Asymmetric Coordination Regulating D-orbital Spin-electron Filling in Single-atom Iron Catalyst for Efficient Oxygen Reduction.

The single-atom Fe-N-C catalyst has shown great promise for the oxygen reduction reaction (ORR), yet the intrinsic activity is not satisfactory. There is a pressing need to gain a deeper understanding of the charge configuration of the Fe-N-C catalyst and to develop rational modulation strategies. Herein, we have prepared a single-atom Fe catalyst with the co-coordination of N and O (denoted as Fe-N/O-C) and adjacent defect, proposing a strategy to optimize the d-orbital spin-electron filling of Fe sites by fine-tuning the first coordination shell. The Fe-N/O-C exhibits significantly better ORR activity compared to its Fe-N-C counterpart and commercial Pt/C, with a much more positive half-wave potential (0.927 V) and higher kinetic current density. Moreover, using the Fe-N/O-C catalyst, the Zn-air battery and proton exchange membrane fuel cell achieve peak power densities of up to 490 and 1179 mW cm-2, respectively. Theoretical studies and in situ electrochemical Raman spectroscopy reveal that Fe-N/O-C undergoes charge redistribution and negative shifting of the d-band center compared to Fe-N-C, thus optimizing the adsorption free energy of ORR intermediates. This work demonstrates the feasibility of introducing an asymmetric first coordination shell for single-atom catalysts and provides a new optimization direction for their practical application.

Inhalable metal-organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy.

Cuproptosis shows enormous application prospects in lung metastasis treatment. However, the glycolysis, Cu+ efflux mechanisms, and insufficient lung drug accumulation severely restrict cuproptosis efficacy. Herein, an inhalable poly (2-(N-oxide-N,N-diethylamino)ethyl methacrylate) (OPDEA)-coated copper-based metal-organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA (siPDK) is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy, namely OMP. After inhalation, OMP shows highly efficient lung accumulation and long-term retention, ascribing to the OPDEA-mediated pulmonary mucosa penetration. Within tumor cells, OMP is degraded to release Cu2+ under acidic condition, which will be reduced to toxic Cu+ to induce cuproptosis under glutathione (GSH) regulation. Meanwhile, siPDK released from OMP inhibits intracellular glycolysis and adenosine-5'-triphosphate (ATP) production, then blocking the Cu+ efflux protein ATP7B, thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis. Moreover, OMP-mediated cuproptosis triggers immunogenic cell death (ICD) to promote dendritic cells (DCs) maturation and CD8+ T cells infiltration. Notably, OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1 (PD-L1) expression and induces soluble PD-L1 secretion, and thus synergizes with anti-PD-L1 antibodies (aPD-L1) to reprogram immunosuppressive tumor microenvironment, finally yielding improved immunotherapy efficacy. Overall, OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.

Stimulation of PSTPIP1 to trigger proinflammatory responses in asymptomatic SARS-CoV-2 infections.

Background: A hyperinflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection gravely worsens the clinical progression of coronavirus disease 2019 (COVID-19). Although the undesirable effects of inflammasome activation have been correlated to the severity of COVID-19, the mechanisms of this process in the asymptomatic infection and disease progression have not yet been clearly elucidated. Methods: We performed strand-specific RNA sequencing in 39 peripheral blood mononuclear cell (PBMC) samples from asymptomatic individuals（n = 10）, symptomatic patients（n = 16） and healthy donors（n = 13）. Results: Dysregulation of pyrin inflammasomes along with the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene was identified in SARS-COV-2 infection. Notably, the PSTPIP1 expression level showed a significant negative correlation with an adjacent long-noncoding RNA (lncRNA) RP11-797A18.6 in the asymptomatic individuals compared with the healthy controls. In addition, a decline in the nuclear factor kappa B subunit 1 (NFKB1) gene expression was observed in asymptomatic infection, followed by a rise in the mild and moderate disease stages, suggesting that altered NFKB1 expression and associated proinflammatory signals may trigger a disease progression. Conclusions: Overall, our results indicate that PSTPIP1-dependent pyrin inflammasomes-mediated pyroptosis and NF-κB activation might be potential preventive targets for COVID-19 disease development and progression.

