CDT1, transcriptionally regulated by E2F2, promotes lung adenocarcinoma progression.

CDT1, a gene that shows excessive expression in various malignancies, functions as a pivotal regulator of replication licensing. In this study, we observed a positive correlation in expression between CDT1 and E2F2 among patients with lung adenocarcinoma (LUAD). Our findings substantiated that E2F2 directly interacted with the promoter region of CDT1, as confirmed by ChIP-qPCR assays, and depletion of E2F2 resulted in a downregulation of CDT1 expression in LUAD cell lines by gene interference technology. Furthermore, we identified an upregulation of CDT1 mRNA level in Chinese LUAD samples. Notably, in the loss-of-function assays, depletion of CDT1 in LUAD cell lines inhibited cell proliferation, migration, and invasion. Concurrently, it promoted cell apoptosis and induced G0/G1 phase arrest using MTT, flow cytometry, and Transwell assays, reinforcing its role as an oncogene.Furthermore, enhanced tumor ablation was determined in a CDT1-downregulated LUAD tumor-bearing nude mouse model. Collectively, our results strongly suggest that E2F2 positively regulates CDT1 expression and actively participates in the progression of lung adenocarcinoma, thereby providing valuable insights into identifying novel therapeutic targets for LUAD treatment.

Safety and feasibility of enhanced recovery after surgery-based management model for ambulatory pediatric surgical procedures.

BACKGROUND: There is still some room for optimizing ambulatory pediatric surgical procedures, and the preoperative and postoperative management quality for pediatric patients needs to be improved. AIM: To discuss the safety and feasibility of the enhanced recovery after surgery (ERAS)-based management model for ambulatory pediatric surgical procedures. METHODS: We selected 320 pediatric patients undergoing ambulatory surgery from June 2023 to January 2024 at The First People's Hospital of Liangshan Yi Autonomous Prefecture. Of these, 220 received ERAS-based management (research group) and 100 received routine management (control group). General information, postoperative ambulation activities, surgical outcomes (operation time, postoperative gastrointestinal ventilation time, and hospital stay), postoperative pain visual analogue scale, postoperative complications (incision infection, abdominal distension, fever, nausea, and vomiting), and family satisfaction were compared. RESULTS: The general information of the research group (sex, age, disease type, single parent, family history, etc.) was comparable to that of the control group (P > 0.05), but the rate of postoperative (2 h, 4 h, and 6 h after surgery) ambulation activities was statistically higher (P < 0.01), and operation time, postoperative gastrointestinal ventilation time, and hospital stay were markedly shorter (P < 0.05). The research group had lower visual analogue scale scores (P < 0.01) at 12 h and 24 h after surgery and a lower incidence of total postoperative complications than the control group (P = 0.001). The research group had higher family satisfaction than the control group (P = 0.007). CONCLUSION: The ERAS-based management model was safe and feasible in ambulatory pediatric surgical procedures and worthy of clinical promotion.

Lactocaseibacillus-deglycosylated isoflavones prevent Aß 40-induced Alzheimer's disease in a rat model.

Alzheimer's disease (AD) is the most common neurodegenerative disease, with symptoms appearing in the cerebral cortex and hippocampus. amyloid ß peptide (Aß) has been shown to deposit in the brain, causing oxidative stress and inflammation, leading to impaired memory and learning. Lactocaseibacillus fermentation can produce deglycosylated isoflavones with high physiological activity, which can scavenge free radicals, enhance total antioxidant capacity and inhibit oxidative inflammatory responses. Therefore, in this study, Lactocaseibacillus paracasei subsp. paracasei NTU101 (NTU101) fermented soybean milk and its extracts were used as test substances, and AD model rats were established by infusion of Aß40 in the brain for 28 days, and the preventive and ameliorating effects of NTU 101 fermented soymilk were discussed. Effects of soymilk and unfermented soymilk on AD, and explore its effects on AD. Main functional ingredients. The results showed that deglycosylated isoflavones in NTU101 fermented soybean milk improved AD symptoms. Mechanisms of actions include the inhibition of oxidative inflammation; reduction in the expression of risk factors for tau protein and apo E protein production, the deposition of Aß40 around the hippocampus, and the expression of TLR-2 and RAGE proteins in astrocytes and microglia; and improvement in the memory and learning ability.

