The safety and efficacy of neoadjuvant PD-1 inhibitor plus chemotherapy for patients with locally advanced gastric cancer: A systematic review and meta-analysis.

BACKGROUND: The extensive utilization of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) has achieved significant advancements in the treatment of diverse solid tumors. The present meta-analysis aims to evaluate the safety and efficacy of neoadjuvant chemotherapy (NCT) plus PD-1 inhibitor for patients with locally advanced gastric cancer (LAGC). METHODS: An electronic search of PubMed, EmBase, and the Cochrane Library was performed to identify the clinical trials of NCT + PD-1 inhibitor vs. NCT in patients with LAGC. The retrieval period extended from the establishment of the corresponding database until April 2024, and meta-analysis was conducted using Stata (version 15) software. Subsequently, direct comparative analysis was used to compare pooled results of neoadjuvant immunochemotherapy (NICT) with NCT. RESULTS: After screening, 6 phase II/III randomized controlled trials (RCTs) and 9 retrospective studies with 2,953 patients were included. In meta-analysis, NICT group demonstrated a significantly higher rate of pathological complete response (pCR) (P<0.001) and R0 resection (P=0.001), and a lower 2-year recurrence rate (P=0.001) compared to the NCT group. The NICT group, however, exhibited a higher incidence of severe treatment-related adverse events (TRAEs) (P=0.044). Additionally, the NICT and NCT groups exhibited no statistical differences in terms of the number of harvested lymph nodes, the occurrence of total TRAEs and postoperative complications, as well as the duration of postoperative hospitalization. CONCLUSIONS: The combination of PD-1 inhibitor + NCT in LAGC patients enhances the likelihood of achieving radical surgery and improves prognosis, albeit to some extent increasing the risk of severe TRAEs. NICT is anticipated to emerge as the preferred neoadjuvant therapy option for patients diagnosed with LAGC.

UBR1 promotes anaplastic thyroid carcinoma progression via stabilizing YAP through monoubiquitylation.

Anaplastic thyroid carcinoma (ATC) is a highly aggressive human malignancy without effective treatment. Yes-associated protein (YAP) is a critical effector of the Hippo pathway, which is essential in thyroid carcinogenesis. However, the underlying mechanisms of aberrant YAP expression in ATC are not completely understood. Ubiquitylation-related enzyme siRNA screening identified the ubiquitin protein ligase E3 component n-recognin 1 (UBR1) as a stabilizer of YAP in ATC cells. UBR1 deficiency reduced YAP protein levels and its target gene expression. UBR1 directly interacted with YAP and promoted its monoubiquitylation, competitively suppressing its polyubiquitylation and resulting in extended protein half-life. UBR1 depletion reduced ATC cell proliferation and migration in vitro. Xenograft tumor studies also suggested that UBR1 knockdown suppressed ATC cell growth in vivo. Furthermore, exogenous YAP expression partially reversed the inhibitive effects of UBR1 depletion on ATC cell proliferation and migration. Our studies demonstrated that UBR1 directly interacts with YAP and stabilized it in a monoubiquitylation-dependent manner, consequently promoting ATC tumorigenesis, suggesting that UBR1 might be a potentially therapeutic target for ATC treatment.

Pericyte loss via glutaredoxin2 downregulation aggravates diabetes-induced microvascular dysfunction.

Diabetic retinopathy (DR) is the leading cause of vision loss and blindness among working-age adults. Pericyte loss is an early pathological feature of DR. Under hyperglycemic conditions, reactive oxygen species (ROS) production increases, leading to oxidative stress and subsequent mitochondrial dysfunction and apoptosis. Dysfunctional pericyte can cause retinal vascular leakage, obliteration, and neovascularization. Glutaredoxin 2 (Grx2) is a mitochondrial glutathione-dependent oxidoreductase which protects cells against oxidative insults by safeguarding mitochondrial function. Whether Grx2 plays a protective role in diabetes-induced microvascular dysfunction remains unclear. Our findings revealed that diabetes-related stress reduced Grx2 expression in pericytes, but not in endothelial cells. Grx2 knock-in ameliorated diabetes-induced microvascular dysfunction in vivo DR models. Decreased Grx2 expression led to significant pericyte apoptosis, and pericyte dysfunction, namely reduced pericyte recruitment towards endothelial cells and increased endothelial cell permeability. Conversely, upregulating Grx2 reversed these effects. Furthermore, Grx2 regulated pericyte apoptosis by modulating complex I activity, which is crucial for pericyte mitochondrial function. Overall, our study uncovered a novel mechanism whereby high glucose inhibited Grx2 expression in vivo and in vitro. Grx2 downregulation exacerbated pericyte apoptosis, pericyte dysfunction, and retinal vascular dysfunction by inactivating complex I and mediating mitochondrial dysfunction in pericytes.

