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Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 μM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg -1 ·d -1 , i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE -/- mice (20, 60 mg·kg -1 ·d -1 , i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg -1 ·d -1 , i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Ferroelectricity in metal-free perovskites (MFPs) has emerged as an academic hotspot for their lightweight, eco-friendly processability, flexibility, and degradability, with considerable progress including large spontaneous polarization, high Curie temperature, large piezoelectric response, and tailoring coercive field. However, their equivalent polarization axes as a key indicator are far from enough, although multiaxial ferroelectrics are highly preferred for performance output and application flexibility that profit from as many equivalent polarization directions as possible with easier reorientation. Here, by implementing the synergistic overlap of regulating anionic geometries (from spherical I - to octahedral [PF 6 ] - and to tetrahedral [ClO 4 ] - or [BF 4 ] - ) and cationic asymmetric modification, we successfully designed multiaxial MFP ferroelectrics CMDABCO-NH 4 -X 3 (CMDABCO = N -chloromethyl- N '-diazabicyclo[2.2.2]octonium; X = [ClO 4 ] - or [BF 4 ] - ) with the lowest P 1 symmetry. More impressively, systemic characterizations indicate that they possess 24 equivalent polarization axes (Aizu notations of 432F1 and m 3̅ m F1, respectively)─the maximum number achievable for ferroelectrics. Benefiting from the multiaxial feature, CMDABCO-NH 4 -[ClO 4 ] 3 has been demonstrated to have excellent piezoelectric sensing performance in its polycrystalline sample and prepared composite device. Our study provides a feasible strategy for designing multiaxial MFP ferroelectrics and highlights their great promise for use in microelectromechanical, sensing, and body-compatible devices.

Background: Co-infection of JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) is uncommon in kidney transplant recipients, and the prognosis is unclear. This study aimed to investigate the effect of concurrent JCPyV-DNAemia on graft outcomes in BKPyV-infected kidney transplant recipients with polyomavirus-associated nephropathy (PyVAN)., Methods: A total of 140 kidney transplant recipients with BKPyV replication and PyVAN, 122 without concurrent JCPyV-DNAemia and 18 with JCPyV-DNAemia were included in the analysis. Least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to identify prognostic factors for graft survival. A nomogram for predicting graft survival was created and evaluated., Results: The median tubulitis score in the JCPyV-DNAemia-positive group was higher than in JCPyV-DNAemia-negative group ( P  = 0.048). At last follow-up, the graft loss rate in the JCPyV-DNAemia-positive group was higher than in the JCPyV-DNAemia-negative group (50% versus 25.4%; P  = 0.031). Kaplan-Meier analysis showed that the graft survival rate in the JCPyV-DNAemia-positive group was lower than in the JCPyV-DNAemia-negative group ( P  = 0.003). Least absolute shrinkage and selection operator regression and multivariate Cox regression analysis demonstrated that concurrent JCPyV-DNAemia was an independent risk factor for graft survival (hazard ratio = 4.808; 95% confidence interval: 2.096-11.03; P  < 0.001). The nomogram displayed favorable discrimination (C-index = 0.839), concordance, and clinical applicability in predicting graft survival., Conclusions: Concurrent JCPyV-DNAemia is associated with a worse graft outcome in BKPyV-infected kidney transplant recipients with PyVAN., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Since the concept of "multiferroic" was first proposed in 1968, the coupling effect between different ferroic orders has attracted great interest in energy, information, and biomedical fields. However, the fully ferroelectric-fully ferroelastic effect has never been experimentally observed in hybrid perovskites, even though this effect was predicted to exist half a century ago. Realizing such cross-linking effects of polarization vectors and strain tensors has always been a huge challenge because of the complex difference in these two ferroic origins. Here, we report a multiferroic with full ferroelectricity and full ferroelasticity in two-dimensional (2D) hybrid perovskites based on ferroelectrochemistry. The dynamic molecular reorientations endow (cyclohexanemethylaminium) 2 PbCl 4 with a desired symmetry change of 4̅2 m F mm 2 at a Curie temperature of 411.8 K. More strikingly, the switchable evolution of ferroelastic domains was directly observed under the control of either electric or mechanical fields, which is the first experimental observation of a fully ferroelectric-fully ferroelastic effect in hybrid perovskites. This work would provide new insights into understanding the intrinsic cross-linking mechanism between ferroelectricity and ferroelasticity toward the development of multichannel interactive microelectronic devices.

