Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer.

BACKGROUND: Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME. METHODS: We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes. RESULTS: Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0-12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97-18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006). The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib. ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1ß.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy. CONCLUSIONS: In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Microbes in lung cancer initiation, treatment, and outcome: Boon or bane?

Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.

Aberrant methylation modifications reflect specific drug responses in small cell lung cancer.

In the study, Methylated DNA immunoprecipitation sequencing, RNA sequencing, and whole-exome sequencing were employed to clinical small cell lung cancer (SCLC) patients. Then, we verified the therapeutic predictive effects of differentially methylated genes (DMGs) in 62 SCLC cell lines. Of 4552 DMGs between chemo-sensitive and chemo-insensitive group, coding genes constituted the largest percentage (85.08%), followed by lncRNAs (10.52%) and miRNAs (3.56%). Both two groups demonstrated two methylation peaks near transcription start site and transcription end site. Two lncRNA-miRNA-mRNA networks suggested the extensive genome connection between chemotherapy efficacy-related non-coding RNAs (ncRNAs) and mRNAs. Combing miRNAs and lncRNAs could effectively predict chemotherapy response in SCLC. In addition, we also verified the predictive values of mutated genes in SCLC cell lines. This study was the first to evaluate multiple drugs efficacy-related ncRNAs and mRNAs which were modified by methylation in SCLC. DMGs identified in our research might serve as promising therapeutic targets to reverse drugs-insensitivity by complex lncRNA-miRNA-mRNA mechanisms in SCLC.

The Ideal Nasion in Chinese: A Preference Analysis of the General Population.

Augmentation rhinoplasty has gained popularity in China in the past decades and nasion profile is a key variable in aesthetic outcomes. The nasion is the deepest portion of the nasofrontal groove and its aesthetic preferences vary between different ethnic groups. At the time of this writing, there is limited research about ideal nasion measurements in the Chinese population. Therefore, we conducted an online survey of plastic surgeons and the public through social media. Participants were asked to rank nasion images according to their preferences. Images were created from a 3-dimensional scan of a Chinese Han female and modified to show various dimensions of nasion height, position, and forehead height. Nasion preferences were compared by age, sex, ethnicity, occupation, and whether had a history of plastic surgery. There were 777 respondents, including 461 (59.3%) women and 74 (9.5%) plastic surgeons. Nasion height of 8 and 10 mm ranked highest among all demographic groups. All respondents preferred nasion position to be level with the center of the pupil and forehead height of 4 mm above the nasion. Our study showed that the ideal Chinese nasion is in line with baseline ethnic characteristics. Therefore, plastic surgeons must be aware of these nasion preferences to guide preoperative discussions and achieve satisfactory outcomes.

The distinct effects of two imidazolium-based ionic liquids, [C4mim][OAc] and [C6mim][OAc], on the phase behaviours of DPPC.

Ionic liquids (ILs) are potential green solvents with very broad application prospects. Their toxicity and other biological effects are largely related to their hydrophobic properties. In this work, the effects of two imidazolium-based ILs with either a butyl or a hexyl chain, [C4mim][OAc] or [C6mim][OAc], on the phase behaviours of a representative phospholipid, dipalmitoylphosphatidylcholine (DPPC), were examined using synchrotron small- and wide-angle X-ray scattering and differential scanning calorimetry techniques. A series of samples with a lipid : IL molar ratio ranging from 1 : 0 to 1 : 4/1 : 5 were prepared as aqueous dispersions in the form of multi-lamellar vesicles. The two ILs were found to have distinct effects on the phase behaviours of DPPC. For [C4mim][OAc], its effect is very limited. In contrast, for [C6mim][OAc], it could eliminate the pre-transition of DPPC, markedly affect the main phase transition of the lipid, and insert into the DPPC bilayer at gel state to form an interdigitated gel phase. The findings increased our understanding on the biological effects of imidazolium-based ILs and might shed light on the design of novel IL-based antimicrobials.

Solution-Based, Anion-Doping of Li4 Ti5 O12 Nanoflowers for Lithium-Ion Battery Applications.

