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Background: Extensive research has established obstructive sleep apnea (OSA) as a contributing factor to numerous cardiovascular and cerebrovascular diseases. However, whether OSA affects in-stent restenosis (ISR) after elective drug-eluting stenting is unclear. Therefore, the objective of this study was to examine the impact of OSA on ISR in patients with coronary heart disease (CHD) who underwent successful elective drug-eluting stent (DES) implantation. Methods: This study retrospectively analyzed CHD patients who successfully underwent elective coronary stent implantation and overnight sleep breathing monitoring and were readmitted for coronary angiography due to symptoms of CHD at 12 to 26 months after percutaneous coronary intervention (PCI). OSA was diagnosed when the apnea-hypopnea index (AHI) was ≥5 events/hour. ISR was defined as >50% restenosis of the vessel diameter in which the DES was implanted. To explore the association between OSA and ISR among patients with CHD, multivariate logistic regression models were developed and utilized. Results: This study enrolled 206 individuals who were diagnosed with CHD, with a mean age of 62.01 ± 10.27 years, and males constituted 76.2% of the patient population. After a median follow-up period of 15 months following DES implantation, there was a significant increase in the incidence of ISR among patients with moderate to severe OSA, increasing from 10.9% to 31.3% (p < 0.001). According to the fully adjusted model, the occurrence of ISR was found to be independently associated with the presence of OSA (OR: 3.247, 95% CI: 1.373–7.677, p = 0.007). Conclusions: In individuals who underwent elective drug-eluting stenting, OSA is an independent risk factor for ISR.

The impact of first-generation covalent KRAS inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.

Site-specific protein modification has been widely used to incorporate a variety of functional groups into proteins and peptides, and consequently modulate and study their physical properties and biological functions. To achieve site-specific protein modification, many chemoselective ligation reactions have been developed. Among these ligations, native chemical ligation (NCL) and copper-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) are the most widely used two ligations. In this thesis, we have utilized NCL and CuAAC to functionalize the N-terminal of expressed proteins and peptides with synthetic molecules to alter their physical properties, improve their biological activities and even create some new functions. In Chapter 2, we present a general approach to increase the solubility of hydrophobic proteins and peptides by site-specific incorporation of a small betaine moiety onto N-terminus via NCL. In Chapter 3, we present an approach to functionalize proteins’ N-terminus with a polymerizable alkene group by NCL. The alkene functionalized proteins can be copolymerized with acrylamide to form protein-polyacrylamide hydrogel. In Chapter 4, we present two general approaches to form N-terminally conjugated expressed protein dimers and trimers that were difficult to prepare before. The first approach utilizes NCL to conjugate the N-terminus of two monomers with a dithioester linker to form a homodimer. In second approach, we develop a combination of NCL with CuAAC to form protein homo- and heterodimers, and homotrimers. In Chapter 5, we apply our protein dimer formation approaches, which are presented in Chapter 4, to prepare dimers of HIV fusion inhibitor peptides with enhanced antiviral activities. Lastly, in Chapter 6, we present the first example of production of homogenously glycosylated glycoproteins with an N-terminal cysteine. As an example, the N-terminal cysteine containing antibody Fc is produced and further labeled with cyclic-RGD peptide for cancer cell targeting. This work has great potential for the development of cancer cell targeting therapy.

● Term of manganese-oxidizing microorganisms should be reconsidered. ● Visible light induces heterotrophic bacteria to produce superoxide. ● Heterotrophic bacteria oxidize Mn(II) ions with a fast oxidation rate. ● Superoxide oxidizing Mn(II) ions is an unintended side reaction of bacteria. ● Superoxide is an important oxidation force of Mn(II) in the environment. Manganese oxides are widely distributed in soils and sediments, affecting the migration and transformation of heavy metals and organic pollutants. The microbial conversion of soluble Mn(II) into insoluble Mn(III/IV) oxides is considered to be the initial source of manganese oxides in the environment; however, whether this process is related to a physiological role remains unclear. Here, we explored the microbial manganese oxidation process under visible light by using coastal surface seawater microorganisms. Visible light greatly promotes the oxidation rate of Mn(II), and the average rate reaches 64 μmol/(L·d). The generated manganese oxides were then conducive to Mn(II) oxidation, thus the rapid manganese oxidation was the result of the combined action of biotic and abiotic, and biological function accounts for 88 % ± 4 %. Extracellular superoxide produced by microorganisms induced by visible light is the decisive factor for the rapid manganese oxidation in our study. But the production of these superoxides does not require the presence of Mn(II) ions, the Mn(II) oxidation process was more like an unintentional side reaction, which did not affect the growth of microorganisms. More than 70 % of heterotrophic microorganisms in nature are capable of producing superoxide, based on the oxidizing properties of free radicals, all these bacteria can participate in the geochemical cycle of manganese. What's more, the superoxide oxidation pathway might be a significant natural source of manganese oxide.