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered. We previously showed that the histone variant H2A.Z suppresses memory, but it is unclear if this role is impacted by H2A.Z acetylation, a PTM that is typically associated with positive effects on transcription and memory. To answer this question, we used a mutation approach to manipulate acetylation on H2A.Z without impacting acetylation of other histone types. Specifically, we used adeno-associated virus (AAV) constructs to overexpress mutated H2A.Z.1 isoforms that either mimic acetylation (acetyl-mimic) by replacing lysines 4, 7 and 11 with glutamine (KQ), or H2A.Z.1 with impaired acetylation (acetyl-defective) by replacing the same lysines with alanine (KA). Expressing the H2A.Z.1 acetyl-mimic (H2A.Z.1 KQ ) improved memory under weak learning conditions, whereas expressing the acetyl-defective H2A.Z.1 KA generally impaired memory, indicating that the effect of H2A.Z.1 on memory depends on its acetylation status. RNA sequencing showed that H2A.Z.1 KQ and H2A.Z.1 KA uniquely impact the expression of different classes of genes in both females and males. Specifically, H2A.Z.1 KA preferentially impacts genes involved in synaptic function, suggesting that acetyl-defective H2A.Z.1 impairs memory by altering synaptic regulation. Finally, we describe, for the first time, that H2A.Z is also involved in alternative splicing of neuronal genes, whereby H2A.Z depletion, as well as expression of H2A.Z.1 lysine mutants influence transcription and splicing of different gene targets, suggesting that H2A.Z.1 can impact behavior through effects on both splicing and gene expression. This is the first study to demonstrate that direct manipulation of H2A.Z post-translational modifications regulates memory, whereby acetylation adds another regulatory layer by which histone variants can fine tune higher brain functions through effects on gene expression and splicing., (© 2024. The Author(s).)

Allicin (AL) is one of garlic-derived organosulfides and has a variety of pharmacological effects. Studies have reported that AL has notable inhibitory effects on liver cancer, gastric cancer, breast cancer, and other cancers. However, there are no relevant reports about its role in human nasopharyngeal carcinoma. Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death. Increasing evidence indicates that induction of ferroptosis can inhibit the proliferation, migration, invasion, and survival of various cancer cells, which act as a tumor suppressor in cancer. In this study, we confirmed that AL can inhibit cell proliferation, migration, invasion, and survival in human nasopharyngeal carcinoma cells. Our finding shows that AL can induce the ferroptosis axis by decreasing the level of GSH and GPX4 and promoting the induction of toxic LPO and ROS. AL-mediated cytotoxicity in human nasopharyngeal carcinoma cells is dependent on ferroptosis. Therefore, AL has good anti-cancer properties and is expected to be a potential drug for the treatment of nasopharyngeal carcinoma.

Objective : The optimal probiotic supplementation in pregnant women has not been thoroughly evaluated. By employing a network meta-analysis (NMA) approach, we compared the effectiveness of different probiotic supplementation strategies for pregnant women. Methods : A comprehensive search across multiple databases was performed to identify studies comparing the efficacy of probiotic supplements with each other or the control (placebo) among pregnant women. Results : This NMA, including 32 studies, systematically evaluated 6 probiotic supplement strategies: Lactobacillus , Lacticaseibacillus rhamnosus and Bifidobacterium (LRB), Lactobacillus acidophilus and Bifidobacterium (LABB), Lactobacillus acidophilus , Lacticaseibacillus casei , and Bifidobacterium bifidum (LLB), multi-combination of four probiotics (MP1), and multi-combination of six or more probiotics (MP2). Among these strategies, LLB, MP1, and MP2 all contain LABB. The NMA findings showed that MP1 was the most effective in reducing fasting blood sugar (FBS) (surface under the cumulative ranking curve [SUCRA]: 80.5%). In addition, MP2 was the most efficacious in lowering the homeostasis model assessment of insulin resistance (HOMA-IR) (SUCRA: 89.1%). LABB was ranked as the most effective in decreasing low-density lipoprotein cholesterol (LDLC) (SUCRA: 95.5%), total cholesterol (TC) (SUCRA: 95.5%), and high-sensitivity C-reactive protein (hs-CRP) (SUCRA: 94.8%). Moreover, LLB was ranked as the most effective in raising total antioxidant capacity (TAC) (SUCRA: 98.5%). Conclusion : Multi-combination of probiotic strains, especially those strategies containing LABB, may be more effective than a single probiotic strain in glycolipid metabolism, inflammation, and oxidative stress of pregnant women.

