Abiotic aerobic oxidation pathways of stibnite revealed by oxygen and sulfur isotope systematics of sulfate.

The environmental threat posed by stibnite is an important geoenvironmental issue of current concern. To better understand stibnite oxidation pathways, aerobic abiotic batch experiments were conducted in aqueous solution with varying δ18OH2O value at initial neutral pH for different lengths of time (15-300 days). The sulfate oxygen and sulfur isotope compositions as well as concentrations of sulfur and antimony species were determined. The sulfur isotope fractionation factor (Δ34SSO4-stibnite) values decreased from 0.8‰ to -2.1‰ during the first 90 days, and increased to 2.6‰ at the 180 days, indicating the dominated intermediate sulfur species such as S2O32-, S0, and H2S (g) involved in Sb2S3 oxidation processes. The incorporation of O into sulfate derived from O2 (∼100%) indicated that the dissociated O2 was only directly adsorbed on the stibnite-S sites in the initial stage (0-90 days). The proportion of O incorporation into sulfate from water (27%-52%) increased in the late stage (90-300 days), which suggested the oxidation mechanism changed to hydroxyl attack on stibnite-S sites promoted by nearby adsorbed O2 on stibnite-Sb sites. The exchange of oxygen between sulfite and water may also contributed to the increase of water derived O into SO42-. The new insight of stibnite oxidation pathway contributes to the understanding of sulfide oxidation mechanism and helps to interpret field data.

E3 ligase RNF2 inhibits porcine circovirus type 3 replication by targeting its capsid protein for ubiquitination-dependent degradation.

Porcine circovirus type 3 (PCV3) is closely associated with various diseases, such as the porcine dermatitis, nephropathy syndrome, and multisystemic clinicopathological diseases. PCV3-associated diseases are increasingly recognized as severe diseases in the global swine industry. Ring finger protein 2 (RNF2), an E3 ubiquitin ligase exclusively located in the nucleus, contributes to various biological processes. This ligase interacts with the PCV3 Cap. However, its role in PCV3 replication remains unclear. This study confirmed that the nuclear localization signal domain of the Cap and the RNF2 N-terminal RING domain facilitate the interaction between the Cap and RNF2. Furthermore, RNF2 promoted the binding of K48-linked polyubiquitination chains to lysine at positions 139 and 140 (K139 and K140) of the PCV3 Cap, thereby degrading the Cap. RNF2 knockdown and overexpression increased or decreased PCV3 replication, respectively. Moreover, the RING domain-deleted RNF2 mutant eliminated the RNF2-induced degradation of the PCV3 Cap and RNF2-mediated inhibition of viral replication. This indicates that both processes were associated with its E3 ligase activity. Our findings demonstrate that RNF2 can interact with and degrade the PCV3 Cap via its N-terminal RING domain in a ubiquitination-dependent manner, thereby inhibiting PCV3 replication.IMPORTANCEPorcine circovirus type 3 is a recently described pathogen that is prevalent worldwide, causing substantial economic losses to the swine industry. However, the mechanisms through which host proteins regulate its replication remain unclear. Here, we demonstrate that ring finger protein 2 inhibits porcine circovirus type 3 replication by interacting with and degrading the Cap of this pathogen in a ubiquitination-dependent manner, requiring its N-terminal RING domain. Ring finger protein 2-mediated degradation of the Cap relies on its E3 ligase activity and the simultaneous existence of K139 and K140 within the Cap. These findings reveal the mechanism by which this protein interacts with and degrades the Cap to inhibit porcine circovirus type 3 replication. This consequently provides novel insights into porcine circovirus type 3 pathogenesis and facilitates the development of preventative measures against this pathogen.

Antimony Isotope Fractionation during Kinetic Sb(III) Oxidation by Antimony-Oxidizing Bacteria Pseudomonas sp. J1.

