Pharmacokinetics and pre-systemic biotransformation of a deuterated clopidogrel-ferulic acid conjugate in rats.

To address the low biotransformation efficiency and high interindividual variability of clopidogrel (Clop), we developed a novel deuterated Clop-ferulic acid derivative (Dclop-FA), featuring an FA ester pharmacophore at the C2 and a deuterated methyl ester at the C7 position. Pharmacokinetic studies in rats showed that a single oral dose of Dclop-FA achieved 6.0-fold greater systemic exposure to the active metabolite versus equimolar coadministration of Clop and FA.

Discovery of a novel broad-spectrum inhibitor against influenza virus A.

The pandemic of influenza A virus (IAV) is on the rise worldwide, however, drug resistance to anti-influenza drugs has been widely found. The viral mutation of IAV highlights the necessitate for discovery of new antiviral agents with broad-spectrum efficacy. Arbidol, an effective pharmaceutical against IAV and other viruses, inhibits viral fusion by targeting a conserved binding region across multiple virus types.

USP13 mediates resistance to Ibrutinib in diffuse large B-cell lymphoma via augmenting FHL1 stabilization.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid malignancy in the world which is mainly divided to ABC type and GCB type. Ibrutinib benefits patients with ABC subtype DLBCL by inhibiting Bruton's tyrosine kinase (BTK), but there are still a lot of patients who are resistant to Ibrutinib. In this study, we found that post-translational modification played a regulatory role in mediating Ibrutinib resistance in DLBCL.

Patients-Derived Organoids Sequencing-based FOXP4 Facilitates Radioresistance by Transcriptionally Modifying GPX4 to Regulate ferroptosis in Colorectal Cancer.

More than 50% of patients with colorectal cancer (CRC) exhibit radioresistance, indicating the need for further research on the disease. Therefore, the aim of this study is to identify radioresistance genes and elucidate the underlying molecular mechanisms using patient-derived organoids (PDOs). Transcriptome analyses are performed on radio-resistant and -sensitive PDOs, CRC cells, and xenograft tissues to screen for radioresistant genes.

The RNF8/OPTN/KDM6A axis controls macrophage polarization to maintain testicular microenvironment homeostasis.

Dysregulated immune responses may erroneously target normal reproductive tissues, thereby compromising the proper functioning of the reproductive system. Macrophages are the most abundant immune cells in the testes, however, the role of macrophages in spermatogenic function is not yet clear. This study indicated that the increase of pro-inflammatory macrophages impaired the development of spermatogenic cells, and the deficiency of RNF8 led to a proinflammatory state in the testicular microenvironment and diminished sperm production in mice.

Structural insights into the roles of PARP4 and NAD binding in the human vault cage.

Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is thought to transport transiently bound "cargo" molecules. Vertebrate vaults house a poly (ADP-ribose) polymerase (known as PARP4 in humans), which is the only MVC with known enzymatic activity.

Influence of UHMWPE on the expansion characteristics of expansive soil: Experimental studies.

This paper investigates the effectiveness of using Ultra-High-Molecular-Weight Polyethylene (UHMWPE) Fiber to improve expansive soil. The test results indicate that the amount and length of UHMWPE significantly affect the swelling pressure and free swelling ratio of the reinforced soil. The swelling pressure of reinforced expansive soil exhibits a significant negative correlation with both the UHMWPE content (p < 0.

Structural basis of voltage-dependent gating in BK channels.

The allosteric communication between the pore domain, voltage sensors, and Ca binding sites in the calcium- and voltage-activated K channel (BK) underlies its physiological role as the preeminent signal integrator in excitable systems. BK displays shallow voltage sensitivity with very fast gating charge kinetics, yet little is known about the molecular underpinnings of this distinctive behavior. Here, we explore the mechanistic basis of coupling between voltage-sensing domains (VSDs) and calcium sensors in Aplysia BK by locking the VSDs in their activated (R196Q and R199Q) and resting (R202Q) states, with or without calcium.

An Assessment of Human-AI Interaction Capability in the Generative AI Era: The Influence of Critical Thinking.