Homoharringtonine synergizes with venetoclax in early T cell progenitor acute lymphoblastic leukemia: Bench and bed.

BACKGROUND: Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a poor prognosis. To find a cure, we examined the synergistic effect of homoharringtonine (HHT) in combination with the BCL-2 inhibitor venetoclax (VEN) in ETP-ALL. METHODS: Using in vitro cellular assays and ETP-ALL xenograft models, we first investigated the synergistic activity of HHT and VEN in ETP-ALL. Next, to explore the underlying mechanism, we employed single-cell RNA sequencing of primary ETP-ALL cells treated with HHT or VEN alone or in combination and validated the results with western blot assays. Based on the promising preclinical results and given that both drugs have been approved for clinical use, we then assessed this combination in clinical practice. FINDINGS: Our results showed that HHT synergizes strongly with VEN both in vitro and in vivo in ETP-ALL. Mechanistic studies demonstrated that the HHT/VEN combination concurrently downregulated key anti-apoptotic proteins, i.e., MCL1, leading to enhanced apoptosis. Importantly, the clinical results were very promising. Six patients with ETP-ALL with either refractory/relapsed (R/R) or newly diagnosed disease were treated with an HHT/VEN-based regimen. All patients achieved complete remission (CR) after only one cycle of treatment. CONCLUSIONS: Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the "backbone" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL. FUNDING: This work was funded by the National Cancer Institute, Gehr Family Foundation, George Hoag Family Foundation, National Natural Science Foundation of China, and Key Research and Development Program of Zhejiang Province of China.

Fluoride induces hepatointestinal damage and vitamin B2 mitigation by regulating IL-17A and Bifidobacterium in ileum.

INTRODUCTION: Fluorosis is a global public health disease affecting more than 50 countries and 500 million people. Excessive fluoride damages the liver and intestines, yet the mechanisms and therapeutic approaches remain unclear. OBJECTIVES: To explore the mechanisms by which fluoride-induced intestinal-hepatic damage and vitamin B2 alleviation. METHODS: Fluoride and/or vitamin B2-treated IL-17A knockout and wild-type mouse models were established, the morphological and functional changes of liver and gut, total bile acid biosynthesis, metabolism, transport, and regulation of FXR-FGF15 signaling pathways were evaluated, the ileal microbiome was further analyzed by 16S rDNA sequence. Finally, Bifidobacterium supplementation mouse model was designed and re-examined the above indicators. RESULTS: The results demonstrated that fluoride induced hepatointestinal injury and enterohepatic circulation disorder by altering the synthesis, transporters, and FXR-FGF15 pathway regulation of total bile acid. Importantly, the ileum was found to be the most sensitive and fluoride changed ileal microbiome particularly by reducing abundance of Bifidobacterium. While vitamin B2 supplementation attenuated fluoride-induced enterohepatic circulation dysfunction through IL-17A and ileal microbiome, Bifidobacterium supplementation also reversed fluoride-induced hepatointestinal injury. CONCLUSION: Fluoride induces morphological and functional impairment of liver and gut tissues, as well as enterohepatic circulation disorder by altering total bile acid (TBA) synthesis, transporters, and FXR-FGF15 signaling regulation. Vitamin B2 attenuated fluoride-induced enterohepatic circulation disorder through IL-17A knockout and ileal microbiome regulation. The ileum was found to be the most sensitive to fluoride, leading to changes in ileal microbiome, particularly the reduction of Bifidobacterium. Furthermore, Bifidobacterium supplementation reversed fluoride-induced hepatointestinal injury. This study not only elucidates a novel mechanism by which fluoride causes hepatointestinal toxicity, but also provides a new physiological function of vitamin B2, which will be useful in the therapy of fluorosis and other hepatoenterological diseases.