Antimony (Sb) isotopic fractionation is frequently used as a proxy for biogeochemical processes in nature. However, to date, little is known about Sb isotope fractionation in biologically driven reactions. In this study, Pseudomonas sp. J1 was selected for Sb isotope fractionation experiments with varying initial Sb concentration gradients (50-200 µM) at pH 7.2 and 30 °C. Compared to the initial Sb(III) reservoir (δ123Sb = 0.03 ± 0.01 ∼ 0.06 ± 0.01‰), lighter isotopes were preferentially oxidized to Sb(V). Relatively constant isotope enrichment factors (ε) of -0.62 ± 0.06 and -0.58 ± 0.02‰ were observed for the initial Sb concentrations ranging between 50 and 200 µM during the first 22 days. Therefore, the Sb concentration has a limited influence on Sb isotope fractionation during Sb(III) oxidation that can be described by a kinetically dominated Rayleigh fractionation model. Due to the decrease in the Sb-oxidation rate by Pseudomonas sp. J1, observed for the initial Sb concentration of 200 µM, Sb isotope fractionation shifted toward isotopic equilibrium after 22 days, with slightly heavy Sb(V) after 68 days. These findings provide the prospect of using Sb isotopes as an environmental tracer in the Sb biogeochemical cycle.

JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease.

Parkinson's disease (PD) poses a significant challenge in neurodegenerative disorders, characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The intricate mechanisms orchestrating DA neurodegeneration in PD are not fully understood, necessitating the exploration of innovative therapeutic approaches. Recent studies have implicated ferroptosis as a major contributor to the loss of DA neurons, revealing a complex interplay between iron accumulation and neurodegeneration. However, the sophisticated nature of this process challenges the conventional belief that mere iron removal could effectively prevent DA neuronal ferroptosis. Here, we report JWA, alternatively referred to as ARL6IP5, as a negative regulator of ferroptosis, capable of ameliorating DA neuronal loss in the context of PD. In this study, synchronized expression patterns of JWA and tyrosine hydroxylase (TH) in PD patients and mice were observed, underscoring the importance of JWA for DA neuronal survival. Screening of ferroptosis-related genes unraveled the engagement of iron metabolism in the JWA-dependent inhibition of DA neuronal ferroptosis. Genetic manipulation of JWA provided compelling evidence linking its neuroprotective effects to the attenuation of NCOA4-mediated ferritinophagy. Molecular docking, co-immunoprecipitation, and immunofluorescence studies confirmed that JWA mitigated DA neuronal ferroptosis by occupying the ferritin binding site of NCOA4. Moreover, the JWA-activating compound, JAC4, demonstrated promising neuroprotective effects in cellular and animal PD models by elevating JWA expression, offering a potential avenue for neuroprotection in PD. Collectively, our work establishes JWA as a novel regulator of ferritinophagy, presenting a promising therapeutic target for addressing DA neuronal ferroptosis in PD.

Seneca valley virus 3C protease blocks EphA2-Mediated mTOR activation to facilitate viral replication.

The Seneca Valley virus (SVV) is a recently discovered porcine pathogen that causes vesicular diseases and poses a significant threat to the pig industry worldwide. Erythropoietin-producing hepatoma receptor A2 (EphA2) is involved in the activation of the AKT/mTOR signaling pathway, which is involved in autophagy. However, the regulatory relationship between SVV and EphA2 remains unclear. In this study, we demonstrated that EphA2 is proteolysed in SVV-infected BHK-21 and PK-15 cells. Overexpression of EphA2 significantly inhibited SVV replication, as evidenced by decreased viral protein expression, viral titers, and viral load, suggesting an antiviral function of EphA2. Subsequently, viral proteins involved in the proteolysis of EphA2 were screened, and the SVV 3C protease (3Cpro) was found to be responsible for this cleavage, depending on its protease activity. However, the protease activity sites of 3Cpro did not affect the interactions between 3Cpro and EphA2. We further determined that EphA2 overexpression inhibited autophagy by activating the mTOR pathway and suppressing SVV replication. Taken together, these results indicate that SVV 3Cpro targets EphA2 for cleavage to impair its EphA2-mediated antiviral activity and emphasize the potential of the molecular interactions involved in developing antiviral strategies against SVV infection.

Antimony isotopic fractionation induced by Sb(V) adsorption on ß-MnO2.

