted the longitudinal alterations of immune cells, especially monocytes/macrophages in the progression of IDD. The OS-related genes CYP1A1, MMP1, CCND1, and NQO1 are highly expressed and might be diagnostic biomarkers for the progression of IDD. Further landscape of IVD microenvironment showed distinct changes in cell proportions and characteristics at late degeneration compared to early degeneration of IDD. Monocytes/macrophages were classified into five distinct subpopulations with different roles. The trajectory lineage analysis revealed transcriptome alterations from effector monocytes/macrophages and regulatory macrophages to other subtypes during the evolution process and identified monocytes/macrophage subpopulations that had rapidly experienced the activation of inflammatory or anti-inflammatory responses. This study further proposed that personalized therapeutic strategies are needed to be formulated based on specific monocyte/macrophage subtypes and degenerative stages of IDD.

A meta-analysis of randomized controlled trials comparing enteral immunonutrition (EIN) and standard enteral nutrition regarding biochemical, immunological, and clinical outcomes in gastrectomy patients with gastric cancer and investigating evidence networks for EIN formulae.

Introduction: For patients with gastric cancer who have undergone gastrectomy, recent research has shown that enteral immunonutrition (EIN) is more successful than enteral nutrition (EN) at boosting host immunity and, in turn, improving prognosis. The claimed outcomes, however, are inconsistent. Aim: This meta-analysis examines how EIN affects biochemical, immunological, and clinical outcomes for gastrectomy (GC) patients following gastrectomy and EIN formulae evidence networks. Material and methods: A comprehensive search of the Medline, EMBASE, Scopus, and Cochrane Library databases identified English-language peer-reviewed journal papers. The odds ratio (OR) and standard mean difference (SMD) were calculated, along with their 95% confidence intervals. The heterogeneity was assessed using Cochrane Q and I2 statistics and the appropriate p-value. The analysis used RevMan 5.3. Results: This meta-analysis included 10 RCTs involving 1409 GC patients, 714 of whom were assigned to EIN and 695 to EN. After EIN treatment, serum proalbumin, serum transferrin, lymphocyte count, and CD4+/CD8+ ratio had statistically significant standardised mean differences (SMDs) of 2.39, 2.39, 1.34, and 0.72, respectively. EIN reduces postoperative infectious complications with an OR of 0.63 (95% CI: 0.41-0.77) for infections, an OR of 0.63 for complications, and an SMD of -1.05 for systemic inflammations. A network diagram with high-quality data and a well-defined network design with consistent and accurate connection shows that EIN can improve serum protein levels, immunological parameters, and post-operative problems. Conclusions: The use of EIN has been shown to enhance cellular immunity, regulate inflammatory response, and decrease postoperative complications in GC patients who underwent major GI surgery.

Revealing oxidative stress-related genes in osteoporosis and advanced structural biological study for novel natural material discovery regarding MAPKAPK2.

Objectives: This study aimed to find novel oxidative stress (OS)-related biomarkers of osteoporosis (OP), together with targeting the macromolecule Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) protein to further discover potential novel materials based on an advanced structural biology approach. Methods: Gene expression profiles of GSE35958 were obtained from the Gene Expression Omnibus (GEO) database, which were included for weighted gene co-expression network analysis (WGCNA) and differential analysis to identify the most correlated module, to identify OS-related hub genes in the progression of OP. Functional annotations were also analyzed on the interested module to get a comprehensive understanding of these genes. Then, a series of advanced structural biology methods, including high-throughput screening, pharmacological characteristic prediction, precise molecular docking, molecular dynamics simulation, etc., was implemented to discover novel natural inhibitor materials against the MAPKAPK2 protein. Results: The brown module containing 720 genes was identified as the interested module, and a group set of genes was determined as the hub OS-related genes, including PPP1R15A, CYB5R3, BCL2L1, ABCD1, MAPKAPK2, HSP90AB1, CSF1, RELA, P4HB, AKT1, HSP90B1, and CTNNB1. Functional analysis demonstrated that these genes were primarily enriched in response to chemical stress and several OS-related functions. Then, Novel Materials Discovery demonstrated that two compounds, ZINC000014951634 and ZINC000040976869, were found binding to MAPKAPK2 with a favorable interaction energy together with a high binding affinity, relatively low hepatoxicity and carcinogenicity, high aqueous solubility and intestinal absorption levels, etc., indicating that the two compounds were ideal potential inhibitor materials targeting MAPKAPK2. Conclusion: This study found a group set of OS-related biomarkers of OP, providing further insights for OS functions in the development of OP. This study then focused on one of the macromolecules, MAPKAPK2, to further discover potential novel materials, which was of great significance in guiding the screening of MAPKAPK2 potential materials.

