Antibody-mediated spike activation promotes cell-cell transmission of SARS-CoV-2.

The COVID pandemic fueled by emerging SARS-CoV-2 new variants of concern remains a major global health concern, and the constantly emerging mutations present challenges to current therapeutics. The spike glycoprotein is not only essential for the initial viral entry, but is also responsible for the transmission of SARS-CoV-2 components via syncytia formation. Spike-mediated cell-cell transmission is strongly resistant to extracellular therapeutic and convalescent antibodies via an unknown mechanism. Here, we describe the antibody-mediated spike activation and syncytia formation on cells displaying the viral spike. We found that soluble antibodies against receptor binding motif (RBM) are capable of inducing the proteolytic processing of spike at both the S1/S2 and S2' cleavage sites, hence triggering ACE2-independent cell-cell fusion. Mechanistically, antibody-induced cell-cell fusion requires the shedding of S1 and exposure of the fusion peptide at the cell surface. By inhibiting S1/S2 proteolysis, we demonstrated that cell-cell fusion mediated by spike can be re-sensitized towards antibody neutralization in vitro. Lastly, we showed that cytopathic effect mediated by authentic SARS-CoV-2 infection remain unaffected by the addition of extracellular neutralization antibodies. Hence, these results unveil a novel mode of antibody evasion and provide insights for antibody selection and drug design strategies targeting the SARS-CoV-2 infected cells.

Lenvatinib in hepatocellular carcinoma: Resistance mechanisms and strategies for improved efficacy.

Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes of cancer-related deaths worldwide, approximately 70% of patients with HCC exhibit advanced disease at diagnosis, limiting the potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib for first-line targeted therapy, has become a key treatment. Unfortunately, despite some progress, the prognosis for advanced HCC remains poor because of drug resistance development. However, the molecular mechanisms underlying lenvatinib resistance and ways to relief drug resistance in HCC are largely unknown and lack of systematic summary; thus, this review not only aims to explore factors contributing to lenvatinib resistance in HCC, but more importantly, summary potential methods to conquer or mitigate the resistance. The results suggest that abnormal activation of pathways, drug transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, and other mechanisms are involved in the development of lenvatinib resistance in HCC and subsequent HCC progression. To improve the therapeutic outcomes of lenvatinib, inhibiting acquired resistance, combined therapies, and nano-delivery carriers may be possible approaches.

Tetraniliprole risk assessment: Unveiling a hidden threat for managing a generalist herbivore.

Insecticide resistance poses a significant challenge in managing generalist herbivores such as the tobacco cutworm (TCW), Spodoptera litura. This study investigates the potential risks associated with using the novel diamide insecticide tetraniliprole to control TCW. A tetraniliprole-resistant strain was developed through twelve generations of laboratory selection, indicating an intermediate risk of resistance development. Field monitoring in China revealed a significant incidence of resistance, particularly in the Nanchang (NC) population (>100-fold). Tetraniliprole showed moderate to high cross-resistance to multiple insecticides and was autosomally inherited with incomplete dominance, controlled by multiple genes, some of which belong to the cytochrome P450 family associated with enhanced detoxification. Life table studies indicated transgenerational hormesis, stimulating TCW female fecundity and increasing population net reproduction rates (R0). These findings suggest a potential for pest resurgence under tetraniliprole use. The integrated risk assessment provides a basis for the sustainable management of TCW using tetraniliprole.

Sulfite Poses a Risk of Hexavalent Chromium Rebound in Vadose Zone: A Challenge of the Stability of CrxFe1-x(OH)3.