Antimony (Sb) isotopes hold immense promise for unraveling Sb biogeochemical cycling in environmental systems. Mn oxides help control the fate of Sb via adsorption reactions, yet the behavior and mechanisms of Sb isotopic fractionation on Mn oxides are poorly understood. In this study, we examine the Sb isotopic fractionation induced by adsorption on ß-MnO2 in different experiments (kinetic, isothermal, effect of pH). We observe that adsorption on ß-MnO2 surfaces preferentially enriches lighter Sb isotopes through equilibrium fractionation, with Δ123Sbaqueous-adsorbed of 0.55-0.79 ‰. Neither the pH or surface coverage affects the fractionation magnitude. The analysis of extended X-ray absorption fine structure (EXAFS) demonstrates that the enrichment of light isotope results from the adsorption of inner-sphere complexation on solids. Our finding of this study enhances our comprehension of the impact of ß-MnO2 on Sb isotopic fractionation behavior and mechanism and facilitate the applicability of Sb isotopes as effective tracers to elucidate the origins and pathways of Sb contamination in environmental systems, as well as provide a new insight into forecasting the isotopic fractionation of other similar metals adsorbed by manganese oxides.

Identification of differentially expressed mRNAs as novel predictive biomarkers for gastric cancer diagnosis and prognosis.

BACKGROUND: Gastric cancer (GC) has a high mortality rate worldwide. Despite significant progress in GC diagnosis and treatment, the prognosis for affected patients still remains unfavorable. AIM: To identify important candidate genes related to the development of GC and identify potential pathogenic mechanisms through comprehensive bioinformatics analysis. METHODS: The Gene Expression Omnibus database was used to obtain the GSE183136 dataset, which includes a total of 135 GC samples. The limma package in R software was employed to identify differentially expressed genes (DEGs). Thereafter, enrichment analyses of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for the gene modules using the clusterProfile package in R software. The protein-protein interaction (PPI) networks of target genes were constructed using STRING and visualized by Cytoscape software. The common hub genes that emerged in the cohort of DEGs that was retrieved from the GEPIA database were then screened using a Venn Diagram. The expression levels of these overlapping genes in stomach adenocarcinoma samples and non-tumor samples and their association with prognosis in GC patients were also obtained from the GEPIA database and Kaplan-Meier curves. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to determine the mRNA and protein levels of glutamic-pyruvic transaminase (GPT) in GC and normal immortalized cell lines. In addition, cell viability, cell cycle distribution, migration and invasion were evaluated by cell counting kit-8, flow cytometry and transwell assays. Furthermore, we also conducted a retrospective analysis on 70 GC patients diagnosed and surgically treated in Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University between January 2017 to December 2020. The tumor and adjacent normal samples were collected from the patients to determine the potential association between the expression level of GPT and the clinical as well as pathological features of GC patients. RESULTS: We selected 19214 genes from the GSE183136 dataset, among which there were 250 downregulated genes and 401 upregulated genes in the tumor samples of stage III-IV in comparison to those in tumor samples of stage I-II with a P-value < 0.05. In addition, GO and KEGG results revealed that the various upregulated DEGs were mainly enriched in plasma membrane and neuroactive ligand-receptor interaction, whereas the downregulated DEGs were primarily enriched in cytosol and pancreatic secretion, vascular smooth muscle contraction and biosynthesis of the different cofactors. Furthermore, PPI networks were constructed based on the various upregulated and downregulated genes, and there were a total 15 upregulated and 10 downregulated hub genes. After a comprehensive analysis, several hub genes, including runt-related transcription factor 2 (RUNX2), salmonella pathogenicity island 1 (SPI1), lysyl oxidase (LOX), fibrillin 1 (FBN1) and GPT, displayed prognostic values. Interestingly, it was observed that GPT was downregulated in GC cells and its upregulation could suppress the malignant phenotypes of GC cells. Furthermore, the expression level of GPT was found to be associated with age, lymph node metastasis, pathological staging and distant metastasis (P < 0.05). CONCLUSION: RUNX2, SPI1, LOX, FBN1 and GPT were identified key hub genes in GC by bioinformatics analysis. GPT was significantly associated with the prognosis of GC, and its upregulation can effectively inhibit the proliferative, migrative and invasive capabilities of GC cells.

Tunable extraordinary optical transmission spectrum properties of long-wavelength infrared metamaterials.

