Women patients with small-cell lung cancer using immunotherapy in a real-world cohort achieved long-term survival.

BACKGROUND: Usage of immune checkpoint inhibitors (ICIs) has prolonged the overall survival (OS) of patients with extensive-stage small-cell lung cancer (ES-SCLC). In clinical trials, males accounted for a large proportion, leading to the uncertainty of its efficacy in female patients. We therefore conducted this study to explore the efficacy and safety of using ICIs in female patients with ES-SCLC. METHODS: We retrospectively enrolled female SCLC patients and subdivided them into two groups. Group A (n = 40) was defined as ES-SCLC patients who received first-line standard chemotherapy with or without ICIs. Group B (n = 47) included relapsed SCLC patients who were administered with second-line therapies. Kaplan-Meier methodology was used to calculate survival analysis. Chi-squared tests were used to analyze the incidence of adverse events (AEs). RESULTS: Median progression-free survival (PFS) and median OS favored the ICI-contained cohorts (Group A PFS: 8.3 vs. 6.1 months; OS: not reached vs. 11.3 months; Group B PFS: 15.1 vs. 3.3 months; OS: 35.3 vs. 8.3 months), especially in those patients who received second-line immunotherapies. Patients who received immunotherapy had a slightly higher incidence rate of grade ≥3 AEs (Group A: 71.4% vs. 46.2%; Group B: 44.5% vs. 13.2%). Those who developed grade ≥3 AEs in first-line ICIs cohort had a more favorable survival (PFS: 8.3 vs. 3.2 months; OS: not reached vs. 5.1 months). CONCLUSIONS: Our study suggested that female ES-SCLC patients treated with immunotherapy tended to achieve a relatively longer survival. The incidence of AEs (grade ≥3) was higher in women patients receiving ICIs, which requires monitoring more closely.

Realizing highly efficient deep-blue organic light-emitting diodes towards Rec.2020 chromaticity by restricting the vibration of the molecular framework.

Deep-blue organic light-emitting diodes (OLEDs) with narrow emission spectra and high efficiency, meeting the Rec.2020 standard, hold significant promise in the realm of 4K/8K ultrahigh-definition displays. However, the development of light-emitting materials exhibiting both narrowband emission and high efficiency, particularly in the realm of deep-blue thermally activated delayed fluorescence (TADF), confronts substantial challenges. Herein, a novel deep-blue TADF emitter, named BOC-PSi, was designed by integrating a rigid B-heterotriangulene acceptor (A) with a rigid phenazasiline donor (D). The replacement of a sp3 carbon atom with a sp3 silicon atom in the D moiety helps to restrict the low-frequency bending vibration throughout the entire D-A molecular backbone, while concurrently accelerating the multi-channel reverse intersystem crossing (RISC) processes. Notably, OLEDs using the BOC-PSi emitter exhibit exceptional performance, with a high maximum external quantum efficiency (EQEmax) approaching 20%, and a superior color purity closely aligning with the Rec.2020 blue standard.

AEGNN-M:A 3D Graph-Spatial Co-Representation Model for Molecular Property Prediction.

Improving the drug development process can expedite the introduction of more novel drugs that cater to the demands of precision medicine. Accurately predicting molecular properties remains a fundamental challenge in drug discovery and development. Currently, a plethora of computer-aided drug discovery (CADD) methods have been widely employed in the field of molecular prediction. However, most of these methods primarily analyze molecules using low-dimensional representations such as SMILES notations, molecular fingerprints, and molecular graph-based descriptors. Only a few approaches have focused on incorporating and utilizing high-dimensional spatial structural representations of molecules. In light of the advancements in artificial intelligence, we introduce a 3D graph-spatial co-representation model called AEGNN-M, which combines two graph neural networks, GAT and EGNN. AEGNN-M enables learning of information from both molecular graphs representations and 3D spatial structural representations to predict molecular properties accurately. We conducted experiments on seven public datasets, three regression datasets and 14 breast cancer cell line phenotype screening datasets, comparing the performance of AEGNN-M with state-of-the-art deep learning methods. Extensive experimental results demonstrate the satisfactory performance of the AEGNN-M model. Furthermore, we analyzed the performance impact of different modules within AEGNN-M and the influence of spatial structural representations on the model's performance. The interpretability analysis also revealed the significance of specific atoms in determining particular molecular properties.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

A spiroacridine-based thermally activated delayed fluorescence emitter for high-efficiency and narrow-band deep-blue OLEDs.