Effect of Counterions on the Physicomechanical Properties of Copper-Nitrogen-Coordinated Metallosupramolecular Elastomers.

Metallosupramolecular elastomers have attracted much attention due to their excellent mechanical properties, flexible tailoring of performance, and responsiveness to photo and thermal stimuli. The physicomechanical properties of metallosupramolecular elastomers are highly dependent on metal salts and ligand units; however, the role of counterions lacks practical exploration. To this end, we synthesized a simple acrylate copolymer model and introduced copper salts with different counterions to construct dynamic copper-nitrogen coordination cross-linked networks. This approach generated a series of elastomers with a tensile strength of over 10 MPa and a laser self-healing efficiency of over 90% within 2 min. In particular, we studied the effects of counterions on the thermodynamic, viscoelastic, mechanical, photothermal, and self-healing properties of the materials. Therefore, this work can provide instruction for the preparation and performance tailoring of metallosupramolecular elastomers.

Ni-O4 as Active Sites for Efficient Oxygen Evolution Reaction with Electronic Metal-Support Interactions.

Precise adjustment of the metal site structure in single-atom catalysts (SACs) plays a key role in addressing the oxygen evolution reaction (OER). Herein, we report the synthesis of O-doped Ni SACs anchored on porous graphene-like carbon (Ni-O-G) using molten salts (ZnCl2 and NaCl) as templates, in which the unique Ni-O4 structure serves as the active sites. Ni-O-G, with an overpotential of only 238 mV (@ 10 mA cm-2), is one of the more advanced catalysts. An array of characterizations and density functional theory calculations show that the Ni-O4 coordination enables Ni to be closer to the Fermi level compared to traditional Ni-N4, enhancing the electronic metal-support interaction to facilitate OER kinetics. Thus, this work offers an alternative strategy for the structural modulation of Ni SACs and the effect of different coordination elements with the same atomic coordination structure on the intrinsic OER activity.

Novel Target Study to Cure Cardiovascular Disease regarding Proprotein Converse Subtilisin/Kexin Type 9.

Objective: This study is aimed at screening the potential ideal lead compounds from natural drug library (ZINC database), which had potential inhibition effects against proprotein converse subtilisin/kexin type 9 (PCSK9), and contributing to enrich the practical basis of PCSK9 inhibitor screening. Methods: A series of computer-aided virtual screening techniques were used to identify potential inhibitors of PCSK9. Structure-based virtual screening by LibDock was carried out to calculate the LibDock scores, followed by ADME (absorption, distribution, metabolism, and excretion) and toxicity predictions. Molecule docking was next employed to demonstrate the binding affinity and mechanism between the candidate ligands and PCSK9 macromolecule. Finally, molecular dynamics simulation was performed to evaluate the stability of ligand-PCSK9 complex under natural circumstance. Results: Two novel natural compounds ZINC000004099069 and ZINC000014952116 from the ZINC database were found to bind with PCSK9 with a higher binging affinity together with more favorable interaction energy. Also, they were predicted to be non-CYP2D6 inhibitors, together with low rodent carcinogenicity and AMES mutagenicity as well as hepatotoxicity. Molecular dynamics simulation analysis demonstrated that these two complex ZINC000004099069- and ZINC000014952116-PCSK9 had more favorable potential energy compared to the reference ligand, which could exist stably whether in vivo or in vitro. Conclusion: This study elucidated that ZINC000004099069 and ZINC000014952116 were finally screened as safe and potential drug candidates, which may have great significance in the development of PCSK9 inhibitor development.