Metamaterial filters represent an essential method for researching the miniaturization of infrared spectral detectors. To realize an 8-2 µm long-wave infrared tunable transmission spectral structure, an extraordinary optical transmission metamaterial model was designed based on the grating diffraction effect and surface plasmon polariton resonance theory. The model consisted of an Al grating array in the upper layer and a Ge substrate in the lower layer. We numerically simulated the effects of different structural parameters on the transmission spectra, such as grating height (h), grating width (w), grating distance (d), grating constant (p), and grating length (S 1), by utilizing the finite-difference time-domain method. Finally, we obtained the maximum transmittance of 81.52% in the 8-12 µm band range, with the corresponding structural parameters set to h=50n m, w=300n m, d=300n m, and S 1=48µm, respectively. After Lorentz fitting, a full width at half maximum of 0.94±0.01µm was achieved. In addition, the Ge substrate influence was taken into account for analyzing the model's extraordinary optical transmission performance. In particular, we first realized the continuous tuning performance at the transmission center wavelength (8-12 µm) of long-wave infrared within the substrate tuning thickness (D) range of 1.9-2.9 µm. The structure designed in this paper features tunability, broad spectral bandwidth, and miniaturization, which will provide a reference for the development of miniaturized long-wave infrared spectral filter devices.

Post-traumatic growth in later-life cognitive function? Evidence from the 1976 Great Tangshan Earthquake.

OBJECTIVES: This study aimed to explore the long-term impacts of exposure to earthquake in adolescence on later-life cognitive function in China. METHODS: Data were from the 2015 China Health and Retirement Longitudinal Study (CHARLS). Our analytical sample comprised 4394 participants aged 49 to 78 from two birth cohorts born between 1937 and 1966: exposed cohort during adolescence (born between 1952 and 1966), and non-exposed cohort during adolescence (born between 1937 and 1951). We defined earthquake exposure as the exposure severity of the 1976 Great Tangshan Earthquake (GTE). We selected community environmental characteristics as our key moderators. A difference-in-differences (DID) method was employed to estimate the long-term impact of the GTE on later-life cognitive function. RESULTS: We found that exposure to the earthquake during adolescence resulted in higher scores of later-life cognitive function (for males: ß = 2.18; 95% CI: 0.70-3.66; for females: ß = 1.22; 95% CI: 0.11-2.33). For males, this impact was moderated by community environmental characteristics including the old-age allowance program (ß = 3.07; 95% CI: 1.94-4.19) and the condition of basic community infrastructures (ß = 1.52; 95% CI: 0.84-2.19). CONCLUSIONS: Our study supports the post-traumatic growth theory. This finding suggest that individuals with early-life traumatic exposure need to be focused on. Additionally, improving the conditions of community infrastructures and establishing a community environment with comfort and security may be pretty important for promoting cognitive function and post-traumatic growth.

Temporal variations in the serogroup distribution of invasive meningococcal disease in Quebec, Canada, due to emerging unique clade of serogroup Y strain belonging to the Sequence Type-23 clonal complex.

OBJECTIVE: To identify recent trends in invasive meningococcal diseases (IMD) in Quebec, Canada, with a focus on MenY cases and MenY strains. METHODS: IMD cases and MenY strains from January 1, 2015 to August 11, 2023 were analyzed for clonal analysis and prediction of susceptibility to MenB vaccines. MenY strains of ST-23 CC from Quebec were analyzed with global MenY strains by core-genomic multi-locus sequence typing (cg-MLST). RESULTS: Since 2015 the serogroup distribution of IMD in Quebec has shifted from predominantly MenB to mainly MenY, with most (80.9 %) of the latter belonging to ST-23 CC. The median age of MenY cases due to ST-23 CC were statistically younger than MenY cases due to non-ST-23 CC. MenY of ST-23 CC showed genetic diversity and the major genetic cluster were similar to the Swedish Y1 strain. The increase in invasive MenY disease in Quebec was due to a sub-clade of Lineage 23.1 which caused an elevated proportion of severe disease in young adults. CONCLUSION: The increase in invasive MenY disease in Quebec, Canada was driven by the expansion of a sub-clade of Lineage 23.1 in young adults. Currently available quadrivalent A,C,W,Y-conjugate meningococcal vaccines were predicted to provide protection against these strains.

Acupuncture for radicular pain: a review of analgesic mechanism.