[Factors affecting the postoperative prognosis of penile cancer].

OBJECTIVE: To investigate the risk factors affecting the prognosis of penile cancer after surgery. METHODS: We retrospectively analyzed the clinical data on 112 cases of penile cancer treated in Weifang People's Hospital from January 2013 to December 2023. Using the Kaplan-Meier survival curve, χ2 test, Fisher's exact test, and univariate and multivariate Cox risk regression analyses, we compared the clinical characteristics among different groups, and determined the independent prognostic risk factors for cancer-specific survival (CSS) of the patients. RESULTS: The 1-, 3- and 5-year CSS rates of the penile cancer patients were 78.2%, 66.1% and 63.7%, respectively. Kaplan-Meier analysis indicated a significant correlation of a higher neutrophil-to-lymphocyte ratio (NLR) with a lower CSS rate (P < 0.001). Multivariate Cox regression analysis showed high NLR (HR = 2.6; 95% CI: 1.031－6.558; P = 0.043) to be an independent risk factor for CSS. CONCLUSION: Preoperative NLR is an independent risk factor for the prognosis of penile cancer. In addition, older age, farmer or worker occupation, lower education, preoperative lymphocyte-to-monocyte ratio (LMR)≤2.81, preoperative fibrinogen (FIB)≥3.41 g/L, advanced tumor stage and tumor differentiation are associated with the poor prognosis the malignancy.

High-efficient M-NC single-atom catalysts for catalytic ozonation in water purification: Performance and mechanisms.

Heterogeneous catalytic ozonation (HCO) holds promise in water purification but suffers from limited accessible metal sites, metal leaching, and unclear structure-activity relationships. This work reported M-NC (M=Co, Ni, Fe, and Mn) single-atom catalysts (SACs) with high atomic efficiency and minimal metal release. The new HCO systems, especially the Co-based system, exhibited impressive performance in various refractory contaminant removal, involving various reactive species generation, such as •OHads, •OHfree, *O, and 1O2. For sulfamethoxazole removal, the normalized kobs for Co-NC, Ni-NC, Fe-NC, and Mn-NC were determined as 13.53, 3.94, 3.55, and 4.13 min-1·mMmetal-1·g·m-2 correspondingly, attributed to the abundant acid sites, faster electron transfer, and lower energy required for O3 decomposition and conversion. The metal atoms and hydroxyl groups, individually serving as Lewis and Bronsted acid sites (LAS and BAS), were the primary centers for •OH generation and O3 adsorption. The relationships between active sites and both O3 utilization and •OH generation were found. LAS and BAS were responsible for O3 adsorption, while strong LAS facilitated O3 conversion into •OH. Theoretical calculations revealed the catalytic mechanisms involved O3→ *O→ *OO→ O3•-→ •OH. This work highlights the significance of SAC design for HCO and advances the understanding of atomic-level HCO behavior.

Supramolecular Polymer Frameworks with Controlled and Uniform Pore Apertures.

Porous frameworks with controlled pore structure and tunable aperture are greatly demanded. However, precise synthesis of this kind of materials is a formidable challenge. Herein, we report the fabrication of two-dimensional (2D) supramolecular polymer frameworks using a precisely synthesized rod-like helical polyisocyanide as link. Four three-arm star-shaped polyisocyanides with the degree of the polymerization of 10, 20, 30 and 40, and having 2-ureido-4[1H]-pyrimidinone (UPy) terminals were synthesized. 2D-Crystalline polymer frameworks with apertures of 5.3, 10.1, 13.9, and 19.1 nm were respectively obtained through intermolecular hydrogen bonding interaction between the terminal Upy units. The pore aperture is dependent on the length of polyisocyanide backbone. Thus, well-defined supramolecular polymer frameworks with controlled and uniform hexagonal pores were obtained, as proved by small-angle X-ray scattering (synchrotron radiation facility), atomic force microscopy, and Brunauer-Emmett-Teller analyses. The frameworks with uniform large pore aperture were used to purify nanomaterials and immobilize biomacromolecules. For instance, the membranes of the polymer frameworks could size-fractionation of silver nanoparticles into uniform nanoparticles with very low dispersity. The frameworks with large aperture facilitated the inclusion of myoglobin and enhanced the stability and catalytic activity.

