Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.

Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-ß1 (TGF-ß1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD+) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.

Red and far-red light improve the antagonistic ability of Trichoderma guizhouense against phytopathogenic fungi by promoting phytochrome-dependent aerial hyphal growth.

Light as a source of information regulates morphological and physiological processes of fungi, including development, primary and secondary metabolism, or the circadian rhythm. Light signaling in fungi depends on photoreceptors and downstream components that amplify the signal to govern the expression of an array of genes. Here, we investigated the effects of red and far-red light in the mycoparasite Trichoderma guizhouense on its mycoparasitic potential. We show that the invasion strategy of T. guizhouense depends on the attacked species and that red and far-red light increased aerial hyphal growth and led to faster overgrowth or invasion of the colonies. Molecular experiments and transcriptome analyses revealed that red and far-red light are sensed by phytochrome FPH1 and further transmitted by the downstream MAPK HOG pathway and the bZIP transcription factor ATF1. Overexpression of the red- and far-red light-induced fluffy gene fluG in the dark resulted in abundant aerial hyphae formation and thereby improvement of its antagonistic ability against phytopathogenic fungi. Hence, light-induced fluG expression is important for the mycoparasitic interaction. The increased aggressiveness of fluG-overexpressing strains was phenocopied by four random mutants obtained after UV mutagenesis. Therefore, aerial hyphae formation appears to be a trait for the antagonistic potential of T. guizhouense.

Overexpressing lipid raft protein STOML2 modulates the tumor microenvironment via NF-κB signaling in colorectal cancer.

Colorectal cancer (CRC) is characterized by a complex tumor inflammatory microenvironment, while angiogenesis and immunosuppression frequently occur concomitantly. However, the exact mechanism that controls angiogenesis and immunosuppression in CRC microenvironment remains unclear. Herein, we found that expression levels of lipid raft protein STOML2 were increased in CRC and were associated with advanced disease stage and poor survival outcomes. Intriguingly, we revealed that STOML2 is essential for CRC tumor inflammatory microenvironment, which induces angiogenesis and facilitates tumor immune escape simultaneously both in vitro and in vivo. Moreover, tumors with STOML2 overexpression showed effective response to anti-angiogenesis treatment and immunotherapy in vivo. Mechanistically, STOML2 regulates CRC proliferation, angiogenesis, and immune escape through activated NF-κB signaling pathway via binding to TRADD protein, resulting in upregulation of CCND1, VEGF, and PD-L1. Furthermore, treatment with NF-κB inhibitor dramatically reversed the ability of proliferation and angiogenesis. Clinically, we also observed a strong positive correlation between STOML2 expression and Ki67, CD31, VEGFC and PD-1 of CD8+T cell expression. Taken together, our results provided novel insights into the role of STOML2 in CRC inflammatory microenvironment, which may present a therapeutic opportunity for CRC.

The presence and role of the intermediary CO reservoir in heterogeneous electroreduction of CO2.

SignificanceThe electroconversion of CO2 to value-added products is a promising path to sustainable fuels and chemicals. However, the microenvironment that is created during CO2 electroreduction near the surface of heterogeneous Cu electrocatalysts remains unknown. Its understanding can lead to the development of ways to improve activity and selectivity toward multicarbon products. This work introduces a method called on-stream substitution of reactant isotope that provides quantitative information of the CO intermediate species present on Cu surfaces during electrolysis. An intermediary CO reservoir that contains more CO molecules than typically expected in a surface adsorbed configuration was identified. Its size was shown to be a factor closely associated with the formation of multicarbon products.

KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis.

OBJECTIVE: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. DESIGN: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. RESULTS: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. CONCLUSIONS: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

SperMD: the expression atlas of sperm maturation.

The impairment of sperm maturation is one of the major pathogenic factors in male subfertility, a serious medical and social problem affecting millions of global couples. Regrettably, the existing research on sperm maturation is slow, limited, and fragmented, largely attributable to the lack of a global molecular view. To fill the data gap, we newly established a database, namely the Sperm Maturation Database (SperMD, http://bio-add.org/SperMD ). SperMD integrates heterogeneous multi-omics data (170 transcriptomes, 91 proteomes, and five human metabolomes) to illustrate the transcriptional, translational, and metabolic manifestations during the entire lifespan of sperm maturation. These data involve almost all crucial scenarios related to sperm maturation, including the tissue components of the epididymal microenvironment, cell constituents of tissues, different pathological states, and so on. To the best of our knowledge, SperMD could be one of the limited repositories that provide focused and comprehensive information on sperm maturation. Easy-to-use web services are also implemented to enhance the experience of data retrieval and molecular comparison between humans and mice. Furthermore, the manuscript illustrates an example application demonstrated to systematically characterize novel gene functions in sperm maturation. Nevertheless, SperMD undertakes the endeavor to integrate the islanding omics data, offering a panoramic molecular view of how the spermatozoa gain full reproductive abilities. It will serve as a valuable resource for the systematic exploration of sperm maturation and for prioritizing the biomarkers and targets for precise diagnosis and therapy of male subfertility.

