Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

Mechanistic insights into the C-type lectin receptor CLEC12A-mediated immune recognition of monosodium urate crystal.

CLEC12A, a member of the C-type lectin receptor family involved in immune homeostasis, recognizes MSU crystals released from dying cells. However, the molecular mechanism underlying the CLEC12A-mediated recognition of MSU crystals remains unclear. Herein, we reported the crystal structure of the human CLEC12A-C-type lectin-like domain (CTLD) and identified a unique "basic patch" site on CLEC12A-CTLD that is necessary for the binding of MSU crystals. Meanwhile, we determined the interaction strength between CLEC12A-CTLD and MSU crystals using single-molecule force spectroscopy. Furthermore, we found that CLEC12A clusters at the cell membrane and seems to serve as an internalizing receptor of MSU crystals. Altogether, these findings provide mechanistic insights for understanding the molecular mechanisms underlying the interplay between CLEC12A and MSU crystals.

Designing a Magnesium/Sodium Hybrid Battery Using Hierarchical Iron Selenide Architecture as Cathode Material and Modified Dual-Ion Salts in Ether as Electrolyte.

We developed a magnesium/sodium (Mg/Na) hybrid battery using a hierarchical disk-whisker FeSe2 architecture (HD-FeSe2) as the cathode material and a modified dual-ion electrolyte. The polarizable Se2- anion reduced the Mg2+ migration barrier, and the 3D configuration possessed a large surface area, which facilitated both Mg2+/Na+ cation diffusion and electron transport. The dual-ion salts with NaTFSI in ether reduced the Mg plating/stripping overvoltage in a symmetric cell. The hybrid battery exhibited an energy density of 260.9 Wh kg-1 and a power density of 600.8 W kg-1 at 0.2 A g-1. It showed a capacity retention of 154 mAh g-1 and a Coulombic efficiency of over 99.5% under 1.0 A g-1 after 800 long cycles. The battery also displayed outstanding temperature tolerance. The findings of 3D architecture as cathode material and hybrid electrolyte provide a pathway to design a highly reliable Mg/Na hybrid battery.

A Novel JAK2 Fusion in T-Cell Prolymphocytic Leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.

BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study.

BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Lipidomics Study of Type 1 Diabetic Rats Using Online Phase Transition Trapping-Supercritical Fluid Extraction-Chromatography Coupled with Quadrupole Time-of-Flight Tandem Mass Spectrometry.

Chromatography-mass spectrometry-based lipidomics represents an essential tool for elucidating lipid dysfunction mechanisms and is extensively employed in investigating disease mechanisms and identifying biomarkers. However, the detection of low-abundance lipids in biological matrices, along with cumbersome operational procedures, complicates comprehensive lipidomic analyses, necessitating the development of highly sensitive, environmentally friendly, and automated methods. In this study, an online phase transition trapping-supercritical fluid extraction-chromatography-mass spectrometry (PTT-SFEC-MS/MS) method was developed and successfully applied to plasma lipidomics analysis in Type 1 diabetes (T1D) rats. The PTT strategy captured entire extracts at the column head by converting CO2 from a supercritical state to a gaseous state, thereby preventing peak spreading, enhancing peak shape for precise quantification, and boosting sensitivity without any sample loss. This method utilized only 5 µL of plasma and accomplished sample extraction, separation, and detection within 27 min. Ultimately, 77 differential lipids were identified, including glycerophospholipids, sphingolipids, and glycerolipids, in T1D rat plasma. The results indicated that the progression of the disease might be linked to alterations in glycerophospholipid and sphingolipid metabolism. Our findings demonstrated a green, highly efficient, and automated method for the lipidomics analysis of biological samples, providing a scientific foundation for understanding the pathogenesis and diagnosis of T1D.

Bortezomib restrains M2 polarization and reduces CXCL16-associated CXCR6+CD4 T cell chemotaxis in bleomycin-induced pulmonary fibrosis.

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.

Efficient Strategy for Characterization and Quantification of Polyunsaturated Lipids by Microwave-Assisted MMPP Epoxidation.