Cr(VI) rebound is the primary risk associated with the reduction remediation of Cr(VI)-contaminated soil. The potential impact of sulfites, which can be produced by microbial activities or originate from sulfur-containing remediation agents, on the Cr(VI) rebound in the vadose zone has been overlooked. When sulfites are present, the stability of CrxFe1-x(OH)3 is compromised and significantly inferior to that of Cr(OH)3, as demonstrated in this paper. First, Fe acts as a catalyst for the conversion of adsorbed sulfite to SO4·-, which subsequently triggers the oxidation of Cr(III) and results in the rebound of Cr(VI). The heterogeneous catalysis by Fe on the surface of CrxFe1-x(OH)3 plays a predominant role, contributing to 78% of the actual oxidation of Cr(III) among all employed catalytic processes. The presence of ambient Cl- can exacerbate the rebound effect of Cr(VI) by promoting the generation of HOCl. Furthermore, a portion of released Cr(VI) was reduced to Cr(III) by dissolved sulfite in the presence of dissolved Fe as a catalyst, thereby increasing the dissolution and migration risk associated with CrxFe1-x(OH)3. Hence, the presence of sulfites results in a significant increase in the Cr(VI) rebound and Cr(III) release from CrxFe1-x(OH)3. This challenges the conventional understanding of the stability of CrxFe1-x(OH)3.

Comparison of outcomes of self-expanding versus balloon-expandable valves for transcatheter aortic valve replacement: a meta-analysis of randomized and propensity-matched studies.

BACKGROUND: The postoperative outcomes of transcatheter aortic valve replacement (TAVR) with the new generation of self-expanding valves (SEV) and balloon-expandable valves (BEV) remain uncertain. METHODS: We conducted a meta-analysis based on randomized controlled trials (RCTs) and propensity score-matched (PSM) studies to evaluate the performance of the new generation TAVR devices, with a focus on Edwards SAPIEN 3/Ultra BEV, Medtronic Evolut R/PRO SEV, and Boston ACURATE neo SEV. Our primary endpoints were mortality and complications at both 30 days and one year post-operation. RESULTS: A total of 4 RCTs and 14 PSM studies were included. Our findings showed no significant difference between SEV and BEV regarding 30-day and 1-year mortality rates. ACURATE SEV required less permanent pacemaker implantation (PPI) at 30-day as compared to SAPIEN BEV, while Evolut SEV required a higher rate of PPI than SAPIEN BEV. The incidence of stroke, major or life-threatening bleeding (MLTB), major vascular complications (MVC), coronary artery obstruction (CAO) and acute kidney injury (AKI) did not differ significantly between the two groups. SEV had a larger effective orifice area (EOA) and lower mean transvalvular gradients (MPG) compared to BEV. However, there was an increased risk of paravalvular leakage (PVL) associated with SEV. CONCLUSIONS: In terms of 30-day mortality, stroke, bleeding, MVC, AKI, CAO, and one-year mortality, there was comparability between the two valve types following TAVR. SEV was associated with better hemodynamic outcomes, except for a higher incidence of PVL. Compared to SAPIEN BEV, ACURATE SEV had a lower risk of PPI at 30 days, while Evolut SEV was associated with a higher risk of PPI. These findings underscore the importance of personalized valve selection.

Value of Group Intervention on Prognosis of Quality of Life in Epileptic Patients Treated With Sodium Valproate and Lamotrigine.