(1) Background: In the era of generative AI (GenAI), assessing AI literacy is essential for understanding how effectively non-expert users can interact with AI. However, existing assessment tools primarily focus on users' understanding of AI principles or rely on self-reported scales, neglecting critical thinking and actual interaction capabilities. To address this gap, this study aims to design and validate evaluation indicators targeting the behavioral process of human-GenAI interactions and analyze the impact of critical thinking.

Neuro-immune interactions: Exploring the anti-inflammatory role of the vagus nerve.

The vagus nerve, the longest cranial nerve, plays a critical role in maintaining homeostasis through its complex anatomical structure and diverse physiological functions. Recent studies highlight its unique anti-inflammatory mechanisms, showing that vagus nerve stimulation (VNS) can activate both the cholinergic anti-inflammatory pathway (CAP) and the hypothalamic-pituitary-adrenal (HPA) axis. This leads to a reduction in the release of pro-inflammatory cytokines and alleviation of inflammation.

Deciphering the cellular and molecular landscape of cervical cancer progression through single-cell and spatial transcriptomics.

Cervical cancer represents a significant global health challenge, with complex cellular and molecular mechanisms driving its progression from HPV infection to invasive malignancy. This study employed an integrated approach combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (stRNA-seq) to comprehensively characterize the tumor microenvironment (TME) across different stages of cervical cancer development. Through analysis of samples from normal cervix, HPV-infected normal cervix, high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer, we identified distinct cellular populations and their dynamic changes during disease progression.

Research advances in the impacts of ectomycorrhizal fungi on the formation and decomposition of soil organic matter in forests.

Ectomycorrhizal (EcM) fungi are one of the important functional groups of soil fungi, playing a crucial role in the formation, stabilization, and decomposition of soil organic matter (SOM). We summarized the main processes and mechanisms by which EcM fungi contribute to SOM formation, stabilization, and decomposition in forests. Plants allocate a portion of photosynthetic products to symbiotic EcM fungi, which participate in SOM formation by importing them into the soil in the form of mycorrhizal exudates or necromass, whose activities promote the formation of soil aggregate structure and SOM stabilization.

Response-adapted zanubrutinib and tislelizumab as a potential strategy to enhance CD19 CAR T-cell therapy in relapsed/refractory large B-cell lymphoma: A retrospective observational study.

Background: CD19 chimeric antigen receptor (CAR) T-cell therapy is a potential treatment for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The combination of targeted therapeutic strategies, particularly bruton tyrosine kinase inhibitor zanubrutinib and programmed death-1 inhibitor tislelizumab, may improve clinical outcomes and modulate the tumour microenvironment (TME).

Methods: We studied patients with R/R LBCL who received response-adapted zanubrutinib plus tislelizumab upon CD19 CAR T-cell therapy between June 2021 and March 2023.

Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers.

Background: Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia.

Methods: We treated C57BL6 mice continuously by gavage for 14 days with either sunitinib, pazopanib, or axitinib. In this study, we set out to decipher the pathophysiological mechanisms of anti-angiogenic TKI haematological toxicity.

RO5126766 attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through mediating the ERK pathway.

Background: Osteoarthritis (OA) is a degenerative joint disease that remains challenging to treat due to lack of complete understanding of its pathogenesis. Previous studies have identified RO5126766 (RO) as a small molecule compound that inhibited RAF/MEK-ERK pathway and garnered much interest for its anti-cancer properties. But its role in the treatment of OA remains unclear.

Effects of polystyrene microparticles exposures on spermatogenic cell differentiation and reproductive endpoints in male mice.

The widespread distribution of microplastics in the environment has raised concerns about their potential implications for human health. Microplastics accumulate in animals and humans, but the risks associated with these pollutants are not fully understood. This study aimed to investigate the effects of polystyrene microplastics on the male reproductive system.

Collaborative removal of microplastics, bacteria, antibiotic resistance genes, and heavy metals in a full-scale wastewater treatment plant.

Plastics are used in large quantities in food packaging and industrial products in China, which results in ecological risks of microplastics (MPs) to the environment. In this study, the MPs' removal efficiency of a full-scale wastewater treatment plant (WWTP) and the internal interaction of microorganisms, antibiotic resistance genes (ARGs), and heavy metals with MPs were investigated. The dominant MPs in urban sewage were polyurethane (PU), acrylate copolymer (ACR), fluororubber, and polyethylene.

