Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment.

The tumor microenvironment (TME) directly determines patients' outcomes and therapeutic efficiencies. An in-depth understanding of the TME is required to improve the prognosis of patients with cervical cancer (CC). This study conducted single-cell RNA and TCR sequencing of six-paired tumors and adjacent normal tissues to map the CC immune landscape. T and NK cells were highly enriched in the tumor area and transitioned from cytotoxic to exhaustion phenotypes. Our analyses suggest that cytotoxic large-clone T cells are critical effectors in the antitumor response. This study also revealed tumor-specific germinal center B cells associated with tertiary lymphoid structures. A high-germinal center B cell proportion in patients with CC is predictive of improved clinical outcomes and is associated with elevated hormonal immune responses. We depicted an immune-excluded stromal landscape and established a joint model of tumor and stromal cells to predict CC patients' prognosis. The study revealed tumor ecosystem subsets linked to antitumor response or prognosis in the TME and provides information for future combinational immunotherapy.

Pseudorabies virus upregulates low-density lipoprotein receptors to facilitate viral entry.

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease in pigs. The low-density lipoprotein receptor (LDLR) is a transcriptional target of the sterol-regulatory element-binding proteins (SREBPs) and participates in the uptake of LDL-derived cholesterol. However, the involvement of LDLR in PRV infection has not been well characterized. We observed an increased expression level of LDLR mRNA in PRV-infected 3D4/21, PK-15, HeLa, RAW264.7, and L929 cells. The LDLR protein level was also upregulated by PRV infection in PK-15 cells and in murine lung and brain. The treatment of cells with the SREBP inhibitor, fatostatin, or with SREBP2-specific small interfering RNA prevented the PRV-induced upregulation of LDLR expression as well as viral protein expression and progeny virus production. This suggested that PRV activated SREBPs to induce LDLR expression. Furthermore, interference in LDLR expression affected PRV proliferation, while LDLR overexpression promoted it. This indicated that LDLR was involved in PRV infection. The study also demonstrated that LDLR participated in PRV invasions. The overexpression of LDLR or inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to LDLR and targets it for lysosomal degradation, significantly enhanced PRV attachment and entry. Mechanistically, LDLR interacted with PRV on the plasma membrane, and pretreatment of cells with LDLR antibodies was able to neutralize viral entry. An in vivo study indicated that the treatment of mice with the PCSK9 inhibitor SBC-115076 promoted PRV proliferation. The data from the study indicate that PRV hijacks LDLR for viral entry through the activation of SREBPs.IMPORTANCEPseudorabies virus (PRV) is a herpesvirus that primarily manifests as fever, pruritus, and encephalomyelitis in various domestic and wild animals. Owing to its lifelong latent infection characteristics, PRV outbreaks have led to significant financial setbacks in the global pig industry. There is evidence that PRV variant strains can infect humans, thereby crossing the species barrier. Therefore, gaining deeper insights into PRV pathogenesis and developing updated strategies to contain its spread are critical. This study posits that the low-density lipoprotein receptor (LDLR) could be a co-receptor for PRV infection. Hence, strategies targeting LDLR may provide a promising avenue for the development of effective PRV vaccines and therapeutic interventions.

TISCH2: expanded datasets and new tools for single-cell transcriptome analyses of the tumor microenvironment.

The Tumor Immune Single Cell Hub 2 (TISCH2) is a resource of single-cell RNA-seq (scRNA-seq) data from human and mouse tumors, which enables comprehensive characterization of gene expression in the tumor microenvironment (TME) across multiple cancer types. As an increasing number of datasets are generated in the public domain, in this update, TISCH2 has included 190 tumor scRNA-seq datasets covering 6 million cells in 50 cancer types, with 110 newly collected datasets and almost tripling the number of cells compared with the previous release. Furthermore, TISCH2 includes several new functions that allow users to better utilize the large-scale scRNA-seq datasets. First, in the Dataset module, TISCH2 provides the cell-cell communication results in each dataset, facilitating the analyses of interacted cell types and the discovery of significant ligand-receptor pairs between cell types. TISCH2 also includes the transcription factor analyses for each dataset and visualization of the top enriched transcription factors of each cell type. Second, in the Gene module, TISCH2 adds functions for identifying correlated genes and providing survival information for the input genes. In summary, TISCH2 is a user-friendly, up-to-date and well-maintained data resource for gene expression analyses in the TME. TISCH2 is freely available at http://tisch.comp-genomics.org/.