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo.

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer.

BACKGROUND: Hematological metastasis has been recognized as a crucial factor contributing to the high rates of metastasis and mortality observed in colorectal cancer (CRC). Notably, exosomes derived from cancer cells participate in the formation of CRC pre-metastatic niches; however, the mechanisms underlying their effects are largely unknown. While our preliminary research revealed the role of exosome-derived disintegrin and metalloproteinase 17 (ADAM17) in the early stages of CRC metastasis, the role of exosomal ADAM17 in CRC hematogenous metastasis remains unclear. METHODS: In the present study, we isolated and purified exosomes using ultracentrifugation and identified exosomal proteins through quantitative mass spectrometry. In vitro, co-culture assays were conducted to evaluate the impact of exosomal ADAM17 on the permeability of the blood vessel endothelium. Vascular endothelial cell resistance, the cell index, membrane protein separation, flow cytometry, and immunofluorescence were employed to investigate the mechanisms underlying exosomal ADAM17-induced vascular permeability. Additionally, a mouse model was established to elucidate the role of exosomal ADAM17 in the modulation of blood vessel permeability and pre-metastatic niche formation in vivo. RESULTS: Our clinical data indicated that ADAM17 derived from the circulating exosomes of patients with CRC could serve as a blood-based biomarker for predicting metastasis. The CRC-derived exosomal ADAM17 targeted vascular endothelial cells, thus enhancing vascular permeability by influencing vascular endothelial cadherin cell membrane localization. Moreover, exosomal ADAM17 mediated the formation of a pre-metastatic niche in nude mice by inducing vascular leakage, thereby promoting CRC metastasis. Nonetheless, ADAM17 selective inhibitors effectively reduced CRC metastasis in vivo. CONCLUSIONS: Our results suggest that exosomal ADAM17 plays a pivotal role in the hematogenous metastasis of CRC. Thus, this protein may serve as a valuable blood-based biomarker and potential drug target for CRC metastasis intervention.

Macrocycles and Acyclic Cucurbit[n]urils as Pseudo[2]catenane Partners for Long-Acting Neuromuscular Blocks and Rapid Reversal In Vivo.

Long-acting neuromuscular blocks followed by rapid reversal may provide prolonged surgeries with improved conditions by omitting repetitive or continuous administration of the neuromuscular blocking agent (NMBA), eliminating residual neuromuscular block and minimizing postoperative recovery, which, however, is not clinically available. Here, we demonstrate that imidazolium-based macrocycles (IMCs) and acyclic cucurbit[n]urils (ACBs) can form such partners by functioning as long-acting NMBAs and rapid reversal agents through a pseudo[2]catenation mechanism based on stable complexation with Ka values of over 109 M-1. In vivo experiments with rats reveal that, at the dose of 2- and 3-fold ED90, one IMC attains a duration of action corresponding to 158 or 442 min for human adults, covering most of prolonged surgeries. The block can be reversed by one ACB with recovery time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, the clinically most widely used intermediate-acting NMBA.

A genome-wide association study reveals the relationship between human genetic variation and the nasal microbiome.

The nasal cavity harbors diverse microbiota that contributes to human health and respiratory diseases. However, whether and to what extent the host genome shapes the nasal microbiome remains largely unknown. Here, by dissecting the human genome and nasal metagenome data from 1401 healthy individuals, we demonstrated that the top three host genetic principal components strongly correlated with the nasal microbiota diversity and composition. The genetic association analyses identified 63 genome-wide significant loci affecting the nasal microbial taxa and functions, of which 2 loci reached study-wide significance (p < 1.7 × 10-10): rs73268759 within CAMK2A associated with genus Actinomyces and family Actinomycetaceae; and rs35211877 near POM121L12 with Gemella asaccharolytica. In addition to respiratory-related diseases, the associated loci are mainly implicated in cardiometabolic or neuropsychiatric diseases. Functional analysis showed the associated genes were most significantly expressed in the nasal airway epithelium tissue and enriched in the calcium signaling and hippo signaling pathway. Further observational correlation and Mendelian randomization analyses consistently suggested the causal effects of Serratia grimesii and Yokenella regensburgei on cardiometabolic biomarkers (cystine, glutamic acid, and creatine). This study suggested that the host genome plays an important role in shaping the nasal microbiome.