A novel deep-blue thermally activated delayed fluorescence molecule of SAC-BOC was reported. The SAC-BOC-based device exhibits a narrow full width at half maximum of 57 nm, an impressive maximum external quantum efficiency (EQEmax) of 15.3% and CIE coordinates of (0.144, 0.129).

Temporal dynamics of genetic architecture governing leaf development in Populus.

Leaf development is a multifaceted and dynamic process orchestrated by a myriad of genes to shape the proper size and morphology. The dynamic genetic network underlying leaf development remains largely unknown. Utilizing a synergistic genetic approach encompassing dynamic genome-wide association study (GWAS), time-ordered gene co-expression network (TO-GCN) analyses and gene manipulation, we explored the temporal genetic architecture and regulatory network governing leaf development in Populus. We identified 42 time-specific and 18 consecutive genes that displayed different patterns of expression at various time points. We then constructed eight TO-GCNs that covered the cell proliferation, transition, and cell expansion stages of leaf development. Integrating GWAS and TO-GCN, we postulated the functions of 27 causative genes for GWAS and identified PtoGRF9 as a key player in leaf development. Genetic manipulation via overexpression and suppression of PtoGRF9 revealed its primary influence on leaf development by modulating cell proliferation. Furthermore, we elucidated that PtoGRF9 governs leaf development by activating PtoHB21 during the cell proliferation stage and attenuating PtoLD during the transition stage. Our study provides insights into the dynamic genetic underpinnings of leaf development and understanding the regulatory mechanism of PtoGRF9 in this dynamic process.

Correction: Enhanced DNA release from disulfide-containing layered nanocomplexes by heparin-electrostatic competition.

Correction for 'Enhanced DNA release from disulfide-containing layered nanocomplexes by heparin-electrostatic competition' by Zhenzhen Chen et al., J. Mater. Chem. B, 2015, 3, 225-237, https://doi.org/10.1039/c4tb01113a.

Urban and suburban decadal variations in air pollution of Beijing and its meteorological drivers.

Air pollution is a major threat to human health and ecosystems. Using 10-year (2013-2022) multi-source observations for the Beijing, China, we showed that clean-air actions have significantly reduced PM2.5, PM10, CO, NO2, and SO2 pollution, with an increase in the surface maximum daily 8-h average ozone (MDA8O3) concentrations during autumn and winter, leading to a rapid diminishment of the urban-suburban gap in air pollution. Secondary sources and vehicle emissions were enhanced in both urban and suburban areas in all seasons except summer from 2013 to 2022. By combining statistical analysis with the convergent cross-mapping model, the varying relationships between air pollution and meteorological conditions in the urban and suburban areas were delineated. The results suggested that boundary layer height and relative humidity exerted strong and stable influences on all air pollutants, except for MDA8O3, whose key meteorological driver was temperature. This study showed that increasing O3 trends in autumn and winter and aggravated O3 formation in summer in urban areas in Beijing became non-negligible from 2013 to 2022, despite the declining levels of air pollutants. Meteorological observations suggested that weather patterns in Beijing, characterized by higher temperatures, sunshine hours, and boundary layer height and lower relative humidity, have become more favorable for O3 formation in autumn and winter. Future mitigation efforts should focus on reducing VOC and NOx emissions to avoid further deterioration of O3 pollution under the frequent adverse meteorological conditions predicted under the background of global warming.

Genomic insights into selection for heterozygous alleles and woody traits in Populus tomentosa.

