Linarin Ameliorates Restenosis After Vascular Injury in Type 2 Diabetes Mellitus via Regulating ADAM10-Mediated Notch Signaling Pathway.

Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN's effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.

ASB6 as an Independent Prognostic Biomarker for Colorectal Cancer Progression Involves Lymphatic Invasion and Immune Infiltration.

Background: ASB6, an E3 ubiquitin ligase, mediates the proteasomal degradation of its substrate proteins via the ubiquitin-proteasome pathway. ASB6 has been reported to play significant roles in several biological processes, including tumor stemness and endoplasmic reticulum stress. However, the underlying role and mechanism of ASB6 in colorectal cancer, particularly its association with immune infiltration levels and its prognostic significance, remain to be fully elucidated. Methods: We identified key prognostic genes in CRC patients through LASSO-penalized Cox regression, Univariate and Multivariate Cox regression analyses. Subsequently, we comprehensively analyzed the prognostic value of hub genes and constructed a prognostic nomogram. Finally, we identified ASB6 interacting proteins through immunoprecipitation-mass spectrometry (IP-MS) and constructed protein-protein interaction (PPI) networks and performed pathway enrichment analysis to explore the potential mechanisms of ASB6. Meanwhile, we evaluated the functions of ASB6 in CRC cells through in vitro cell experiments. Results: We identified ASB6 as a hub gene in CRC. ASB6 was highly expressed in CRC, and patients with high ASB6 expression had worse Disease-Free Interval (DFI), Disease-Specific Survival (DSS), Overall Survival (OS), and Progression-Free Interval (PFI). Correlation analysis showed that ASB6 expression were positively correlated with lymph node invasion and distal metastasis. Overexpression of ASB6 enhanced the migration ability of CRC cells. Multivariate Cox regression analysis revealed that ASB6 was an independent prognostic factor for OS and DSS in CRC. The nomogram model constructed based on multivariate analysis results had good predictive effects, with C-indexes of 0.811 and 0.934 for OS and DSS, respectively. Furthermore, analysis of immune infiltration levels showed that ASB6 expression were positively correlated with M2-type macrophage infiltration levels in CRC, and patients with high levels of both ASB6 and M2-type macrophages had a worse prognosis. Furthermore, pathway enrichment analysis of ASB6 interacting proteins identified by IP-MS suggested that ASB6 may play a crucial role through the response to unfolded protein pathway and protein processing in the endoplasmic reticulum pathway. Conclusions: ASB6 is significantly upregulated in CRC tissues and is a risk factor for prognosis in CRC patients. ASB6 enhances the migration ability of CRC cells. Therefore, ASB6 may be an independent prognostic biomarker and potential therapeutic target for CRC patients.

Channel erosion and its impact on environmental flow of riparian habitat in the Middle Yangtze River.

Evaluating environmental flow (EF) is pivotal for conserving and restoring riverine ecosystems. Yet, prevalent EF evaluations presume that a river reach's hydraulic conditions are exclusively governed by inflow discharge, presupposing a state of equilibrium in the river channel. This presumption narrows the scope of EF evaluations in expansive alluvial rivers like the Middle Yangtze River (MYR), characterized by marked channel alterations. Here we show the profound channel erosion process and its impact on EF requirements for riparian habitats within the MYR. Our research unveils that: (i) pronounced erosion has led to a mean reduction of 1.0-2.7 m in the riverbed across four sub-reaches of the MYR; (ii) notwithstanding a 37-107% increase in minimal discharges post the Three Gorges Project, the lowest river stages at some hydrometric stations diminished owing to bed erosion, signifying a notable transformation in MYR's hydraulic dynamics; (iii) a discernible rightward shift in the correlation curve between the weighted useable area and discharge from 2002 to 2020 in a specific sub-reach of the MYR, instigated by alterations in hydraulic conditions, necessitated an increase of 1500-2600 m³ s-1 in the required EF for the sub-reach; (iv) it is deduced that macroinvertebrate biomass rapidly decreases as the flow entrains the riverbed substrate, with the maximum survivable velocity for macroinvertebrates being contingent on their entrainment threshold. These findings highlight the importance of incorporating channel morphological changes in devising conservation strategies for the MYR ecosystem.

