Atmosphere Induces Tunable Oxygen Vacancies to Stabilize Single-Atom Copper in Ceria for Robust Electrocatalytic CO2 Reduction to CH4.

Electrochemical carbon dioxide reduction (ECO2RR) shows great potential to create high-value carbon-based chemicals, while designing advanced catalysts at the atomic level remains challenging. The ECO2RR performance is largely dependent on the catalyst microelectronic structure that can be effectively modulated through surface defect engineering. Here, we provide an atmosphere-assisted low-temperature calcination strategy to prepare a series of single-atomic Cu/ceria catalysts with varied oxygen vacancy concentrations for robust electrolytic reduction of CO2 to methane. The obtained Cu/ceria catalyst under H2 environment (Cu/ceria-H2) exhibits a methane Faraday efficiency (FECH4) of 70.03% with a turnover frequency (TOFCH4) of 9946.7 h-1 at an industrial-scale current density of 150 mA cm-2 in a flow cell. Detailed studies indicate the copious oxygen vacancies in the Cu/ceria-H2 are conducive to regulating the surface microelectronic structure with stabilized Cu+ active center. Furthermore, density functional theory calculations and operando ATR-SEIRAS demonstrate that the Cu/ceria-H2 can markedly enhance the activation of CO2, facilitate the adsorption of pivotal intermediates *COOH and *CO, thus ultimately enabling the high selectivity for CH4 production. This study presents deep insights into designing effective electrocatalysts for CO2 to CH4 conversion by controlling the surface microstructure via the reaction atmosphere.

Prediction of Spread Through Air Spaces (STAS) By Intraoperative Frozen Section for Patients with cT1N0M0 Invasive Lung Adenocarcinoma: A Multi-Center Observational Study (ECTOP-1016).

OBJECTIVE: To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma. BACKGROUND: Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection. METHODS: We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections. RESULTS: This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Inter-observer agreement was substantial (κ=0.756) among the three pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. Additionally, true positive cases showed more high-grade histological patterns and more advanced p-TNM stages than false negative cases. CONCLUSIONS: This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed.

Human-unique brain cell clusters are associated with learning disorders and human episodic memory activity.

The advanced evolution of the human cerebral cortex forms the basis for our high-level cognitive functions. Through a comparative analysis of single-nucleus transcriptome data from the human neocortex and that of chimpanzees, macaques, and marmosets, we discovered 20 subgroups of cell types unique to the human brain, which include 11 types of excitatory neurons. Many of these human-unique cell clusters exhibit significant overexpression of genes regulated by human-specific enhancers. Notably, these specific cell clusters also express genes associated with disease risk, particularly those related to brain dysfunctions like learning disorders. Furthermore, genes linked to cortical thickness and human episodic memory encoding activities show heightened expression within these cell subgroups. These findings underscore the critical role of human brain-unique cell clusters in the evolution of human brain functions.

Ratiometric Imaging Detection of Amyloid-ß Fibrils by a Dual-Emissive Tris-Heteroleptic Ruthenium Complex.

Two dual fluorescent/phosphorescent tris-heteroleptic mononuclear Ru(ΙΙ) complexes (2 and 3) were designed and applied in amyloid-ß (Aß) sensing. These complexes have a general formula of [Ru(phen)(dppz)(L)](PF6)2, where L is (2-pyrazinyl)(2-pyridyl)(methyl)amine (H-L) with different substituents (-OMe for 2, -H for 3), phen is 1,10-phenanthroline, and dppz is dipyridophenazine, respectively. Compared with the previously reported ratiometric probe 1 with a di(pyrid-2-yl)(methyl)amine ligand, complex 2 can be employed for not only ratiometric emissive detection of Aß aggregation but also ratiometric imaging detection of Aß fibrils. In ratiometric emissive detection, as the incubation time of the Aß sample (Aß40 and Aß42) was prolonged, a new phosphorescence emission band appeared with gradual enhancement of the emission intensity, while the fluorescence emission was basically unchanged, which could be treated as an intrinsic internal reference signal. In comparison, a larger ratiometric photoluminescence enhancement (I640/I440) was observed for Aß40 aggregation with respect to Aß42. In ratiometric imaging detection, the imaging signals obtained from the phosphorescence emission are much brighter than the fluorescence emission in both Aß40 and Aß42 fibrils. As indicated by molecular docking results, stronger interactions were found between complex 2 with Aß40 fibrils, which included π/π, π/C-H, and π/H interactions between bidentate ligands dppz and phen with amino acid residues. Moreover, computational calculations were carried out to assist the interpretation of these experimental findings.