Lipids play integral roles in biological processes, with carbon-carbon double bonds (C═C) markedly influencing their structure and function. Precise characterization and quantification of unsaturated lipids are crucial for understanding lipid physiology and discovering disease biomarkers. However, using mass spectrometry for these purposes presents significant challenges. In this study, we developed a microwave-assisted magnesium monoperoxyphthalate hexahydrate (MMPP) epoxidation reaction, coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS), to analyze unsaturated lipids. Microwave irradiation expedited the MMPP epoxidation, achieving complete derivatization in 10 min without byproducts. A diagnostic ion pair, displaying a 16 Da mass difference, effectively identified the location of the C═C bond in mass spectra. Microwave irradiation also significantly facilitated the epoxidation reaction of polyunsaturated lipids, achieving yields greater than 85% and yielding a complete epoxidation product. This simplifies chromatographic separation and aids in accurate quantification. Additionally, a purification process was implemented to remove excess derivatization reagents, significantly reducing mass spectrometry response suppression and enhancing analytical reproducibility. The method's effectiveness was validated by analyzing unsaturated lipids in rat plasma from a type I diabetes model. We quantified nine unsaturated lipids and characterized 42 fatty acids and glycerophospholipids. The results indicated that unsaturated fatty acids increased in diabetic plasma while unsaturated glycerophospholipids decreased. Furthermore, the relative abundances of Δ9/Δ11 isomer pairs also exhibited a close association with diabetes. In conclusion, microwave-assisted MMPP epoxidation coupled with LC-MS/MS provides an effective strategy for characterization and quantification of polyunsaturated lipids, offering deeper insight into the physiological impact of unsaturated lipids in related diseases.

PGRN inhibits CD8+T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM.

BACKGROUND: Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. METHODS: We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn-/-) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. RESULTS: We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. CONCLUSION: These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.

Revealing critical mechanisms in determining sorghum resistance to drought and salt using mRNA, small RNA and degradome sequencing.

BACKGROUND: Plant growth and development are severely threatened by drought and salt stresses. Compared with structural genes, transcription factors (TFs) play more pivotal roles in plant growth and stress adaptation. However, the underlying mechanisms of sorghum adapting to drought and salt are insufficient, and systematic analysis of TFs in response to the above stresses is lacking. RESULTS: In this study, TFs were identified in sorghum and model plants (Arabidopsis thaliana and rice), and gene number and conserved domain were compared between sorghum and model plants. According to syntenic analysis, the expansion of sorghum and rice TFs may be due to whole-genome duplications. Between sorghum and model plants TFs, specific conserved domains were identified and they may be related to functional diversification of TFs. Forty-five key genes in sorghum, including four TFs, were likely responsible for drought adaption based on differently expression analysis. MiR5072 and its target gene (Sobic.001G449600) may refer to the determination of sorghum drought resistance according to small RNA and degradome analysis. Six genes were associated with drought adaptation of sorghum based on weighted gene co-expression network analysis (WGCNA). Similarly, the core genes in response to salt were also characterized using the above methods. Finally, 15 candidate genes, particularly two TFs (Sobic.004G300300, HD-ZIP; Sobic.003G244100, bZIP), involved in combined drought and salt resistance of sorghum were identified. CONCLUSIONS: In summary, the findings in this study help clarify the molecular mechanisms of sorghum responding to drought and salt. We identified candidate genes and provide important genetic resource for potential development of drought-tolerant and salt-tolerant sorghum plants.

Biochar Meets Single-Atom: A Catalyst for Efficient Utilization in Environmental Protection Applications and Energy Conversion.

Single-atom catalysts (SACs), combining the advantages of multiphase and homogeneous catalysis, have been increasingly investigated in various catalytic applications. Carbon-based SACs have attracted much attention due to their large specific surface area, high porosity, particular electronic structure, and excellent stability. As a cheap and readily available carbon material, biochar has begun to be used as an alternative to carbon nanotubes, graphene, and other such expensive carbon matrices to prepare SACs. However, a review of biochar-based SACs for environmental pollutant removal and energy conversion and storage is lacking. This review focuses on strategies for synthesizing biochar-based SACs, such as pre-treatment of organisms with metal salts, insertion of metal elements into biochar, or pyrolysis of metal-rich biomass, which are more simplistic ways of synthesizing SACs. Meanwhile, this paper attempts to 1) demonstrate their applications in environmental remediation based on advanced oxidation technology and energy conversion and storage based on electrocatalysis; 2) reveal the catalytic oxidation mechanism in different catalytic systems; 3) discuss the stability of biochar-based SACs; and 4) present the future developments and challenges regarding biochar-based SACs.