Integrated modelling of flow-sediment transport and power generation in the Three Gorges Reservoir.

Reservoirs play a crucial role in regulating runoff and generating energy. However, they also lead to significant sedimentation in the reservoir area. In this study, we propose an integrated model that combines a 1-D hydro- and sediment dynamic module with a power generation module. The model considers both suspended and bed load transports. This model is applied to the Three Gorges Reservoir (TGR) and evaluate its performance against corresponding measurements. The results demonstrate that:① the proposed model accurately reproduces the processes of flow and sediment transport, bed deformation, and power generation during the hydrological years of 2019 and 2020. The relative errors for average discharge and bed deformation volume are <6 % and 10 %, respectively. Moreover, the calculated total power (982 × 108-1115 × 108 kW·h) closely agree with the measured values (969 × 108-1118 × 108 kW·h); ② the inflows of small tributaries have a noticeable impact on the calculated water discharge in the TGR. This impact will lead to a 16 % increase in average discharge and alter the magnitudes and occurrence times of flood peaks; ③ the flocculation of fine sediment particles significantly affects sediment transport, particularly in the sub-reach close to the dam. This flocculation will result in a 37 %-57 % reduction in average suspended sediment discharge and a 63 %-93 % reduction in peak sediment discharge. This research provides a comprehensive tool for simulating flow and sediment transport as well as power generation, which can support the optimal regulation of the TGR.

Benzofuran Derivatives from Cortex Mori Radicis and Their Cholinesterase-Inhibitory Activity.

The phytochemical investigation of Cortex Mori Radicis led to the isolation and identification of a new prenylated benzofuranone (1) and four ring-opening derivatives (2-5) named albaphenol A-E, as well as nigranol A (6), together with ten 2-arylbenzofuran derivatives (7-16). The characterization of the structures of the new compounds and the structural revision of nigranol A (6) were conducted using the comprehensive analysis of spectroscopic data (1D/2D NMR, HRESIMS, CD, and XRD). Compounds 1-16 were tested for their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1 and 4 showed weak BChE-inhibitory activity (IC50 45.5 and 61.0 µM); six 2-arylbenzofuran derivatives showed more-potent BChE-inhibitory activity (IC50 2.5-32.8 µM) than the positive control galantamine (IC50 35.3 µM), while being inactive or weakly inhibitory toward AChE. Cathafuran C (14) exhibited the most potent and selective inhibitory activity against BChE in a competitive manner, with a Ki value of 1.7 µM. The structure-activity relationships of the benzofuran-type stilbenes were discussed. Furthermore, molecular docking and dynamic simulations were performed to clarify the interactions of the inhibitor-enzyme complex.

Synthesis of sewage sludge biochar in molten salt environment for advanced wastewater treatment: Performance enhancement, carbon footprint and environmental impact reduction.

Sewage sludge (SS) pyrolysis to produce biochar is a vital approach for treating and utilizing SS, while reducing the carbon footprint of SS disposal. However, the high inorganic content in SS results in low carbon content and underdeveloped pore structure of biochar prepared under inert atmospheres. There is a significant risk of secondary pollutant emissions, including CO2, SO2, and NOx. In this study, we propose an innovative approach that utilizes excess molten salts, specifically a Li-Na-K molten carbonate (MC) and a Li-Na-K molten chloride (MCH), to create a medium-temperature liquid phase reaction environment (500 °C) for SS pyrolysis. This environment promotes the functional enhancement of biochar (SSB-MC and SSB-MCH) and in-situ absorption of secondary pollutants. The pore structure of SSB-MC and SSB-MCH are greatly optimized. Thanks to the dissolution of calcium-silicon-aluminum-based minerals by molten salt, the carbon content is also significantly increased. The increased specific surface area and surface-enriched functional groups (O, N, P, etc.) of SSB-MC result in greatly enhanced adsorption performance for Rhodamine B (27.9 to 89.1 mg g-1). SSB-MCH, due to the increased iron and phosphorus doping, also exhibits enhanced Fenton oxidation capability. Life cycle assessments demonstrate that the molten salt processes effectively reduce the carbon footprint, energy consumption, and environmental impact.