Inhibition of DNA Topoisomerase Ι by Flavonoids and Polyacetylenes Isolated from Bidens pilosa L.

Human DNA topoisomerase I (Topo I) is an essential enzyme in regulating DNA supercoiling during transcription and replication, and it is an important therapeutic target for anti-tumor agents. Bidens pilosa L. is a medicinal herb that is used as a folk medicine for cancers in China. A new flavonoid (1) and a new polyacetylene (20), along with eighteen flavonoids (2-19) and nine polyacetylenes (21-29), were isolated and identified from the methanol extract of the whole plant of B. pilosa, and some of the compounds (4, 5, 6 and 7) exhibited potent cytotoxicity against a panel of five human cancer cell lines. The DNA relaxation assay revealed that some flavonoids and polyacetylenes exerted inhibitory activities on human DNA Topo I, among them compounds 1, 2, 5, 6, 7, 8, 15, 19, 20, 22, and 24 were the most active ones, with IC50 values of 393.5, 328.98, 145.57, 239.27, 224.38, 189.84, 89.91, 47.5, 301.32, 178.03, and 218.27 µM, respectively. The structure-activity analysis of flavonoids was performed according to the results from the Topo I inhibition assay. The DNA content analysis revealed that 5, 6, and 7 potently arrested cell cycle at the G1/S and G2/M phases in human colon cancer cell DLD-1 depending on the concentration of the inhibitors. The levels of protein expression related to the G1/S and G2/M cell cycle checkpoints were in accordance with the results from the DNA content analysis. These findings suggest that flavonoids are one of the key active ingredients accounting for the anti-tumor effect of B. pilosa.

Dual-pathway charge transfer mechanism of anatase/rutile TiO2-Ag3PO4 hollow photocatalyst promotes efficient degradation of pesticides.

Exploring high-performance photocatalysts still remains a big challenge due to poor charge separation efficiency. Herein, we prepare a novel anatase/rutile TiO2-Ag3PO4 hollow photocatalyst (A/R-TiO2-Ag3PO4) for addressing this challenge. Microstructural characterization and photoelectric measurements confirm that the synergy of hollow structure and dual-heterojunction can provide abundant active sites and boost efficient charge separation through dual-pathway charge transfer mechanism. The A/R-TiO2-Ag3PO4 photocatalyst exhibits the highest photocurrent density (15.25 µA cm-2), which is 8.4 and 5.2 times than that of A-TiO2-Ag3PO4 (1.82 µA cm-2) and P25-Ag3PO4 (2.93 µA cm-2), respectively. Photo-degradation experiment shows that A/R-TiO2-Ag3PO4 presents a high degradation percentage (98.7 %) of thiamethoxam (THX) within 30 min, which is 1.45 and 1.23 times than that of A-TiO2-Ag3PO4 (68.1 %) and P25-Ag3PO4 (80.7 %), respectively. Furthermore, the degradation percentage of THX by A/R-TiO2-Ag3PO4 is as high as 96.4 % after seven successive cycles, indicating excellent cycling stability. Therefore, this work provides a new insight into exploring other high-performance photocatalysts by combining hollow structure and dual-heterojunction.

Toxicity profile of camrelizumab-based immunotherapy in older adults with advanced cancer.

Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and < 70 years), and comparisons were made based on the type of camrelizumab-based therapy (monotherapy, combined chemotherapy, or combined anti-VEGF therapy). A total of 185 patients were administered camrelizumab-based immunotherapy, 55 (30%) of whom were ≥ 70 years old. A total of 146 (78.9%) patients received camrelizumab-based combination treatment. The incidence of all-grade AEs was 56.8% (105 patients), while that of irAEs was 36.8% (68 patients). There was no difference in the percentage of patients experiencing any grade or grade ≥ 3 AEs between age groups. However, the frequency of irAEs (both any grade and grade ≥ 3) significantly differed by age group (P = 0.001 and 0.009, respectively). The results of multivariable analysis revealed that age ≥ 70 years was the only independent risk factor for irAEs. The results of subgroup analysis revealed that the incidence of irAEs was higher in older patients treated with camrelizumab-chemotherapy, while the incidence rates were similar between age groups in the monotherapy and combination anti-VEGF treatment subgroups. Immune-related diabetes mellitus occurred more frequently among older adults. The spectrum of irAEs showed that combination immunotherapy had more widely effects on the organ system than monotherapy. In this study, older (≥ 70 years) patients had a higher risk of all-grade and high-grade irAEs when receiving camrelizumab chemotherapy combination treatment. Notably, long-term random glucose monitoring should be performed during ICI-based immunotherapy in older cancer patients.

Imaging Single Prussian Blue Nanoparticles with Extraordinary Low-Spin Iron Capacity.

In attempts to obtain high-capacity Prussian blue nanomaterials, current efforts are predominantly focused on the particle-ensemble-level understanding of their structure-activity relationships. Complementarily, it would be insightful to screen out extraordinary individuals from the nanoparticle population. Using a simple and efficient technique of bright-field microscopy, this work enables, for the first time, quantitative characterization of the overall two-redox-center electrochemistry of single Prussian blue nanoparticles many at a time. Quantitative optical voltammograms with little interference from solvent breakdown and non-Faradaic electrode charging/discharging are extracted for each single nanoparticle, revealing clear heterogeneity among them. On this basis, the microscopic method allows a detailed comparative analysis between the two redox-active sites. It is found that while the synthesized nanoparticles show a similar specific capacity of the high-spin (HS-Fe) sites with STD/mean = 30%, most individual nanoparticles exhibit monodispersedly small capacities of the low-spin iron (LS-Fe) sites, only about 17±1 of the HS-Fe capacity. Most importantly, it is discovered that there is always a small fraction (∼8%) of the single nanoparticles showing an impressively tripled LS-Fe capacity. Facilitated by optical imaging, the discovery of this easily overlooked extraordinary subpopulation confers alternative opportunities for targeted efforts for material chemists to improve synthesis and material design based on these unusual individuals, which in turn implies the general significance of nanoparticle screening.

Human placental mesenchymal stromal cells alleviate intestinal oxidative damage in mice with graft-versus-host disease via CD73/adenosine/PI3K/Akt/GSK-3ß axis.

BACKGROUND: Intestinal damage is a common and serious complication in patients with graft-versus-host disease (GVHD). Human placental mesenchymal stromal cells (hPMSCs) ameliorate GVHD tissue damage by exerting anti-oxidative effects; however, the underlying mechanisms remain not fully clear. METHODS: A GVHD mouse model and tumor necrosis factor-α (TNF-α)-stimulated human colon epithelial cell lines NCM460 and HT-29 cells were used to investigate the mechanisms of hPMSCs alleviating GVHD-induced intestinal oxidative damage. RESULTS: hPMSCs reduced TNF-α concentrations and the number of CD3+TNF-α+ T-cells, which were negatively correlated with the expression of claudin-1, occludin, and ZO-1, through CD73 in the colon tissue of GVHD mice. Meanwhile, hPMSCs reduced the mean fluorescence intensity (MFI) of reactive oxygen species (ROS) and the concentration of malondialdehyde (MDA), promoted superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, as well as claudin-1, occludin, and ZO-1 expression, in colonic epithelial cells of GVHD mice and TNF-α-stimulated cells via CD73. Moreover, hPMSCs upregulated adenosine (ADO) concentrations in GVHD mice and TNF-α-stimulated cells and mitigated the loss of tight junction proteins via the CD73/ADO/ADO receptors. Further analysis showed that hPMSCs diminished Fyn expression and enhanced Nrf2, GCLC, and HO-1 expression in both TNF-α-stimulated cells and colonic epithelial cells of GVHD mice by activating PI3K/Akt/GSK-3ß pathway. CONCLUSIONS: The results suggested that hPMSC-mediated redox metabolism balance and promoted tight junction protein expression were achieved via CD73/ADO/PI3K/Akt/GSK-3ß/Fyn/Nrf2 axis, by which alleviating intestinal oxidative injury in GVHD mice.