Effect of Spatter Behavior on Mechanical Properties and Surface Roughness of Printed Parts during PBF-LM of 316L.

The spatter generated by the interaction between laser and powder during Powder Bed Fusion-Laser Melting (PBF-LM) can significantly affect the quality of printed parts. A high-speed camera is used to observe the dynamic process of spatter's behavior under different layer thickness and laser powers during the printing process, and to analyze the printed samples' surface roughness, microstructure, and mechanical properties. In terms of spatter image processing, employing an optical flow approach to track and quantify the number of spatters efficiently eliminates statistical redundancy and improves statistical correctness. It is found that under the same laser power, the number of spatters produced by the laser scan direction with the gas flow (LSD-W) is more than that by the laser scan direction against the gas flow (LSD-A), and the number of spatters produced increases with the increase of laser power. Analyzing the mechanical properties and surface roughness of the printed samples under different process parameters quantitatively reveals that differences in the spatter amount generated under different process parameters in the PBF-LM process is not the determining factor affecting the difference in tensile strength of printed parts. During LSD-W, the number of spatters generated at laser power of 170 W and layer thickness of 0.03 mm is 87, and the tensile strength of the printed sample is 618 MPa. During LSD-W, the number of spatters generated at laser power of 320 W and layer thickness of 0.05 mm is 211, and the tensile strength of the printed sample is 680 MPa. Instead, spatter generation has a more direct impact on the surface roughness of printed parts. The layer thickness is 0.03 mm, the laser power is 170 W, and (Ra = 2.372 µm) is the surface roughness of the sample. The layer thickness is 0.05 mm, the laser power is 320 W, and (Ra = 8.163 µm) is the surface roughness of the sample.

Current Status and Perspectives of Dual-Atom Catalysts Towards Sustainable Energy Utilization.

The exploration of sustainable energy utilization requires the implementation of advanced electrochemical devices for efficient energy conversion and storage, which are enabled by the usage of cost-effective, high-performance electrocatalysts. Currently, heterogeneous atomically dispersed catalysts are considered as potential candidates for a wide range of applications. Compared to conventional catalysts, atomically dispersed metal atoms in carbon-based catalysts have more unsaturated coordination sites, quantum size effect, and strong metal-support interactions, resulting in exceptional catalytic activity. Of these, dual-atomic catalysts (DACs) have attracted extensive attention due to the additional synergistic effect between two adjacent metal atoms. DACs have the advantages of full active site exposure, high selectivity, theoretical 100% atom utilization, and the ability to break the scaling relationship of adsorption free energy on active sites. In this review, we summarize recent research advancement of DACs, which includes (1) the comprehensive understanding of the synergy between atomic pairs; (2) the synthesis of DACs; (3) characterization methods, especially aberration-corrected scanning transmission electron microscopy and synchrotron spectroscopy; and (4) electrochemical energy-related applications. The last part focuses on great potential for the electrochemical catalysis of energy-related small molecules, such as oxygen reduction reaction, CO2 reduction reaction, hydrogen evolution reaction, and N2 reduction reaction. The future research challenges and opportunities are also raised in prospective section.

The promoting effects of pyriproxyfen on autophagy and apoptosis in silk glands of non-target insect silkworm, Bombyx mori.