The ciliate Euplotes balteatus is resistant to Paralytic Shellfish Toxins from Alexandrium minutum (Dinophyceae).

Research on interactions between grazers and toxigenic algae is fundamental for understanding toxin dynamics within aquatic ecosystems and developing biotic approaches to mitigate harmful algal blooms. The dinoflagellate Alexandrium minutum is a well-known microalga responsible for paralytic shellfish toxins (PSTs) contamination in many coastal regions worldwide. This study investigated the impact of the ciliate Euplotes balteatus on cell density and PSTs transfer in simulated A. minutum blooms under controlled conditions. E. balteatus exhibited resistance to the PSTs produced by A. minutum with a density of up to 10,000 cells/mL, sustaining growth and reproduction while eliminating algal cells within a few days. The cellular PSTs content of A. minutum increased in response to the grazing pressure from E. balteatus. However, due to the substantial reduction in density, the overall toxicity of the algal population decreased to a negligible level. Most PSTs contained within algal cells were temporarily accumulated in E. balteatus before being released into the water column, suggesting unclear mechanisms for PSTs excretion in unicellular grazers. In principle, the grazing of E. balteatus on A. minutum promotes the transfer of the majority of intracellular PSTs into extracellular portions, thereby mitigating the risk of their accumulation and contamination through marine trophic pathways. However, this process also introduces an increase in the potential environmental hazards posed by extracellular PSTs to some extent.

The impact of a growth mindset on high school students' learning subjective well-being: the serial mediation role of achievement motivation and grit.

Purpose: The learning subjective well-being of high school students has significant value for their academic achievement and future life development. A growth mindset is one of the key factors affecting the learning subjective well-being of high school students. However, research on the mechanism by which a growth mindset affects learning subjective well-being is still relatively limited. Therefore, the study aims to investigate the impact of a growth mindset on the learning subjective well-being of high school students, as well as the role that achievement motivation and grit play as serial mediators in this relationship. Methods: This study employed a convenience sampling method to select 708 high school students from Chinese public high schools as participants. The research utilized the Growth Mindset Scale, Achievement Motivation Scale, Grit Scale, and the Learning Subjective Well-being Questionnaire for High School Students to collect data. All data were analyzed using SPSS 26.0, employing Model 6 from Hayes' SPSS PROCESS macro to test the serial mediation model. Results: Our results found that (1) high school students' growth mindset positively predicted their learning subjective well-being. (2) Achievement motivation played a mediating role between a growth mindset and learning subjective well-being among high school students. (3) Grit acted as a mediator between learning subjective well-being and growth mindset among high school students. (4) Achievement motivation and grit served as serial mediators between a growth mindset and learning subjective well-being among high school students. Conclusion: A growth mindset can influence the learning subjective well-being of high school students through achievement motivation and grit. Educators can enhance the learning subjective well-being of high school students by implementing intervention strategies that foster a growth mindset, achievement motivation, and grit.

Cryptococcal endophthalmitis and meningitis in an immunocompetent middle-aged woman: A case report.

Cryptococcus neoformans is a global invasive mycosis that is known to cause significant morbidity and mortality. It is commonly observed that individuals with compromised immune systems are more prone to developing cryptococcal meningitis. Although ocular involvement is rare, previous studies have indicated that ocular lesions precede symptomatic meningitis in only 27 % of patients with central nervous system involvement. Intraocular infections typically manifest as chorioretinopathy and vitreous inflammation, often leading to severe vision loss. In this case, we present the clinical details of a 57-year-old immunocompetent woman who visited the ophthalmology department of West China Hospital of Sichuan University with a progressive loss of vision in her right eye. After a thorough evaluation, she was diagnosed with fungal endophthalmitis, and subsequently initiated on appropriate induction anti-fungal therapy for cryptococcal meningoencephalitis. This case highlights the importance of early recognition and treatment, which can potentially improve the prognosis for patients.

Clinical significance, molecular characterization, and immune microenvironment analysis of coagulation-related genes in clear cell renal cell carcinoma.