Objective: The study intended to analyze the effects of a group nursing intervention on quality of life (QoL) of patients with epilepsy (EP) after treatment with sodium valproate combined with lamotrigine. Design: The research team performed a randomized controlled trial. Setting: The study took place in the Department of Neurology at the Affiliated Brain Hospital of Nanjing Medical University in Nanjing, Jiangsu, China. Participants: Participants were 170 EP patients at the hospital between January 2019 and August 2022. Intervention: The research team randomly assigned participants to one of two groups: (1) 85 to the intervention group, and they took part in a group nursing intervention; and (2) 85 to the control group (n = 85) and they received conventional care. Outcome Measures: To evaluate participants' risk of suicide, psychological state, and QOL, participants completed at baseline and postintervention: (1) the Mini-International Neuropsychiatric Interview (MINI), (2) the Self-Rating Scale for Psychiatric Symptoms 90 (SCL-90), and (3) the Short Form Health Survey (SF-36) To assess participants' management ability, self-efficacy, and social functioning, they also completed at those time points: (1) the EP Self-Management Behavior Scale (ESMS), (2) the General Self-Efficacy Scale (GSES), and (3) the Social Functioning Deficit Screening Scale (SDSS). Finally, the research also investigated participants' satisfaction with the nursing care. Results: The intervention group's risk of suicide decreased between baseline and postintervention, and its SCL-90 scores were significantly lower and SF-36 scores were significantly higher than those of the control group (both P < .05). In addition, the intervention group's ESMS and GSES scores were also significantly higher than those of the control group, while its SDSS score was significantly lower than that of the control group (all P < .05). Finally, the intervention group's nursing satisfaction was also significantly higher than that of the control group (P < .05). Conclusions: The group nursing intervention can effectively improve the psychological states of EP patients, reduce their pain, improve their self-management skills and QoL, provide them with better and more detailed nursing care, and facilitate the treatment and recovery of EP patients, which can have a significant value in clinical practice.

Baseline Susceptibility, Cross-Resistance, and Sublethal Effects of Broflanilide, a Novel Meta-Diamide Pesticide, in Spodoptera litura.

Spodoptera litura is a damaging and notorious insect pest of agricultural crops that has developed resistance to various insecticides. Broflanilide is a novel pesticide with a unique mode of action that displays high efficiency against lepidopterous larvae. We here determined the baseline susceptibility of a laboratory strain of S. litura to broflanilide and 10 other popular insecticides. Furthermore, we measured susceptibility and cross-resistance using three common insecticides in 11 field-collected S. litura populations. Broflanilide caused the highest toxicity among all tested insecticides, with the laboratory strain and all field-collected populations showing high susceptibility. Moreover, no cross-resistance was detected between broflanilide and the other tested insecticides. We subsequently evaluated the sublethal effects of broflanilide and found that treatment with the 25% lethal concentration (LC25) prolonged the development duration in the larvae, reduced the pupation rate and pupae weight, and decreased egg hatchability. Finally, the activities of three detoxifying enzymes were measured in S. litura after treatment with the LC25 dose. The results suggested that enhanced cytochrome P450 monooxygenase (P450) activity could be involved in broflanilide detoxification. Overall, these findings demonstrate the strong toxicity and significant sublethal effects of broflanilide in S. litura and suggest that increased P450 activity may be associated with broflanilide detoxification.

Profiles of Intolerance of Uncertainty Among 108,540 Adolescents: Associations with Sociodemographic Variables and Mental Health.

Intolerance of uncertainty (IU) is widely considered a transdiagnostic risk and maintaining factor for psychiatric disorders. However, little is known about the overall nature and profile of IU among adolescents. This study aims to investigate the profiles of IU among Chinese adolescents and explore their associations with sociodemographic characteristics and mental health problems. A sample of 108,540 adolescents provided data on IU, sociodemographic characteristics, and mental health via an online platform. Latent profile analysis revealed three profiles: Low IU, Medium IU, and High IU. Girls, older adolescents, and those with specific sociodemographics were more likely to belong to the "High IU" profile. Furthermore, the "High IU" profile was associated with the highest risk of several mental health problems. These findings provided valuable information for early prevention and intervention strategies targeting IU and highlighted the importance of IU-based interventions for mental health among adolescents.

Single-molecule long-read sequencing reveals the chromatin basis of gene expression.