Pyriproxyfen is a juvenile hormone analogue. The physiological effects of its low-concentration drift during the process of controlling agricultural and forestry pests on non-target organisms in the ecological environment are unpredictable, especially the effects on organs that play a key role in biological function are worthy of attention. The silk gland is an important organ for silk-secreting insects. Herein, we studied the effects of trace pyriproxyfen on autophagy and apoptosis of the silk gland in the lepidopteran model insect, Bombyx mori (silkworm). After treating fifth instar silkworm larvae with pyriproxyfen for 24 h, we found significant shrinkage, vacuolization, and fragmentation in the posterior silk gland (PSG). In addition, the results of autophagy-related genes of ATG8 and TUNEL assay also demonstrated that autophagy and apoptosis in the PSG of the silkworm was induced by pyriproxyfen. RNA-Seq results showed that pyriproxyfen treatment resulted in the activation of juvenile hormone signaling pathway genes and inhibition of 20-hydroxyecdysone (20E) signaling pathway genes. Among the 1808 significantly differentially expressed genes, 796 were upregulated and 1012 were downregulated. Among them, 30 genes were identified for autophagy-related signaling pathways, such as NOD-like receptor signaling pathway and mTOR signaling pathway, and 30 genes were identified for apoptosis-related signaling pathways, such as P53 signaling pathway and TNF signaling pathway. Further qRT-PCR and in vitro gland culture studies showed that the autophagy-related genes Atg5, Atg6, Atg12, Atg16 and the apoptosis-related genes Aif, Dronc, Dredd, and Caspase1 were responsive to the treatment of pyriproxyfen, with transcription levels up-regulated from 24 to 72 h. In addition, ATG5, ATG6, and Dronc genes had a more direct response to pyriproxyfen treatment. These results suggested that pyriproxyfen treatment could disrupt the hormone regulation in silkworms, promoting autophagy and apoptosis in the PSG. This study provides more evidence for the research on the damage of juvenile hormone analogues to non-target organisms or organs in the environment, and provides reference information for the scientific and rational use of juvenile hormone pesticides.

Epidemiology, genetic characteristics, and association with meteorological factors of human metapneumovirus infection in children in southern China: A 10-year retrospective study.

OBJECTIVES: This study aimed to determine the epidemiological and genetic features of human metapneumovirus (HMPV) infection in children in southern China, and the effect of meteorological factors on infection. METHODS: 14,817 children (≤14 years) with acute respiratory tract infections from 2010 to 2019 were examined for HMPV and other respiratory viruses by real-time quantitative polymerase chain reaction. Full-length F gene of 54 positive samples were sequenced and subjected to phylogenetic analysis. The correlation between the HMPV-positive rate and meteorological factors was analyzed by linear regression analysis. RESULTS: HMPV was detected in 524 (3.5%) children, who were mostly younger than 1 year. The seasonal peak of HMPV prevalence mainly occurred in spring. Respiratory syncytial virus was the most common virus coinfected with HMPV (5.3%). Phylogenetic analysis revealed that the sequenced HMPV strains belonged to four sublineages, including A2b (1.9%), A2c (31.5%), B1 (50.0%), and B2 (16.7%). After adjusting for all meteorological factors, sunshine duration was inversely correlated with the HMPV-positive rate. CONCLUSION: HMPV is an important respiratory pathogen that causes acute respiratory tract infections in children in southern China, particularly in children ≤5 years old. The prevalence peak of HMPV in this area appeared in spring, and the predominant subtype was B1. Meteorological factors, especially long sunshine duration, might decrease the HMPV prevalence.

Protocol for PPP1R15A-inhibited mouse model establishment with subcutaneous B16F1 tumor and single-cell analysis.

Here, we present a protocol for exploring the effects of PPP1R15A inhibitor, Sephin1, on antitumor immunity of B16F1 subcutaneous tumor in mice. We describe steps for constructing single-cell transcriptome and TCR libraries, sequencing, and using sequencing data for the integration of expression and TCR data. We then detail procedures for gene differentiation, regulon and cell-cell communication analysis, and validation of single-cell analysis results. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

The instantly blocking-based fluorescent immunochromatographic assay for the detection of SARS-CoV-2 neutralizing antibody.

Introduction: At present, there is an urgent need for the rapid and accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs) to evaluate the ability of the human body to resist coronavirus disease 2019 (COVID-19) after infection or vaccination. The current gold standard for neutralizing antibody detection is the conventional virus neutralization test (cVNT), which requires live pathogens and biosafety level-3 (BSL-3) laboratories, making it difficult for this method to meet the requirements of large-scale routine detection. Therefore, this study established a time-resolved fluorescence-blocking lateral flow immunochromatographic assay (TRF-BLFIA) that enables accurate, rapid quantification of NAbs in subjects. Methods: This assay utilizes the characteristic that SARS-CoV-2 neutralizing antibody can specifically block the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2) to rapidly detect the content of neutralizing antibody in COVID-19-infected patients and vaccine recipients. Results: When 356 samples of vaccine recipients were measured, the coincidence rate between this method and cVNT was 88.76%, which was higher than the coincidence rate of 76.97% between cVNT and a conventional chemiluminescence immunoassay detecting overall binding anti-Spike-IgG. More importantly, this assay does not need to be carried out in BSL-2 or 3 laboratories. Discussion: Therefore, this product can detect NAbs in COVID-19 patients and provide a reference for the prognosis and outcome of patients. Simultaneously, it can also be applied to large-scale detection to better meet the needs of neutralizing antibody detection after vaccination, making it an effective tool to evaluate the immunoprotective effect of COVID-19 vaccines.

