Distinct Characteristic Binding Modes of Benzofuran Core Inhibitors to Diverse Genotypes of Hepatitis C Virus NS5B Polymerase: A Molecular Simulation Study.

The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse ß-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.

Efficient solar-driven crude oil cleanup via graphene/cellulose aerogel with radial and centrosymmetric design.

Frequent oil spills pose significant threats to ecosystems; therefore, strict requirements are needed for prompt remediation and reclamation of spilled oil. Influenced by the structure of coniferous trees and their water transport, this experiment used cellulose nanofiber (CNF), polyvinyl alcohol (PVA), and methyltrimethoxysilane (MTMS) to prepare radially centrosymmetric aerogels. By utilizing the in-situ polycondensation reaction of MTMS, CNF, and PVA were connected, and the hydrophobicity and mechanical properties of the aerogel were greatly enhanced. Furthermore, the introduction of graphene oxide (GO), enshrouded within the cross-linked network, engenders heightened photo-thermal effects. The resultant composite aerogel exhibits expeditious oil absorption under solar irradiation and radial layered channel architecture, significantly curtailing the crude oil absorption timeframe (achieving a maximum absorption capacity of 51.7 g/g). Moreover, it demonstrates superior performance in rapidly and repeatedly adsorbing highly viscous crude oil, surpassing existing literature. Notably, continuous absorption of high-viscosity crude oil is achieved by integrating the composite aerogel with a peristaltic pump. This study offers a novel approach to the absorption and retrieval of high-viscosity crude oil, broadening the potential application horizons of CNF-based aerogels within environmental remediation.

Construction of a Titanium-Magnesium Composite Internal Fixation System for Repairing Bone Defects.

The repair and regeneration of maxillofacial bone defects are major clinical challenges. Titanium (Ti)-magnesium (Mg) composites are a new generation of revolutionary internal fixation materials encompassing the mechanical strength and bioactive advantages of Ti and Mg alloys, respectively. This study was aimed to construct a Ti-Mg composite internal plate/screw fixation system to fix and repair bone defects. Further, the effects of different internal fixation systems on bone repair were analyzed through radiological and histological analyses. Notably, Ti6Al4V with rolled Mg foil was used as the experimental group, and a bone defect model of transverse complete amputation of the ulna in rabbits similar to the clinical condition was established. The internal fixation system with the highest osteogenic efficiency was selected based on in vivo results, and the direct and indirect bone repair abilities of the selected materials were evaluated in vitro. Notably, the thin Mg foil-Ti6Al4V internal fixation system exhibited the best fixation effect in the bone defect model and promoted the formation of new bone and early healing of bone defect areas. In vitro, the thin Mg foil-Ti6Al4V composite enhanced the activity of MC3T3-E1 cells; promoted the proliferation, adhesion, extension, and osteogenic differentiation of MC3T3-E1 cells; and regulated new bone formation. Further, it also promoted the polarization of RAW264.7 cells to M2 macrophages, induced the osteogenic immune microenvironment, and indirectly regulated the bone repair process. Therefore, a internal fixation system holds a promising potential for the internal fixation of maxillofacial bone defects. Our findings provide a theoretical and scientific basis for the design and clinical application of Ti-Mg internal fixation systems.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Unraveling the Binding Mode of Cyclic Adenosine-Inosine Monophosphate (cAIMP) to STING through Molecular Dynamics Simulations.

The stimulator of interferon genes (STING) plays a significant role in immune defense and protection against tumor proliferation. Many cyclic dinucleotide (CDN) analogues have been reported to regulate its activity, but the dynamic process involved when the ligands activate STING remains unclear. In this work, all-atom molecular dynamics simulations were performed to explore the binding mode between human STING (hSTING) and four cyclic adenosine-inosine monophosphate analogs (cAIMPs), as well as 2',3'-cGMP-AMP (2',3'-cGAMP). The results indicate that these cAIMPs adopt a U-shaped configuration within the binding pocket, forming extensive non-covalent interaction networks with hSTING. These interactions play a significant role in augmenting the binding, particularly in interactions with Tyr167, Arg238, Thr263, and Thr267. Additionally, the presence of hydrophobic interactions between the ligand and the receptor further contributes to the overall stability of the binding. In this work, the conformational changes in hSTING upon binding these cAIMPs were also studied and a significant tendency for hSTING to shift from open to closed state was observed after binding some of the cAIMP ligands.