Heterozygous alleles are widespread in outcrossing and clonally propagated woody plants. The variation in heterozygosity that underlies population adaptive evolution and phenotypic variation, however, remains largely unknown. Here, we describe a de novo chromosome-level genome assembly of Populus tomentosa, an economic and ecologically important native tree in northern China. By resequencing 302 natural accessions, we determined that the South subpopulation (Pop_S) encompasses the ancestral strains of P. tomentosa, while the Northwest subpopulation (Pop_NW) and Northeast subpopulation (Pop_NE) experienced different selection pressures during population evolution, resulting in significant population differentiation and a decrease in the extent of heterozygosity. Analysis of heterozygous selective sweep regions (HSSR) suggested that selection for lower heterozygosity contributed to the local adaptation of P. tomentosa by dwindling gene expression and genetic load in the Pop_NW and Pop_NE subpopulations. Genome-wide association studies (GWAS) revealed that 88 single nucleotide polymorphisms (SNPs) within 63 genes are associated with nine wood composition traits. Among them, the selection for the homozygous AA allele in PtoARF8 is associated with reductions in cellulose and hemicellulose contents by attenuating PtoARF8 expression, and the increase in lignin content is attributable to the selection for decreases in exon heterozygosity in PtoLOX3 during adaptive evolution of natural populations. This study provides novel insights into allelic variations in heterozygosity associated with adaptive evolution of P. tomentosa in response to the local environment and identifies a series of key genes for wood component traits, thereby facilitating genomic-based breeding of important traits in perennial woody plants.

New-Onset Fulminant Type 1 Diabetes Following SARS-CoV-2 Protein Subunit Vaccine: A Case Report and Literature Review.

The ravages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide have sped up the development of relevant vaccines, which is accompanied by public concerns over possible adverse effects. We report a rare case of a 39-year-old woman who suffered from severe hyperglycemia and ketoacidosis with normal hemoglobin A1c four days after SARS-CoV-2 protein subunit vaccine, which is consistent with the diagnosis of fulminant type 1 diabetes (FT1D). She received insulin therapy and recovered after 24 days from onset of the symptoms. This is the first case of new-onset FT1D after SARS-CoV-2 protein subunit vaccination and one of only six that developed after any form of SARS-CoV-2 vaccination. We hope to raise awareness of this potential adverse consequence and recommend careful monitoring after vaccination in patients even without a medical history of diabetes.

Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.

Solid-liquid transition induced by rigidity disparity in a binary mixture of cell tissues.

The two-dimensional melting of a binary mixture of cell tissues is numerically investigated in the presence of rigidity disparity. We present the full melting phase diagrams of the system by using the Voronoi-based cellular model. It is found that the enhancement of rigidity disparity can induce a solid-liquid transition at both zero temperature and finite temperature. (i) In the case of zero temperature, the system undergoes a continuous solid-hexatic transition followed by a continuous hexatic-liquid transition for zero rigidity disparity, but a discontinuous hexatic-liquid transition for finite rigidity disparity. Remarkably, the solid-hexatic transitions always arise when the soft cells reach the rigidity transition point of monodisperse systems. (ii) In the case of finite temperature, the melting occurs via a continuous solid-hexatic transition followed by a discontinuous hexatic-liquid transition. Our study may contribute to the understanding of solid-liquid transitions in binary mixture systems with rigidity disparity.

Regeneratively mode-locked optoelectronic oscillator.

A regeneratively mode-locked optoelectronic oscillator is proposed to realize multi-mode phase locking in optoelectronic oscillators by coupling a modulating signal generation loop. To verify the feasibility of the scheme, a numerical simulation model is established. In addition, a proof-of-concept experiment is demonstrated in a single-loop optoelectronic oscillator with a 2.2 km polarization-maintaining single-mode fiber, using an electric amplitude modulator/Mach-Zehnder modulator as an active mode-locking device. The generated microwave pulse signal has a center frequency of 10 GHz and a repetition rate of 95 kHz. We believe this scheme can provide a new approach to overcome the problem of detuning between the modulating frequency and the mode spacing during long-term operation.

Oxygen vacancies engineering in electrocatalysts nitrogen reduction reaction.