Microflora for improving the Auricularia auricula spent mushroom substrate for Protaetia brevitarsis production.

Mushroom cultivation is a sustainable agricultural waste utilization method, but the lack of high-value utilization of the produced spent mushroom substrate (SMS) has hindered the development of mushroom cultivation-based circular agricultural systems. Conversion and utilization of SMS via Protaetia brevitarsis larvae (PBL) have proven to be a high-value AASMS utilization strategy. However, Auricularia auricula SMS (AASMS), which contains woodchips, is less palatable and digestible for PBL. To solve this problem, in this investigation, we screened out microflora (MF) for AASMS fermentation by comparing the fermentation performance as well as the effect on PBL feed intake, weight gain, and AASMS phytotoxic compound removal efficiency. In addition, by bacterial community analysis, the genera Luteimonas, Moheibacter, and Pseudoxanthomonas were predicted to be functional bacteria for AASMS fermentation and contribute to palatability and digestibility improvement.

Innovative immune mechanisms and antioxidative therapies of intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is the basic pathological process of many degenerative diseases of the spine, characterized by series of symptoms, among which low back pain (LBP) is the most common symptom that patients suffer a lot, which not only makes patients and individual families bear a huge pain and psychological burden, but also consumes a lot of medical resources. IDD is usually thought to be relevant with various factors such as genetic predisposition, trauma and aging, and IDD progression is tightly relevant with structural and functional alterations. IDD processes are caused by series of pathological processes, including oxidative stress, matrix decomposition, inflammatory reaction, apoptosis, abnormal proliferation, cell senescence, autophagy as well as sepsis process, among which the oxidative stress and inflammatory response are considered as key link in IDD. The production and clearance of ROS are tightly connected with oxidative stress, which would further simulate various signaling pathways. The phenotype of disc cells could change from matrix anabolism-to matrix catabolism- and proinflammatory-phenotype during IDD. Recent decades, with the relevant reports about oxidative stress and inflammatory response in IDD increasing gradually, the mechanisms researches have attracted much more attention. Consequently, this study focused on the indispensable roles of the oxidative stress and inflammatory response (especially macrophages and cytokines) to illustrate the origin, development, and deterioration of IDD, aiming to provide novel insights in the molecular mechanisms as well as significant clinical values for IDD.

Intratympanic steroid treatments rescued recurrent hearing loss following COVID-19 vaccination and detection of an intralabyrinthine schwannoma.

It remains unclear how to effectively treat rare cases of sudden and recurrent hearing losses which might coincidently follow vaccination. We report the first case, to our knowledge, of systemic and local steroid administration to successfully treat sudden and recurrent left-ear hearing loss, respectively, following a second dose of the BNT162b2 COVID-19 mRNA vaccination which inflammatory response potentially affected an existing left intralabyrinthine schwannoma in a young male patient. This case highlights the importance and timing of intratympanic steroid treatment strategies to suppress the progressive symptoms and restore hearing to a stable condition, and therefore avoid permanent hearing loss which would otherwise demand a surgical removal of the schwannoma to improve vertigo and reconstitute artificial hearing.

Bioinspired Design of High Vibration-Damping Supramolecular Elastomers Based on Multiple Energy-Dissipation Mechanisms.