Radicular pain, a common and complex form of neuropathic pain, presents significant challenges in treatment. Acupuncture, a therapy originating from ancient traditional Chinese medicine and widely utilized for various pain types, including radicular pain, has shown promising outcomes in the management of lumbar radicular pain, cervical radicular pain, and radicular pain due to spinal stenosis. Despite its efficacy, the exact mechanisms through which acupuncture achieves analgesia are not fully elucidated and are the subject of ongoing research. This review sheds light on the current understanding of the analgesic mechanisms of acupuncture for radicular pain, offering valuable perspectives for both clinical application and basic scientific research. Acupuncture is postulated to relieve radicular pain by several mechanisms: peripherally, it reduces muscle spasms, lessens mechanical pressure on nerve roots, and improves microcirculation; at the molecular level, it inhibits the HMGB1/RAGE and TLR4/NF-κB signaling pathways, thereby decreasing the release of pro-inflammatory cytokines; within the spinal cord, it influences synaptic plasticity; and centrally, it modulates brain function, particularly affecting the medial prefrontal cortex, anterior cingulate cortex, and thalamus within the default mode network. By acting across these diverse biological domains, acupuncture presents an effective treatment modality for radicular pain, and deepening our understanding of the underlying mechanisms regarding analgesia for radicular pain is crucial for enhancing its clinical efficacy and advancement in pain management.

Serum ferritin and the risk of myocardial infarction: A Mendelian randomization study.

The potential role of serum ferritin as a risk factor for myocardial infarction (MI) is controversial, necessitating a systematic exploration of the causal relationship between ferritin and MI through Mendelian randomization (MR) methods. Genetic data were derived from a genome-wide association study (GWAS), employing the inverse variance-weighted (IVW) method as the primary approach. Comprehensive sensitivity analyses were conducted to validate the robustness of the results. Evaluation of instrumental variables was performed using the F-statistic, and a meta-analysis was employed to assess the average gene-predicted effect between ferritin and MI. The MR study revealed a negative correlation between ferritin and MI. The odds ratios (ORs) in the IVW method were 0.83 [95% confidence interval (CI) = 0.72-0.97; P = .017] and 0.86 (95% CI = 0.72-1.02; P = .080). Additionally, meta-analysis consistently indicated a negative causal relationship between ferritin and MI, with no heterogeneity or horizontal pleiotropy, thereby indicating a negative correlation between ferritin levels and the risk of MI. The genetic evidence sheds light on the causal relationship between ferritin levels and MI risk, providing new perspectives for future interventions in acute myocardial infarction (AMI).

Cycling and heart failure: A 2-sample Mendelian randomization.

Heart failure (HF) is a major cause of mortality worldwide. Cycling, an aerobic exercise, is believed to have a more effective rehabilitative impact on patients with heart failure. Previous studies have demonstrated the benefits of exercise in patients with HF. However, a precise causal relationship remains unknown. Two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between regular cardiac cycling and heart failure (HF) development. Data from the IEU OpenGWAS project, an extensive genetic study involving a diverse group of European males and females was used to determine how choices related to physical activity, such as cycling, impact cardiovascular well-being. To ensure reliability and robustness, the MR-Egger regression, weighted median, and random effects with inverse variance weighting methods were used. The key findings were summarized using odds ratio (OR) and 95% confidence intervals (CI). The MR-Egger, weighted mean, and inverse variance weighted (IVW) estimated superiority ratios were 0.960 (95% CI: 0.909-1.013), 0.985 (95% CI: 0.962-1.009), and 0.982 (95% CI: 0.966-0.998), respectively, indicating a significant association between cycling and a decreased risk of heart failure. These findings suggest that cycling, a form of moderate and easily accessible physical activity, may be a protective factor against HF. These findings correlate with those of previous studies regarding the crucial role of regular physical activity for the prevention and management of cardiovascular disease. The outcomes of this MR analysis can be used in the development of public health policies and aid individuals making lifestyle choices that promote heart health.

SQSTM1 downregulates avian metapneumovirus subgroup C replication via mediating selective autophagic degradation of viral M2-2 protein.