Ammonia is important, both as a fertilizer and as a carrier of clean energy, mainly produced by the Haber-Bosch process, which consumes hydrogen and emits large amounts of carbon dioxide. The ENRR (Electronchemical Nitrogen Reduction Reaction) is considered a promising method for nitrogen fixation owing to their low energy consumption, green and mild. However, the ammonia yield and Faraday efficiency of the ENRR catalysts are low due to the competitive reaction between HER and NRR, the weak adsorption of N2 andthe strong N≡N triple bond. Oxygen vacancy engineering is the most important method to improve NRR performance, not only for fast electron transport but also for effective breaking of the N≡N bond by capturing metastable electrons in the antibonding orbitals of nitrogen molecules. In this review, the recent progress of OVs (oxygen vacancies) in ENRR has been summarized. First, the mechanism of NRR is briefly introduced, and then the generation methods of OVs and their applicationin NRR are discussed, including vacuum annealing, hydrothermal method, hydrogen reduction, wet chemical reduction, plasma treatment and heterogeneous ion doping. Finally, the development and challenges of OVs in the field of electrochemical nitrogen fixation are presented. This review shows the important areas of development of catalysts to achieve industrially viable NRR.

Eliciting national and subnational sets of disability weights in mainland China: Findings from the Chinese disability weight measurement study.

Background: The disability weight (DW) quantifies the severity of health states from disease sequela and is a pivotal parameter for disease burden calculation. We conducted a national and subnational DW measurement in China. Methods: In 2020-2021, we conducted a web-based survey to assess DWs for 206 health states in 31 Chinese provinces targeting health workers via professional networks. We fielded questions of paired comparison (PC) and population health equivalence (PHE). The PC data were analysed by probit regression analysis, and the regression results were anchored by results from the PHE responses on the DW scale between 0 (no loss of health) and 1 (health loss equivalent to death). Findings: We used PC responses from 468,541 respondents to estimate DWs of health states. Eight of 11 domains of health had significantly negative coefficients in the regression of the difference between Chinese and Global Burden of Disease (GBD) DWs, suggesting lower DW values for health states with mention of these domains in their lay description. We noted considerable heterogeneity within domains, however. After applying these Chinese DWs to the 2019 GBD estimates for China, total years lived with disability (YLDs) increased by 14·9% to 177 million despite lower estimates for musculoskeletal disorders, cardiovascular diseases, mental disorders, diabetes and chronic kidney disease. The lower estimates of YLDs for these conditions were more than offset by higher estimates of common, low-severity conditions. Interpretation: The differences between the GBD and Chinese DWs suggest that there might be some contextual factors influencing the valuation of health states. While the reduced estimates for mental disorders, alcohol use disorder, and dementia could hint at a culturally different valuation of these conditions in China, the much greater shifts in YLDs from low-severity conditions more likely reflects methodological difficulty to distinguish between health states that vary a little in absolute DW value but a lot in relative terms. Funding: This work was supported by the National Natural Science Foundation of China [grant number 82173626], the National Key Research and Development Program of China [grant numbers 2018YFC1315302], Wuhan Medical Research Program of Joint Fund of Hubei Health Committee [grant number WJ2019H304], and Ningxia Natural Science Foundation Project [grant number 2020AAC03436].

Combatting Antibiotic Resistance Using Supramolecular Assemblies.

Antibiotic resistance has posed a great threat to human health. The emergence of antibiotic resistance has always outpaced the development of new antibiotics, and the investment in the development of new antibiotics is diminishing. Supramolecular self-assembly of the conventional antibacterial agents has been proved to be a promising and versatile strategy to tackle the serious problem of antibiotic resistance. In this review, the recent development of antibacterial agents based on supramolecular self-assembly strategies will be introduced.

Measurement of three-dimensional track profiles on CR-39s based on the photometric stereo method.

To obtain more information about incident particles, a new method for measuring three-dimensional track profiles formed on CR-39s based on the photometric stereo method was developed. A new optical microscope system with 16 lasers and a complementary metal-oxide-semiconductor camera was built to automatically capture the reflecting track images illuminated by the laser beams from different angles, and the track profiles were three-dimensionally reconstructed using a self-developed software. To verify the reconstruction results of the track profiles, both the openings and depth were measured with an atomic force microscope. The results showed that the relative deviations between the two methods of the openings were about 5.5% and the deviations of the depth were about 8.0%. At present, the reconstruction speed of a three-dimensional track profile is a factor of 400 greater than that of the atomic force microscope. The new method shows great potential for rapid reconstruction of numerous track morphologies. It is expected to be helpful for further studies on the energy and angle discrimination of incident particles in the field of nuclear measurements.