[Analysis of correlation between high expression of nucleoporin 85 (NUP85) and immune cell infiltration in hepatocellular carcinoma].

Objective To investigate the significance of nucleoporin 85 (NUP85) ex-pression in hepatocellular carcinoma (HCC) and analyze its relevance to immune response. Methods A comprehensive analysis was conducted using various online databases to assess the mRNA and protein expression of NUP85 in HCC, as well as its mutation status and prognostic diagnostic value. The immune relevance of NUP85 was evaluated using single-cell sequencing data and resources from the Tumor Immune Estimation Resource (TIMER) and the Gene Expression Profiling Interactive Analysis 2021 (GEPIA2021) databases. The drug sensitivity of NUP85 was analyzed through the Genomic Landscape of Cancer (GSCA) and the Clinical Bioinformatics Home. Co-expressed genes of NUP85 in HCC were filtered using the Hepatocellular Carcinoma Comprehensive Molecular Database (HCCDB), and the correlation between NUP85 and its related genes was analyzed using the R language "limma" package. The gene ontology (GO) functions, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) of NUP85 and its related genes were performed using the R language "clusterProfiler" package. The Clinical Bioinformatics Home was utilized to construct heatmaps and prognostic risk scoring models for NUP85 and its related genes. Results NUP85 mRNA and protein expression were upregulated in HCC, showing high levels across dif-ferent stages and grades, which indicates a poor prognosis for patients. The mutation rate of NUP85 in HCC samples was 19%, significantly affecting the overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) of patients. NUP85 was highly expressed in various immune cells, including macrophages, B cells, and T cells, and was positively correlated with the infiltration levels of multiple immune cells. The expression of NUP85 was significantly correlated with multiple drugs, such as Milademetan (PD0325901), a structural analog of Vemurafenib (PLX4720), and Regorafenib (PD0325901). The GO functions of NUP85 and its co-expressed genes were mainly enriched in organelle fission, nuclear division, and chromosome segregation, while the KEGG pathways were primarily enriched in the cell cycle and kinesin proteins. These factors significantly and unfavorably affected the OS of HCC patients, and the areas under the ROC curve (AUC) for the 1-year, 3-year, and 5-year OS prognostic diagnosis of HCC patients were all greater than 0.7. Conclusion The high expression of NUP85 in HCC is correlated with a poor prognosis and is related to various immune cells and drugs, making it a potential biomarker for di-agnosis, treatment, and prognosis in HCC.

LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway.

BACKGROUND: Leukocyte Ig-like receptor B family 4 (LILRB4) as an immune checkpoint on myeloid cells is a potential target for tumor therapy. Extensive osteolytic bone lesion is the most characteristic feature of multiple myeloma. It is unclear whether ectopic LILRB4 on multiple myeloma regulates bone lesion. METHODS: The conditioned medium (CM) from LILRB4-WT and -KO cells was used to analyze the effects of LILRB4 on osteoclasts and osteoblasts. Xenograft, syngeneic and patient derived xenograft models were constructed, and micro-CT, H&E staining were used to observe the bone lesion. RNA-seq, cytokine array, qPCR, the activity of luciferase, Co-IP and western blotting were used to clarify the mechanism by which LILRB4 mediated bone damage in multiple myeloma. RESULTS: We comprehensively analyzed the expression of LILRB4 in various tumor tissue arrays, and found that LILRB4 was highly expressed in multiple myeloma samples. The patient's imaging data showed that the higher the expression level of LILRB4, the more serious the bone lesion in patients with multiple myeloma. The conditioned medium from LILRB4-WT not -KO cells could significantly promote the differentiation and maturation of osteoclasts. Xenograft, syngeneic and patient derived xenograft models furtherly confirmed that LILRB4 could mediate bone lesion of multiple myeloma. Next, cytokine array was performed to identify the differentially expressed cytokines, and RELT was identified and regulated by LILRB4. The overexpression or exogenous RELT could regenerate the bone damage in LILRB4-KO cells in vitro and in vivo. The deletion of LILRB4, anti-LILRB4 alone or in combination with bortezomib could significantly delay the progression of bone lesion of multiple myeloma. CONCLUSIONS: Our findings indicated that LILRB4 promoted the bone lesion by promoting the differentiation and mature of osteoclasts through secreting RELT, and blocking LILRB4 singling pathway could inhibit the bone lesion.