Electrically-assisted anaerobic digestion under ammonia stress: Facilitating propionate oxidation and activating methanogenesis via direct interspecies electron transfer.

Electrical assistance is an effective strategy for promoting anaerobic digestion (AD) under ammonia stress. However, the underlying mechanism of electrical assistance affecting AD is insufficiently understood. Here, electrical assistance to AD under 5 g N/L ammonia stress was provided, by employing a 0.6 V voltage to the carbon electrodes. The results demonstrated remarkable enhancements in methane production (104.6 %) and the maximal methane production rate (207.7 %). The critical segment facilitated by electro-stimulation was the microbial metabolism of propionate-to-methane, rather than ammonia removal. Proteins in extracellular polymer substances were enriched, boosting microbial resilience to ammonia intrusion. Concurrently, the promoted humic/fulvic-substances amplified the microbial electron transfer capacity. Metagenomics analysis identified the upsurge of propionate oxidation at the anode (by e.g. unclassified_c__Bacteroidia), and the stimulations of acetoclastic and direct interspecies electron transfer-dependent CO2-reducing methanogenesis at the cathode (by e.g. Methanothrix). This study provides novel insights into the effect of electrical assistance on ammonia-stressed AD.

Recovery capability of anaerobic digestion from ammonia stress: Metabolic activity, energy generation, and genome-centric metagenomics.

Excessive ammonia stresses anaerobic digestion (AD) significantly. Although there has been progress in understanding AD under ammonia exposure, investigations on AD liberated from ammonia exposure are limited. Here, the recovery capability of AD from ammonia stress was evaluated, by examining specific methanogenic activity, energy-conserving capability, microbial community succession, and metabolic pathway reconstruction. The findings demonstrated that ammonia stress relief resulted in < 50% methane recovery, with propionate conversion identified as the critical impediment to AD reactivation. Energy generation could not recovered either. Efforts to mitigate ammonia stress failed to restore acetoclastic methanogens, e.g., Methanothrix soehngenii, and proved futile in awakening propionate oxidizers, e.g., Desulfobulbus. Interestingly, a symbiotic metabolism emerged, prevailing in stress-relieved AD due to its energy-conserving advantage. This study underscores the importance of targeted interventions, including stimulating acetoclastic methanogenesis, propionate oxidation, and energy generation, as priorities for AD recovery following ammonia stress, rather than focusing solely on ammonia level management.

METTL3 Regulates the m6A Modification of NEK7 to Inhibit the Formation of Osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a common degenerative joint disease. The occurrence of OA slowly destroys the soft tissue structure of the patient's joint. Severe cases could lead to disability. Current studies had shown that inhibition of chondrocytes pyroptosis could slow down the progression of OA. Our work aimed to explore the specific mechanisms and ways of regulating this process. DESIGN: In this work, the level of N6-methyladenosine (m6A) in clinical tissues was detected by ribonucleic acid (RNA) m6A dot blot. qRT-PCR (quantitative real-time polymerase chain reaction) was used to detect the messenger RNA (mRNA) expression level of m6A modified enzyme in clinical tissues. MTT (3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromid) and flow cytometry were used to detect the effect of sh-METTL3 (methyltransferase like 3) and NIMA-related kinase 7 (NEK7) transfection on chondrocytes pyroptosis in OA. Western blot was used to detect the protein expression levels of pyroptosis-related proteins. ELISA (enzyme-linked immunosorbent assay) was used to measure the protein concentration of inflammatory cytokines. The SRAMP online database was used to predict the m6A site of NEK7. HE staining was used to assess the progression of OA in mice. RESULTS: The level of m6A in clinical samples of OA patients was higher, and METTL3 was significantly higher expressed in clinical samples of OA patients. We provided evidence that low expression of METTL3 inhibited chondrocytes pyroptosis. In addition, Rescue experiments and in vivo experiments had shown that METTL3 in combination with NEK7 inhibited the progression of OA by promoting chondrocytes pyroptosis. CONCLUSIONS: METTL3 regulates m6A modification of NEK7 and inhibits OA progression.