The ratio of circulating CD56dim NK cells to follicular T helper cells as a promising predictor for disease activity of relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system primarily mediated by CD4+ T helper cells. This study investigated the dynamic changes of natural killer (NK) cells and follicular T helper (Tfh) cells and their associations in relapsing-remitting MS patients. The findings revealed inverse relationships between NK cells and CD4+ T cells or Tfh cells. Specifically, CD56dim NK cells, not CD56bright NK cells, were negatively correlated with CD4+ T cells and Tfh cells. However, no significant correlations were found between NK cells and sNfL levels or EDSS scores. The ratio of CD56dim NK cells to circulating Tfh (cTfh) cells demonstrated superior discriminatory ability in distinguishing relapsing MS patients from healthy controls (HCs) and remitting patients, as determined by receiver operating characteristic (ROC) analysis. Following treatment with immunosuppressants or disease-modifying therapies (DMTs), a significant increase in the CD56dim NK/cTfh ratio was observed. These findings suggest that the CD56dim NK/cTfh ratio holds promise as a prognostic indicator for clinical relapse and treatment response in MS.

Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

3D printed zirconia used as dental materials: a critical review.

In view of its high mechanical performance, outstanding aesthetic qualities, and biological stability, zirconia has been widely used in the fields of dentistry. Due to its potential to produce suitable advanced configurations and structures for a number of medical applications, especially personalized created devices, ceramic additive manufacturing (AM) has been attracting a great deal of attention in recent years. AM zirconia hews out infinite possibilities that are otherwise barely possible with traditional processes thanks to its freedom and efficiency. In the review, AM zirconia's physical and adhesive characteristics, accuracy, biocompatibility, as well as their clinical applications have been reviewed. Here, we highlight the accuracy and biocompatibility of 3D printed zirconia. Also, current obstacles and a forecast of AM zirconia for its development and improvement have been covered. In summary, this review offers a description of the basic characteristics of AM zirconia materials intended for oral medicine. Furthermore, it provides a generally novel and fundamental basis for the utilization of 3D printed zirconia in dentistry.

Short-term safety of inactivated SARS-Cov-2 vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases.

Objective: This study aims to evaluate the short-term safety of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases (CNS IDDs). Methods: A web-based survey was conducted among patients with CNS IDDs from April 15 to 19, 2022 in China. In total, 645 patients with CNS IDDs were identified, including 425 patients with multiple sclerosis (MS), 194 with neuromyelitis optica spectrum disorder (NMOSD), and 26 with other CNS IDDs. The questionnaire consisted of demographic data, clinical records, history of SARS-CoV-2 vaccination, and vaccination-related symptoms within one month after vaccination. The demographic data, clinical information, and relapse rates between vaccinated and non-vaccinated patients were compared. Results: Among 645 patients with CNS IDDs, 78 were vaccinated and 567 were non-vaccinated with the vaccination rate of 12.1 %. Compared to non-vaccinated group, a lower percentage of patients on DMDs therapy (41.0 % vs. 71.8 %, P < 0.001) and an increased proportion of patients with other vaccination in past 3 years (17.9 % vs. 4.8 %, P < 0.001) were observed in vaccinated group. Six patients experienced a relapse within 30 days of a vaccination. Additionally, vaccine-associated relapse rates in vaccinated patients did not significantly differ from these in non-vaccinated patients among 2020, 2021, and from January 1 to October 1, 2022. Conclusions: No increased risk of vaccination-associated relapses among Chinese patients with CNS IDDs indicated that inactivated SARS-CoV-2 vaccines appear to be safe for this population.

Polarity Conversion of the Ag2S/AgInS2 Heterojunction by Radical-Induced Positive Feedback Polydopamine Adhesion for Signal-Switchable Photoelectrochemical Biosensing.

Efficient tuning of the polarity of photoactive nanomaterials is of great importance in improving the performance of photoelectrochemical (PEC) sensing platforms. Herein, polarity of the Ag2S/AgInS2 heterojunction is converted by radical-induced positive feedback polydopamine (PDA) adhesion, which is further employed to develop a signal-switchable PEC biosensor. In the nanocomposites, Ag2S and AgInS2 achieve electron-hole separation, exhibiting a strong anodic PEC response. Under the irradiation of light, the Ag2S/AgInS2 heterojunction is able to produce superoxide radical and hydroxyl radical intermediate species, leading to the polymerization of dopamine (DA) and the subsequent adhesion of PDA onto the Ag2S/AgInS2 heterojunction (Ag2S/AgInS2@PDA). By constructing a new electron-transfer pathway with PDA, the polarity of the Ag2S/AgInS2 heterojunction is converted, and the PEC response changes from anodic to cathodic photocurrents. In addition, since the photoreduction activity of PDA is stronger than that of the Ag2S/AgInS2 heterojunction, more superoxide radical can be produced by Ag2S/AgInS2@PDA once PDA is generated, thereby promoting the generation of PDA. Consequently, a positive feedback mechanism is established to enhance the polarity conversion of the Ag2S/AgInS2 heterojunction and amplify the responding to DA. As a result, the bioanalytical method is capable of sensitively quantifying DA in 10 orders of magnitude with an ultralow limit of detection. Moreover, the applicability of this biosensor in real samples is identified by measuring DA in fetal bovine serum and compared with a commercial ELISA method. Overall, this work offers an alternative perspective for adjusting photogenerated carriers of nanomaterials and designing high-performance PEC biosensors.