The development and application of pseudoviruses: assessment of SARS-CoV-2 pseudoviruses.

Although most Coronavirus disease (COVID-19) patients can recover fully, the disease remains a significant cause of morbidity and mortality. In addition to the consequences of acute infection, a proportion of the population experiences long-term adverse effects associated with SARS-CoV-2. Therefore, it is still critical to comprehend the virus's characteristics and how it interacts with its host to develop effective drugs and vaccines against COVID-19. SARS-CoV-2 pseudovirus, a replication-deficient recombinant glycoprotein chimeric viral particle, enables investigations of highly pathogenic viruses to be conducted without the constraint of high-level biosafety facilities, considerably advancing virology and being extensively employed in the study of SARS-CoV-2. This review summarizes three methods of establishing SARS-CoV-2 pseudovirus and current knowledge in vaccine development, neutralizing antibody research, and antiviral drug screening, as well as recent progress in virus entry mechanism and susceptible cell screening. We also discuss the potential advantages and disadvantages.

I-C-F-6 attenuates chronic cerebral hypoperfusion-induced neurological injury in mice by modulating microglia polarization.

Chronic cerebral hypoperfusion (CCH) is the leading cause of chronic cerebral dysfunction syndrome with its complex pathological mechanisms involving cortical and hippocampal neuronal loss, white matter lesions, and neuroinflammation. I-C-F-6 is a septapeptide, which has anti-inflammatory and anti-fibrotic effects. This study aimed to evaluate the neuroprotective effect of I-C-F-6 in chronic cerebral hypoperfusion (CCH)-induced neurological injury. C57BL/6 J mice were subjected to bilateral common carotid artery stenosis (BCAS), and BV2 microglia cells were induced with oxygen-glucose deprivation (OGD). In vivo, mice were divided randomly into four groups: Sham, BCAS, GBE (30 mg/kg), and I-C-F-6 (0.5 mg/kg). In vitro, microglia were divided randomly into four groups: control, OGD, I-C-F-6 (25 µg/mL), and Shikonin (800 nmol/L). Through LFB, TUNEL, and NeuN staining, we found that I-C-F-6 was able to mitigate myelin pathology and reduce the number of apoptotic neurons. Furthermore, immunofluorescence staining revealed that I-C-F-6 was able to reduce microglia clustering and downregulate NF-κB p65. We also observed a significant downregulation of M1 phenotype microglia signature genes, such as TNF-α, iNOS, and upregulation of anti-inflammatory cytokines, such as Arg-1 and IL-10, indicating that I-C-F-6 may mainly reduce polarization towards the M1 phenotype in microglia. Notably, I-C-F-6 downregulated the expression of NF-κB signaling pathway-related proteins IKK-ß and NF-κB p65, as well as pro-inflammatory cytokines IL-1ß and iNOS. In conclusion, I-C-F-6 can improve neurological damage, alleviate neuroinflammation, and inhibit microglia polarization to the M1 phenotype via the NF-κB signaling pathway.

Integrating multifunctional highly efficient flame-retardant coatings with superhydrophobicity, antibacterial property on cotton fabric.