Solution-based, anionic doping represents a convenient strategy with which to improve upon the conductivity of candidate anode materials such as Li4 Ti5 O12 (LTO). As such, novel synthetic hydrothermally-inspired protocols have primarily been devised herein, aimed at the large-scale production of unique halogen-doped, micron-scale, three-dimensional, hierarchical LTO flower-like motifs. Although fluorine (F) doping has been explored, the use of chlorine (Cl) dopants is the primary focus here. Several experimental variables, such as dopant amount, lithium hydroxide concentration, and titanium butoxide purity, were probed and perfected. Furthermore, the Cl doping process did not damage the intrinsic LTO morphology. The analysis, based on interpreting a compilation of SEM, XRD, XPS, and TEM-EDS results, was used to determine an optimized dopant concentration of Cl. Electrochemical tests demonstrated an increased capacity via cycling of 12 % for a Cl-doped sample as compared with pristine LTO. Moreover, the Cl-doped LTO sample described in this study exhibited the highest discharge capacity yet reported at an observed rate of 2C for this material at 143mAh g-1 . Overall, these data suggest that the Cl dopant likely enhances not only the ion transport capabilities, but also the overall electrical conductivity of our as-prepared structures. To help explain these favorable findings, theoretical DFT calculations were used to postulate that the electronic conductivity and Li diffusion were likely improved by the presence of increased Ti3+ ion concentration coupled with widening of the Li migration channel.

Fabrication of Asymmetric Phosphatidylserine-Containing Lipid Vesicles: A Study on the Effects of Size, Temperature, and Lipid Composition.

The asymmetric distribution of lipids in plasma membranes is closely related to the physiological functions of cells. To improve our previous approach in fabricating asymmetric vesicles, we defined a parameter, asymmetric degree, in this work and investigated the effects of vesicle size, incubation temperature, and lipid composition on the formation process of asymmetric phosphatidylserine (PS)-containing lipid vesicles. The results indicate that all of the three factors have marked but different effects on the time-dependent asymmetric degree of the vesicles as well as the flip and flop rate constants of the PS lipids. However, only vesicle size and PS content show significant influence on the maximal asymmetric degree of the vesicles, while the incubation temperature exhibits negligible effect. This work not only deepens our understanding on the packing property of PS molecules in self-assembled membranes and the formation mechanism of asymmetric vesicles but also practically provides a solution to regulate the asymmetric degree of the PS-containing vesicles using the established kinetic equation. In addition, the method would facilitate researches related to asymmetric vesicles or reconstruction of biological membranes.

(De)lithiation of spinel ferrites Fe3O4, MgFe2O4, and ZnFe2O4: a combined spectroscopic, diffraction and theory study.

Iron based materials hold promise as next generation battery electrode materials for Li ion batteries due to their earth abundance, low cost, and low environmental impact. The iron oxide, magnetite Fe3O4, adopts the spinel (AB2O4) structure. Other 2+ cation transition metal centers can also occupy both tetrahedral and/or octahedral sites in the spinel structure including MgFe2O4, a partially inverse spinel, and ZnFe2O4, a normal spinel. Though structurally similar to Fe3O4 in the pristine state, previous studies suggest significant differences in structural evolution depending on the 2+ cation in the structure. This investigation involves X-ray absorption spectroscopy and X-ray diffraction affirmed by density functional theory (DFT) to elucidate the role of the 2+ cation on the structural evolution and phase transformations during (de)lithiation of the spinel ferrites Fe3O4, MgFe2O4, and ZnFe2O4. The cation in the inverse, normal and partially inverse spinel structures located in the tetrahedral (8a) site migrates to the previously unoccupied octahedral 16c site by 2 electron equivalents of lithiation, resulting in a disordered [A]16c[B2]16dO4 structure. DFT calculations support the experimental results, predicting full displacement of the 8a cation to the 16c site at 2 electron equivalents. Substitution of the 2+ cation results in segregation of oxidized phases in the charged state. This report provides significant structural insight into the (de)lithiation mechanisms for an intriguing class of iron oxide materials.

Extraction of molecular features for the drug discovery targeting protein-protein interaction of Helicobacter pylori CagA and tumor suppressor protein ASSP2.