Single-Cell Landscape of Bronchoalveolar Lavage Fluid Identifies Specific Neutrophils during Septic Immunosuppression.

Sepsis-induced immunosuppression is related to increased susceptibility to secondary infections and death. Lung is the most vulnerable target organ in sepsis, but the understanding of the pulmonary immunosuppression state is still limited. Here, single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) is performed to map the landscape of immune cells, revealing a neutrophil-driven immunosuppressive program in the lungs of patients with immunosuppressive sepsis.

MiR-363-3p induces tamoxifen resistance in breast cancer cells through PTEN modulation.

Nowadays, the investigation for overcoming tamoxifen (TAM) resistance is confronting a considerable challenge. Therefore, immediate attention is required to elucidate the mechanism underlying TAM resistance in breast cancer. This research primarily aimed to define how miRNA-363-3p facilitates resistance to TAM in breast cancer.

Exploring the Function of OPTN From Multiple Dimensions.

Autophagy is an essential intracellular degradation system responsible for delivering cytoplasmic components to lysosomes. Within this intricate process, optineurin (OPTN), an autophagy receptor, has attracted extensive attention due to its multifaceted roles in the autophagy process. OPTN is regulated by various posttranslational modifications and actively participates in numerous signaling pathways and cellular processes.

Role of four and a half LIM domain protein 1 in tumors (Review).

As a cytoskeletal protein, the four and a half LIM domain protein 1 (FHL1) is widely expressed in various cells, particularly skeletal and cardiac muscle cells. FHL1 is involved in the development of the skeletal muscle and myocardium, regulations of gene transcription and thyroid function, and other physiological processes. Its expression is closely related to numerous diseases, such as skeletal muscle disease and viral infections.

Crotonylation of MCM6 enhances chemotherapeutics sensitivity of breast cancer via inducing DNA replication stress.

Breast cancer is associated with high morbidity and mortality, which are closely influenced by protein post-translational modifications (PTMs). Lysine crotonylation (Kcr) serves as a newly identified PTM type that plays a role in various biological processes; however, its involvement in breast cancer progression remains unclear. Minichromosome maintenance 6 (MCM6) is a critical component of DNA replication and has been previous confirmed to exhibit a significant role in tumorigenesis.

Phillyrin inhibits oxidative stress and neutrophil extracellular trap formation through the KEAP1/NRF2 pathway in gouty arthritis.

Gouty arthritis (GA) is an inflammatory disorder characterized by deposition of monosodium urate (MSU) crystal in joints. Phillyrin, a natural compound with anti-inflammatory properties, shows promise in mitigating inflammatory responses. This study investigates the therapeutic potential of phillyrin in GA and explores its mechanisms of action.

Comparative analysis of PD-L1 expression and molecular alterations in primary versus metastatic lung adenocarcinoma: a real-world study in China.

Objectives: Programmed death-ligand 1 (PD-L1) is the only Food and Drug Administration-approved biomarker for monitoring response to immune checkpoint inhibitor (ICI) therapy in patients with lung adenocarcinoma. Understanding the nuances of molecular phenotypes, clinical attributes, and PD-L1 expression levels in primary and metastatic lung adenocarcinoma may help predict response to therapy and assist in the clinical management of lung adenocarcinoma.

Methods: A total of 235 primary and metastatic lesion specimens from patients with non-small cell lung cancer (NSCLC) an institution in Shandong, China were analyzed.

Local TSH/TSHR signaling promotes CD8 T cell exhaustion and immune evasion in colorectal carcinoma.

Background: Dysfunction of CD8 T cells in the tumor microenvironment (TME) contributes to tumor immune escape and immunotherapy tolerance. The effects of hormones such as leptin, steroid hormones, and glucocorticoids on T cell function have been reported previously. However, the mechanism underlying thyroid-stimulating hormone (TSH)/thyroid-stimulating hormone receptor (TSHR) signaling in CD8 T cell exhaustion and tumor immune evasion remain poorly understood.