Design, synthesis, and biological evaluation of dual-site HIV-1 inhibitors simultaneously targeting the NNRTI binding pocket and an adjacent site with favorable resistance profiles.

Given high mutation rate of HIV-1 and its impact on NNRTIs' efficacy, targeting novel binding pockets has emerged as a viable strategy to overcome the drug resistance. In this study, we designed and synthesized 26 novel "dual-site" HIV-1 inhibitors that simultaneously target two distinct sites on reverse transcriptase (RT): the classical non-nucleoside inhibitor binding pocket (NNIBP) and a newly identified NNRTIs-adjacent site (NNIAS). Antiviral evaluation demonstrated that all compounds possessed potent activity against the wild-type (WT) HIV-1 strain, with EC values ranging from 4.

Advances in click chemistry for drug discovery and development.

Introduction: Click chemistry, first introduced by Sharpless and colleagues in 2001, has been an essential tool of drug research owing to its modularity, high efficiency, excellent yields, chemoselectivity, and mild reaction conditions.

Areas Covered: This review provides an overview of recent advances in drug development based on click chemistry over the past five years. It highlights key applications including fluorescent probes, lead identification and optimization, drug delivery systems, as well as emerging therapeutic modalities such as antibody-drug conjugates and protein degraders.

ROS-induced allosteric regulation of NikR coordinates HP0910-mediated OMP2 methylation to modulate H. pylori biofilm dynamics and therapeutic targeting.

Biofilm formation represents a critical survival strategy for Helicobacter pylori (H. pylori), facilitating antibiotic resistance and chronic colonization. In this study, we demonstrate that reactive oxygen species (ROS) released by macrophages enhance H.

A Global ERA5-based Tropical Cyclone Wind Field Dataset Enhanced by Integrated Parametric Correction Methods.

Tropical cyclones (TCs) are among the most destructive weather phenomena, significantly impacting atmosphere-ocean interactions and coastal regions. Accurate and high-resolution TC wind field datasets are critical for enhancing storm forecasting, disaster risk assessment, and understanding ocean-atmosphere interactions. Existing reanalysis datasets, such as ERA5, typically underestimate peak wind speeds and inadequately capture inner-core structural characteristics of TCs.

Structural Analysis of HIV-1 RNase H Bound to a Galloyl Active Site Inhibitor and Computational Compound Modification.

The emergence of drug-resistant viruses is a significant concern for the treatment of human immunodeficiency virus type-1 (HIV-1) infection, despite the availability of various drugs that block viral replication and propagation. Drugs that act upon unexploited targets of the viral replicative cycle may be able to circumvent resistance. The RNase H activity of HIV-1 reverse transcriptase is a viral enzymatic function for which no approved inhibitors are available.

Ultrasonic Bone Scalpel in Anterior Cervical Discectomy and Fusion Enhances Outcomes and Foraminal Decompression in Cervical Radiculopathy: A Retrospective Cohort Study.

Study Design Retrospective Cohort Study Objective: This study compared the safety and efficacy of ultrasonic bone scalpel-assisted direct decompression versus conventional direct decompression (using high-speed drills and Kerrison rongeurs) in anterior cervical discectomy and fusion (ACDF) for cervical radiculopathy with foraminal bone stenosis. This retrospective cohort study included 94 patients who underwent cervical foraminal stenosis surgery from 2019 to 2022. Group A (n=48) received traditional direct decompression using a high-speed drill and Kerrison rongeur, while Group B (n=46) underwent direct decompression using a combination of drilling and ultrasonic bone scalpel.

Inversed design of microstructure for vortex beam generation via perturbative backpropagation neural network.

Close attention has been paid to vortex beams recently; designing and constructing artificial microstructures capable of deliberate generation and manipulation of vortex beams are vital for the development of on-chip functionalized optical devices. However, the generation of complex vortex beams often relies on the stacking of metasurfaces, which undoubtedly increases the difficulty of on-chip device design. Therefore, it is of great significance to construct complex vortex beams using a single metasurface.

Discovery of multi-target anti-gout agents from Eurycoma longifolia Jack through phenotypic screening and structural optimization.

Developing anti-gout medications that simultaneously reduce uric acid and exert anti-inflammatory effects represents a critical breakthrough for managing gout progression. Natural products with polypharmacological properties offer promising leads for drug discovery. In this study, β-carboline-1-propionic acid, a bioactive constituent of Eurycoma longifolia Jack, served as the starting point for drug design.

Structure-Based Drug Design Yields Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

Human immunodeficiency virus type-1 (HIV-1) resistance severely compromises the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This study developed novel DAPY-derived NNRTIs via a structure-based drug design strategy with as the lead. All designed compounds demonstrate potent antiviral activity against the HIV-1 wild-type (WT) strain (EC = 3.