A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies.

We described the diagnosis and treatment of a patient with autoinflammatory disease, named "Deficiency in ELF4, X-linked (DEX)". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-ß activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet's-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-ß responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.

Ca2 Ln(BS3 )(SiS4 ) (Ln = La, Ce, and Gd): Mixed Metal Thioborate-Thiosilicates as Well-Performed Infrared Nonlinear Optical Materials.

The first examples of thioborate-thiosilicates, namely Ca2 Ln(BS3 )(SiS4 ) (Ln = La, Ce, and Gd), are synthesized by rationally designed high-temperature solid-state reactions. They crystalize in the polar space group P63 mc and feature a novel three-dimensional crystal structure in which the discrete [BS3 ]3- and [SiS4 ]4- anionic groups are linked by Ca2+ and Ln3+ cations occupying the same atomic site. Remarkably, all three compounds show comprehensive properties required as promising infrared nonlinear optical materials, including phase-matchable strong second harmonic generation (SHG) responses at 2.05 µm (1.1-1.2 times that of AgGaS2 ), high laser-induced damage thresholds (7-10 times that of AgGaS2 ), wide light transmission range (0.45-11 µm), high thermal stabilities (>800 °C), and large calculated birefringence (0.126-0.149 @1064 nm), which justify the material design strategy of combining [BS3 ]3- and [SiS4 ]4- active units. Theoretical calculations suggest that their large SHG effects originate mainly from the synergy effects of the LnS6 , BS3 , and SiS4 groups. This work not only broadens the scope of research on metal chalcogenides but also provides a new synthetic route for mixed anionic thioborates.

Ticagrelor with or without aspirin following percutaneous coronary intervention in high-risk patients with concomitant peripheral artery disease: A subgroup analysis of the TWILIGHT randomized clinical trial.

BACKGROUND: The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI. METHODS: In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization. RESULTS: Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P-value .830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P-value .446). CONCLUSIONS: Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. CLINICAL TRIAL REGISTRY INFORMATION:: https://www. CLINICALTRIALS: gov/study/NCT02270242.

Impact of Pulmonary Ventilation Dysfunction on Prognosis of Patients with Coronary Artery Disease: A Single-Center, Observational Study.

Background: Patients with coronary artery disease (CAD) often experience pulmonary ventilation dysfunction following their initial event. However, there is insufficient research exploring the relationship between this dysfunction and CAD prognosis. Methods: To address this gap, a retrospective observational study was conducted involving 3800 CAD patients without prior pulmonary ventilation disease who underwent cardiopulmonary exercise testing (CPET) during hospitalization between November 2015 and September 2021. The primary endpoint was a composite of major adverse cardiovascular events (MACE), such as death, myocardial infarction (MI), repeat revascularization, and stroke. Propensity score matching (PSM) was used to minimize selection bias between the two groups, with a subgroup analysis stratified by smoking status. Results: The results showed that patients were divided into normal (n = 2159) and abnormal (n = 1641) groups based on their pulmonary ventilation function detected by CPET, with 1469 smokers and 2331 non-smokers. The median follow-up duration was 1237 (25-75% interquartile range 695-1596) days. The primary endpoint occurred in 390 patients (10.26%). 1472 patients in each of the two groups were enrolled in the current analysis after PSM, respectively. However, pulmonary function was not associated with MACE before (hazard ratio (HR) 1.20, 95% confidence interval (95% CI) 0.99-1.47; Log-rank p = 0.069) or after PSM (HR 1.07, 95% CI 0.86-1.34; Log-rank p = 0.545) among the entire population. Nonetheless, pulmonary ventilation dysfunction was significantly associated with an increased risk of MACE in smoking patients (HR 1.65, 95% CI 1.25-2.18; p < 0.001) but not in non-smoking patients (HR 0.81, 95% CI 0.60-1.09; p = 0.159). In addition, there was a significant interaction between current smoking status and pulmonary ventilation dysfunction on MACE (p for interaction < 0.001). Conclusions: Pulmonary ventilation dysfunction identified through CPET was independently associated with long-term poor prognosis in smoking patients with CAD but not in the overall population.

Vagus nerve stimulation (VNS) preventing postoperative cognitive dysfunction (POCD): two potential mechanisms in cognitive function.