Hybrid organic-inorganic perovskite (HOIP) ferroelectric materials have great potential for developing self-powered electronic transducers owing to their impressive piezoelectric performance, structural tunability and low processing temperatures. Nevertheless, their inherent brittle and low elastic moduli limit their application in electromechanical conversion. Integration of HOIP ferroelectrics and soft polymers is a promising solution. In this work, a hybrid organic-inorganic rare-earth double perovskite ferroelectric, [RM3HQ] 2 RbPr(NO 3 ) 6 (RM 3 HQ = (R)-N-methyl-3-hydroxylquinuclidinium) is presented, which possesses multiaxial nature, ferroelasticity and satisfactory piezoelectric properties, including piezoelectric charge coefficient (d 33 ) of 102.3 pC N -1 and piezoelectric voltage coefficient (g 33 ) of 680 × 10 -3  V m N -1 . The piezoelectric generators (PEG) based on composite films of [RM3HQ] 2 RbPr(NO 3 ) 6 @polyurethane (PU) can generate an open-circuit voltage (V oc ) of 30 V and short-circuit current (I sc ) of 18 µA, representing one of the state-of-the-art PEGs to date. This work has promoted the exploration of new HOIP ferroelectrics and their development of applications in electromechanical conversion devices., (© 2023 Wiley‐VCH GmbH.)

Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N = 168), antigen A carriers (blood types A and AB) exhibited an extended progression-free survival (PFS; hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N = 202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR = 0.61, 95% CI = 0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P value = 0.003, HR = 0.60, 95% CI = 0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

The ability of drugs to cross the blood-brain barrier (BBB) is crucial for treating central nervous system (CNS) disorders. Inspired by natural viruses, here we report a glucose and polydopamine (GPDA) coating method for the construction of delivery platforms for efficient BBB crossing. Such platforms are composed of nanoparticles (NPs) as the inner core and surface functionalized with glucose-poly(ethylene glycol) (Glu-PEG) and polydopamine (PDA) coating. Glu-PEG provides selective targeting of the NPs to brain capillary endothelial cells (BCECs), while PDA enhances the transcytosis of the NPs. This strategy is applicable to gold NPs (AuNPs), silica, and polymeric NPs, which achieves as high as 1.87% of the injected dose/g of brain in healthy brain tissues. In addition, the GPDA coating manages to deliver NPs into the tumor tissue in the orthotopic glioblastoma model. Our study may provide a universal strategy for the construction of delivery platforms for efficient BBB crossing and brain drug delivery.

Hydrogels are prevailing drug delivery depots to improve antitumor efficacy and reduce systemic toxicity. However, the application of conventional free drug-loaded hydrogel is hindered by poor drug penetration in solid tumors. Here, an injectable ferritin-based nanocomposite hydrogel is constructed to facilitate tumor penetration and improve cancer chemoimmunotherapy. Specifically, doxorubicin-loaded human ferritin (Dox@HFn) and oxidized dextran (Dex-CHO) are used to construct the injectable hydrogel (Dox@HFn Gel) through the formation of pH-sensitive Schiff-base bonds. After peritumoral injection, the Dox@HFn Gel is retained locally for up to three weeks, and released intact Dox@HFn gradually, which can not only facilitate tumor penetration through active transcytosis but also induce immunogenic cell death (ICD) to tumor cells to generate an antitumor immune response. Combining with anti-programmed death-1 antibody (αPD-1), Dox@HFn Gel induces remarkable regression of orthotopic 4T1 breast tumors, further elicits a strong systemic anti-tumor immune response to effectively suppress tumor recurrence and lung metastasis of 4T1 tumors after surgical resection. Besides, the combination of Dox@HFn Gel L with anti-CD47 antibody (αCD47) inhibits postsurgical tumor recurrence of aggressive orthotopic glioblastoma tumor model and significantly extends mice survival. This work sheds light on the construction of local hydrogels to potentiate antitumor immune response for improved cancer therapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining spermatogenesis. The single-cell RNA sequencing (scRNA-seq) analysis of the testis was performed to identify genes upregulated in spermatogonia. Using scRNA-seq analysis, we identified the spermatogonia upregulated gene origin recognition complex subunit 6 ( Orc6 ), which is involved in DNA replication and cell cycle regulation; its protein expression in the human and mouse testis was detected by western blot and immunofluorescence. To explore the potential function of Orc6 in spermatogonia, the C18-4 cell line was transfected with control or Orc6 siRNA. Subsequently, 5-ethynyl-2-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, flow cytometry, and western blot were used to evaluate its effects on proliferation and apoptosis. It was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 cells. Bulk RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated (Wnt)/β-catenin signaling. Western blot revealed that the expression of β-catenin protein and its phosphorylation (Ser675) were significantly decreased when silencing the expression of ORC6. Our findings indicated that Orc6 was upregulated in spermatogonia, whereby it regulated proliferation and apoptosis by activating Wnt/β-catenin signaling., (Copyright © 2023 Copyright: © The Author(s)(2023).)