Iron-related gene mutations driving global Mycobacterium tuberculosis transmission revealed by whole-genome sequencing.

BACKGROUND: Iron plays a crucial role in the growth of Mycobacterium tuberculosis (M. tuberculosis). However, the precise regulatory mechanism governing this system requires further elucidation. Additionally, limited studies have examined the impact of gene mutations related to iron on the transmission of M. tuberculosis globally. This research aims to investigate the correlation between mutations in iron-related genes and the worldwide transmission of M. tuberculosis. RESULTS: A total of 13,532 isolates of M. tuberculosis were included in this study. Among them, 6,104 (45.11%) were identified as genomic clustered isolates, while 8,395 (62.04%) were classified as genomic clade isolates. Our results showed that a total of 12 single nucleotide polymorphisms (SNPs) showed a positive correlation with clustering, such as Rv1469 (ctpD, C758T), Rv3703c (etgB, G1122T), and Rv3743c (ctpJ, G676C). Additionally, seven SNPs, including Rv0104 (T167G, T478G), Rv0211 (pckA, A302C), Rv0283 (eccB3, C423T), Rv1436 (gap, G654T), ctpD C758T, and etgB C578A, demonstrated a positive correlation with transmission clades across different countries. Notably, our findings highlighted the positive association of Rv0104 T167G, pckA A302C, eccB3 C423T, ctpD C758T, and etgB C578A with transmission clades across diverse regions. Furthermore, our analysis identified 78 SNPs that exhibited significant associations with clade size. CONCLUSIONS: Our study reveals the link between iron-related gene SNPs and M. tuberculosis transmission, offering insights into crucial factors influencing the pathogenicity of the disease. This research holds promise for targeted strategies in prevention and treatment, advancing research and interventions in this field.

Stable Interfacial Ruthenium Species for Highly Efficient Polyolefin Upcycling.

The present polyolefin hydrogenolysis recycling cases acknowledge that zerovalent Ru exhibits high catalytic activity. A pivotal rationale behind this assertion lies in the propensity of the majority of Ru species to undergo reduction to zerovalent Ru within the hydrogenolysis milieu. Nonetheless, the suitability of zerovalent Ru as an optimal structural configuration for accommodating multiple elementary reactions remains ambiguous. Here, we have constructed stable Ru0-Ruδ+ complex species, even under reaction conditions, through surface ligand engineering of commercially available Ru/C catalysts. Our findings unequivocally demonstrate that surface-ligated Ru species can be stabilized in the form of a Ruδ+ state, which, in turn, engenders a perturbation of the σ bond electron distribution within the polyolefin carbon chain, ultimately boosting the rate-determining step of C-C scission. The optimized catalysts reach a solid conversion rate of 609 g·gRu-1·h-1 for polyethylene. This achievement represents a 4.18-fold enhancement relative to the pristine Ru/C catalyst while concurrently preserving a remarkable 94% selectivity toward valued liquid alkanes. Of utmost significance, this surface ligand engineering can be extended to the gentle mixing of catalysts in ligand solution at room temperature, thus rendering it amenable for swift integration into industrial processes involving polyolefin degradation.

The health burden of air pollution in the UK: a modelling study using updated exposure-risk associations.