hPMSCs prevent erythrocytes dysfunction caused by graft versus host disease via promoting GSH synthesis.

BACKGROUND: Oxidative stress is increased in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and leads to the development of graft versus host disease (GVHD). Mesenchymal stromal cells (MSCs) can ameliorate GVHD by regulating the function of T cells. However, whether MSCs can modulate erythrocyte antioxidant metabolism and thus reduce GVHD is not known. METHODS: Forty female BALB/c mice were randomly assigned to four groups: the control, GVHDhigh, hPMSC, and PBS groups. A hypoxanthine/xanthine oxidase system was used to steadily and gradually produce superoxide in an in vitro experiment. A scanning microscope was used to examine the ultrastructure of erythrocytes. Laser diffraction analyses were used to analyze erythrocyte deformability. Western blotting was used to measure the expression of the erythrocyte membrane skeleton proteins Band 3 and ß-Spectrin. Corresponding kits were used to assess the levels of oxidative damage and the activity of antioxidant enzymes. RESULTS: Morphological and deformability defects were significantly increased in erythrocytes from GVHD patients. Band 3 and ß-Spectrin expression was also reduced in GVHD patients and model mice. Furthermore, we observed significantly increased oxidative stress-induce injury and decreased antioxidant capability in erythrocytes from both GVHD patients and model mice. Subsequent research showed that human placenta-derived MSC (hPMSC) therapy decreased the GVHD-induced redox imbalance in erythrocytes. Furthermore, our findings suggested that upregulating glucose metabolism promoted both the de novo synthesis and recycling of GSH, which is the primary mechanism by which hPMSCs mediate the increase in antioxidant capacity in erythrocytes. CONCLUSION: Together, our findings suggest that hPMSCs can increase antioxidant capacity by increasing erythrocyte GSH production and thus ameliorate GVHD.

Application of network pharmacology and dock of molecules on the exploration of the mechanism of frankincense-myrrh for lumbar intervertebral disc degeneration: A review.

To investigate the efficacy of Frankincense-Myrrh in lumbar Intervertebral degenerative diseases (LIDD). The active components of frankincense-myrrh was retrieved with a unique system pharmacology platform for Traditional Chinese Medicine Systems Pharmacology (TCMSP). The LIDD-related target genes were screened with DisGeNET and Genecards databases. Then, STRING & Cytoscape were used for analyzing the Protein-Protein Interaction network. DAVID was used for analyzing Gene Ontology (GO) & Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, molecules of AutoDockVina and Pymol were used for docking the molecules for verifying active ingredients and key targets' binding force. The 105 LIDD-related targets identified in Ruxiang (RX)-Moyao (MY) involve 53 active ingredients. In addition, topological analysis was conducted for identifying the 12 key targets. According to the analysis results of GO & KEGG, RX-MY is significant for treating LIDD through participating in many pathways and biological processes, such as signaling pathways of inflammatory response reactive process, MAP kinase activity, TNF, and MAPK, etc. According to the dock results, the active components oxo-tirucalic, acid, isofouquierone, (7S, 8R, 9S, 10R, 13S, 14S,17Z)-17-ethylidene-7-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta [a] phenanthrene-3,16-dion in RX-MY binds actively. The basic pharmacological action and RX-MY-related mechanism in the treatment of LIDD was revealed in this study for the first time. It is predicted that the results may provide a treatment plan for RX-MY with replacement of NSAIDs and warrant investigation of new therapeutic alternatives for LIDD. However, these predictions should be validated by relevant pharmacological trials.