Half of the world population is infected by the Gram-negative bacterium Helicobacter pylori (H. pylori). It colonizes in the stomach and is associated with severe gastric pathologies including gastric cancer and peptic ulceration. The most virulent factor of H. pylori is the cytotoxin-associated gene A (CagA) that is injected into the host cell. CagA interacts with several host proteins and alters their function, thereby causing several diseases. The most well-known target of CagA is the tumor suppressor protein ASPP2. The subdomain I at the N-terminus of CagA interacts with the proline-rich motif of ASPP2. Here, in this study, we carried out alanine scanning mutagenesis and an extensive molecular dynamics simulation summing up to 3.8 µs to find out hot spot residues and discovered some new protein-protein interaction (PPI)-modulating molecules. Our findings are in line with previous biochemical studies and further suggested new residues that are crucial for binding. The alanine scanning showed that mutation of Y207 and T211 residues to alanine decreased the binding affinity. Likewise, dynamics simulation and molecular mechanics with generalized Born surface area (MMGBSA) analysis also showed the importance of these two residues at the interface. A four-feature pharmacophore model was developed based on these two residues, and top 10 molecules were filtered from ZINC, NCI, and ChEMBL databases. The good binding affinity of the CHEMBL17319 and CHEMBL1183979 molecules shows the reliability of our adopted protocol for binding hot spot residues. We believe that our study provides a new insight for using CagA as the therapeutic target for gastric cancer treatment and provides a platform for a future experimental study.

A first principles study of spinel ZnFe2O4 for electrode materials in lithium-ion batteries.

Zinc ferrite (ZnFe2O4) is a prospective lithium ion battery (LIB) material, owing to its large theoretical capacity (1000 mA h g-1). Here, we report a density functional study of the discharge process at an early stage from ZnFe2O4 up to LixZnFe2O4 (x = 2), aiming to provide a fundamental understanding of the mechanism. According to our calculations, with x increasing up to 1 the intercalation of Li+ ions prefers octahedral 16c sites, which is accompanied by Zn2+ ion displacement from tetrahedral 8a sites to 16c sites starting at x = 0.25 and a gain in stability, while the stability decreases for 1 < x ≤ 2 due to the occupation of Li+ ions at the less active tetrahedral 8a/48f/8b sites. The open-circuit voltages estimated based on the structures of stable intermediates identified by DFT calculations are in good agreement with the experimental values. Our results highlight the importance of the interplay among Li, O2-, Fe3+ and Zn2+ in enabling their high performance as LIB materials.

In Situ Visualization of Lipid Raft Domains by Fluorescent Glycol Chitosan Derivatives.

Lipid rafts are highly ordered small microdomains mainly composed of glycosphingolipids, cholesterol, and protein receptors. Optically distinguishing lipid raft domains in cell membranes would greatly facilitate the investigations on the structure and dynamics of raft-related cellular behaviors, such as signal transduction, membrane transport (endocytosis), adhesion, and motility. However, current strategies about the visualization of lipid raft domains usually suffer from the low biocompatibility of the probes, invasive detection, or ex situ observation. At the same time, naturally derived biomacromolecules have been extensively used in biomedical field and their interaction with cells remains a long-standing topic since it is closely related to various fundamental studies and potential applications. Herein, noninvasive visualization of lipid raft domains in model lipid bilayers (supported lipid bilayers and giant unilamellar vesicles) and live cells was successfully realized in situ using fluorescent biomacromolecules: the fluorescein isothiocyanate (FITC)-labeled glycol chitosan molecules. We found that the lipid raft domains in model or real membranes could be specifically stained by the FITC-labeled glycol chitosan molecules, which could be attributed to the electrostatic attractive interaction and/or hydrophobic interaction between the probes and the lipid raft domains. Since the FITC-labeled glycol chitosan molecules do not need to completely insert into the lipid bilayer and will not disturb the organization of lipids, they can more accurately visualize the raft domains as compared with other fluorescent dyes that need to be premixed with the various lipid molecules prior to the fabrication of model membranes. Furthermore, the FITC-labeled glycol chitosan molecules were found to be able to resist cellular internalization and could successfully visualize rafts in live cells. The present work provides a new way to achieve the imaging of lipid rafts and also sheds new light on the interaction between biomacromolecules and lipid membranes.