This comparative study aims to identify a biocompatible and effective crosslinker for preparing gelatin sponges. Glutaraldehyde (GTA), genipin (GP), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC), and microbial transglutaminase (mTG) were used as crosslinking agents. The physical properties of the prepared samples were characterized, and material degradation was studied in vitro with various proteases and in vivo through subcutaneous implantation of the sponges in rats. Adipose-derived stromal stem cells (ADSCs) were cultured and inoculated onto the scaffolds to compare the cellular biocompatibility of the sponges. Cellular seeding efficiency and digestion time of the sponges were also evaluated. Cellular viability and proliferation in scaffolds were analyzed by fluorescence staining and MTT assay. All the samples exhibited high porosity, good swelling ratio, and hydrolysis properties; however, material strength, hydrolysis, and enzymolytic properties varied among the samples. GTA–sponge and GP–sponge possessed high compressive moduli, and EDC–sponge exhibited fast degradation performance. GTA and GP sponge implants exerted strong in vivo rejections, and the former showed poor cell growth. mTG–sponge exhibited the optimal comprehensive performance, with good porosity, compressive modulus, anti-degradation ability, and good biocompatibility. Hence, mTG–sponge can be used as a scaffold material for tissue engineering applications.

Persistent luminescence nanoparticles (PLNPs) are unique optical materials that emit afterglow luminescence after ceasing excitation. They exhibit unexpected advantages for in vivo optical imaging of tumors, such as autofluorescence-free, high sensitivity, high penetration depth, and multiple excitation sources (UV light, LED, NIR laser, X-ray, and radiopharmaceuticals). Besides, by incorporating other functional molecules, such as photosensitizers, photothermal agents, or therapeutic drugs, PLNPs are also widely used in persistent luminescence (PersL) imaging-guided tumor therapy. In this review, we first summarize the recent developments in the synthesis and surface functionalization of PLNPs, as well as their toxicity studies. We then discuss the in vivo PersL imaging and multimodal imaging from different excitation sources. Furthermore, we highlight PLNPs-based cancer theranostics applications, such as fluorescence-guided surgery, photothermal therapy, photodynamic therapy, drug/gene delivery and combined therapy. Finally, future prospects and challenges of PLNPs in the research of translational medicine are also discussed.

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14 + monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients. Some patients with COVID-19 fail to clear the viral infection quickly, yet our understanding for the underlying immune characteristics is still lacking. Here the authors use single-cell RNA sequencing and other data form such patients to show that persistent infection is associated with immune suppression and reduced expression of ribosomal protein genes.

BackgroundDietary polyphenol treatment of non-alcoholic fatty liver disease (NAFLD) is a novel direction, and the existing clinical studies have little effective evidence for its therapeutic effect, and some studies have inconsistent results. The effectiveness of dietary polyphenols in the treatment of NAFLD is still controversial. The aim of this study was to evaluate the therapeutic efficacy of oral dietary polyphenols in patients with NAFLD.MethodsThe literature (both Chinese and English) published before 30 April 2022 in PubMed, Cochrane, Medline, CNKI, and other databases on the treatment of NAFLD with dietary polyphenols was searched. Manual screening, quality assessment, and data extraction of search results were conducted strictly according to the inclusion and exclusion criteria. RevMan 5.3 software was used to perform the meta-analysis.ResultsThe RCTs included in this study involved dietary supplementation with eight polyphenols (curcumin, resveratrol, naringenin, anthocyanin, hesperidin, catechin, silymarin, and genistein) and 2,173 participants. This systematic review and meta-analysis found that 1) curcumin may decrease body mass index (BMI), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Triglycerides (TG) total cholesterol (TC), and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) compared to placebo; and curcumin does not increase the occurrence of adverse events. 2) Although the meta-analysis results of all randomized controlled trials (RCTs) did not reveal significant positive changes, individual RCTs showed meaningful results. 3) Naringenin significantly decreased the percentage of NAFLD grade, TG, TC, and low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) but had no significant effect on AST and ALT, and it is a safe supplementation. 4) Only one team presents a protocol about anthocyanin (from Cornus mas L. fruit extract) in the treatment of NAFLD. 5) Hesperidin may decrease BMI, AST, ALT, TG, TC, HOMA-IR, and so on. 6) Catechin may decrease BMI, HOMA-IR, and TG level, and it was well tolerated by the patients. 7) Silymarin was effective in improving ALT and AST and reducing hepatic fat accumulation and liver stiffness in NAFLD patients.ConclusionBased on current evidence, curcumin can reduce BMI, TG, TC, liver enzymes, and insulin resistance; catechin can reduce BMI, insulin resistance, and TG effectively; silymarin can reduce liver enzymes. For resveratrol, naringenin, anthocyanin, hesperidin, and catechin, more RCTs are needed to further evaluate their efficacy and safety.

Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

Mining bioactive secondary metabolites from microorganisms originating from deep-sea cold seep holds significant potential for discovering novel drug lead compounds. In this study, three known indole derivatives (1–3) were isolated from cold-seep-derived Halomonas meridiana OUCLQ22-B7. Subsequently, two-new indole dimers, meribisindole A (4) and meribisindole B (5), with nine known metabolites (6–14) were obtained via indole precursor feeding strategy. The structure of these compounds was elucidated via a combination of spectroscopic methods and circular dichroism (CD) measurement. Antimicrobial assays revealed that compounds 4, 7 and 8 exhibited potent inhibitory activity against Fusarium oxysporum CICC 41029 with minimal inhibitory concentrations (MICs) of 0.39−12.5 μg/mL, and compound 11 showed significant growth inhibition against Staphylococcus aureus CCARM 3090 with MIC value at 0.098 μg/mL.