There has been a growing interest in bio-based flame-retardant coating layer with good antibacterial activity for cotton fabric owing to the arising environmental pollution and viral and bacterial infectious risks. In this study, multifunctional flame-retardant coatings with superhydrophobicity and antibacterial property were integrated on cotton fabric through two-step method. The first layer of phosphorylated chitosan (PCS) biobased coating (C4) endowed the fabric highly efficient flame retardancy and antibacterial activity, and the second layer of modified poly(2-hydroxyethyl methacrylate phosphate ester) (PHEMAP) coating by perfluorooctyltriethoxysilane (P/F) provided the fabric excellent superhydrophobicity and self-cleaning ability. The C4-P/F fabric exhibited a shorter damage length of only 6.2 cm and achieved a higher char yield of 22.3 % than the C4 fabric in the vertical combustion test, and the limited oxygen index of the C4-P/F fabric increased to 32.5 %. The water contact angle (WCA) of the C4-P/F fabric reached above 150 o. Moreover, the C4-P/F fabric exhibited excellent antibacterial activity against Escherichia coli and Staphylococcus aureus. The highly efficient flame-retardant, superhydrophobic, antibacterial fabric is promising in home and public decoration, fire protection fields.

A promising nucleic acid therapy drug: DNAzymes and its delivery system.

Based on the development of nucleic acid therapeutic drugs, DNAzymes obtained through in vitro selection technology in 1994 are gradually being sought. DNAzymes are single-stranded DNA molecules with catalytic function, which specifically cleave RNA under the action of metal ions. Various in vivo and in vitro models have recently demonstrated that DNAzymes can target related genes in cancer, cardiovascular disease, bacterial and viral infection, and central nervous system disease. Compared with other nucleic acid therapy drugs, DNAzymes have gained more attention due to their excellent cutting efficiency, high stability, and low cost. Here, We first briefly reviewed the development and characteristics of DNAzymes, then discussed disease-targeting inhibition model of DNAzymes, hoping to provide new insights and ways for disease treatment. Finally, DNAzymes were still subject to some restrictions in practical applications, including low cell uptake efficiency, nuclease degradation and interference from other biological matrices. We discussed the latest delivery strategy of DNAzymes, among which lipid nanoparticles have recently received widespread attention due to the successful delivery of the COVID-19 mRNA vaccine, which provides the possibility for the subsequent clinical application of DNAzymes. In addition, the future development of DNAzymes was prospected.

Analysis of coexisting pathogens in nasopharyngeal swabs from COVID-19.

Background: The impact of COVID-19 on the world is still ongoing, and it is currently under regular management. Although most infected people have flu-like symptoms and can cure themselves, coexisting pathogens in COVID-19 patients should not be taken lightly. The present study sought to investigate the coexisting pathogens in SARS-CoV-2 infected patients and identify the variety and abundance of dangerous microbes to guide treatment strategies with a better understanding of the untested factors. Methods: We extracted total DNA and RNA in COVID-19 patient specimens from nasopharyngeal swabs to construct a metagenomic library and utilize Next Generation Sequencing (NGS) to discover chief bacteria, fungi, and viruses in the body of patients. High-throughput sequencing data from Illumina Hiseq 4000 were analyzed using Krona taxonomic methodology for species diversity. Results: We studied 56 samples to detect SARS-CoV-2 and other pathogens and analyzed the species diversity and community composition of these samples after sequencing. Our results showed some threatening pathogens such as Mycoplasma pneumoniae, Klebsiella pneumoniae, Streptococcus pneumoniae, and some previously reported pathogens. SARS-CoV-2 combined with bacterial infection is more common. The results of heat map analysis showed that the abundance of bacteria was mostly more than 1000 and that of viruses was generally less than 500. The pathogens most likely to cause SARS-CoV-2 coinfection or superinfection include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoniae, and Human gammaherpesvirus 4. Conclusions: The current coinfection and superinfection status is not optimistic. Bacteria are the major threat group that increases the risk of complications and death in COVID-19 patients and attention should be paid to the use and control of antibiotics. Our study investigated the main types of respiratory pathogens prone to coexisting or superinfection in COVID-19 patients, which is valuable for identifying and treating SARS-CoV-2.

Causality between heart failure and epigenetic age: a bidirectional Mendelian randomization study.