Integration of MoS2 Memtransistor Devices and Analogue Circuits for Sensor Fusion in Autonomous Vehicle Target Localization.

In contemporary autonomous driving systems relying on sensor fusion, traditional digital processors encounter challenges associated with analogue-to-digital conversion and iterative vector-matrix operations, which are encumbered by limitations in terms of response time and energy consumption. In this study, we present an analogue Kalman filter circuit based on molybdenum disulfide (MoS2) memtransistor, designed to accelerate sensor fusion for precise localization in autonomous vehicle applications. The nonvolatile memory characteristics of the memtransistor allow for the storage of a fixed Kalman gain, which eliminates the data convergence and thus accelerates the processing speeds. Additionally, the modulation of multiple conductance states by the gate terminal enables fast adaptability to diverse autonomous driving scenarios by tuning multiple Kalman filter gains. Our proposed analogue Kalman filter circuit accurately estimates the position coordinates of target vehicles by fusing sensor data from light detection and ranging (LiDAR), millimeter-wave radar (Radar), and camera, and it successfully solves real-word problems in a signal-free crossroad intersection. Notably, our system achieves a 1000-fold improvement in energy efficiency compared to that of digital circuits. This work underscores the viability of a memtransistor for achieving fast, energy-efficient real-time sensing, and continuous signal processing in advanced sensor fusion technology.

Comprehensive analysis of clinicopathological profiles in adenosquamous carcinoma of the lung.

OBJECTIVES: Adenosquamous carcinoma (ASC), an uncommon subtype within non-small cell lung cancer (NSCLC), manifests distinctive traits of aggressiveness, embodying a fusion of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. The clinicopathological characteristics of distinct subtypes of ASC remain unclear. METHODS: This retrospective study included 226 patients diagnosed with lung ASC who consecutively underwent surgical resection at Shanghai Pulmonary Hospital, Tongji University, between January 2015 and March 2021. Data regarding the clinical features and pathological features were collected. RESULTS: Out of this study cohort, 125 patients exhibited AC-predominant ASC, while 81 had SCC-predominant ASC. No significant differences were observed between the two subgroups in terms of age, gender, smoking history, primary site, and T, N classification. AC-Predominant ASC displayed a higher susceptibility to genetic alterations compared to SCC-Predominant ASC (P=0.02). Additionally, we showed that irrespective of the predominant pathological subtype in ASC, when lymph node metastasis occurred, the lymph node biopsies were more likely to exhibit AC, and a chi-square test confirmed that the primary predominant pathological subtype was not associated with the lymph node metastasis subtype. CONCLUSIONS: In conclusion, we describe an overview of ASC in the Chinese population, and upon stratifying into predominant pathological subgroups, we observed a higher frequency of driver gene mutations in AC-predominant ASC. We found that the AC component in ASC has a higher propensity for lymph node metastasis. These findings may suggest the predominant role of the AC component within the context of ASC.

Progress in Research on Key Factors Regulating Lactation Initiation in the Mammary Glands of Dairy Cows.

Lactation initiation refers to a functional change in the mammary organ from a non-lactating state to a lactating state, and a series of cytological changes in the mammary epithelium from a non-secreting state to a secreting state. Like the development of the mammary gland, it is regulated by many factors (including hormones, cytokines, signaling molecules, and proteases). In most non-pregnant animals, a certain degree of lactation also occurs after exposure to specific stimuli, promoting the development of their mammary glands. These specific stimuli can be divided into two categories: before and after parturition. The former inhibits lactation and decreases activity, and the latter promotes lactation and increases activity. Here we present a review of recent progress in research on the key factors of lactation initiation to provide a powerful rationale for the study of the lactation initiation process and mammary gland development.

YAP1 expression is associated with survival and immunosuppression in small cell lung cancer.

Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of malignancy and high heterogeneity, SCLC is difficult to treat in the clinic. A new combination strategy is urgently needed to further improve the efficacy of immunotherapy in patients with SCLC. By immunofluorescence, 100 SCLC patients in a local cohort were classified into the SCLC-A (high ASCL1 expression; n = 36), SCLC-N (high NEUROD1 expression; n = 32), SCLC-P (high POU2F3 expression; n = 14), and SCLC-Y (high YAP1 expression; n = 18) subtypes. Each SCLC molecular subtype represented different prognoses, tumor microenvironment traits, and immunotherapy sensitivities. Analysis of both the local and public cohorts suggested that the SCLC-Y subtype exhibited the worst clinical outcome (p < 0.05) when compared with other subtypes. SCLC with high YAP1 expression was characterized by high PD-L1 expression, high stromal score, T-cell functional impairment, and a close relationship with immune-related pathways. YAP1 upregulated PD-L1 expression and suppressed T cell activation, thus leading to immune evasion. In in vitro experiments, blockade of YAP1 promoted cancer cell apoptosis, immune cell proliferation, T-cell activation, and cytotoxic T-cell infiltration, thus further potentiating the efficacy of immunotherapy in patients with the SCLC-Y subtype.

Tumour microenvironment changes after osimertinib treatment resistance in non-small cell lung cancer.

BACKGROUND: Growing evidence suggests that acquired resistance to targeted therapy in non-small cell lung cancer patients is linked to the mutual domestication between the tumour and its surrounding microenvironment. AIM: Our study aims to explore the remodelling of tumour microenvironment after osimertinib treatment resistance. METHODS: We took RNA-seq-based tumour immune infiltration analysis using the TIMER 2.0. We carried out flow cytometry assay and real-time cell analysis to explore the interaction between tumour cells and immune cells. In addition, we analysed exosomes via miRNA-seq and label-free proteomics. RESULTS: Immune infiltration estimation showed a significant decrease in the immune score (P < 0.001), microenvironment score (P < 0.001) and CD8+ T cells (P < 0.05), but an increase in M0 macrophages (P < 0.01) at osimertinib resistance compared to pre-treatment patients. It was demonstrated that exosomes from H1975OR cells could be taken up by macrophages and drove their polarisation towards the M2 phenotype, and the polarised M2 macrophages could reduce the inhibitory effect on tumour cell proliferation. Pre-activated peripheral blood mononuclear cells exhibited a more potent killing effect on H1975OR cells. We also detected a decrease in CD4+HLA-DR- T cells and an increase in CD4+PD1+ T cells after being co-cultured with H1975OR derived exosomes or conditioned medium. Further miRNA-seq and proteomics analysis of exosomes demonstrated that mir-1258-3p and miR-17-5p might participate in this interaction. CONCLUSIONS: An immunosuppressive environment, characterised by decreased T cell infiltration and activation, whereas increased macrophage infiltration and M2 polarisation, was identified at osimertinib resistance. This interaction may be carried out by tumour-derived exosomes.

Simulated sulfur K-edge X-ray absorption spectroscopy database of lithium thiophosphate solid electrolytes.

X-ray absorption spectroscopy (XAS) is a premier technique for materials characterization, providing key information about the local chemical environment of the absorber atom. In this work, we develop a database of sulfur K-edge XAS spectra of crystalline and amorphous lithium thiophosphate materials based on the atomic structures reported in Chem. Mater., 34, 6702 (2022). The XAS database is based on simulations using the excited electron and core-hole pseudopotential approach implemented in the Vienna Ab initio Simulation Package. Our database contains 2681 S K-edge XAS spectra for 66 crystalline and glassy structure models, making it the largest collection of first-principles computational XAS spectra for glass/ceramic lithium thiophosphates to date. This database can be used to correlate S spectral features with distinct S species based on their local coordination and short-range ordering in sulfide-based solid electrolytes. The data is openly distributed via the Materials Cloud, allowing researchers to access it for free and use it for further analysis, such as spectral fingerprinting, matching with experiments, and developing machine learning models.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer harboring BRAF mutations.