Background: Numerous studies have revealed a tight connection between tumor development and the coagulation system. However, the effects of coagulation on the prognosis and tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) remain poorly understood. Methods: We employed the consensus clustering method to characterize distinct molecular subtypes associated with coagulation patterns. Subsequently, we examined variations in the overall survival (OS), genomic profiles, and TME characteristics between these subtypes. To develop a prognostic coagulation-related risk score (CRRS) model, we utilized the least absolute shrinkage and selection operator Cox regression and stepwise multivariate Cox regression analyses. We also created a nomogram to aid in the clinical application of the risk score, evaluating the relationships between the CRRS and the immune microenvironment, responsiveness to immunotherapy, and targeted treatment. The clinical significance of PLAUR and its biological function in ccRCC were also further analyzed. Results: There were significant differences in clinical features, prognostic stratification, genomic variation, and TME characteristics between the two coagulation-related subtypes. We established and validated a CRRS using six coagulation-related genes that can be employed as an effective indicator of risk stratification and prognosis estimation for ccRCC patients. Significant variations in survival outcomes were observed between the high- and low-risk groups. The nomogram was proficient in predicting the 1-, 3-, and 5-year OS. Additionally, the CRRS emerged as a novel tool for evaluating the clinical effectiveness of immunotherapy and targeted treatments in ccRCC. Moreover, we confirmed upregulated PLAUR expression in ccRCC samples that was significantly correlated with poor patient prognosis. PLAUR knockdown notably inhibited ccRCC cell proliferation and migration. Conclusion: Our data suggested that CRRS may be employed as a reliable predictive biomarker that can provide therapeutic benefits for immunotherapy and targeted therapy in ccRCC.

CT Quantitation and Prediction of the Risk of Type 2 Diabetes Mellitus in Non-Obese Patients with Pancreatic Fatty Infiltration.

Purpose: To examine the risk of type 2 diabetes mellitus in non-obese patients with pancreatic fatty infiltration through abdominal computed tomography (CT) quantitation. Patients and Methods: We carried out a retrospective analysis of abdominal CT and inpatient medical records of 238 inpatients from July 2019 to April 2021. The patients were divided into a normal non-obese group (BMI < 25, n = 135) and diabetic non-obese group (BMI < 25, n = 103). Abdominal CT-related parameters included body width; mean CT values of the pancreas, liver, and spleen; difference between pancreas and spleen CT values (P-S); pancreas-to-spleen attenuation ratio (P/S); and liver-to-spleen attenuation ratio (L/S). Logistic regression was used to estimate the risk factors for comorbid diabetes in a non-obese population. Results: The P-values of the pancreas CT value, P-S, P/S, body width, and L/S were all <0.05 and correlated to comorbid diabetes in non-obese patients. Worsening pancreatic fatty infiltration increased the risk of developing diabetes. Using a P/S of 1.0 as reference, every successive decrease in this ratio by 0.1 increases patient risk by 3.981, 4.452, 6.037, and 12.937 times. Conclusion: The risk of developing type 2 diabetes mellitus in non-obese patients increases with the degree of pancreatic fatty infiltration as assessed by CT.

Anti-CTLA-4 m2a Antibody Exacerbates Cardiac Injury in Experimental Autoimmune Myocarditis Mice By Promoting Ccl5-Neutrophil Infiltration.

The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.

An HIV-1 CRISPR-Cas9 membrane trafficking screen reveals a role for PICALM intersecting endolysosomes and immunity.

HIV-1 hijacks host proteins involved in membrane trafficking, endocytosis, and autophagy that are critical for virus replication. Molecular details are lacking but are essential to inform on the development of alternative antiviral strategies. Despite their potential as clinical targets, only a few membrane trafficking proteins have been functionally characterized in HIV-1 replication. To further elucidate roles in HIV-1 replication, we performed a CRISPR-Cas9 screen on 140 membrane trafficking proteins. We identified phosphatidylinositol-binding clathrin assembly protein (PICALM) that influences not only infection dynamics but also CD4+ SupT1 biology. The knockout (KO) of PICALM inhibited viral entry. In CD4+ SupT1 T cells, KO cells exhibited defects in intracellular trafficking and increased abundance of intracellular Gag and significant alterations in autophagy, immune checkpoint PD-1 levels, and differentiation markers. Thus, PICALM modulates a variety of pathways that ultimately affect HIV-1 replication, underscoring the potential of PICALM as a future target to control HIV-1.

Monitoring landfill volatile organic compounds emissions by an uncrewed aerial vehicle platform with infrared and visible-light cameras, remote monitoring, and sampling systems.