High-Q chiral metasurfaces with in-plane symmetric C-point engineering for nonlinear circular dichroism.

C-points in momentum space correspond to circularly polarized states, with broad applications in light-matter interactions, chiral lasing, and nonlinear optics. However, achieving a circularly polarized state at the Γ point requires relocating C-points to this position, which necessitates breaking both in-plane and out-of-plane symmetries. Besides, the chiral responses are typically confined to a narrow range of incident angles.

Further exploring the tolerant region II: Identification of 2,4,5-trisubstituted pyrimidines as HIV-1 reverse transcriptase allosteric inhibitors with desirable antiviral activities and reduced cytotoxicity.

Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by further exploring the potential tolerant region II within NNIBP. Most compounds were identified with potent inhibitory activity against HIV-1 wild-type (WT) strain with lower cytotoxicity. Among them, 14l exhibited the most outstanding antiviral activity (EC = 6.

Recent research progress of β-carbolines as privileged scaffold in the discovery of anticancer agent (2019-2024).

Cancer remains a formidable global health challenge, driving the need for targeted therapeutic agents to improve clinical outcomes. Natural and synthetic β-carboline alkaloids, characterized by their indole-based heterocyclic structures, have emerged as privileged scaffolds in oncology drug development due to their multimodal antitumor mechanisms. This review systematically evaluates recent advancements in β-carboline derivatives research, with emphasis on structural modification strategies, structure-activity relationships, and mechanistic elucidation of tumor suppression pathways.

Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway.

Sorafenib is an antiangiogenic and antiproliferative chemotherapeutic drug that plays a crucial role in the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib greatly limits its therapeutic efficacy. This highlights the importance of determining the mechanisms underlying resistance to antiangiogenic therapy.

Probing the Dominant Motifs within the Hydrophobic Channel Yields Oxadiazole-Containing Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

To develop effective non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved antidrug resistance profiles and drug-like properties, a series of novel diarylpyrimidine derivatives targeting the hydrophobic domain of the NNRTI-binding pocket was strategically designed, synthesized, and evaluated. Following structural optimization, (EC = 5.06-54.

Preparation of Glass Fiber Reinforced Polypropylene Bending Plate and Its Long-Term Performance Exposed in Alkaline Solution Environment.

Glass fiber reinforced polypropylene composite plates have gradually attracted more attention because of their repeated molding, higher toughness, higher durability, and fatigue resistance compared to glass fiber reinforced thermosetting composites. In practical engineering applications, composite plates have to undergo bending effect at different angles in corrosive environment of concrete, including bending bars from 0~90°, and stirrups of 90°, which may lead to long-term performance degradation. Therefore, it is important to evaluate the long-term performance of glass fiber reinforced polypropylene composite bending plates in an alkali environment.

Integrative analysis of high-dimensional quantile regression with contrasted penalization.

In the era of big data, the simultaneous analysis of multiple high-dimensional, heavy-tailed datasets has become essential. Integrative analysis offers a powerful approach to combine and synthesize information from these various datasets, and often outperforming traditional meta-analysis and single-dataset analysis. In this paper, we introduce a novel high-dimensional integrative quantile regression that can accommodate the complexities inherent in multi-dataset analysis.

Discovery and mechanism verification of first-in-class hydrophobic tagging-based degraders of HBV core protein.

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology.

Second-harmonic radiation by on-chip integrable mirror-symmetric nanodimers with sub-nanometric plasmonic gap.

Second-harmonic generation (SHG) facilitated by plasmonic nanostructures has drawn considerable attention, owing to its efficient frequency up-conversion at the nanoscale and potential applications in on-chip integration and nanophotonic devices. Herein, we present a nanodimer array fabricated by nanoimprinting, composed of nanofinger-pair symmetrically leaning at an off-angle with a well-defined sub-nanometric gap. Commonly, geometric symmetry would suppress the far-field SHG due to the near-field cancelling of symmetric surface SH polarization.

Molecular basis of the urate transporter URAT1 inhibition by gout drugs.

Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population.

Multi-spatial-attention U-Net: a novel framework for automated gallbladder segmentation on CT images.

Objective: This study aimed to construct a novel model, Multi-Spatial Attention U-Net (MSAU-Net) by incorporating our proposed Multi-Spatial Attention (MSA) block into the U-Net for the automated segmentation of the gallbladder on CT images.

Methods: The gallbladder dataset consists of CT images of retrospectively-collected 152 liver cancer patients and corresponding ground truth delineated by experienced physicians. Our proposed MSAU-Net model was transformed into two versions V1(with one Multi-Scale Feature Extraction and Fusion (MSFEF) module in each MSA block) and V2 (with two parallel MSEFE modules in each MSA blcok).