Genome-wide chromatin accessibility and nucleosome occupancy profiles have been widely investigated, while the long-range dynamics remain poorly studied at the single-cell level. Here, we present a new experimental approach, methyltransferase treatment followed by single-molecule long-read sequencing (MeSMLR-seq), for long-range mapping of nucleosomes and chromatin accessibility at single DNA molecules and thus achieve comprehensive-coverage characterization of the corresponding heterogeneity. MeSMLR-seq offers direct measurements of both nucleosome-occupied and nucleosome-evicted regions on a single DNA molecule, which is challenging for many existing methods. We applied MeSMLR-seq to haploid yeast, where single DNA molecules represent single cells, and thus we could investigate the combinatorics of many (up to 356) nucleosomes at long range in single cells. We illustrated the differential organization principles of nucleosomes surrounding the transcription start site for silent and actively transcribed genes, at the single-cell level and in the long-range scale. The heterogeneous patterns of chromatin status spanning multiple genes were phased. Together with single-cell RNA-seq data, we quantitatively revealed how chromatin accessibility correlated with gene transcription positively in a highly heterogeneous scenario. Moreover, we quantified the openness of promoters and investigated the coupled chromatin changes of adjacent genes at single DNA molecules during transcription reprogramming. In addition, we revealed the coupled changes of chromatin accessibility for two neighboring glucose transporter genes in response to changes in glucose concentration.

Pd-Catalyzed Aerobic Intermolecular 1,2-Diamination of Conjugated Dienes: Regio- and Chemoselective Synthesis of Piperazines and 2-Piperazinones.

Dinitrogen heterocycles are among the most important molecular structures, and the synthesis of these types of structures through intermolecular 1,2-diamination of olefins is a direct and efficient method. However, the types of nitrogen sources are mostly derived from ureas or arylamines, and nitrogen sources from aliphatic amines are still limited due to their distinct electronic and steric effects. Herein, we report a palladium-catalyzed aerobic intermolecular 1,2-diamination of conjugated dienes, using ethanediamine and α-amino amide derivatives as nitrogen sources respectively, for the synthesis of piperazines and 2-piperazinones in good yields (up to 95 %) and with high regio- and chemoselectivities.

Oil contamination drives the transformation of soil microbial communities: Co-occurrence pattern, metabolic enzymes and culturable hydrocarbon-degrading bacteria.

The land-based oil extraction activity has led to serious pollution of the soil. While microbes may play an important role in the remediation of contaminated soils, ecological effects of oil pollution on soil microbial relationships remain poorly understood. Here, typical contaminated soils and undisturbed soils from seven oilfields of China were investigated in terms of their physicochemical characteristics, indigenous microbial assemblages, bacterial co-occurrence patterns, and metabolic enzymes. Network visualization based on k-core decomposition illustrated that oil pollution reduced correlations between co-existing bacteria. The core genera were altered to those related with oil metabolism (Pseudarthrobacter, Alcanivorax, Sphingomonas, Chromohalobacter and Nocardioides). Under oil pollution pressure, the indigenous bacteria Gammaproteobacteria was domesticated as biomarker and the enzyme expression associated with the metabolism of toxic benzene, toluene, ethylbenzene, xylene and polycyclic aromatic hydrocarbons was enhanced. Functional pathways of xenobiotics biodegradation were also stimulated under oil contamination. Finally, twelve culturable hydrocarbon-degrading microbes were isolated from these polluted soils and classified into Stenotrophomonas, Delftia, Pseudomonas and Bacillus. These results show that the soil microbial communities are transformed under oil pollution stress, and also provide useful information for future bioremediation processes.

Sparse Adaptive Iteratively-Weighted Thresholding Algorithm (SAITA) for Lp-Regularization Using the Multiple Sub-Dictionary Representation.

Both L1/2 and L2/3 are two typical non-convex regularizations of Lp (0

Remediation of hexavalent chromium contamination in chromite ore processing residue by sodium dithionite and sodium phosphate addition and its mechanism.