Sustainable All-Day Thermoelectric Power Generation From the Hot Sun and Cold Universe.

Energy conversion from the environment into electricity is the most direct and effective electricity source to sustainably power off-grid electronics, once the electricity requirement exceeds the capability of traditional centralized power supply systems. Normally photovoltaic cells have enabled distributed power generation during the day, but do not work at night. Thus, efficient electricity generation technologies for a sustainable all-day power supply with no necessity for energy storage remain a challenge. Herein, an innovative all-day power generation strategy is reported, which self-adaptively integrates the diurnal photothermal and nocturnal radiative cooling processes into the thermoelectric generator (TEG) via the spectrally dynamic modulated coating, to continuously harvest the energy from the hot sun and the cold universe for power generation. Synergistic with the optimized latent heat phase change material, the electricity generation performance of the TEG is dramatically enhanced, with a maximum power density exceeding 1000 mW m-2 during the daytime and up to 25 mW m-2 during the nighttime, corresponding to an improvement of 123.1% and 249.1%, compared with the conventional strategy. This work maximizes the utilization of ambient energy resources to provide an environmentally friendly and uninterrupted power generation strategy. This opens up new possibilities for sustained power generation both daytime and nighttime.

Dysregulation of mucosal-associated invariant T cells correlates with altered placental microenvironment in preterm birth.

Preterm birth (PTB) is a major problem affecting perinatal health, directly increasing the mortality risk of mother and infant that often results from the breakdown of the maternal-fetal immune balance. Increasing evidence shows the essential role of mucosal-associated invariant T (MAIT) cells to balance antibacterial function and immune tolerance function during pregnancy. However, the phenotype and function of placental MAIT cells and their specific mechanisms in PTB remain unclear. Here, we report that MAIT cells in placentas from PTBs show increased activation levels and decreased IFN-γ secretion capacity compared with those from normal pregnancies. Moreover, our data indicate gravidity is a factor affecting placental MAIT cells during pregnancies. Multi-omics analysis indicated aberrant immune activation and abnormal increase of lipids and lipid-like metabolites in the PTB placental microenvironment. Moreover, the proportion and activation of MAIT cells were positively correlated with the abnormal increase of lipids and lipid-like metabolites. Together, our work revealed that abnormal activation and impaired function of MAIT cells may be related to abnormal elevation of lipids and lipid-like metabolites in PTB.

Integrated analysis of single-cell and bulk RNA sequencing data reveals a myeloid cell-related regulon predicting neoadjuvant immunotherapy response across cancers.

BACKGROUND: Immunotherapy has brought about a paradigm shift in the treatment of cancer. However, the majority of patients exhibit resistance or become refractory to immunotherapy, and the underlying mechanisms remain to be explored. METHODS: Sing-cell RNA sequencing (scRNA­seq) datasets derived from 1 pretreatment and 1 posttreatment achieving pathological complete response (pCR) patient with lung adenocarcinoma (LUAD) who received neoadjuvant immunotherapy were collected, and pySCENIC was used to find the gene regulatory network (GRN) between cell types and immune checkpoint inhibitor (ICI) response. A regulon predicting ICI response was identified and validated using large­scale pan-cancer data, including a colorectal cancer scRNA­seq dataset, a breast cancer scRNA­seq dataset, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 5 ICI transcriptomic cohorts. Symphony reference mapping was performed to construct the myeloid cell map. RESULTS: Thirteen major cluster cell types were identified by comparing pretreatment and posttreatment patients, and the fraction of myeloid cells was higher in the posttreatment group (19.0% vs. 11.8%). A PPARG regulon (containing 23 target genes) was associated with ICI response, and its function was validated by a colorectal cancer scRNA­seq dataset, a breast cancer scRNA­seq dataset, TCGA pan-cancer cohort, and 5 ICI transcriptomic cohorts. Additionally, a myeloid cell map was developed, and cluster I, II, and III myeloid cells with high expression of PPARG were identified. Moreover, we constructed a website called PPARG ( https://pparg.online/PPARG/ or http://43.134.20.130:3838/PPARG/ ), which provides a powerful discovery tool and resource value for researchers. CONCLUSIONS: The PPARG regulon is a predictor of ICI response. The myeloid cell map enables the identification of PPARG subclusters in public scRNA-seq datasets and provides a powerful discovery tool and resource value.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation.