BACKGROUND: Long-term exposure to ambient air pollution, in particular fine particles or PM2·5, is a leading global disease burden. PM2·5 in the UK, dominated by agricultural emissions of ammonia (NH3), has been estimated to be responsible for 29 000-34 000 adult early deaths a year. These estimates use models that relate exposure to health risk that predate cohort studies that have identified a supralinear relationship between exposure and risk at relatively low PM2·5 concentrations typical of the UK (5-12 mg m-3). Here we used this new knowledge to estimate adult premature mortality in the UK in 2019. METHODS: For this modelling study, we used the GEOS-Chem model nested over the UK to simulate ambient PM2·5 concentrations, UK Office for National Statistics (ONS) health data provided by the Global Burden of Disease (GBD), and a hybrid health-risk assessment model. The hybrid model fuses a well established linear relationship between PM2·5 and risk for PM2·5 exceeding 10 mg m-3 with a supralinear curve at lower concentrations that is constrained with cohort studies conducted in Canada and confirmed with similar relationships from cohort studies in the USA and Europe. FINDINGS: We estimated that adult premature mortality attributable to exposure to ambient PM2·5 in the UK totalled 48 625 deaths in 2019 (95% CI 45 118-52 595); 15 000-20 000 more deaths than those estimated using outdated health-risk assessment models. Older people (aged 65 years or older) account for most UK deaths (86%). All adult premature mortality (in people aged 25 years and older) in Greater London (4861, 95% CI 4549-5247) exceeded that in Scotland (3673, 3214-4073), Wales (2462, 2270-2660), and Northern Ireland (1052, 934-1156). INTERPRETATION: According to our findings, PM2·5 is more hazardous to UK adults than previously reported, but a supralinear exposure-response curve also suggests that there are substantial public health gains in targeting dominant source contributors to PM2·5, in particular the unregulated agricultural sector. FUNDING: Department for the Environment, Food and Rural Affairs (DEFRA).

Evaluating the Kinetics and Molecular Mechanism for Biomimetic Metabolic Activation of PAHs by Surface-Enhanced Raman Scattering Spectroscopy.

Biomimetic cytochrome P450 for chemical activation of environmental carcinogens is an efficient in vitro model for evaluating their mutagenicity and ultimately acquiring the metabolites that cannot be easily accessed by conventional routes of organic synthesis. Different kinds of mutagen derived from polyaromatic hydrocarbons (PAHs) by metalloporphyrin/oxidant model systems have been reported, but the underlying molecular mechanisms are poorly understood. Herein, we have for the first time demonstrated an effective surface-enhanced Raman scattering (SERS) protocol to study the dynamics and biomimetic metabolic behaviors of pyrene (Pyr) in the presence of various oxygen donors. Quantitative information on the relative concentration of Pyr and its metabolites in the biomimetic system can be extracted from the SERS spectra. On the basis of our results, we conclude that the oxidative metabolism of Pyr is highly influenced by the types and concentrations of oxygen donors, leading to the formation of 1-hydroxypyrene and dioxygenated products. Besides, the addition of an appropriate amount of an organic solvent can promote the formation of secondary oxidation products. These results offer valuable insights into the dynamics of PAHs metabolism and the regulation of their metabolic pathways in biomimetic activation. In comparison to traditional liquid chromatography-mass spectrometry, the present SERS approach is more suitable for high-throughput evaluation of the metabolic process and kinetics of PAHs. We anticipate that this approach will enable a more general and comprehensive tracking of metabolic dynamics and molecular mechanisms involved in the biomimetic activation of other xenobiotics, such as procarcinogens, promutagens, and drugs.

Network pharmacology prediction and molecular docking analysis reveal the mechanism of modified Bushen Yiqi formulas on chronic obstructive pulmonary disease.

BACKGROUND: The present study aimed to explore the mechanism of the modified Bushen Yiqi formula (MBYF) in the treatment of chronic obstructive pulmonary disease (COPD) based on network pharmacology and molecular docking. METHODS: First, the active ingredients and corresponding targets in MBYF were mined through the Traditional Chinese Medicine Systems Pharmacology database. Subsequently, Online Mendelian Inheritance in Man, DrugBank, and GeneCard were used to screen COPD-related targets. Cytoscape was used to construct a network of candidate components of MBYF in COPD treatment. The overlapping targets of COPD and MBYF were used to treat COPD, and then CytoHubba and CytoNAC plug-ins in Cytoscape were used for topology analysis to build the core network. In addition, core targets were used for Gene Ontology analysis and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes. Finally, AutoDock Vina software was used to conduct a molecular docking study on the core active ingredients and core targets to verify the above network pharmacological analysis. RESULTS: Seventy-nine active components of MBYF were screened and 261 corresponding targets were found. At the same time, 1307 related targets corresponding to COPD were screened and 111 overlapping targets were matched. By bioinformatics analysis, 10 core targets were identified, and subsequently, enrichment analysis revealed 385 BP, two CC, eight MF and 78 related signaling pathways. The binding of the core active components in MBYF to the core target was further verified by molecular docking, and all showed good binding. CONCLUSIONS: The active components of MBYF, such as quercetin, kaempferol, luteolin, and baicalein, may be the material basis for the treatment of chronic obstructive pulmonary disease. They affect the expression of inflammatory cells and inflammatory factors, protein phosphorylation, and smooth muscle hyperplasia through tumor necrosis factor, interleukin-17, mitogen-activated protein kinase, nuclear factor-kappa B and other signaling pathways.