Large amounts of chromite ore processing residue (COPR) wastes have been deposited in many countries worldwide, generating significant contamination issues from the highly mobile and toxic hexavalent chromium species (Cr(VI)). In this study, sodium dithionite (Na2S2O4) was used to reduce Cr(VI) to Cr(III) in COPR containing high available Fe, and then sodium phosphate (Na3PO4) was utilized to further immobilize Cr(III), via a two-step procedure (TSP). Remediation and immobilization processes and mechanisms were systematically investigated using batch experiments, sequential extraction studies, X-ray diffraction (XRD) and X-ray Photoelectron Spectroscopy (XPS). Results showed that Na2S2O4 effectively reduced Cr(VI) to Cr(III), catalyzed by Fe(III). The subsequent addition of Na3PO4 further immobilized Cr(III) by the formation of crystalline CrPO4·6H2O. However, addition of Na3PO4 simultaneously with Na2S2O4 (via a one-step procedure, OSP) impeded Cr(VI) reduction due to the competitive reaction of Na3PO4 and Na2S2O4 with Fe(III). Thus, the remediation efficiency of the TSP was much higher than the corresponding OSP. Using an optimal dosage in the two-step procedure (Na2S2O4 at a dosage of 12× the stoichiometric requirement for 15 days, and then Na3PO4 in a molar ratio (i.e. Na3PO4: initial Cr(VI)) of 4:1 for another 15 days), the total dissolved Cr in the leachate determined via Toxicity Characteristic Leaching Procedure (TCLP Cr) testing of our samples was reduced to 3.8 mg/L (from an initial TCLP Cr of 112.2 mg/L, i.e. at >96% efficiency).

Streptococcus pneumoniae and Haemophilus influenzae type b carriage in Chinese children aged 12-18 months in Shanghai, China: a cross-sectional study.

BACKGROUND: The bacteria Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) are leading causes of childhood pneumonia and meningitis and are major contributors to worldwide mortality in children younger than 5 years of age. Asymptomatic nasopharyngeal carriage of pneumococcus and Hib was determined for healthy children in Shanghai in 2009. METHODS: Children from 5 immunization clinics were enrolled in this study. Specimens from the nasopharynx were collected and cultured in Columbia and chocolate agar to identify pneumococcal and Hib carriage. Pneumococcal specimens were serotyped with the Neufeld test, and antibiotic resistance for pneumococcal and Hib specimens used the E-test method. Significance of risk factors for carriage was assessed through chi-square tests. RESULTS: Among 614 children, 16.6% had pneumococcal carriage and 8.0% Hib carriage. The predominant serotype of pneumococcus that was isolated was 19 F (52.9%); serotype coverage was 68.6% for both 7-valent pneumococcal conjugate vaccine (PCV) and PCV-10, and 82.3% for PCV-13. Household residency and father's education were both significantly related to pneumococcal and Hib carriage. The majority of S. pneumoniae isolates were sensitive to most antimicrobials but there were high levels of resistance to azithromycin (51.0 %) and erythromycin (51.0%). Haemophilus influenzae isolates were sensitive to almost all antimicrobials tested although 12.2% of isolates were resistant to ampicillin. CONCLUSIONS: The pneumococcal and Hib vaccines require payment, and the children with the highest burden of disease may not be receiving these vaccines. Moreover, the presence of high antibiotic susceptibility towards pneumococcus, and to a lesser extent towards Hib, underscores the need for preventive protection against these diseases. Public funding of pneumococcal and Hib vaccines would be one mechanism to increase uptake of these vaccines.

Acute myocardial infarction due to spontaneous coronary artery dissection in a young male with systemic lupus erythematosus: A case report.

Systemic lupus erythematosus (SLE) is an autoimmune disease which typically presents in young women. Patients with SLE exhibit features of accelerated atherosclerosis. Here, the present study reported a rare case of acute myocardial infarction (AMI) in a male patient diagnosed with SLE. A 29-year-old male with no cardiovascular history was diagnosed with AMI and underwent coronary angiography, which showed a long-extended spiral-shaped dissection of the right coronary artery (RCA). The patient's autoimmune panel tested positive for antinuclear, anti-nuclear ribonucleoprotein/Smith and anti-Sjogren's syndrome A antibodies. The patient was diagnosed with SLE and was administered prednisone, hydroxychloroquine and calcium carbonate therapy. At the 3-month follow-up, a repeat coronary angiography showed no dissection in the RCA. Intravascular ultrasound and optical coherence tomography also showed an isolated atherosclerotic lesion without arterial dissection in the RCA. To the best of our knowledge, this is the first reported case of a male patient with SLE who developed myocardial infarction caused by spontaneous coronary artery dissection (SCAD). The present report may provide new insights into possible future treatments for SCAD. SCAD should be considered in patients with SLE and AMI, particularly in young patients without cardiovascular risk factors. Early diagnosis of SCAD is important to provide accurate therapy that differs from the treatment of AMI caused by atherosclerosis.