Suppressing vibrations and noises is essential for our automated society. Here, inspired by the hierarchical dynamic bonds and phase separation of mussel byssal threads, we synthesize high-damping supramolecular elastomers (HDEs) via simple one-pot radical polymerization of butyl acrylate (BA), acrylic acid (AA), and vinylimidazole (VI). Interestingly, AA and VI not only form hydrogen bonds and ionic bonds simultaneously but also segregate into aggregates of different sizes, thereby successfully mimicking the hierarchical structure of mussel byssal threads. When applying external forces, the weak hydrogen bonds are broken at first and then the ionic bonds and aggregates are disrupted progressively from small to large deformations. Such multiple energy-dissipation mechanisms lead to the outstanding damping property of the HDEs. Therefore, the HDEs outperform commercially available rubbers in terms of sound absorption and vibration damping. Furthermore, the multiple energy-dissipation mechanisms impart the HDEs with high toughness (41.1 MJ/m3), tensile strength (21.3 MPa), and self-healing ability.

Revealing the Key MSCs Niches and Pathogenic Genes in Influencing CEP Homeostasis: A Conjoint Analysis of Single-Cell and WGCNA.

Degenerative disc disease (DDD), a major contributor to discogenic pain, which is mainly resulted from the dysfunction of nucleus pulposus (NP), annulus fibrosis (AF) and cartilage endplate (CEP) cells. Genetic and cellular components alterations in CEP may influence disc homeostasis, while few single-cell RNA sequencing (scRNA-seq) report in CEP makes it a challenge to evaluate cellular heterogeneity in CEP. Here, this study conducted a first conjoint analysis of weighted gene co-expression network analysis (WGCNA) and scRNA-seq in CEP, systematically analyzed the interested module, immune infiltration situation, and cell niches in CEP. WGCNA and protein-protein interaction (PPI) network determined a group of gene signatures responsible for degenerative CEP, including BRD4, RAF1, ANGPT1, CHD7 and NOP56; differentially immune analysis elucidated that CD4+ T cells, NK cells and dendritic cells were highly activated in degenerative CEP; then single-cell resolution transcriptomic landscape further identified several mesenchymal stem cells and other cellular components focused on human CEP, which illuminated niche atlas of different cell subpopulations: 8 populations were identified by distinct molecular signatures. Among which, NP progenitor/mesenchymal stem cells (NPMSC), also served as multipotent stem cells in CEP, exhibited regenerative and therapeutic potentials in promoting bone repair and maintaining bone homeostasis through SPP1, NRP1-related cascade reactions; regulatory and effector mesenchymal chondrocytes could be further classified into 2 different subtypes, and each subtype behaved potential opposite effects in maintaining cartilage homeostasis; next, the potential functional differences of each mesenchymal stem cell populations and the possible interactions with different cell types analysis revealed that JAG1, SPP1, MIF and PDGF etc. generated by different cells could regulate the CEP homeostasis by bone formation or angiogenesis, which could be served as novel therapeutic targets for degenerative CEP. In brief, this study mainly revealed the mesenchymal stem cells populations complexity and phenotypic characteristics in CEP. In brief, this study filled the gap in the knowledge of CEP components, further enhanced researchers' understanding of CEP and their cell niches constitution.

High-Throughput Sequencing Reveals CXCR4 and IGF1 Behave Different Roles in Weightlessness Osteoporosis.

Objective: This study is aimed at screening the differential expression profiles of mRNA under weightlessness osteoporosis through high-throughput sequencing technology, as well as investigating the pathogenesis of weightlessness osteoporosis at the molecular level especially in bone marrow mesenchymal stem cells (BMSCs). Methods: The mouse bone marrow mesenchymal stem cell line was divided into ground group and simulated microgravity (SMG) group. BMP-2 was used to induce osteogenic differentiation, and SMG group was placed into 2D-gyroscope to simulate weightless condition. Transcriptome sequencing was performed by Illumina technology, DEGs between ground and SMG group was conducted using the DEseq2 algorithm. Molecular functions and signaling pathways enriched by DEGs were then comprehensively analyzed via multiple bioinformatic approaches including but not limited to GO, KEGG, GSEA, and PPI analysis. Results: A total of 263 DEGs were identified by comparing these 2 groups, including 186 upregulated genes and 77 downregulated genes. GO analysis showed that DEGs were enriched in osteoblasts, osteoclasts cell proliferation, differentiation, and apoptosis; KEGG analysis revealed that DEGs were significantly enriched in the TNF signaling pathway and FoxO signaling pathway; the enrichment results from Reactome database displayed that DEGs were mainly involved in the transcription of Hoxb3 gene, RUNX1 recruitment KMT2A gene, and activation of Hoxa2 chromatin signaling pathway. The four genes, IL6, CXCR4, IGF1, and PLOD2, were identified as hub genes for subsequent analysis. Conclusions: This study elucidated the significance of 10 hub genes in the development of weightlessness osteoporosis. In addition, the results of this study provide a theoretical basis and novel ideas for the subsequent research of the pathogenesis and clinical treatment of weightlessness osteoporosis.