INTRODUCTION: Lung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear. METHODS: Firstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan-Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed. RESULTS: Firstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis. CONCLUSION: Our study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Genomic and transcriptomic profiling of combined small-cell lung cancer through microdissection: unveiling the transformational pathway of mixed subtype.

BACKGROUND: Combined small-cell lung carcinoma (cSCLC) represents a rare subtype of SCLC, the mechanisms governing the evolution of cancer genomes and their impact on the tumor immune microenvironment (TIME) within distinct components of cSCLC remain elusive. METHODS: Here, we conducted whole-exome and RNA sequencing on 32 samples from 16 cSCLC cases. RESULTS: We found striking similarities between two components of cSCLC-LCC/LCNEC (SCLC combined with large-cell carcinoma/neuroendocrine) in terms of tumor mutation burden (TMB), tumor neoantigen burden (TNB), clonality structure, chromosomal instability (CIN), and low levels of immune cell infiltration. In contrast, the two components of cSCLC-ADC/SCC (SCLC combined with adenocarcinoma/squamous-cell carcinoma) exhibited a high level of tumor heterogeneity. Our investigation revealed that cSCLC originated from a monoclonal source, with two potential transformation modes: from SCLC to SCC (mode 1) and from ADC to SCLC (mode 2). Therefore, cSCLC might represent an intermediate state, potentially evolving into another histological tumor morphology through interactions between tumor and TIME surrounding it. Intriguingly, RB1 inactivation emerged as a factor influencing TIME heterogeneity in cSCLC, possibly through neoantigen depletion. CONCLUSIONS: Together, these findings delved into the clonal origin and TIME heterogeneity of different components in cSCLC, shedding new light on the evolutionary processes underlying this enigmatic subtype.

Cough flows as a criterion for decannulation of autonomously breathing patients with tracheostomy tubes.

BACKGROUND: Adequate cough or exsufflation flow can indicate an option for safe tracheostomy decannulation to noninvasive management. Cough peak flow via the upper airways with the tube capped is an outcome predictor for decannulation readiness in patients with neuromuscular impairment. However, this threshold value is typically measured with tracheotomy tube removed, which is not acceptable culturally in China. The aim of this study was to assess the feasibility and safety of using cough flow measured with tracheostomy tube and speaking valve (CFSV) > 100 L/min as a cutoff value for decannulation. STUDY DESIGN: Prospective observational study conducted between January 2019 and September 2022 in a tertiary rehabilitation hospital. METHODS: Patients with prolonged tracheostomy tube placement were referred for screening. Each patient was assessed using a standardized tracheostomy decannulation protocol, in which CFSV greater than 100 L/min indicated that the patients' cough ability was sufficient for decannulation. Patients whose CFSV matched the threshold value and other protocol criteria were decannulated, and the reintubation and mortality rates were followed-up for 6 months. RESULTS: A total of 218 patients were screened and 193 patients were included. A total of 105 patients underwent decannulation, 103 patients were decannulated successfully, and 2 patients decannulated failure, required reinsertion of the tracheostomy tube within 48 h (failure rate 1.9%). Three patients required reinsertion or translaryngeal intubation within 6 months. CONCLUSIONS: CFSV greater than 100 L/min could be a reliable threshold value for successful decannulation in patients with various primary diseases with a tracheostomy tube. TRIAL REGISTRATION: This observational study was not registered online.

A Temperature-Tolerant Magnesium-Ion Battery Using Ball Cactus-like MgV2O4 as High-Performance Cathode.

Safe and high-performance secondary batteries using for all-climate conditions with different temperatures are highly required. Here, we develop a three-dimensional ball cactus-like MgV2O4 as cathode material for magnesium-ion (Mg-ion) batteries. After cycling 300 times, the capacity maintains 111.7 mAh g-1, while Coulombic efficiency stabilizes at about 100 %. Under temperatures of 45 °C and -5 °C, the capacities remain stable after 200 cycles. After three rounds of rate-performance tests, the capacity keeps quite stable. It is ascribed to the ball cactus-like morphology buffers the volumetric change during Mg2+ insertion/extraction, and provides sufficient pathways for ion diffusion, which has been verified by constant-current intermittent titration technology. It is believed that the good performance enables the Mg-ion batteries to have a all-climate capability.

