Structure-based design of novel 2,4,5-trisubstituted pyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the tolerant regions in NNTRIs binding pocket.

To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the "tolerant region I″ and "tolerant region II" of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC values ranging from 0.0062 to 0.

Design and biochemical evaluation of 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV capsid assembly modulators targeting a novel binding site.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach in the treatment of chronic HBV infection. In the quest for effective therapeutics against chronic Hepatitis B virus (HBV) infection, we employed a novel binding site occupancy strategy to develop novel 2-cyclopropyl-thioureidobenzamide (CP-TBA) derivatives as potent HBV CAMs. Our diversity modification approach led to the identification of compound 17e, which demonstrated remarkable anti-HBV activity with an EC of 0.

ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.

Highly aggressive tumours have evolved to restrain the cGAS-STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ.

Effects of previous arthroscopic knee surgery on the outcomes of primary total knee arthroplasty: a systematic review and PRISMA-compliant meta-analysis.

Objective: The aim of this study was to evaluate the potential adverse effects of prior arthroscopic knee surgery on the prognosis of primary total knee arthroplasty (TKA).

Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was performed in the PubMed, Embase, Cochrane Library, and other relevant databases up to October 2024.

A patent review of hepatitis B virus core protein allosteric modulators (2019-present).

Introduction: The hepatitis B virus (HBV) core protein is a significant therapeutic target due to its essential role in HBV replication. Over the past five years, numerous structurally unique CpAMs have been patented. However, no compounds have been approved due to various issues such as poor pharmacokinetics (PK) and hepatotoxicity.

Cryo-EM structures of Nipah virus polymerase complex reveal highly varied interactions between L and P proteins among paramyxoviruses.

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery.

Continuous-wave second-harmonic generation of green light in periodically poled thin-film lithium tantalate.

Thin-film lithium tantalate (TFLT) is attracting increasing attention in nonlinear generation of visible lasers due to its large second-order nonlinearity and reduced photorefractive effect. In this Letter, we design and fabricate a periodically poled TFLT waveguide for frequency doubling of a near-infrared laser operating at around 1064 nm. Continuous-wave 1.

Advances in the development of phosphodiesterase 5 inhibitors.

Phosphodiesterase 5 (PDE5) can hydrolyze cyclic guanosine monophosphate (cGMP), which is critical for maintaining various physiological processes in organisms. Currently, clinically approved indications for PDE5 inhibitors encompass therapeutic agents for erectile dysfunction (ED), symptoms associated with lower urinary tract symptoms (LUTS), and pulmonary artery hypertension (PAH). Despite the fact that the development of selective PDE5 inhibitors has been a significant focus in drug development for some time following the proven success of sildenafil as a PDE5 inhibitor for ED treatment, fewer than ten drugs in this therapeutic class have been marketed in the past 25 years, often accompanied by adverse effects.

Diagnosis for Band Topology under Crystal Symmetries Based on Bulk Measurements.

Topological gapped crystalline materials are a class of topological materials characterized by invariants protected by spatial symmetries, allowing for the emergence of robust boundary states. The band topology of gapped materials with crystal symmetries can be theoretically labeled by symmetry-indicator invariants, such as the Fu-Kane parity criterion for inversion-symmetric topological gapped materials. Here, we propose an approach to measuring these invariants and diagnosing topological gapped crystalline materials, which is experimentally validated in two-dimensional photonic crystals with finite size.

A Dehydrogenative Diels-Alder/Aromatization Sequence to Access 6/6/6/6/5 Pentacyclic Steroids: Their Anti-inflammatory Activities.

6/6/6/6/5 Pentacyclic steroids represent an emerging class of architecturally unique and biologically promising steroids. Herein, we developed a DDQ-mediated dehydrogenative Diels-Alder/aromatization cascade reaction between ergosterol derivatives and dienophiles inspired by plausible biosynthetic pathways, which enabled straightforward access to various 6/6/6/6/5 pentacyclic steroids in 24-66% yields. This work offers significant advantages in assembling 6/6/6/6/5 pentacyclic steroids such as the use of inexpensive starting materials, mild reaction conditions, and simple operations.

Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner.

Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation.

ADSL promotes autophagy and tumor growth through fumarate-mediated Beclin1 dimethylation.