AIMS: Heart failure (HF) is a prevalent age-related cardiovascular disease with poor prognosis in the elderly population. This study aimed to establish the causal relationship between ageing and HF by conducting a bidirectional Mendelian randomization (MR) analysis on epigenetic age (a marker of ageing) and HF. METHODS AND RESULTS: Genome-wide association study data for epigenetic age (GrimAge, HorvathAge, HannumAge, and PhenoAge) and HF were collected and assessed for significant genetic variables. A bidirectional MR analysis was carried out using the random-effects inverse-variance weighted (IVW) method as the primary approach, while other methods (MR-Egger, weighted median, simple mode, and weighted mode) and multiple sensitivity analyses (heterogeneity analysis, leave-one-out sensitivity analysis, and horizontal pleiotropy analysis) were employed to evaluate the impact of epigenetic age on HF and vice versa. Bidirectional MR analysis of two samples revealed that the epigenetic PhenoAge clock increased the risk of HF [IVW odds ratio (OR) 1.015, 95% confidence interval (CI) 1.002-1.028, P = 0.028 and weighted median OR 1.020, 95% CI 1.001-1.038, P = 0.039]. Other results were not statistically significant. CONCLUSIONS: The bidirectional MR analysis demonstrated a causal link between genetically predicted epigenetic age and HF in individuals of European descent. Further research into epigenetic age in other populations and additional genetic information related to HF is warranted.

Modelling of phosphorus and nonuniform sediment transport in the Middle Yangtze River with the effects of channel erosion , tributary confluence and anthropogenic emission.

Phosphorus (P) transport plays a crucial role in the aquatic ecology of natural rivers. However, our understanding still remains unclear that how P transport is affected in a river-lake connected system downstream of a dam. This system usually undergoes both severe channel degradation and complex exchange of flow-sediment-phosphorus between the mainstem and tributaries. In the current study, a method was proposed firstly to determine the individual contribution of different sources to P recover based on the calculation of phosphorus budget; then an integrated model was developed, covering the modules of flow, nonuniform sediment and phosphorus transport. The application of the proposed method in the 955-km-long Middle Yangtze River (MYR) shows that the type of P transportation was predominantly changed from particulate phosphorus to dissolved phosphorus after the operation of the Three Gorges Project (TGP), but a significant longitudinal recovery of total phosphorus (TP) flux was observed. The TP flux exporting from the MYR was mainly from the Upper Yangtze River (44%), and 12%, 18% and 26% of that were originated from channel erosion, tributary confluence and anthropogenic emission. Moreover, the effects were investigated of nonuniform sediment transport and bed-material coarsening on P transport in the MYR, based on the proposed integrated model. Obtained results show that the TP transport process in the MYR was more reasonable simulated using the nonuniform sediment mode, and it is also confirmed that the process of bed-material coarsening after the TGP operation would lead to the decrease of particulate phosphorus flux in the MYR.

Lactic acid bacteria with a strong antioxidant function isolated from "Jiangshui," pickles, and feces.

Excessive free radicals and iron death lead to oxidative damage, which is one of the main causes of aging and diseases. In this field of antioxidation, developing new, safe, and efficient antioxidants is the main research focus. Lactic acid bacteria (LAB) are natural antioxidants with good antioxidant activity and can regulate gastrointestinal microecological balance and immunity. In this study, 15 LAB strains from fermented foods ("Jiangshui" and pickles) or feces were evaluated in terms of their antioxidant attributes. Strains with strong antioxidant capacity were preliminarily screened by the following tests: 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl radical, superoxide anion radical scavenging capacity; ferrous ion chelating assay; hydrogen peroxide tolerance capacity. Then, the adhesion of the screened strains to the intestinal tract was examined using hydrophobic and auto-aggregation tests. The safety of the strains was analyzed based on their minimum inhibitory concentration and hemolysis, and 16S rRNA was used for molecular biological identification. Antimicrobial activity tests showed them probiotic function. The cell-free supernatant of selected strains were used to explore the protective effect against oxidative damage cells. The scavenging rate of DPPH, hydroxyl radicals, and ferrous ion-chelating of 15 strains ranged from 28.81-82.75%, 6.54-68.52%, and 9.46-17.92%, respectively, the scavenging superoxide anion scavenging activity all exceeded 10%. According to all the antioxidant-related tests, strains possessing high antioxidant activities J2-4, J2-5, J2-9, YP-1, and W-4 were screened, these five strains demonstrated tolerance to 2 mM hydrogen peroxide. J2-4, J2-5, and J2-9 were Lactobacillus fermentans and γ-hemolytic (non-hemolytic). YP-1 and W-4 were Lactobacillus paracasei and α-hemolytic (grass-green hemolytic). Although L. paracasei has been proven as a safe probiotic without hemolytic characteristics, the hemolytic characteristics of YP-1 and W-4 should be further studied. Due to the weak hydrophobicity and antimicrobial activity of J2-4, finally, we selected J2-5, J2-9 for cell experiment, J2-5 and J2-9 showed an excellent ability that resistant to oxidative damage by increasing SOD, CAT, T-AOC activity of 293T cells. Therefore, J2-5, and J2-9 strains from fermented foods "Jiangshui" could be used as potential antioxidants for functional food, health care, and skincare.