Longitudinal change trend of the TCR repertoire reveals the immune response intensity of the inactivated COVID-19 vaccine.

Evidence concerning the individual differences in neutralizing antibody responses after receiving the COVID-19 vaccine remains lacking. In this study, we collected the serum and Peripheral blood mononuclear cells(PBMC) of 16 subjects who had never suffered from COVID-19 before during the course of two vaccine doses. Microneutralization assay is used to determine the immune response intensity of vaccine subjects. we revealed the change trend of TCR diversity using T cell receptor (TCR) sequencing. Then, we analyzed the correlation between HLA class II allele frequencies and the intensity of immune response. Finally, we identified several CDR3 sequences related to the intensity of the immune response. We analyzed the differences in D50 (DD50) between different time points, and found that there were two patterns in the change trend of TCR diversity, and the increased diversity group has stronger immune response. The inactivated vaccine is different from the mRNA vaccine against the spike protein, resulting in differences in TCR repertoire response patterns and antibody responses, which are related to HLA-DRB1 * 09:01. The presence of specific CDR3 sequences in the increased diversity group, rather than gene usage of the VJ gene, determines the intensity and persistence of neutralizing antibody titers. Finally, We identified the different response patterns of the human TCR repertoire to inactivated vaccines. The pattern with increased diversity is more likely to appear strong and more lasting immune response.

A Comparative Study of CCM and CCS Membrane Electrode Assemblies for High-Temperature Proton Exchange Membrane Fuel Cells with a CsH5(PO4)2-Doped Polybenzimidazole Membrane.

Membrane electrode assemblies (MEAs) are critical components in influencing the electrochemical performance of high-temperature proton exchange membrane fuel cells (HT-PEMFCs). MEA manufacturing processes are mainly divided into the catalyst-coated membrane (CCM) and the catalyst-coated substrate (CCS) methods. For conventional HT-PEMFCs based on phosphoric acid-doped polybenzimidazole (PBI) membranes, the wetting surface and extreme swelling of the PA-doped PBI membranes make the CCM method difficult to apply to the fabrication of MEAs. In this study, by taking advantage of the dry surface and low swelling of a CsH5(PO4)2-doped PBI membrane, an MEA fabricated by the CCM method was compared with an MEA made by the CCS method. Under each temperature condition, the peak power density of the CCM-MEA was higher than that of the CCS-MEA. Furthermore, under humidified gas conditions, an enhancement in the peak power densities was observed for both MEAs, which was attributed to the increase in the conductivity of the electrolyte membrane. The CCM-MEA exhibited a peak power density of 647 mW cm-2 at 200 °C, which was ~16% higher than that of the CCS-MEA. Electrochemical impedance spectroscopy results showed that the CCM-MEA had lower ohmic resistance, which implied that it had better contact between the membrane and catalyst layer.

Effects of artificial diet rearing during all instars on silk secretion and gene transcription in Bombyx mori (Lepidoptera: Bombycidae).

Silkworms (Bombyx mori) reared on artificial diets during all instars have the advantages of simplicity and efficiency, year-round production, and reduced risk of poisoning. However, low silk yield remains a challenge, limiting its industrial application. To address this issue, the spinning behavior, nutrient absorption, and transcriptomics of silkworms were investigated. Compared with silkworms reared on mulberry leaves during all instars, those fed with artificial diets showed significantly lower cocoon weight, cocoon shell weight, cocoon shell rate, and silk gland tissue somatic index at the end of the fifth instar (P < 0.01). The spinning duration and crawling distance of silkworms reared on artificial diets were also significantly lower than those reared on mulberry leaves (P < 0.01). Regarding nutrient absorption, the dietary efficiency indexes of silkworms fed with artificial diets were significantly lower than those fed with mulberry leaves, except for the efficiency conversion of digesta to cocoon (P < 0.01). Further RNA-Seq analysis revealed 386 differentially transcribed genes between the 2 groups, with 242 upregulated and 144 downregulated genes. GO enrichment analysis showed that differential transcriptional genes were mainly enriched in organic acid metabolism, oxidation-reduction, and drug catabolism. KEGG enrichment analysis showed that differential transcriptional genes were mainly enriched in genetic information processing and metabolism pathways. Our findings provide new insights into the silk secretion and can serve as a reference for future research and application of silkworms fed with artificial diets.