Comparative physiology and transcriptome response patterns in cold-tolerant and cold-sensitive varieties of Solanum melongena.

BACKGROUND: Climate change has led to severe cold events, adversely impacting global crop production. Eggplant (Solanum melongena L.), a significant economic crop, is highly susceptible to cold damage, affecting both yield and quality. Unraveling the molecular mechanisms governing cold resistance, including the identification of key genes and comprehensive transcriptional regulatory pathways, is crucial for developing new varieties with enhanced tolerance. RESULTS: In this study, we conducted a comparative analysis of leaf physiological indices and transcriptome sequencing results. The orthogonal partial least squares discriminant analysis (OPLS-DA) highlighted peroxidase (POD) activity and soluble protein as crucial physiological indicators for both varieties. RNA-seq data analysis revealed that a total of 7024 and 6209 differentially expressed genes (DEGs) were identified from variety "A" and variety "B", respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of DEGs demonstrated that the significant roles of starch and sucrose metabolism, glutathione metabolism, terpenoid synthesis, and energy metabolism (sucrose and starch metabolism) were the key pathways in eggplant. Weighted gene co-expression network analysis (WGCNA) shown that the enrichment of numerous cold-responsive genes, pathways, and soluble proteins in the MEgrep60 modules. Core hub genes identified in the co-expression network included POD, membrane transporter-related gene MDR1, abscisic acid-related genes, growth factor enrichment gene DELLA, core components of the biological clock PRR7, and five transcription factors. Among these, the core transcription factor MYB demonstrated co-expression with signal transduction, plant hormone, biosynthesis, and metabolism-related genes, suggesting a pivotal role in the cold response network. CONCLUSION: This study integrates physiological indicators and transcriptomics to unveil the molecular mechanisms responsible for the differences in cold tolerance between the eggplant cold-tolerant variety "A" and the cold-sensitive variety "B". These mechanisms include modulation of reactive oxygen species (ROS), elevation in osmotic carbohydrate and free proline content, and the expression of terpenoid synthesis genes. This comprehensive understanding contributes valuable insights into the molecular underpinnings of cold stress tolerance, ultimately aiding in the improvement of crop cold tolerance.

Spontaneous Rise of Hydrogen Microbubbles in Interfacial Gas Evolution Reaction.

Liquid organic hydrogen carrier is a promising option for the transport and storage of hydrogen as a clean energy source. This study examines the stability and behavior of organic drops immobilized on a substrate during an interfacial hydrogen-evolution reaction (HER) at the drop surface and its surrounding aqueous solution. Hydrogen microbubbles form within the drop and rise to the drop apex. The growth rate of the hydrogen in-drop bubble increases with the concentration of the reactant in the surrounding medium. The drop remains stable till the buoyancy acting on the in-drop bubble is large enough to overcome the capillary force and the external viscous drag. The bubble spontaneously rises and carries a portion drop liquid to the solution surface. These spontaneous rising in-drop bubbles are detected in measurements using a high-precision sensor placed on the upper surface of the aqueous solution, reversing the settling phase from phase separation in the reactive emulsion. The finding from this work provides new insights into the behaviors of drops and bubbles in many interfacial gas evolution reactions in clean technologies.

HIV-1 infections with multiple founders associate with the development of neutralization breadth.

Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth.

Perovskite photodetector-based laser absorption spectroscopy for gas detection.

A gas detection method based on CH3NH3PbI3 (MAPbI3) and poly (3,4-ethylenedioxythiophene): poly (4-styrene sulfonate) (PEDOT:PSS) composite photodetectors (PDs) is proposed. The operation of the PD primarily relies on the photoelectric effect within the visible light band. Our study involves constructing a gas detection system based on tunable diode laser spectroscopy (TDLAS) and MAPbI3/PEDOT:PSS PD, and O2 was selected as the target analyte. The system has achieved a minimum detection limit (MDL) of 0.12% and a normalized noise equivalent absorption coefficient (NNEA) of 8.83 × 10-11 cm-1⋅W⋅Hz-1/2. Furthermore, the Allan deviation analysis results indicate that the system can obtain sensitivity levels as low as 0.058% over an averaging time of 328 seconds. This marks the first use of MAPbI3/PEDOT:PSS PD in gas detection based on TDLAS. Despite the detector's performance leaves much to be desired, this innovation offers a new approach to developing spectral based gas detection system.