An uncrewed aerial vehicle (UAV) platform equipped with dual imaging cameras, a gas sampling system, and a remote synchronous monitoring system was developed to sample and analyze volatile organic compounds (VOCs) emitted from landfills. The remote synchronous monitoring system provided real-time video to administrators with specific permissions to assist in identifying sampling sites within extensive landfill areas. The sampling system included four kits capable of collecting samples from different locations during a single flight mission. Each kit comprised a 1 L Tedlar bag for measuring landfill VOC concentrations according to the TO-15 method prescribed by the US Environmental Protection Agency. The air sample was introduced into a Tedlar bag via pumping. A known volume of the sample was subsequently concentrated using a solid multisorbent concentrator. Following this, the sample underwent cold trap concentration and thermal desorption. The concentrated sample was then transferred to a chromatography-mass spectrometry system for separation and analysis. Since the anaerobic catabolism of organic waste is exothermic and emits VOCs, this study employed UAV thermal imaging to locate principal emission sources for sampling. Visible-light imaging helped identify newer or older landfill sections, aiding in the selection of appropriate sampling sites, particularly when surfaces were thermally disturbed by solar radiation. Field measurements were conducted under three meteorological conditions: sunny morning, cirrus morning, and thin cloud evening (2 h after sunset), identifying 119, 122, and 111 chemical species respectively. The sequence of total VOC concentrations measured correlated with the meteorological conditions as follows: cirrus morning > thin cloud evening > sunny morning. The results indicated that ambient temperature and global solar radiation significantly influenced daytime gas emissions from landfills. Evening thermal images, unaffected by solar heating, facilitated more accurate identification of major VOC emission points, resulting in higher VOC concentrations compared to those recorded in the sunny morning. VOCs from the landfill were categorized into nine organic groups: alkanes, alkenes, carbonyls, aromatics, alcohols, esters, ethers, organic oxides, and others. The classification was based on carbon-containing compounds (Cn, where the compound contains n carbon atoms). Alkanes were predominant in terms of Cn presence, followed by alcohols and carbonyls. Among the organic groups, organic oxides, particularly 2-heptyl-1,3-dioxolane, exhibited the highest concentrations, succeeded by alkenes. Sampling under cloudy conditions or in the evening is recommended to minimize the effects of surface temperature anomalies caused by solar radiation, which vary due to differences in land composition.

UPLC-LTQ-Orbitrap Study on Rat Urinary Metabolites of 5-Methoxy-Alpha-Methyltryptamine.

OBJECTIVE: 5-Methoxy-α-Methyltryptamine (5-MeO-AMT) is a new psychoactive substance which is abused due to its hallucinogenic and euphoric effects. This study aimed to study the metabolic characteristics of 5-MeO-AMT. METHODS: Five rats were given intraperitoneal injection at a dose of 50 mg/kg of 5-MeO-AMT, and their urine was subsequently collected at different times within 7 days. Ultra-high performance liquid chromatography-- tandem high-resolution mass spectrometry (UPLC-LTQ-Orbitrap) was used to detect the precise molecular weight and fragment ions of 5-MeO-AMT and its possible metabolites in the urine sample extracted with benzene-ethyl acetate. RESULTS: Three metabolites, including OH-5-MeO-AMT, α-Me-5-HT, and N-Acetyl-5-MeO-AMT were identified in rats' urine. The major metabolic pathways involved O-demethylation, hydroxylation of indole ring, and Acetylation on aliphatic amines. CONCLUSION: The results of this study are an important reference for the identification and screening of toxicants of 5-MeO-AMT.

Fluoride induces immunotoxicity by regulating riboflavin transport and metabolism partly through IL-17A in the spleen.