Treated wastewater and weak removal mechanisms enhance nitrate pollution in metropolitan rivers.

The focus of urban water environment renovation has shifted to high nitrate (NO3-) load. Nitrate input and nitrogen conversion are responsible for the continuous increase in nitrate levels in urban rivers. This study utilized nitrate stable isotopes (δ15N-NO3- and δ18O-NO3-) to investigate NO3- sources and transformation processes in Suzhou Creek, located in Shanghai. The results demonstrated that NO3- was the most common form of dissolved inorganic nitrogen (DIN), accounting for 66 ± 14% of total DIN with a mean value of 1.86 ± 0.85 mg L-1. The δ15N-NO3- and δ18O-NO3- values ranged from 5.72 to 12.42‰ (mean value: 8.38 ± 1.54‰) and -5.01 to 10.39‰ (mean value: 0.58 ± 1.76‰), respectively. Based on isotopic evidence, the river received a significant amount of nitrate through direct exogenous input and sewage ammonium nitrification, while nitrate removal (denitrification) was insignificant, resulting in nitrate accumulation. Analysis using the MixSIAR model revealed that treated wastewater (68.3 ± 9.7%), soil nitrogen (15.7 ± 4.8%) and nitrogen fertilizer (15.5 ± 4.9%) were the main sources of NO3- in rivers. Despite the fact that Shanghai's urban domestic sewage recovery rate has reached 92%, reducing nitrate concentrations in treated wastewater is crucial for addressing nitrogen pollution in urban rivers. Additional efforts are needed to upgrade urban sewage treatment during low flow periods and/or in the main stream, and to control non-point sources of nitrate, such as soil nitrogen and nitrogen fertilizer, during high flow periods and/or tributaries. This research provides insights into NO3- sources and transformations, and serves as a scientific basis for controlling NO3- in urban rivers.

Host factor DUSP5 potently inhibits dengue virus infection by modulating cytoskeleton rearrangement.

Cytoskeleton has been reported to play an essential role in facilitating the viral life cycle. However, whether the host can exert its antiviral effects by modulating the cytoskeleton is not fully understood. In this study, we identified that host factor DUSP5 was upregulated after dengue virus (DENV) infection. In addition, we demonstrated that overexpression of DUSP5 remarkably inhibited DENV replication. Conversely, the depletion of DUSP5 led to an increase in viral replication. Moreover, DUSP5 was found to restrain viral entry into host cells by suppressing F-actin rearrangement via negatively regulating the ERK-MLCK-Myosin IIB signaling axis. Depletion of dephosphorylase activity of DUSP5 abolished its above inhibitory effects. Furthermore, we also revealed that DUSP5 exhibited broad-spectrum antiviral effects against DENV and Zika virus. Taken together, our studies identified DUSP5 as a key host defense factor against viral infection and uncovered an intriguing mechanism by which the host exerts its antiviral effects through targeting cytoskeleton rearrangement.

The contribution of wetland plant litter to soil carbon pool: Decomposition rates and priming effects.