Binding of Acetylated Lysine by Using a Water Soluble Aryl Extended Calix[4]pyrrole.

Post-translational modifications of lysine in histones, as methylation and acetylation, have well established functions in epigenetics and are emerging as important actors in broader biological regulation. Currently, the detection of acetylated lysine (Kac) in water solution as free amino acid or protein residue remains challenging. Acetylated lysine is a neutral amino acid, and the lack of ion-dipole interactions causes the decrease in binding affinity displayed by synthetic molecular receptors with respect to the other lysine modifications. Here, we report molecular modeling calculations and 1H NMR experiments to investigate the binding properties of two different calix[4]pyrrole receptors towards Kac. Computational analyses reveal that tetra-aryl-extended calix[4]pyrrole (1) preferentially binds the cis-Kac conformer over the trans one due to steric considerations and more favorable interactions. Experimental 1H NMR titration experiments confirm the formation of a 1 : 1 complex between receptor 1 and cis-Kac, with a Ka exceeding 103 M-1. Conversely, the super-aryl-extended calix[4]pyrrole 2 is less efficient in binding Kac, due to unfavorable solvation/desolvation effects, as proven by 1H NMR experiments. Moreover, receptor 1 showed a higher affinity for Kac over other lysine modifications, such as methylated lysines.

Identification of the cytoplasmic DNA-Sensing cGAS-STING pathway-mediated gene signatures and molecular subtypes in prostate cancer.

BACKGROUND: Considering the age relevance of prostate cancer (PCa) and the involvement of the cGAS-STING pathway in aging and cancer, we aim to classify PCa into distinct molecular subtypes and identify key genes from the novel perspective of the cGAS-STING pathway. It is of significance to guide personalized intervention of cancer-targeting therapy based on genetic evidence. METHODS: The 430 patients with PCa from the TCGA database were included. We integrated 29 key genes involved in cGAS-STING pathway and analyzed differentially expressed genes and biochemical recurrence (BCR)-free survival-related genes. The assessments of tumor stemness and heterogeneity and tumor microenvironment (TME) were conducted to reveal potential mechanisms. RESULTS: PCa patients were classified into two distinct subtypes using AURKB, TREX1, and STAT6, and subtype 1 had a worse prognosis than subtype 2 (HR: 21.19, p < 0.001). The findings were validated in the MSKCC2010 cohort. Among subtype 1 and subtype 2, the top ten mutation genes were MUC5B, DNAH9, SLC5A10, ZNF462, USP31, SIPA1L3, PLEC, HRAS, MYOM1, and ITGB6. Gene set variation analysis revealed a high enrichment of the E2F target in subtype 1, and gene set enrichment analysis showed significant enrichment of base excision repair, cell cycle, and DNA replication in subtype 1. TME evaluation indicated that subtype 1 had a significantly higher level of T cells follicular helper and a lower level of plasma cells than subtype 2. CONCLUSIONS: The molecular subtypes mediated by the cGAS-STING pathway and the genetic risk score may aid in identifying potentially high-risk PCa patients who may benefit from pharmacologic therapies targeting the cGAS-STING pathway.

Intraocular cetuximab: Safety and effect on axial elongation in young Guinea pigs with lens-induced myopization.

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2-3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 µg, 12.5 µg, and 25 µg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (-0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.

The gut microbiome modulates the transformation of microglial subtypes.

Clinical and animal studies have shown that gut microbiome disturbances can affect neural function and behaviors via the microbiota-gut-brain axis, and may be implicated in the pathogenesis of several brain diseases. However, exactly how the gut microbiome modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize the cell type-specific transcriptomic changes in the prefrontal cortex and hippocampus derived from germ-free (GF), specific pathogen free, and colonized-GF mice. We found that the absence of gut microbiota resulted in cell-specific transcriptomic changes. Furthermore, microglia transcriptomes were preferentially influenced, which could be effectively reversed by microbial colonization. Significantly, the gut microbiome modulated the mutual transformation of microglial subpopulations in the two regions. Cross-species analysis showed that the transcriptome changes of these microglial subpopulations were mainly associated with Alzheimer's disease (AD) and major depressive disorder (MDD), which were further supported by animal behavioral tests. Our findings demonstrate that gut microbiota mainly modulate the mutual transformation of microglial subtypes, which may lead to new insights into the pathogenesis of AD and MDD.