Cyclo (MQCNS) has the potential to treat ischemic stroke.

We previously found that monocyte locomotion inhibitory factor has a neuroprotective effect on ischemic brain injury during the acute phase of stroke. Therefore, we modified the structure of an anti-inflammatory monocyte locomotion inhibitory factor peptide to construct an active cyclic peptide-Cyclo (MQCNS) (LZ-3)-and investigated its effects on ischemic stroke. In this study, we established a rat model of ischemic stroke by occluding the middle cerebral artery and then administered LZ-3 (2 or 4 mg/kg) via the tail vein for 7 consecutive days. Our results showed that LZ-3 (2 or 4 mg/kg) substantially decreased infarct volume, reduced cortical nerve cell death, improved neurological function, reduced cortical and hippocampal injury, and decreased the levels of inflammatory factors in the blood and brain tissues. In a well-differentiated, oxygen-glucose deprivation/reoxygenation-induced BV2 cell model of post-stroke, LZ-3 (100 µM) inhibited the JAK1-STAT6 signaling pathway. LZ-3 regulated microglia/macrophage polarization from the M1 to the M2 type and inhibited microglia/macrophage phagocytosis and migration via the JAK1/STAT6 signaling pathway. To conclude, LZ-3 regulates microglial activation by inhibiting the JAK1/STAT6 signaling pathway and improves functional recovery post-stroke.

Effect of WeChat-based continuous care intervention on the somatic function, depression, anxiety, social function and cognitive function for cancer patients: Meta-analysis of 18 RCTs.

AIM: This meta-analysis systematically reviewed and identified the effects of WeChat-based continuous care (WCC) interventions on various outcomes in cancer patients. DESIGN: Systematic review and meta-analysis. METHODS: In this study, outcome measures included somatic function, anxiety, depression, social function, and cognitive function. The standardized mean differences and 95% CIs of pooled effect sizes were calculated using fixed- and random-effects models. NFail-safe and Begg's tests were performed to evaluate publication bias, and sensitivity analysis was performed to evaluate the robustness of the meta-analysis results. RESULTS: The meta-analysis included 18 RCTs of moderate quality. WCC interventions significantly improved somatic function, depression, anxiety, social function, and cognitive function in cancer patients. There was no significant publication bias, and the sensitivity analysis indicated robust results. PATIENT OR PUBLIC CONTRIBUTION: WCC interventions improved depression, anxiety, social function, and cognitive function in cancer patients.

Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models.

Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, α-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/ß-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.

The antiviral activity of a small molecule drug targeting the NSP1-ribosome complex against Omicron, especially in elderly patients.