A 3D-Printed Integrated Handheld Biosensor for the Detection of Vibrio parahaemolyticus.

Vibrio parahaemolyticus (V. parahaemolyticus) is one of the important seafood-borne pathogens that cause a serious gastrointestinal disorder in humans. Recently, biosensors have attracted serious attention for precisely detecting and tracking risk factors in foods. However, a major consideration when fabricating biosensors is to match the low cost of portable devices to broaden its application. In this study, a 3D-printed integrated handheld biosensor (IHB) that combines RPA-CRISPR/Cas12a, a lateral flow strip (LFS), and a handheld device was developed for the ultrasensitive detection of V. parahaemolyticus. Using the preamplification of RPA on tlh gene of V. parahaemolyticus, a specific duplex DNA product was obtained to activate the trans-cleavage activity of CRISPR/Cas12a, which was then utilized to cleave the ssDNA probe. The ssDNA probe was then detected by the LFS, which was negatively correlated with the content of amplified RPA products of the tlh gene. The IHB showed high selectivity and excellent sensitivity for V. parahaemolyticus detection, and the limit of detection was 4.9 CFU/mL. The IHB also demonstrated great promise for the screening of V. parahaemolyticus in samples and had the potential to be applied to the rapid screening of other pathogen risks for seafood and marine environmental safety.

Regulatory T cells protect against diabetic cardiomyopathy in db/db mice.

AIMS/INTRODUCTION: Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM) using a db/db mouse model. MATERIALS AND METHODS: Eight-week-old male db/db mice were randomly divided into four groups: the control group, administered 200 µL phosphate-buffered saline; the small-dose Treg group, administered 105 Tregs; the large-dose Treg group, administered 106 Tregs; and the PC group, administered 100 µg anti-CD25 specific antibody (PC61) and 106 Tregs. After 12 weeks, mice were euthanized. Transthoracic echocardiography was carried out at the beginning and end of the experiment. Relevant basic experiments to evaluate the effects of Tregs on DCM were carried out. RESULTS: Echocardiography showed that the impaired diastolic and systolic functions were significantly improved in mice administered large-dose Tregs. Large-dose Tregs significantly ameliorated myocardial hypertrophy and fibrosis, and decreased hypertrophic gene expression and collagen deposition. The protective effects of Tregs on diabetic hearts were associated with decreased oxidative stress, inflammatory response and apoptosis. In addition, Tregs promoted the activation of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, whereas they inhibited extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase phosphorylation, which might be responsible for the cardioprotective role of Tregs against DCM. CONCLUSIONS: Tregs ameliorated myocardial hypertrophy and fibrosis, improved cardiac dysfunction, and protected against DCM progression in db/db mice. The mechanisms involved a decrease of inflammatory response, oxidative stress and apoptosis, which might be mediated by phosphatidylinositol 3-kinase-protein kinase B and mitogen-activated protein kinase pathways. Hence, Tregs might serve as a promising therapeutic approach for DCM treatment.

Is crystalline chromium phosphate environmentally stable? A study on the formation, dissolution and oxidation risk of CrPO4·6H2O.