Clinical utility of a rapid two-dimensional balanced steady-state free precession sequence with deep learning reconstruction.

BACKGROUND: Cardiovascular magnetic resonance (CMR) cine imaging is still limited by long acquisition times. This study evaluated the clinical utility of an accelerated two-dimensional (2D) cine sequence with deep learning reconstruction (Sonic DL) to decrease acquisition time without compromising quantitative volumetry or image quality. METHODS: A sub-study using 16 participants was performed using Sonic DL at two different acceleration factors (8× and 12×). Quantitative left-ventricular volumetry, function, and mass measurements were compared between the two acceleration factors against a standard cine method. Following this sub-study, 108 participants were prospectively recruited and imaged using a standard cine method and the Sonic DL method with the acceleration factor that more closely matched the reference method. Two experienced clinical readers rated images based on their diagnostic utility and performed all image contouring. Quantitative contrast difference and endocardial border sharpness were also assessed. Left- and right-ventricular volumetry, left-ventricular mass, and myocardial strain measurements were compared between cine methods using Bland-Altman plots, Pearson's correlation, and paired t-tests. Comparative analysis of image quality was measured using Wilcoxon-signed-rank tests and visualized using bar graphs. RESULTS: Sonic DL at an acceleration factor of 8 more closely matched the reference cine method. There were no significant differences found across left ventricular volumetry, function, or mass measurements. In contrast, an acceleration factor of 12 resulted in a 6% (5.51/90.16) reduction of measured ejection fraction when compared to the standard cine method and a 4% (4.32/88.98) reduction of measured ejection fraction when compared to Sonic DL at an acceleration factor of 8. Thus, Sonic DL at an acceleration factor of 8 was chosen for downstream analysis. In the larger cohort, this accelerated cine sequence was successfully performed in all participants and significantly reduced the acquisition time of cine images compared to the standard 2D method (reduction of 37% (5.98/16) p < 0.0001). Diagnostic image quality ratings and quantitative image quality evaluations were statistically not different between the two methods (p > 0.05). Left- and right-ventricular volumetry and circumferential and radial strain were also similar between methods (p > 0.05) but left-ventricular mass and longitudinal strain were over-estimated using the proposed accelerated cine method (mass over-estimated by 3.36 g/m2, p < 0.0001; longitudinal strain over-estimated by 1.97%, p = 0.001). CONCLUSION: This study found that an accelerated 2D cine method with DL reconstruction at an acceleration factor of 8 can reduce CMR cine acquisition time by 37% (5.98/16) without significantly affecting volumetry or image quality. Given the increase of scan time efficiency, this undersampled acquisition method using deep learning reconstruction should be considered for routine clinical CMR.

PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing.

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma (HNSCC) using single-cell and bulk RNA-sequencing data. Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes (DEGs) between nivolumab resistant and nivolumab sensitive patients using R software. The Least Absolute Shrinkage Selection Operator (LASSO) regression and Recursive Feature Elimination (RFE) algorithm were performed to identify key genes associated with nivolumab resistance. Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The relationships of key genes with immune cell infiltration, differentation trajectory, dynamic gene expression profiles, and ligand-receptor interaction were explored. Results We found 83 DEGs. They were mainly enriched in T-cell differentiation, PD-1 and PD-L1 checkpoint, and T-cell receptor pathways. Among six key genes identified using machine learning algorithms, only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy (P < 0.05). The high PPP1R14A gene expression group had lower immune score (P < 0.01), higher expression of immunosuppressive factors (such as PDCD1, CTLA4, and PDCD1LG2) (r > 0, P < 0.05), lower differentiation of infiltrated immune cells (P < 0.05), and a higher degree of interaction between HLA and CD4 (P < 0.05). Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients. Therefore, PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Near-infrared visualisation of single microparticle electrochemistry for batteries.