Introduction: With the emergence of SARS-CoV-2 mutant strains, especially the epidemic of Omicron, it continues to evolve to strengthen immune evasion. Omicron BQ. 1 and XBB pose a serious threat to the current COVID-19 vaccine (including bivalent mRNA vaccine for mutant strains) and COVID-19-positive survivors, and all current therapeutic monoclonal antibodies are ineffective against them. Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalization and death after the initial vaccine booster. However, small-molecule drugs for conserved targets remain effective and urgently needed. Methods: The non-structural protein of SARS-CoV-2 non-structural protein 1(Nsp1) can bind to the host 40S ribosomal subunit and activate the nuclease to hydrolyze the host RNA, while the viral RNA is unaffected, thus hijacking the host system. First, the present study analyzed mutations in the Nsp1 protein and then constructed a maximum-likelihood phylogenetic tree. A virtual drug screening method based on the Nsp1 structure (Protein Data Bank ID: 7K5I) was constructed, 7495 compounds from three databases were collected for molecular docking and virtual screening, and the binding free energy was calculated by the MM/GBSA method. Results: Our study shows that Nsp1 is relatively conserved and can be used as a comparatively fixed drug target and that therapies against Nsp1 will target all of these variants. Golvatinib, Gliquidone, and Dihydroergotamine were superior to other compounds in the crystal structure of binding conformation and free energy. All effectively interfered with Nsp1 binding to 40S protein, confirming the potential inhibitory effect of these three compounds on SARS-CoV-2. Discussion: In particular, Golwatinib provides a candidate for treatment and prophylaxis in elderly patients with Omicjon, suggesting further evaluation of the anti-SARS-CoV-2 activity of these compounds in cell culture. Further studies are needed to determine the utility of this finding through prospective clinical trials and identify other meaningful drug combinations.

Nurses' knowledge, attitude and behaviour on medical adhesive related skin injury in neonatal department: A survey.

AIM: To evaluate the status quo of knowledge, attitude and behaviour of neonatal nurses on medical adhesive related skin injury (MARSI). DESIGN: A survey. METHODS: We conducted a survey on the knowledge, attitude and behaviour of neonatal nurses from September 1-30, 2022. The characteristics, knowledge, attitude and behaviour of neonatal nurses were evaluated and analysed. RESULTS: A total of 116 neonatal nurses were included. Multivariate regression analysis indicated that had accepted MARSI training, education level, year of work experience are the influencing factors of nurses' MARSI knowledge score (all p < 0.05). Had accepted MARSI training, year of work experience are the influencing factors of nurses' MARSI attitude score (all p < 0.05). Had accepted MARSI training, year of work experience are the influencing factors of nurses' MARSI behaviour score (p = 0.015). PATIENT CONTRIBUTION: Neonatal nurses should strengthen their learning and training of MARSI related knowledge, and standardize their protective behaviours to reduce MARSI.

Constructing and Analyzing Competing Endogenous RNA Networks Reveal Potential Biomarkers in Human Colorectal Cancer.

BACKGROUND: The role of the lncRNA-miRNA-mRNA competing endogenous RNA network in human colorectal cancer remains largely unknown, and accurate prognostics still elude us. This study aimed to identify differentially expressed mRNAs and lncRNAs between tumor and normal samples, delineate their interactions and find reliable biomarkers. MATERIAL AND METHODS: We downloaded the RNA sequencing profiles and clinical information of 624 CRC patients from The Cancer Genome Atlas database. After expression difference analysis and interaction prediction, we identified 37 miRNAs, 5 lncRNAs, and 93 mRNAs to construct the ceRNA network (|log2 Fold Change| > 1, P-value < 0.05), and assessed relationships between them and clinical characteristics by t-test, Spearman correlation analysis, and Kaplan-Meier curve analysis. Besides, we validated PIGR and CD3D protein expression by immunohistochemistry staining. RESULTS: PIGR and CD3D mRNAs showed a negative correlation with tumor stage and their protein levels were lower in tumor tissues than in normal tissues. By survival analysis, MYC, F2RL2, and GINS2 positively correlated with the overall survival of CRC patients. CONCLUSION: Our study provides a novel comprehension of lncRNA-related ceRNA network in CRC and candidate molecules that serve as potential biomarkers of tumor stage and patient survival.