Avian metapneumovirus subgroup C (aMPV/C), an important pathogen causing acute respiratory infection in chickens and turkeys, contributes to substantial economic losses in the poultry industry worldwide. aMPV/C has been reported to induce autophagy, which is beneficial to virus replication. Sequestosome 1 (SQSTM1/P62), a selective autophagic receptor, plays a crucial role in viral replication by clearing ubiquitinated proteins. However, the relationship between SQSTM1-mediated selective autophagy and aMPV/C replication is unclear. In this study, we found that the expression of SQSTM1 negatively regulates aMPV/C replication by reducing viral protein expression and viral titers. Further studies revealed that the interaction between SQSTM1 and aMPV/C M2-2 protein is mediated via the Phox and Bem1 (PB1) domain of the former, which recognizes a ubiquitinated lysine at position 67 of the M2-2 protein, and finally degrades M2-2 via SQSTM1-mediated selective autophagy. Collectively, our results reveal that SQSTM1 degrades M2-2 via a process of selective autophagy to suppress aMPV/C replication, thereby providing novel insights for the prevention and control of aMPV/C infection.IMPORTANCEThe selective autophagy plays an important role in virus replication. As an emerging pathogen of avian respiratory virus, clarification of the effect of SQSTM1, a selective autophagic receptor, on aMPV/C replication in host cells enables us to better understand the viral pathogenesis. Previous study showed that aMPV/C infection reduced the SQSTM1 expression accompanied by virus proliferation, but the specific regulatory mechanism between them was still unclear. In this study, we demonstrated for the first time that SQSTM1 recognizes the 67th amino acid of M2-2 protein by the interaction between them, followed by M2-2 degradation via the SQSTM1-mediated selective autophagy, and finally inhibits aMPV/C replication. This information supplies the mechanism by which SQSTM1 negatively regulates viral replication, and provides new insights for preventing and controlling aMPV/C infection.

STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance.

Background: Cervical cancer poses a significant global threat to women's health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of the disease. Given the immunosuppressive microenvironment in cervical cancer, it is imperative to explore novel perspectives. In this regard, STING agonists have emerged as promising candidates. Methods: The expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Prognostic analysis of STING downstream genes (CCL5, CXCL9, CXCL10) and immune infiltration analysis were conducted using Kaplan-Meier Plotter, ESTIMATE, and deconvo_CIBERSOR. Single-cell RNA-seq (scRNA-seq) analysis was conducted to evaluate the potential of MSA-2 in cervical cancer treatment employing SingleR, chi-squared test, and Gene Set Enrichment Analysis (GSEA). Cellular interaction analysis utilized the CellChat package to assess the potentiation of cellular interaction following MSA-2 administration. Murine tumor models involving U14 and TC-1, were conducted, and the IF of tissue was subsequently conducted to assess the tumor microenvironment status after treatment. Results: Prognosis in cervical cancer correlated with elevated expression of STING downstream genes, indicating prolonged survival and reduced recurrence. These genes positively correlated with immune infiltration, influencing stromal scores, immune scores, and estimate scores. Specific immune cell populations, including CD8+ T cells, M1-type macrophages, NK cells, and T follicular helper cells, were associated with STING downstream genes. scRNA-seq in a classic immune-excluded model revealed that MSA-2 exerts priming and activating functions on vital components within TME, and intensifies their intercellular communications. The in vivo assay ultimately demonstrated that MSA-2, either as a standalone treatment or in combination with anti-PD-1, effectively suppressed the growth of subcutaneous cervical tumors. Moreover, the combination strategy significantly augmented efficacy compared to anti-PD-1 monotherapy by eliciting a robust antitumor immune response. Conclusion: This study highlights the pivotal role of the STING pathway and the potential of MSA-2 in reshaping the immune microenvironment in cervical cancer. Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling.

The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become a focal point in cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result in T cell exhaustion and immune evasion, fostering tumor progression. The advent of PD-1/PD-L1 inhibitor has demonstrated clinical success by unleashing T cells from exhaustion. Nevertheless, challenges such as resistance and adverse effects have spurred the exploration of innovative strategies, with bispecific antibodies (BsAbs) emerging as a promising frontier. BsAbs offer a multifaceted approach to cancer immunotherapy by simultaneously targeting PD-L1 and other immune regulatory molecules. We focus on recent advancements in PD-1/PD-L1 therapy with a particular emphasis on the development and potential of BsAbs, especially in the context of solid tumors. Various BsAb products targeting PD-1 signaling are discussed, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFß × PD-L1, anti-CD47 × PD-L1, anti-VEGF × PD-L1, anti-4-1BB × PD-L1, anti-LAG-3 × PD-L1, and anti-PD-1 × CTLA-4 BsAbs. Besides, we summarize ongoing clinical studies evaluating the efficacy and safety of these innovative BsAb agents. By unraveling the intricacies of the tumor microenvironment and harnessing the synergistic effects of anti-PD-1/PD-L1 BsAbs, there exists the potential to elevate the precision and efficacy of cancer immunotherapy, ultimately enabling the development of personalized treatment strategies tailored to individual patient profiles.