Hexavalent chromium (Cr(VI)) contamination in soil and groundwater is usually remediated via reduction techniques. The formation of crystalline chromium phosphate (CrPO4·6 H2O) occurs as a byproduct during Cr(VI) remediation processes in the presence of phosphate, yet its stability in the environment has received limited attention. In this study, the formation conditions, structure, properties, and risks associated with the dissolution and oxidation of CrPO4·6 H2O were comprehensively assessed. Results showed that crystalline CrPO4·6 H2O was formed under pH 5 - 7 at room temperature. CrPO4·6 H2O exhibits higher dissolution risk compared to Cr(OH)3·3 H2O due to a long Cr-P bond (4.2 Å). H+ and OH- increased the risk of dissolution at pH 5 and 11, respectively, owing to the formation of CrH2PO42+ and Cr(OH)4-. In addition, under faintly acidic conditions, the high solubility of CrPO4·6 H2O increases the risk of oxidation; under neutral and weakly alkaline conditions, the presence of positively charged Cr(H2O)63+ structures on the surface elevates its susceptibility to contact and oxidation by δ-MnO2 compared to Cr(OH)3·3 H2O. Specifically, at pH 11, the conversion of CrPO4·6 H2O to Cr(OH)3·3 H2O results in similar oxidation risks for both Cr(III) precipitates.

Effects of warming on soil organic carbon pools mediated by mycorrhizae and hyphae on the Eastern Tibetan Plateau, China.

Mycorrhizae and their hyphae play critical roles in soil organic carbon (SOC) accumulation. However, their individual contributions to SOC components and stability under climate warming conditions remain unclear. This study investigated the effects of warming on the SOC pools of Picea asperata (an ectomycorrhizal plant) and Fargesia nitida (an arbuscular mycorrhizal plant) mycorrhizae/hyphae on the eastern Tibetan Plateau. The results indicated that mycorrhizae made greater contributions to SOC accumulation than hyphae did by increasing labile organic carbon (LOC) components, such as particle organic carbon (POC), easily oxidizable organic carbon, and microbial biomass carbon, especially under warming conditions. Plant species also had different effects on SOC composition, resulting in higher mineral-associated organic carbon (MAOC) contents in F. nitida plots than in P. asperata plots; consequently, the former favored SOC stability more than the latter, with a lower POC/MAOC. Partial least-squares path modelling further indicated that mycorrhizae/hyphae indirectly affected LOC pools, mainly by changing soil pH and enzyme activities. Warming had no significant effect on SOC content but did change SOC composition by reducing LOC through affecting soil pH and iron oxides and ultimately increasing SOC stability in the presence of mycorrhizae for both plants. Therefore, the mycorrhizae of both plants are major contributors to the variation of SOC components and stability under warming conditions.

A novel LAG3 neutralizing antibody improves cancer immunotherapy by dual inhibition of MHC-II and FGL1 ligand binding.

LAG3 is an inhibitory immune checkpoint expressed on activated T and NK cells. Blocking the interaction of LAG3 with its ligands MHC-II and FGL1 renders T cells improved cytotoxicity to cancer cells. Current study generated a panel of LAG3 monoclonal antibodies (mAbs) through immunization of mice followed by phage display. Some of them bound to the D1-D2 domain of LAG3, which is known for the engagement of its ligands FGL1 and MHC-II. Three outperformers, M208, M226, and M234, showed stronger blocking activity than Relatlimab in the FGL1 binding. Furthermore, M234 showed dual inhibition of FGL1 (IC50 of 20.6 nM) and MHC-II binding (IC50 of 6.2 nM) to LAG3. In vitro functional tests showed that M234 significantly stimulated IFN-γ secretion from activated PBMC cells. In vivo studies in a mouse model of hepatocellular carcinoma xenografts demonstrated that combining M234 IgG with GPC3-targeted bispecific antibodies significantly improved efficacy. In addition, GPC3-targeted CAR-T cells secreting IL-21-M234 scFv fusion protein exhibited enhanced activity in inhibiting tumor growth and greatly increased the survival rate of mice. Taken together, M234 has potential in cancer immunotherapy and warrants further clinical trial.