As an enzyme with a critical role in de novo purine synthesis, adenylosuccinate lyase (ADSL) expression is upregulated in various malignancies. However, whether ADSL possesses noncanonical functions that contribute to cancer progression remains poorly understood. Here, we demonstrate that protein kinase R-like endoplasmic reticulum kinase (PERK) activated by lipid deprivation or ER stress phosphorylates ADSL at S140, leading to an enhanced association between ADSL and Beclin1.

Nucleoside antiviral agents with atypical structures and new targets.

Nucleoside analogs (NAs), as antiviral drugs, play a significant role in clinical medicine, constituting approximately 50 % of all antiviral therapies in current use. Nucleoside inhibitors function by mimicking the structure of natural nucleosides, integrating themselves into viral genetic material during replication, and subsequently inhibiting the virus's ability to reproduce. They are used to treat a variety of viral infections, including herpes simplex, hepatitis B, and acquired immunodeficiency syndrome (AIDS).

IdenHerb: A strategy for identifying constitutive herbs of herbal products by screening exclusive ions of each herb from large-scale multi-group LC-MS data.

Identification of constitutive herbs in an herbal product is critical for ensuring its quality and efficacy. However, current identification methods often lack universality, entail long durations, and involve complex procedures. Therefore, there is an urgent need to develop innovative methods for identifying constitutive herbs.

Optimization of SARS-CoV-2 M Inhibitors by a Structure-Based Multilevel Virtual Screening Method.

With the aim of developing novel anti-SARS-CoV-2 drugs to address the ongoing evolution and emergence of drug-resistant strains, the reported SARS-CoV-2 M inhibitor was selected as a lead to find novel, highly potent, and broad-spectrum inhibitors. Using a fragment-based multilevel virtual screening strategy, 15 hit compounds were identified and subsequently synthesized. Among them, (IC = 1.

Integrated Genetic Diversity and Multi-Omics Analysis of Colour Formation in Safflower.

Safflower ( L.) is a medicinal and edible cash crop that is widely cultivated worldwide. However, the genetic diversity of safflower germplasm resources and the reasons for the variations in safflower flower colour remain unclear.

Discovery of Brain-Penetrative Negative Allosteric Modulators of NMDA Receptors Using FEP-Guided Structure Optimization and Membrane Permeability Prediction.

-Methyl-d-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors in the central nervous system (CNS), have garnered attention for their role in brain disorders. Specifically, GluN2A-containing NMDA receptors have emerged as a potential therapeutic target for the treatment of depressive disorders and epilepsy. However, the development of GluN2A-containing NMDA receptor-selective antagonists, represented by -(4-(2-benzoylhydrazine-1-carbonyl)benzyl)-3-chloro-4-fluorobenzenesulfonamide (TCN-201) and its derivatives, faces a significant challenge due to their limited ability to penetrate the blood-brain barrier (BBB), hampering their characterization and further advancement.

Nanomolar activity of coumarin-3-thiosemicarbazones targeting Trypanosoma cruzi cruzain and the T. brucei cathepsin L-like protease.

Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) urgently demand innovative drug development due to their impact on public health worldwide.

Elaborate Structural Modifications Yielding Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Potent Neuraminidase Inhibitors with Significantly Improved Broad-Spectrum Antiresistance Profiles.

Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure-activity relationship (SAR) studies led to the identification of compounds and as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC = 0.

Case report: A rare case of breast and multiorgan metastases secondary to papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is generally considered a highly indolent endocrine malignancy, often accompanied by cervical lymph node metastasis and rarely involving distant metastases. We present a rare case of a 37-year-old woman with PTC, who exhibited regional lymph node metastasis, right breast metastasis, and probable right psoas major and multiple bone metastases. Initial symptoms included hoarseness, and subsequent examination revealed a secondary malignant tumor in the right breast, originating from the thyroid gland.

Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity.

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys).

Coupling of photonic topological states and their dynamical control based on liquid crystal.

Optical field manipulation inspired by topology theory has recently drawn great research attention in nanophotonic. For flexible and programmable light management, the capacity to dynamically regulate the photonic topological states in fixed optical artificial microstructures is essential. Here, we propose a dynamic light manipulation of a two-dimensional (2D) photonic lattice aided by liquid crystals, which is composed of all-dielectric photonic crystals with distinct topological phases.

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile.

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC = 0.