Plant litter input is an important driver of soil/sediment organic carbon (SOC) turnover. A large number of studies have targeted litter-derived C input tracing at a global level. However, little is known about how litter carbon (C) input via various plant tissues affects SOC accumulation and mineralization. Here, we conducted laboratory incubation to investigate the effects of leaf litter and stem litter input on SOC dynamics using the natural 13C isotope technique. A 122-day laboratory incubation period showed that litter input facilitated SOC accumulation. Leaf and stem litter inputs increased soil total organic carbon content by 37.6% and 15.5%, respectively. Leaf litter input had a higher contribution to SOC accumulation than stem litter input. Throughout the incubation period, the δ13C values of stem litter and leaf litter increased by 1.5‰ and 3.3‰, respectively, while δ13CO2 derived from stem litter and δ13CO2 derived from leaf litter decreased by 4.2‰ and 6.1‰, respectively, suggesting that the magnitude of δ13C in litter and δ13CO2 shifts varied, depending on litter tissues. The cumulative CO2-C emissions of leaf litter input treatments were 27.56%-42.47% higher than those of the stem litter input treatments, and thus leaf litter input promoted SOC mineralization more than stem litter input. Moreover, the proportion of increased CO2-C emissions to cumulative CO2-C emissions (57.18%-92.12%) was greater than the proportion of litter C input to total C (18.7%-36.8%), indicating that litter input could stimulate native SOC mineralization, which offsets litter-derived C in the soil. Overall, litter input caused a net increase in SOC accumulation, but it also accelerated the loss of native SOC. These findings provide a reliable basis for assessing SOC stability and net C sink capacity in wetlands.

H-CNN combined with tissue Raman spectroscopy for cervical cancer detection.

Cervical cancer is one of the most common cancers with a long latent period and slow onset process. Early and accurate identification of the stage of cervical cancer can significantly improve the cure rate and patient survival time. In this study, we collected 699 Raman spectral data of tissue sections from 233 different patients. We analyzed and compared the characteristics and differences of the mean Raman spectra of the seven tissues and pointed out the main differences in the biochemical composition of the seven tissues. In this study, 1D hierarchical convolutional neural network (H-CNN) is proposed by integrating the prior knowledge of hierarchical classification relations with the research of deep learning in Raman spectroscopy. H-CNN is based on CNN and is added with three network branches. Hierarchical classification is performed from coarse to fine for tissue samples of cervicitis, Low-grade Squamous Cell Carcinoma, High-grade Squamous Cell Carcinoma, Well Differentiated Squamous Cell Carcinoma, Moderately Differentiated Squamous Cell Carcinoma, Poorly Differentiated Squamous Cell Carcinoma and cervical adenocarcinoma. To evaluate the recognition performance of H-CNN, we compared it with traditional methods such as Bayesian classifier (NB), decision tree classifier (DT), support vector machine classifier (SVM) and CNN. The experimental results show that H-CNN can accurately identify different classes of tissue sections and has apparent advantages in several aspects such as recognition accuracy, stability and sensitivity compared with the other four traditional recognition methods. The classification Macro-Accuracy of H-CNN can reach 94.91%, Macro-Recall can reach 95.31%, Macro-F1 can reach 95.23%, and Macro-AUC can reach 97.35%. The hierarchical classification method proposed in this study can diagnose patients more accurately. This could lay the foundation for further research on Raman spectroscopy as a clinical diagnostic method for cervical cancer.

Single-cell RNA sequencing reveals the suppressive effect of PPP1R15A inhibitor Sephin1 in antitumor immunity.

Protein phosphatase 1 regulatory subunit 15A (PPP1R15A) is an important factor in the integrated stress response (ISR) in mammals and may play a crucial role in tumorigenesis. In our studies, we found an inhibitor of PPP1R15A, Sephin1, plays a protumorigenic role in mouse tumor models. By analyzing the single-cell transcriptome data of the mouse tumor models, we found that in C57BL/6 mice, Sephin1 treatment could lead to higher levels of ISR activity and lower levels of antitumor immune activities. Specifically, Sephin1 treatment caused reductions in antitumor immune cell types and lower expression levels of cytotoxicity-related genes. In addition, T cell receptor (TCR) repertoire analysis demonstrated that the clonal expansion of tumor-specific T cells was inhibited by Sephin1. A special TCR + macrophage subtype in tumor was identified to be significantly depleted upon Sephin1 treatment, implying its key antitumor role. These results suggest that PPP1R15A has the potential to be an effective target for tumor therapy.

Targeting ferroptosis: Paving new roads for drug design and discovery.