Background: Despite immune checkpoint inhibitors (ICI) being widely used to treat patients with advanced non-small cell lung cancer (NSCLC), few studies examine the role of ICI in patients with proto-oncogene B-Raf, serine/threonine kinase (BRAF) mutations. Methods: A retrospective study was conducted for patients with BRAF-mutant NSCLC who received treatment at Shanghai Pulmonary Hospital between 2014 and 2022. Primary end point was progression-free survival (PFS). Secondary end point was best response (RECIST, version 1.1). Results: The study involved a total of 34 patients with 54 treatments recorded. The median PFS for the whole cohort was 5.8 months and the overall objective response rate (ORR) was 24%. Patients who were treated with ICI combined with chemotherapy reported a median PFS of 12.6 months and an ORR of 44%. Those who were treated with non-ICI therapy came with a median PFS of 5.3 months and an ORR of 14%. Specifically, patients had better clinical benefits with first-line ICI-combined therapy. The PFS was 18.5 months whereas that of non-ICI group was 4.1 months. The ORR was 56% in ICI-combined group and 10% in non-ICI cohort. Conclusions: The findings observed an evidential and significant susceptibility to ICIs combined therapy in patients with BRAF-mutant NSCLC, especially in first-line treatment.

Single-Cell Profiling of Tumor-Associated Neutrophils in Advanced Non-Small Cell Lung Cancer.

Purpose: Neutrophils act as a non-negligible regulator in the initiation and progression of malignancies, playing bifacial roles in the process. Thus, to understand the heterogeneity of tumor-associated neutrophils (TANs) comprehensively in advanced non-small cell lung cancer (NSCLC) at single-cell resolution is necessary and urgent. Materials and Methods: We applied single-cell RNA-sequencing (scRNA-seq) to portray the subtype-specific transcriptome landscape of TANs in advanced NSCLC using nine freshly obtained specimens. The scRNA-seq data were further processed for pseudo-time analysis to depict the developmental trajectory of TANs. Meanwhile, the interplay between TANs and other cell types within tumor microenvironment (TME) was revealed by intercellular interaction analysis. Results: Seven distinct TAN subtypes were defined, of which, the N3 cluster was considered inflammatory phenotype expressing genes encoding multiple chemotactic cytokines, and correlated with inferior overall survival, indicating that N3 might be a pro-tumorigenic TAN subtype. N1 and N5 clusters were considered to be well differentiated and mature neutrophils based on CXCR2 expression and pseudo-time patterns, and both accounted for relatively high proportions in lung adenocarcinoma. In addition, genes related to neutrophil differentiation were discovered. We also found that TAN subtypes interacted most closely with macrophages through chemokine signaling pathways within TME. Conclusion: Our study refined TAN subtypes and mapped the transcriptome landscape of TANs at single-cell resolution in advanced NSCLC, collectively indicating the heterogeneity of TANs in NSCLC. Neutrophil differentiation- and maturation-related genes were also discovered, which shed light on different functions of TAN subclones in tumor immune escape, and may further provide novel targets for immunotherapy.

Artificial Intelligence-Aided Mapping of the Structure-Composition-Conductivity Relationships of Glass-Ceramic Lithium Thiophosphate Electrolytes.

Lithium thiophosphates (LPSs) with the composition (Li2S) x (P2S5)1-x are among the most promising prospective electrolyte materials for solid-state batteries (SSBs), owing to their superionic conductivity at room temperature (>10-3 S cm-1), soft mechanical properties, and low grain boundary resistance. Several glass-ceramic (gc) LPSs with different compositions and good Li conductivity have been previously reported, but the relationship among composition, atomic structure, stability, and Li conductivity remains unclear due to the challenges in characterizing noncrystalline phases in experiments or simulations. Here, we mapped the LPS phase diagram by combining first-principles and artificial intelligence (AI) methods, integrating density functional theory, artificial neural network potentials, genetic-algorithm sampling, and ab initio molecular dynamics simulations. By means of an unsupervised structure-similarity analysis, the glassy/ceramic phases were correlated with the local structural motifs in the known LPS crystal structures, showing that the energetically most favorable Li environment varies with the composition. Based on the discovered trends in the LPS phase diagram, we propose a candidate solid-state electrolyte composition, (Li2S) x (P2S5)1-x (x ∼ 0.725), that exhibits high ionic conductivity (>10-2 S cm-1) in our simulations, thereby demonstrating a general design strategy for amorphous or glassy/ceramic solid electrolytes with enhanced conductivity and stability.