Selective abatement of electron-rich organic contaminants by trace complexed Mn(II)-catalyzed periodate via high-valent manganese-oxo species.

Mn(II) is among the most efficient catalysts for the periodate (PI)-based oxidation process. In-situ formed colloidal MnO2 simultaneously serves as the catalyst and oxidant during the degradation of organic contaminants by PI. Here, it is revealed that the complexation of Mn(II) by ethylene diamine tetraacetic acid (EDTA) further enhances the performance of PI-based oxidation in the selective degradation of organic contaminants. As evidenced by methyl phenyl sulfoxide probing, 18O-isotope labeling, and mass spectroscopy, EDTA complexation modulates the reaction pathway between Mn(II) and PI, triggering the generation of high-valent manganese-oxo (MnV-oxo) as the dominant reactive species. PI mediates the single-electron oxidation of Mn(II) to Mn(III), which is stabilized by EDTA complexation and then further oxidized by PI via the oxygen-atom transfer step, ultimately producing the MnV-oxo species. Ligands analogous to EDTA, namely, [S,S]-ethylenediaminedisuccinic acid and L-glutamic acid N,N-diacetic acid, also enhances the Mn(II)/PI process and favors MnV-oxo as the dominant species. This study demonstrates that functional ligands can tune the efficiency and reaction pathways of Mn(II)-catalyzed peroxide and peroxyacid-based oxidation processes.

Beam dynamics optimization design of Rhodotron electron accelerator based on genetic algorithm and sensitivity analysis.

The beam dynamics optimization study of Rhodotron electron accelerator for irradiation sterilization is introduced in this paper. The Rhodotron accelerator acceleration principle and the RF field distribution in the coaxial resonant cavity are described in detail. Beam dynamics in the Rhodotron accelerator are analyzed from both transverse and longitudinal directions. Beam dynamics of two kinds of Rhodotron electron accelerators with maximum beam energy of 10 MeV and 40 MeV were optimized based on multi-objective genetic algorithm. The key parameters of Rhodotron accelerators are determined, and the influence of some parameters on the overall acceleration effect is quantitatively analyzed. This paper provides some references for the research, manufacture, installation, and commissioning of this type of accelerator.

Integrated Human Skin Bacteria Genome Catalog Reveals Extensive Unexplored Habitat-Specific Microbiome Diversity and Function.

The skin is the largest organ in the human body. Various skin environments on its surface constitutes a complex ecosystem. One of the characteristics of the skin micro-ecosystem is low biomass, which greatly limits a comprehensive identification of the microbial species through sequencing. In this study, deep-shotgun sequencing (average 21.5 Gigabyte (Gb)) from 450 facial samples and publicly available skin metagenomic datasets of 2069 samples to assemble a Unified Human Skin Genome (UHSG) catalog is integrated. The UHSG encompasses 813 prokaryotic species derived from 5779 metagenome-assembled genomes, among which 470 are novel species covering 20 phyla with 1385 novel assembled genomes. Based on the UHSG, the core functions of the skin microbiome are described and the differences in amino acid metabolism, carbohydrate metabolism, and drug resistance functions among different phyla are identified. Furthermore, analysis of secondary metabolites of the near-complete genomes further find 1220 putative novel secondary metabolites, several of which are found in previously unknown genomes. Single nucleotide variant (SNV) reveals a possible skin protection mechanism: the negative selection process of the skin environment to conditional pathogens. UHSG offers a convenient reference database that will facilitate a more in-depth understanding of the role of skin microorganisms in the skin.