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis.

Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.

Silver Nanoparticles Encapped by Dihydromyricetin: Optimization of Green Synthesis, Characterization, Toxicity, and Anti-MRSA Infection Activities for Zebrafish (Danio rerio).

To achieve the environmentally friendly and rapid green synthesis of efficient and stable AgNPs for drug-resistant bacterial infection, this study optimized the green synthesis process of silver nanoparticles (AgNPs) using Dihydromyricetin (DMY). Then, we assessed the impact of AgNPs on zebrafish embryo development, as well as their therapeutic efficacy on zebrafish infected with Methicillin-resistant Staphylococcus aureus (MRSA). Transmission electron microscopy (TEM) and dynamic light-scattering (DLS) analyses revealed that AgNPs possessed an average size of 23.6 nm, a polymer dispersity index (PDI) of 0.197 ± 0.0196, and a zeta potential of -18.1 ± 1.18 mV. Compared to other published green synthesis products, the optimized DMY-AgNPs exhibited smaller sizes, narrower size distributions, and enhanced stability. Furthermore, the minimum concentration of DMY-AgNPs required to affect zebrafish hatching and survival was determined to be 25.0 µg/mL, indicating the low toxicity of DMY-AgNPs. Following a 5-day feeding regimen with DMY-AgNP-containing food, significant improvements were observed in the recovery of the gills, intestines, and livers in MRSA-infected zebrafish. These results suggested that optimized DMY-AgNPs hold promise for application in aquacultures and offer potential for further clinical use against drug-resistant bacteria.

[Analysis of 41 cases of non-metastatic Ewing's sarcoma in children]. / 儿童非转移性尤文肉瘤41例分析.

OBJECTIVES: To summarize the clinical characteristics, treatment outcomes, and prognostic factors of children with non-metastatic Ewing's sarcoma (ES). METHODS: A retrospective analysis was conducted on the clinical data of 41 children with non-metastatic ES diagnosed and treated at the Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2018. All patients underwent chemotherapy based on the RMS-2009 protocol of the center, and local treatment such as surgery and/or radiotherapy was performed according to risk grouping. The Kaplan-Meier method was used to calculate the overall survival (OS) and event-free survival (EFS) rates. Univariate prognostic analysis was performed using the log-rank test, and multivariate analysis was conducted with Cox regression. RESULTS: Of the 41 children, 21 were male and 20 were female. The median age at diagnosis was 7.7 years (range: 1.2-14.6 years). The median follow-up time for patients with event-free survival was 68.1 months (range: 8.1-151.7 months). As of the last follow-up, 33 patients were in complete remission, and the overall 5-year EFS and OS rates were (78±6)% and (82±6)%, respectively. Univariate analysis by the log-rank test showed that a tumor diameter ≥8 cm, time from diagnosis to start of local treatment ≥16 weeks, and incomplete surgical resection were associated with poor prognosis (P<0.05). Multivariate Cox regression analysis indicated that incomplete surgical resection (HR=8.381, 95%CI: 1.681-41.801, P=0.010) was an independent risk factor for poor prognosis in children with ES. Secondary tumors occurred in 2 cases. CONCLUSIONS: A comprehensive treatment strategy incorporating chemotherapy, surgery, and radiotherapy can improve the prognosis of children with ES. Poor prognosis is associated with an initial tumor diameter ≥8 cm, while complete surgical resection and early initiation of local treatment can improve outcomes.

Advanced glycation end products initiate the mutual promoting cycle between centrosome amplification and the release of inflammatory cytokines in human vascular endothelial cells.

Inflammation is implicated in the development of diabetic complications including vascular pathology. Centrosome is known to play a role in cell secretion. We have reported that diabetes can trigger centrosome amplification (CA). Thus, in the present study, we investigated the relationship between CA and the release of proinflammatory cytokines interleukin-1ß, tumor necrosis factor-α and interleukin-6 in hCMEC/D3 human endothelial cells treated with advanced glycation end products (AGEs). We found that AGEs induced CA via PLK4 and increased the biosynthesis of the three cytokines via NF-κB. Importantly, treatment of the cells with AGEs also increased the release of the three cytokines. Inhibiting CA by knockdown of polo like kinase 4 (PLK4) attenuated the cytokine release but not their biosynthesis. Knockdown of the cytokines inhibited the CA, while addition of the cytokines individually to the cell culture increased the protein level of PLK4 and CA to a moderate level. Addition of the three cytokines together into the cell culture markedly enhanced the CA, to a level higher than that in the AGEs-treated group. In conclusion, our results provide the direct evidence that the cytokines can induce CA, and suggest that there is a mutual promoting cycle between CA and cytokine release in the treated samples. It is proposed that the cycle of CA-cytokine release is a candidate biological link between diabetes and its complications such as vascular pathologies.