The impairment of the immune system by fluoride is a public health concern worldwide, yet the underlying mechanism is unclear. Both riboflavin and IL-17A are closely related to immune function and regulate the testicular toxicity of fluoride. However, whether riboflavin or IL-17A is involved in fluoride-induced immunotoxicity is unknown. Here, we first established a male ICR mouse model by treating mice with sodium fluoride (NaF) (100 mg/L) via the drinking water for 91 days. The results showed that fluoride increased the expression of the proinflammatory factors IL-1ß and IL-17A, which led to splenic inflammation and morphological injury. Moreover, the expression levels of the riboflavin transporters SLC52A2 and SLC52A3; the transformation-related enzymes RFK and FLAD1; and the key mitochondrial functional determinants SDH, COX, and ATP in the spleen were measured via real-time PCR, Western blotting, and ELISA. The results revealed that fluoride disrupted riboflavin transport, transformation, metabolism, and mitochondrial function. Furthermore, wild-type (WT) and IL-17A knockout (IL-17A-/-) C57BL/6 J male mice of the same age were treated with NaF (24 mg/kg·bw, equivalent to 100 mg/L) and/or riboflavin sodium phosphate (5 mg/kg·bw) via gavage for 91 days. Similar parameters were evaluated as above. The results confirmed that fluoride increased riboflavin metabolism through RFK but not through FLAD1. Fluoride also affected mitochondrial function and activated neutrophils (marked with Ly6g) and macrophages (marked with CD68) in the spleen. Interestingly, IL-17A partly mediated fluoride-induced riboflavin metabolism disorder and immunotoxicity in the spleen. This work not only reveals a novel toxic mechanism for fluoride but also provides new clues for exploring the physiological function of riboflavin and for diagnosing and treating the toxic effects of fluoride in the environment.

SARS-CoV-2 Accessory Protein ORF8 Targets the Dimeric IgA Receptor pIgR.

SARS-CoV-2 is a highly pathogenic respiratory virus that successfully initiates and establishes its infection at the respiratory mucosa. However, little is known about how SARS-CoV-2 antagonizes the host's mucosal immunity. Recent findings have shown a marked reduction in the expression of the polymeric Ig receptor (pIgR) in COVID-19 patients. This receptor maintains mucosal homeostasis by transporting the dimeric IgA (dIgA) and pentameric IgM (pIgM) across mucosal epithelial cells to neutralize the invading respiratory pathogens. By studying the interaction between pIgR and SARS-CoV-2 proteins, we discovered that the viral accessory protein Open Reading Frame 8 (ORF8) potently downregulates pIgR expression and that this downregulation activity of ORF8 correlates with its ability to interact with pIgR. Importantly, the ORF8-mediated downregulation of pIgR diminishes the binding of dIgA or pIgM, and the ORF8 proteins of the variants of concern of SARS-CoV-2 preserve the function of downregulating pIgR, indicating the importance of this conserved activity of ORF8 in SARS-CoV-2 pathogenesis. We further observed that the secreted ORF8 binds to cell surface pIgR, but that this interaction does not trigger the cellular internalization of ORF8, which requires the binding of dIgA to pIgR. These findings suggest the role of ORF8 in SARS-CoV-2 mucosal immune evasion.

Biomimetic Porous Ti6Al4V Implants: A Novel Interbody Fusion Cage via Gel-Casting Technique to Promote Spine Fusion.

An interbody fusion cage (Cage) is crucial in spinal decompression and fusion procedures for restoring normal vertebral curvature and rebuilding spinal stability. Currently, these Cages suffer from issues related to mismatched elastic modulus and insufficient bone integration capability. Therefore, a gel-casting technique is utilized to fabricate a biomimetic porous titanium alloy material from Ti6Al4V powder. The biomimetic porous Ti6Al4V is compared with polyetheretherketone (PEEK) and 3D-printed Ti6Al4V materials and their respective Cages. Systematic validation is performed through mechanical testing, in vitro cell, in vivo rabbit bone defect implantation, and ovine anterior cervical discectomy and fusion experiments to evaluate the mechanical and biological performance of the materials. Although all three materials demonstrate good biocompatibility and osseointegration properties, the biomimetic porous Ti6Al4V, with its excellent mechanical properties and a structure closely resembling bone trabecular tissue, exhibited superior bone ingrowth and osseointegration performance. Compared to the PEEK and 3D-printed Ti6Al4V Cages, the biomimetic porous Ti6Al4V Cage outperforms in terms of intervertebral fusion performance, achieving excellent intervertebral fusion without the need for bone grafting, thereby enhancing cervical vertebra stability. This biomimetic porous Ti6Al4V Cage offers cost-effectiveness, presenting significant potential for clinical applications in spinal surgery.

All-RNA-mediated targeted gene integration in mammalian cells with rationally engineered R2 retrotransposons.