Systematic evaluation of the efficacy of treatments for cesarean scar pregnancy.

STUDY OBJECTIVE: Cesarean scar pregnancy (CSP) is a type of ectopic pregnancy associated with severe complications, including significant hemorrhage, the potential need for hysterectomy, and life-threatening risks. Currently, two classification methods exist for CSP: Vial (type Ia and IIa) and Chinese Expert's Consensus (type Ib, type IIb, and type IIIb). However, these methods have limitations in guiding the selection of appropriate treatment plans for CSP. The purpose of this study was to systematically evaluate the effectiveness of various treatments for CSP within our clinic. METHOD: Our study included 906 patients with CSP from January 2013 to December 2018. The chi-squared test and logistic analysis were used to compare the clinical characteristics. The median and interquartile range (IQR) was calculated. We also analyzed whether preoperative application of methotrexate (MTX) could improve surgical outcomes and the relevant characteristics of misdiagnosed CSP patients. RESULTS: There was a significant difference in gestational age, gestational sac diameter, gestational sac width, gestational sac area, remnant myometrial thickness, vaginal bleeding and preoperative hemoglobin levels (p < 0.001) but not in the incidence of residual tissue (p = 0.053). The other factors (intraoperative blood loss, hemoglobin decline, first hemoglobin after operation, total hospital stay, hospital stay after operation, transfusion and duration of catheter drain) were significantly different (p < 0.001). For type Ia and type Ib CSP, 39.3% and 40.2% of patients were treated with dilatation and curettage (D&E) under ultrasound, respectively. For type IIa and type IIIb CSP, 29.9% and 62.7% of patients were treated with laparotomy, respectively. There were no differences in surgical methods, residual tissue and reoperation between the MTX and non-MTX groups (p = 0.20), but liver damage, hospital stay and pain perception were more remarkable in the MTX group. It is noteworthy that 14% of the patients were misdiagnosed with an intrauterine pregnancy. The incidence of misdiagnosis in type IIa CSP patients was higher than that in type Ia CSP patients (p < 0.001). CONCLUSION: For type I CSP patients, D&E under ultrasound or D&E under hysteroscopy should be recommended. For type IIIb CSP patients, operative resection should be used. It is currently difficult to choose the appropriate treatment methods for type IIa or type IIb CSP patients.

Pectin demethylation-mediated cell wall Na+ retention positively regulates salt stress tolerance in oilseed rape.

KEY MESSAGE: Integrated phenomics, ionomics, genomics, transcriptomics, and functional analyses present novel insights into the role of pectin demethylation-mediated cell wall Na+ retention in positively regulating salt tolerance in oilseed rape. Genetic variations in salt stress tolerance identified in rapeseed genotypes highlight the complicated regulatory mechanisms. Westar is ubiquitously used as a transgenic receptor cultivar, while ZS11 is widely grown as a high-production and good-quality cultivar. In this study, Westar was found to outperform ZS11 under salt stress. Through cell component isolation, non-invasive micro-test, X-ray energy spectrum analysis, and ionomic profile characterization, pectin demethylation-mediated cell wall Na+ retention was proposed to be a major regulator responsible for differential salt tolerance between Westar and ZS11. Integrated analyses of genome-wide DNA variations, differential expression profiling, and gene co-expression networks identified BnaC9.PME47, encoding a pectin methylesterase, as a positive regulator conferring salt tolerance in rapeseed. BnaC9.PME47, located in two reported QTL regions for salt tolerance, was strongly induced by salt stress and localized on the cell wall. Natural variation of the promoter regions conferred higher expression of BnaC9.PME47 in Westar than in several salt-sensitive rapeseed genotypes. Loss of function of AtPME47 resulted in the hypersensitivity of Arabidopsis plants to salt stress. The integrated multiomics analyses revealed novel insights into pectin demethylation-mediated cell wall Na+ retention in regulating differential salt tolerance in allotetraploid rapeseed genotypes. Furthermore, these analyses have provided key information regarding the rapid dissection of quantitative trait genes responsible for nutrient stress tolerance in plant species with complex genomes.