Mode thermo-optic coefficient engineering of sub-wavelength gratings and its application for a mode-insensitive switch.

It is shown that the thermo-optic (TO) coefficients of various waveguide modes of a sub-wavelength grating (SWG)-assisted strip waveguide is closely dependent on the various waveguide parameters with different dependencies, including the SWG width, strip waveguide width, duty cycle, and pitch. This offers what we believe to be new degrees of freedom in the design of TO coefficients for integrated-optic waveguides, opening the door to engineering the TO coefficients of individual spatial modes or polarization states using sub-wavelength structures. Such a capability is expected to offer new design possibilities for a variety of integrated photonic, thermo-optic devices. To demonstrate the application of the concept, a mode-insensitive switch on silicon-on-insulator using a TO coefficient-engineered SWG as a mode-independent, thermo-optic phase shifter is designed and experimentally demonstrated. The experimental results show that the switching powers of the TE0-TE2 modes are only ∼29 mW, and the maximum extinction ratios for the cross (bar) states are 38.2 dB (31 dB), 37.9 dB (37 dB), and 31.9 dB (20.5 dB) for the TE0-TE2 modes, respectively, at the wavelength of 1550 nm.

Palladium-Catalyzed Enantioselective Intramolecular Heck Dearomative Annulation of Indoles with N-Tosylhydrazones.

An elegant Pd(dba)2-catalyzed enantioselective Heck dearomative annulation of indoles and N-tosylhydrazones for the straightforward assembly of structurally diverse optically active indoline scaffolds containing the quaternary carbon centers at the C2 position has been developed. The tandem protocol, which utilized a Pd(dba)2/BINOL-based phosphoramidite ligand as the catalytic system, proceeded smoothly through successive oxidative addition, intramolecular carbon palladation, migratory insertion, and ß-elimination sequences, leading to the chiral indoline derivatives in moderate to excellent yields, with excellent enantioselectivities and diastereoselectivities. In addition, the synthetic practicability of the catalytic system was underlined by a scaled-up experiment and the late-stage derivatization of the products, thus highlighting the potential applications in synthetic chemistry, medicinal chemistry, and material science.

Lewis Acid Catalyzed [4 + 2] Annulation of Propargylic Alcohols with 2-Vinylanilines.

An elegant Lewis acid catalyzed, protection-free, and straightforward synthetic strategy for the assembly of a series of sophisticated polycyclic quinoline skeletons employing propargylic alcohols and 2-vinylanilines as the substrates in the presence of Yb(OTf)3 (10 mol %) and AgOTf (10 mol %) in tetrahydrofuran has been described. This annulation protocol, which proceeds through a sequential Meyer-Schuster rearrangement/nucleophilic substitution/deprotonation sequence, provides a versatile, practical, and atom-economical approach for accessing quinoline derivatives in moderate-to-good yields.

Cost-effectiveness analysis of dinutuximab ß for the treatment of high-risk neuroblastoma in China.

BACKGROUND: Dinutuximab ß can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab ß is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab ß in children with high-risk NB is of high importance. METHODS: The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab ß (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. RESULTS: Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab ß was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold. CONCLUSION: Results found that dinutuximab ß is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.

New synthetic approaches toward OCF3-containing compounds.

Fluorinated organic compounds are an important class of organic molecules and play a key role in both academic and industrial communities due to the unique nature of fluorine. Among the fluorine-containing functional groups, the OCF3 group is of vital importance because of its favorable physicochemical properties, so it frequently acts as the pivotal skeletal motif in a broad spectrum of pharmaceutical molecules, agrochemicals, natural products, and materials. Over the past few decades, a wider range of strategies for the efficient, versatile, and practical synthesis of trifluoromethoxylated compounds have been the focus of a number of research initiatives. These synthesis approaches are especially fascinating in the context of the design of agrochemicals and new drugs as established pathways for installing the OCF3 moiety. In this review, the state of the art of the synthesis of OCF3-containing compounds is summarized. It can be segmented into six categories: (1) de novo formation of the OCF3 group; (2) construction of trifluoromethoxylated compounds via trifluoromethylation of the corresponding alcohol or phenol; (3) construction of trifluoromethoxylated compounds via installing the entire OCF3 group straightaway onto a complex molecule; (4) visible-light-induced trifluoromethoxylation; (5) transition metal-catalyzed trifluoromethoxylation; and (6) construction of the trifluoromethoxylated compounds via rearrangement reactions.