While optical microscopy of single particle electrochemistry has proven insightful for future nanoparticle-based batteries, little is explored for micron-sized particles of more practical interest. This is largely hindered by the currently limited methodology. Accordingly, we report transmission optical microscopy using near-infrared light for accessing intra-particle electrochemistry in virtue of strong light penetration as compared to visible light. Using near-infrared (λ > 730 nm) bright-field microscopy, the redox electrochemistry of single LiCoO2 microparticles can be readily measured based on the measurements of optical contrast changes during electrochemical cycling. Further using the established methodology, we discover that the solid-state diffusion inside most single microparticles is distinctly directional, instead of in an isotropic manner from outer to inner as observed for the other particles. This phenomenon is also observed using dark field scattering microscopy with near-infrared light, suggesting non-uniform crystal inner structures responsible for the geometrically asymmetric heterogeneity of charge transfer kinetics within each single particle. These results indicate potential opportunities offered by the near-infrared optical methodology for operando studying practical battery materials.

Circadian-driven tissue specificity is constrained under caloric restricted feeding conditions.

Tissue specificity is a fundamental property of an organ that affects numerous biological processes, including aging and longevity, and is regulated by the circadian clock. However, the distinction between circadian-affected tissue specificity and other tissue specificities remains poorly understood. Here, using multi-omics data on circadian rhythms in mice, we discovered that approximately 35% of tissue-specific genes are directly affected by circadian regulation. These circadian-affected tissue-specific genes have higher expression levels and are associated with metabolism in hepatocytes. They also exhibit specific features in long-reads sequencing data. Notably, these genes are associated with aging and longevity at both the gene level and at the network module level. The expression of these genes oscillates in response to caloric restricted feeding regimens, which have been demonstrated to promote longevity. In addition, aging and longevity genes are disrupted in various circadian disorders. Our study indicates that the modulation of circadian-affected tissue specificity is essential for understanding the circadian mechanisms that regulate aging and longevity at the genomic level.

Human CD127 negative ILC2s show immunological memory.

ILC2s are key players in type 2 immunity and contribute to maintaining homeostasis. ILC2s are also implicated in the development of type 2 inflammation-mediated chronic disorders like asthma. While memory ILC2s have been identified in mouse, it is unknown whether human ILC2s can acquire immunological memory. Here, we demonstrate the persistence of CD45RO, a marker previously linked to inflammatory ILC2s, in resting ILC2s that have undergone prior activation. A high proportion of these cells concurrently reduce the expression of the canonical ILC marker CD127 in a tissue-specific manner. Upon isolation and in vitro stimulation of CD127-CD45RO+ ILC2s, we observed an augmented ability to proliferate and produce cytokines. CD127-CD45RO+ ILC2s are found in both healthy and inflamed tissues and display a gene signature of cell activation. Similarly, mouse memory ILC2s show reduced expression of CD127. Our findings suggest that human ILC2s can acquire innate immune memory and warrant a revision of the current strategies to identify human ILC2s.

Design, synthesis and biological evaluation of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety as iron chelators.

The avidity of cancer cells for iron highlights the potential for iron chelators to be used in cancer therapy. Herein, we designed and synthesized a novel series of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety using a ring-fusion strategy based on the structure of an iron chelator, VLX600. The antiproliferative activity evaluation against cancer cells and normal cells led to the identification of compound 3k, which displayed the strongest antiproliferative activity in vitro against A549, MCF-7, Hela and HepG-2 with IC50 values of 0.59, 0.86, 1.31 and 0.92 µM, respectively, and had lower cytotoxicity against HEK293 than VLX600. Further investigations revealed that unlike VLX600, compound 3k selectively bound to ferrous ions, but not to ferric ions, and addition of Fe2+ abolished the cytotoxicity of 3k. Flow cytometry assays demonstrated that 3k arrested the cell cycle at the G1 phase and induced significant apoptosis in A549 cells in dose and time-dependent manners, corresponding to JC-1 staining assay results. Western blot analysis of Bcl-2, Bax and cleaved caspase-3 proteins further provided evidences that induction of apoptosis by 3k in A549 cells might be at least via the mitochondria pathway. These above results highlight that 3k is a valuable lead compound that deserves further investigation as an iron chelator for the treatment of cancer.