The Roles of Blood Lipid-Metabolism Genes in Immune Infiltration Could Promote the Development of IDD.

Objectives: Intervertebral disc degeneration is a progressive and chronic disease, usually manifesting as low back pain. This study aimed to screen effective biomarkers for medical practice as well as figuring out immune infiltration situations between circulation and intervertebral discs. Methods: Gene expression profiles of GSE124272 was included for differentially analysis, WGCNA and immune infiltration analysis from GEO database, and other GSE series were used as validation datasets. A series of validation methods were conducted to verify the robustness of hub genes, such as principal component analysis, machine learning models, and expression verification. Lastly, nomogram was established for medical practice. Results: 10 genes were commonly screened via combination of DEGs, WGCNA analysis and lipid metabolism related genes. Furthermore, 3 hub gens CYP27A1, FAR2, CYP1B1 were chosen for subsequent analysis based on validation of different methods. GSEA analysis discovered that neutrophil extracellular traps formation and NOD-like receptor signaling pathway was activated during IDD. Immune infiltration analysis demonstrated that the imbalance of neutrophils and γδT cells were significantly correlated with IDD progression. Nomogram was established based on CYP27A1, FAR2, CYP1B1 and age, the calibration plot confirmed the stability of our model. Conclusion: CYP27A1, FAR2, CYP1B1 were considered as hub lipid metabolism related genes (LMRGs) in the development of IDD, which were regarded as candidate diagnostic biomarkers especially in circulation. The effects are worth expected in the early diagnosis of IDD through detecting these genes in blood.

Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

Hepatocellular carcinoma (HCC) is a world leading cause of cancer-related mortality, and currently no curative treatment for advanced HCC is available. Glypican-3 (GPC3) is an attractive target for HCC immunotherapy. This study explored the efficacy of six GPC3-targeted bispecific antibodies, alone or in combination with chemotherapeutic drug Irinotecan, for the treatment of HCC. The bispecific antibodies were constructed using three different structures, knob-into-hole (KH), scFv-scFv-hFc, and scFv-hFc-scFv, where CD3-targeting mAb OKT3 (scFv) was paired with two representative GPC3 mAbs hYP7 (scFv) and HN3 (VH only) that target different epitopes. The In vitro cell killing assay revealed that all bispecific antibodies efficiently killed GPC3 positive cancer cells, with hYP7-KH, hYP7-OKT3-hFc, and HN3-KH being most potent. In vivo xenograft mouse studies demonstrated that all bispecific antibodies suppressed tumor growth similarly, with hYP7-OKT3-hFc performing slightly better. Combination of hYP7-OKT3-hFc with Irinotecan dramatically improved the efficacy and arrested tumor growth of HepG2, Hep3B, and G1 in xenograft mice. Our results demonstrated that the cell surface proximal bispecific antibody hYP7-OKT3-hFc was superior in terms of potency and the GPC3-targeted bispecific antibody combined with Irinotecan was much potent to control HCC growth.

Fragment-interconnected nitrogen-doped porous carbon nanosheets loaded with platinum group metals for highly boosted hydrogen evolution reaction in alkaline solution.