Novel dual-reference approach facilitates the activation mapping and catheter ablation of premature atrial complexes with non-pulmonary vein and non-superior vena cava origins.

AIMS: Activation mapping of premature atrial complexes (PACs) proves challenging due to interference by mechanical bumping and non-targeted ectopies. This study aims to compare the mapping efficacy, instant success, and long-term recurrence of catheter ablation for PACs with non-pulmonary vein (PV) and non-superior vena cava (SVC) origins between the novel dual-reference approach (DRA) and the routine single-reference approach (SRA) of mapping. METHODS AND RESULTS: Patients with symptomatic, drug-refractory PACs, or frequent residual PACs after atrial tachyarrhythmia ablation were enrolled. During activation mapping, the coronary sinus (CS) catheter was used as the only timing reference in the SRA group. In the DRA group, another catheter, which was spatially separated from the CS catheter, was used as the second reference. The timing difference between the two references was used to discriminate the targeted PACs from the uninterested rhythms. Procedural parameters and long-term recurrence were compared. A total of 188 patients (109 in SRA and 79 in DRA) were enrolled. The baseline characteristics were similar. Compared with the SRA group, the DRA group had less repeated mapping (1.2 ± 0.4 vs. 1.4 ± 0.5, P = 0.004), shorter mapping (15 ± 6 vs. 23 ± 7 min, P < 0.001) and procedural time (119 ± 28 vs. 132 ± 22 min, P = 0.001), similar procedural complication rates (3.6 vs. 3.8%, P > 0.999), higher instant success (96.2 vs. 87.2%, P = 0.039), and lower recurrence rate (15.2 vs. 29.3%, hazard ratio 1.943, P = 0.033) during a 24-month follow-up. CONCLUSION: As a novel strategy, the DRA shortens the procedural time and improves both instant and long-term success of PAC ablation, serving as a promising approach in mapping PACs with non-PV and non-SVC origins.

TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment.

Cancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors but posed computational challenges on integrating and utilizing the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH, http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly 2 million cells from 76 high-quality tumor datasets across 27 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, clustering, cell-type annotation, malignant cell classification, differential expression analysis and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.

Quantitative relationship between soil pH and electrical conductivity values and cadmium phytoavailability for Chinese cabbage under simulated conditions.

Pot experiments were conducted to investigate the impacts of continuous addition of different concentrations of calcium chloride (CaCl2) and/or low-molecular-weight organic acids (LMWOAs) on soil pH, electrical conductivity (EC), and cadmium (Cd) transformation. These factors subsequently affected Cd phytoavailability in a system consisting of Cd-contaminated soil and Chinese cabbage (Brassica chinensis L.). The results indicate that CaCl2 addition had a greater impact on reducing soil pH value, increasing soil EC value, and enhancing Cd phytoaccumulation in Chinese cabbage compared to LMWOAs. When soil pH dropped by 0.3 unit and the soil EC increased by 500 µS cm-1, the Cd concentration in the Chinese cabbage shoots was 3 times higher than that in the control group. Throughout two planting terms of Chinese cabbage, the addition of CaCl2 (1.6-3.2 g kg-1) and LMWOAs (≤ 1.0 g kg-1) led to phytoextracted Cd concentration exceeding exchangeable Cd concentration in soil samples before the pot experiment. Regarding phytoextracted Cd, desorption from carbonate-bound Cd contributes more than desorption from bound to organic matter Cd and adsorption to Fe/Mn oxide Cd. This study underscores the influence of soil pH and EC value variations and Cd transformation on Cd phytoavailability. Special attention should be given to leafy vegetables grown in Cd-contaminated soil, as the phytoavailable Cd concentration reaches approximately 2.0 µg kg-1, which may lead to Cd levels surpassing acceptable limits for Chinese cabbage.