Ferroptosis, first proposed in 2012, is an iron-dependent form of regulated cell death characterized by excessive polyunsaturated fatty acid oxidation. In the past decade, researchers have revealed the formation and mechanisms of ferroptosis. Cancer drug resistance can be reversed by ferroptosis induction, and inhibiting ferroptosis has been shown to block certain disease processes. As a result, several ferroptosis-targeting drugs have been developed. However, the first-generation ferroptosis-targeting agents remain hampered from clinical use, mainly due to poor selectivity and pharmacokinetics. The discoveries of FSP1, GCH1, and other potential ferroptosis-regulating pathways independent of Xc--GSH-GPX4 provide novel targets for drug design. Recently, protein-targeted degradation and antibody-drug conjugate strategy show promise in future drug design. With novel targets, further optimizations, and new technologies, the next-generation ferroptosis-targeting agents show a promising future with improved selectivity and efficacy. In this review, we summarize mechanisms, target types, drug design, and novel technologies of ferroptosis, aiming to pave the way for future drug design and discovery in the next decade.

Development of receptor binding domain-based double-antigen sandwich lateral flow immunoassay for the detection and evaluation of SARS-CoV-2 neutralizing antibody in clinical sera samples compared with the conventional virus neutralization test.

Vaccination is an effective strategy to fight COVID-19. However, the effectiveness of the vaccine varies among different populations in varying immune effects. Neutralizing antibody (NAb) level is an important indicator to evaluate the protective effect of immune response after vaccination. Lateral flow immunoassay (LFIA) is a rapid, safe and sensitivity detection method, which has great potential in the detection of SARS-CoV-2 NAb. In this study, a fluorescent beads-based lateral flow immunoassay (FBs-LFIA) and a latex beads-based LFIA (LBs-LFIA) using double antigen sandwich (DAS) strategy were established to detect NAbs in the serum of vaccinated people. The limit of detection (LoD) of the FBs-LFIA was 1.13 ng mL- 1 and the LBs-LFIA was 7.11 ng mL- 1. The two LFIAs were no cross-reactive with sera infected by other pathogenic bacteria. Furthermore, the two LFIAs showed a good performance in testing clinical samples. The sensitivity of FBs-LFIA and LBs-LFIA were 97.44% (95%CI: 93.15%-99.18%) and 98.29% (95%CI: 95.84%-99.37%), and the specificity were 98.28% (95%CI: 95.37%-99.45%) and 97.70% (95%CI: 94.82%-99.06%) compared with the conventional virus neutralization test (cVNT), respectively. Notably, the LBs-LFIA was also suitable for whole blood sample, requiring only 3 µL of whole blood, which provided the possibility to detect NAbs at home. To sum up, the two LFIAs based on double antigen sandwich established by us can rapidly, safely, sensitively and accurately detect SARS-CoV-2 NAb in human serum.

Toxicological effects of trace amounts of pyriproxyfen on the midgut of non-target insect silkworm.

Pyriproxyfen is an insect growth regulator that is widely used in public health and pest control in agriculture. Our previous studies have shown that trace amounts of pyriproxyfen in the environment can cause serious toxic effects in the non-target insect silkworm, including failing to pupate, metamorphose and spin cocoons. However, it is unknown why pyriproxyfen not only has no lethal effects on fifth instar larvae but also tend to increase their body weight. The midgut is the main digestive organs of the silkworm, our results showed that the residual of pyriproxyfen in the silkworm at 24 h after 1 × 10-4 mg/L pyriproxyfen treatment caused severe damage to the midgut microvilli, goblet cells, and nuclei of the silkworm, but body weight and digestibility of the larval were both increased. In addition, pyriproxyfen significantly (p < 0.05) increased the activities of digestive enzymes (α-amylase, trehalase, trypsin and lipase) in the midgut of silkworm. However, it caused down-regulation of ecdysone synthesis-related genes at the end of the fifth instar silkworm, decreased ecdysone titer, and prolonged larval instar. At the same time, pyriproxyfen also activated transcription of detoxification enzymes-related genes such as the cytochrome P450 enzyme genes Cyp9a22 and Cyp15C1, the carboxylesterase genes CarE-8 and CarE-11, and the glutathione S-transferase gene GSTo2. This study elucidated a novel toxicological effect of pyriproxyfen to insects, which not only expands the understanding of the effects of juvenile hormone pesticides on lepidopteran insects but also provides a reference for exploring the ecological security of non-target organisms.