Evaluation of multiscale mechanisms of ultrasound-assisted extraction from porous plant materials: Experiment and modeling on this intensified process.

Ultrasound-assisted extraction (UAE) is an intensified mass transfer process, which can utilize natural resources effectively, but still lacks detailed mechanisms for multiscale effects. This study investigates the mass transfer mechanisms of UAE combined with material's pore structure at multiscale. Porous material was prepared by roasting green coffee beans (GCB) at 120 °C (RCB120) and 180 °C (RCB180), and their UAE efficiency for phytochemicals (caffeine, trigonelline, chlorogenic acid, caffeic acid) were evaluated by experiment and modeling. Besides, the physicochemical properties, mass transfer kinetics, and multi-physical field simulation were studied. Results indicated that positive synergy effects on extraction existed between ultrasound and material's pore structure. Higher mass transfer coefficients of UAE (GCB 0.16 min-1, RCB120 0.38 min-1, RCB180 0.46 min-1) was achieved with higher total porosity (4.47 %, 9.17 %, 13.52 %) and connected porosity (0 %, 3.79 %, 5.98 %). Moreover, simulation results revealed that micro acoustic streaming and pressure difference around particles were the main driving force for enhancing mass transfer, and the velocity (0.29-0.36 m/s) increased with power density (0.64-1.01 W/mL). The microscale model proved that increased yield from UAE-RCB was attributed to internal convection diffusion within particles. This study exploited a novel benefit of ultrasound on extraction and inspired its future application in non-thermal food processing.

DEAD-box RNA helicase 21 interacts with porcine circovirus type 2 Cap protein and facilitates viral replication.

Porcine circovirus type 2 (PCV2) is the etiological agent of PCV2-associated diseases that pose a serious threat to the swine industry. PCV2 capsid (Cap) protein has been shown to interact with DEAD-box RNA helicase 21 (DDX21), an important protein that regulates RNA virus replication. However, whether the interaction between DDX21 and the PCV2 Cap regulates PCV2 replication remains unclear. Herein, by using western blotting, interaction assays, and knockdown analysis, we found that PCV2 infection induced the cytoplasmic relocation of DDX21 from the nucleolus in cultured PK-15 cells. Moreover, the nuclear localization signal (NLS) of PCV2 Cap interacted directly with DDX21. The NLS of PCV2 Cap and 763GSRSNRFQNK772 residues at the C-terminal domain (CTD) of DDX21 were essential for the dual interaction. Upon shRNA-mediated DDX21 depletion in PK-15 cells, we observed impaired PCV2 replication via a lentivirus-delivered system, as evidenced by decreased levels of viral protein expression and virus production. In contrast, the replication of PCV2 increased in transiently DDX21-overexpressing cells. Our results indicate that DDX21 interacts with PCV2 Cap and plays a crucial role in virus replication. These results provide a reference for developing novel potential targets for prevention and control of PCV2 infection.

CAR-NK cells for cancer immunotherapy: recent advances and future directions.

Natural Killer (NK) cells, intrinsic to the innate immune system, are pivotal in combating cancer due to their independent cytotoxic capabilities in antitumor immune response. Unlike predominant treatments that target T cell immunity, the limited success of T cell immunotherapy emphasizes the urgency for innovative approaches, with a spotlight on harnessing the potential of NK cells. Despite tumors adapting mechanisms to evade NK cell-induced cytotoxicity, there is optimism surrounding Chimeric Antigen Receptor (CAR) NK cells. This comprehensive review delves into the foundational features and recent breakthroughs in comprehending the dynamics of NK cells within the tumor microenvironment. It critically evaluates the potential applications and challenges associated with emerging CAR-NK cell therapeutic strategies, positioning them as promising tools in the evolving landscape of precision medicine. As research progresses, the unique attributes of CAR-NK cells offer a new avenue for therapeutic interventions, paving the way for a more effective and precise approach to cancer treatment.