All-RNA-mediated targeted gene integration methods, rendering reduced immunogenicity, effective deliverability with non-viral vehicles, and a low risk of random mutagenesis, are urgently needed for next-generation gene addition technologies. Naturally occurring R2 retrotransposons hold promise in this context due to their site-specific integration profile. Here, we systematically analyzed the biodiversity of R2 elements and screened several R2 orthologs capable of full-length gene insertion in mammalian cells. Robust R2 system gene integration efficiency was attained using combined donor RNA and protein engineering. Importantly, the all-RNA-delivered engineered R2 system showed effective integration activity, with efficiency over 60% in mouse embryos. Unbiased high-throughput sequencing demonstrated that the engineered R2 system exhibited high on-target integration specificity (99%). In conclusion, our study provides engineered R2 tools for applications based on hit-and-run targeted DNA integration and insights for further optimization of retrotransposon systems.

Designing Symmetric Gradient Honeycomb Structures with Carbon-Coated Iron-Based Composites for High-Efficiency Microwave Absorption.

The impedance matching of absorbers is a vital factor affecting their microwave absorption (MA) properties. In this work, we controllably synthesized Material of Institute Lavoisier 88C (MIL-88C) with varying aspect ratios (AR) as a precursor by regulating oil bath conditions, followed by one-step thermal decomposition to obtain carbon-coated iron-based composites. Modifying the precursor MIL-88C (Fe) preparation conditions, such as the molar ratio between metal ions and organic ligands (M/O), oil bath temperature, and oil bath time, influenced the phases, graphitization degree, and AR of the derivatives, enabling low filler loading, achieving well-matched impedance, and ensuring outstanding MA properties. The MOF-derivatives 2 (MD2)/polyvinylidene Difluoride (PVDF), MD3/PVDF, and MD4/PVDF absorbers all exhibited excellent MA properties with optimal filler loadings below 20 wt% and as low as 5 wt%. The MD2/PVDF (5 wt%) achieved a maximum effective absorption bandwidth (EAB) of 5.52 GHz (1.90 mm). The MD3/PVDF (10 wt%) possessed a minimum reflection loss (RLmin) value of - 67.4 at 12.56 GHz (2.13 mm). A symmetric gradient honeycomb structure (SGHS) was constructed utilizing the high-frequency structure simulator (HFSS) to further extend the EAB, achieving an EAB of 14.6 GHz and a RLmin of - 59.0 dB. This research offers a viable inspiration to creating structures or materials with high-efficiency MA properties.

Clinical, Imaging, and Pathological-Molecular Characteristics Associated with Stage IA Invasive Lung Adenocarcinoma Recurrence After Sub-lobar Resection.

RATIONALE AND OBJECTIVES: This study aimed to investigate the association of clinical, imaging, and pathological-molecular characteristics with the prediction of patient prognosis with stage IA invasive lung adenocarcinoma (ILADC) after sub-lobar resection. MATERIALS AND METHODS: This study assessed 360 patients, including 91 and 269 with and without recurrence 3 years postoperatively, respectively, with stage IA ILADC undergoing preoperative chest computed tomography (CT) scans and subsequent sub-lobar resection at our institution. Their clinical and CT features and histological subtypes and gene mutation status were compared. Binary logistic regression analysis was conducted to identify the independent risk factors for recurrence. An external validation cohort included 113 patients, used to test the model's efficiency. RESULTS: For clinical features, old age, male gender, smokers, and high age-adjusted Charlson comorbidity index (ACCI) were frequently observed in patients with recurrence than those without (all p < 0.05). For CT features, large tumor size, solid-predominant density, spiculation, peripheral fibrosis, type II pleural tag, and pleural adhesion were more common in recurrent patients than non-recurrent ones (all p < 0.05). The regression model revealed old age, large tumor size, solid-predominant density, spiculation, type II pleural tag, and pleural adhesion as independent risk factors for recurrence, with an area under the curve (AUC) of 0.942. The external validation cohort obtained an AUC of 0.958. For phological-molecular features, micropapillary/solid-predominant growth pattern, KRAS, ALK, and NRAS mutation or fusion were more common in the recurrent group, whereas EGFR mutation was more frequent in the non-recurrent group (all p < 0.05). CONCLUSION: Clinical and CT features help predict the prognosis of patients with stage IA ILADC after sub-lobar resection and decide for individualized treatment. Moreover, patients with different prognosis demonstrated different pathological-molecular features.