The rational design and preparation of advanced electrocatalysts for the hydrogen evolution reaction (HER) under alkaline conditions is the key to achieving sustainable hydrogen production. Herein, a new type of nitrogen-doped porous carbon nanosheets (NPCN) loaded with platinum group metals (Pd, Pt or Ru) were prepared. The introduction of melamine not only realized the doping of N-species, but also optimized the morphology and surface functional groups of the prepared catalysts. The prepared Pd-NPCN, Pt-NPCN and Ru-NPCN with a metal loading of about 10 wt% showed outstanding HER activity (21, 9 and 11 mv at 10 mA cm-2 current density), small Tafel slopes (49, 30 and 30 mV dec-1) and good stability in 1.0 M KOH. In addition, the mechanism of the introduction of melamine to improve the catalytic performance of HER was also discussed. Therefore, this work provides promising alternatives to traditional Pt-based catalysts, and is instructive for the design of high-efficiency alkaline HER catalysts.

Novel Natural Inhibitors Targeting Enhancer of Zeste Homolog 2: A Comprehensive Structural Biology Research.

The enhancer of zeste homolog 2 (EZH2) is a methylated modification enzyme of Histone H3-Lys 27. The high expression of EZH2 in cells is closely related to the progression, invasion, and metastasis of neoplasm. Therefore, this target is gradually becoming one of the research hot spots of tumor pathogenesis, and the inhibitors of the EZH2 enzyme are expected to become new antitumor drugs. This study used a series of virtual screening technologies to calculate the affinity between the compounds obtained from the ZINC15 database and the target protein EZH2, the stability of the ligand-receptor complex. This experiment also predicted the toxicity and absorption, distribution, metabolism, and excretion (ADME) properties of the candidate drugs in order to obtain compounds with excellent pharmacological properties. Finally, the ligand-receptor complex under in vivo situation was estimated by molecular dynamics simulation to observe whether the complex could exist steadily in the body. The experimental results showed that the two natural compounds ZINC000004217536 and ZINC000003938642 could bind tightly to EZH2, and the ligand-receptor complex could exist stably in vivo. Moreover, these two compounds were calculated to be nontoxic. They also had a high degree of intestinal absorption and high bioavailability. In vitro experiments confirmed that drug ZINC000003938642 could inhibit the proliferation and migration of osteosarcoma, which could serve as potential lead compounds. Therefore, the discovery of these two natural products had broad prospects in the development of EZH2 inhibitors, providing new clues for the treatment or adjuvant treatment of tumors.

Transcriptome research identifies four hub genes related to primary myelofibrosis: a holistic research by weighted gene co-expression network analysis.

OBJECTIVES: This study aimed to identify specific diagnostic as well as predictive targets of primary myelofibrosis (PMF). METHODS: The gene expression profiles of GSE26049 were obtained from Gene Expression Omnibus (GEO) dataset, WGCNA was constructed to identify the most related module of PMF. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) and Protein-Protein interaction (PPI) network were conducted to fully understand the detailed information of the interested green module. Machine learning, Principal component analysis (PCA), and expression pattern analysis including immunohistochemistry and immunofluorescence of genes and proteins were performed to validate the reliability of these hub genes. RESULTS: Green module was strongly correlated with PMF disease after WGCNA analysis. 20 genes in green module were identified as hub genes responsible for the progression of PMF. GO, KEGG revealed that these hub genes were primarily enriched in erythrocyte differentiation, transcription factor binding, hemoglobin complex, transcription factor complex and cell cycle, etc. Among them, EPB42, CALR, SLC4A1 and MPL had the most correlations with PMF. Machine learning, Principal component analysis (PCA), and expression pattern analysis proved the results in this study. CONCLUSIONS: EPB42, CALR, SLC4A1 and MPL were significantly highly expressed in PMF samples. These four genes may be considered as candidate prognostic biomarkers and potential therapeutic targets for early stage of PMF. The effects are worth expected whether in the diagnosis at early stage or as therapeutic target.