Multi-site isomerization of synergistically regulated stimuli-responsive AIE materials toward multi-level decryption.

Stimuli-responsive aggregation-induced emission (AIE) materials are highly sensitive and rapidly responsive to external signals, making them ideal solid materials for anti-counterfeiting encryption. However, the limited conformational and packing variations resulting from regio-isomerization with a single substituent restricts the stimuli-responsive behavior of these materials. In this work, several AIE-active regio-structural isomers based on the salicylaldehyde Schiff base scaffold have been straightforwardly obtained through multiple substitutions with bromide and triphenylamine moieties. Solvent-effect experiments demonstrate their different orders of charge-transfer and excited-state intramolecular proton transfer upon photoexcitation, indicating the regulation of excited-state processes via multi-site isomerization. These isomers also demonstrate mechanochromism and acidichromism, allowing for adjustable stimuli-responsive effects. As a demonstration, p-Br-TPA with both mechanochromism and acidichromism can be synergistically utilized for multi-level decryption. This study successfully regulates the evolution of excited states through multi-site isomerization, offering a general approach for achieving tunable stimuli-responsive properties in AIE-active salicylaldehyde Schiff bases toward multi-level decryption.

Natural Acceptor of Coumarin-Isomerized Red-Emissive BioAIEgen for Monitoring Cu2+ Concentration in Live Cells via FLIM.

Artificial aggregation-induced emission luminogens (AIEgens) have flourished in bio-applications with the development of synthetic chemistry, which however are plagued by issues like singularity in structures and non-renewability. The unique structures and renewability of biomass moieties can compensate for these drawbacks, but their properties are hard to design and regulate due to their confined structures. Therefore, it appears to be a reasonable approach to derive AIEgens from abundant biomass (BioAIEgens), integrating the bilateral advantages of both synthetic and natural AIEgens. In this work, the blue-violet emissive coumarin with its lactone structure serving as a rare natural acceptor, is utilized to construct donor-π-acceptor typed BioAIE isomers incorporating the propeller-like and electron-donating triphenylamine (TPA) unit. The results show that Cm-p-TPA undergoes charge transfer with its keto form, emitting red light at 600 nm, which can be applied to monitor Cu2+ concentration during mitophagy using fluorescence lifetime imaging microscopy because of the excellent biocompatibility, photostability, and specific recognition to Cu2+ . This work not only demonstrates the feasibility of utilizing positional isomerization to modulate excited-state evolutions and resultant optical properties, but also provides evidence for the rationality of constructing biologically-active BioAIEgens via a biomass-derivatization concept.

Multi-Stimuli-Responsive and Cell Membrane Camouflaged Aggregation-Induced Emission Nanogels for Precise Chemo-photothermal Synergistic Therapy of Tumors.

Targeted and controllable drug release at lesion sites with the aid of visual navigation in real-time is of great significance for precise theranostics of cancers. Benefiting from the marvelous features (e.g., bright emission and phototheranostic effects in aggregates) of aggregation-induced emission (AIE) materials, constructing AIE-based multifunctional nanocarriers that act as all-arounders to integrate multimodalities for precise theranostics is highly desirable. Here, an intelligent nanoplatform (P-TN-Dox@CM) with homologous targeting, controllable drug release, and in vivo dual-modal imaging for precise chemo-photothermal synergistic therapy is proposed. AIE photothermic agent (TN) and anticancer drug (Dox) are encapsulated in thermo-/pH-responsive nanogels (PNA), and the tumor cell membranes are camouflaged onto the surface of nanogels. Active targeting can be realized through homologous effects derived from source tumor cell membranes, which advantageously elevates the specific drug delivery to tumor sites. After being engulfed into tumor cells, the nanogels exhibit a burst drug release at low pH. The near-infrared (NIR) photoinduced local hyperthermia can activate severe cytotoxicity and further accelerate drug release, thus generating enhanced synergistic chemo-photothermal therapy to thoroughly eradicate tumors. Moreover, P-TN-Dox@CM nanogels could achieve NIR-fluorescence/photothermal dual-modal imaging to monitor the dynamic distribution of therapeutics in real-time. This work highlights the great potential of smart P-TN-Dox@CM nanogels as a versatile nanoplatform to integrate multimodalities for precise chemo-photothermal synergistic therapy in combating cancers.

Deep learning-based lung sound analysis for intelligent stethoscope.

Auscultation is crucial for the diagnosis of respiratory system diseases. However, traditional stethoscopes have inherent limitations, such as inter-listener variability and subjectivity, and they cannot record respiratory sounds for offline/retrospective diagnosis or remote prescriptions in telemedicine. The emergence of digital stethoscopes has overcome these limitations by allowing physicians to store and share respiratory sounds for consultation and education. On this basis, machine learning, particularly deep learning, enables the fully-automatic analysis of lung sounds that may pave the way for intelligent stethoscopes. This review thus aims to provide a comprehensive overview of deep learning algorithms used for lung sound analysis to emphasize the significance of artificial intelligence (AI) in this field. We focus on each component of deep learning-based lung sound analysis systems, including the task categories, public datasets, denoising methods, and, most importantly, existing deep learning methods, i.e., the state-of-the-art approaches to convert lung sounds into two-dimensional (2D) spectrograms and use convolutional neural networks for the end-to-end recognition of respiratory diseases or abnormal lung sounds. Additionally, this review highlights current challenges in this field, including the variety of devices, noise sensitivity, and poor interpretability of deep models. To address the poor reproducibility and variety of deep learning in this field, this review also provides a scalable and flexible open-source framework that aims to standardize the algorithmic workflow and provide a solid basis for replication and future extension: https://github.com/contactless-healthcare/Deep-Learning-for-Lung-Sound-Analysis .

Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) complex (Rh-Mito) as the mtDNA intercalator. Rh-Mito can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh-Mito activates the mitochondrial retrograde signaling by disturbing the key metabolites involved in epigenetic modifications, which alters the nuclear genome methylation landscape to influence the expression of genes related to immune signaling pathways. Finally, we demonstrate that ferritin-encapsulated Rh-Mito elicits potent anticancer activities and evokes intense immune responses in vivo by intravenous injection. Overall, we report for the first time that small molecules targeting mtDNA can activate the cGAS-STING pathway, which gives insights into the development of biomacromolecule-targeted immunotherapeutic agents.

Metals and inorganic molecules in regulating protein and nucleic acid phase separation.

The realization that liquid-liquid phase separation (LLPS) underlies the formation of membraneless compartments in cells has motivated efforts to modulate the condensation process of biomolecules. Increasing evidence shows that metals and inorganic molecules abundantly distributed in cells play important roles in the regulation of biomolecular condensation. Herein, we briefly reviewed the background of biomacromolecular phase separation and summarized the recent research progress on the roles of metals and inorganic molecules in regulating protein and nucleic acid phase separation in vitro and in cells.

Disruption of Zinc Homeostasis by a Novel Platinum(IV)-Terthiophene Complex for Antitumor Immunity.

Zinc homeostatic medicine is of great potential for cancer chemo-immunotherapy; however, there are few reports on antitumor compounds that can trigger Zn2+ -mediated immune responses. In this work, we developed a novel cyclometalated PtIV -terthiophene complex, Pt3, that not only induces DNA damage and cellular metabolism dysregulation, but also disrupts zinc homeostasis as indicated by the abnormal transcriptional level of zinc regulatory proteins, excess accumulation of Zn2+ in cytoplasm, and down-regulation of metallothioneins (MTs), which further caused redox imbalance. The simultaneous disruption of zinc and redox homeostasis in response to Pt3 treatment activated gasdermin-D mediated pyroptosis accompanied by cytoskeleton remodeling, thus releasing pro-inflammatory cytokines to promote dendritic cell (DC) maturation and T cell tumor-infiltration, eventually eliminating both primary and distant tumors in vivo. As far as we know, this is the first metal complex that can regulate zinc homeostasis to activate antitumor immunity.

Self-Amplifying Iridium(III) Photosensitizer for Ferroptosis-Mediated Immunotherapy Against Transferrin Receptor-Overexpressing Cancer.

Photoimmunotherapy is attractive for cancer treatment due to its spatial controllability and sustained responses. This work presents a ferrocene-containing Ir(III) photosensitizer (IrFc1) that can bind with transferrin and be transported into triple-negative breast cancer (TNBC) cells via a transferrin receptor-mediated pathway. When the ferrocene in IrFc1 is oxidized by reactive oxygen species, its capability to photosensitize both type I (electron transfer) and type II (energy transfer) pathways is activated through a self-amplifying process. Upon irradiation, IrFc1 induces the generation of lipid oxidation to cause ferroptosis in TNBC cells, which promotes immunogenic cell death (ICD) under both normoxia and hypoxia. In vivo, IrFc1 treatment elicits a CD8+ T-cell response, which activates ICD in TNBC resulting in enhanced anticancer immunity. In summary, this work reports a small molecule-based photosensitizer with enhanced cancer immunotherapeutic properties by eliciting ferroptosis through a self-amplifying process.

Ru(II)-modified TiO2 nanoparticles for hypoxia-adaptive photo-immunotherapy of oral squamous cell carcinoma.

The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiO2@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiO2 nanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiO2@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiO2@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4+ and CD8+ T lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiO2@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.

Simultaneous Photoactivation of cGAS-STING Pathway and Pyroptosis by Platinum(II) Triphenylamine Complexes for Cancer Immunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way to stimulate the anticancer immune responses. Herein, two PtII complexes (Pt1 and Pt2) were designed as photoactivators of the cGAS-STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activate the cGAS-STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo. Overall, we present the first photoactivator of the cGAS-STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.

Identifying Modulated Functional Connectivity in Corresponding Cerebral Networks in Facial Nerve Lesions Patients With Facial Asymmetry.

Facial asymmetry is the major complaint of patients with unilateral facial nerve lesions. Frustratingly, although patients experience the same etiology, the extent of oral commissure asymmetry is highly heterogeneous. Emerging evidence indicates that cerebral plasticity has a large impact on clinical severity by promoting or impeding the progressive adaption of brain function. However, the precise link between cerebral plasticity and oral asymmetry has not yet been identified. In the present study, we performed functional magnetic resonance imaging on patients with unilateral facial nerve transections to acquire in vivo neural activity. We then identified the regions of interest corresponding to oral movement control using a smiling motor paradigm. Next, we established three local networks: the ipsilesional (left) intrahemispheric, contralesional (right) intrahemispheric, and interhemispheric networks. The functional connectivity of each pair of nodes within each network was then calculated. After thresholding for sparsity, we analyzed the mean intensity of each network connection between patients and controls by averaging the functional connectivity. For the objective assessment of facial deflection, oral asymmetry was calculated using FACEgram software. There was decreased connectivity in the contralesional network but increased connectivity in the ipsilesional and interhemispheric networks in patients with facial nerve lesions. In addition, connectivity in the ipsilesional network was significantly correlated with the extent of oral asymmetry. Our results suggest that motor deafferentation of unilateral facial nerve leads to the upregulated ipsilesional hemispheric connections, and results in positive interhemispheric inhibition effects to the contralesional hemisphere. Our findings provide preliminary information about the possible cortical etiology of facial asymmetry, and deliver valuable clues regarding spatial information, which will likely be useful for the development of therapeutic interventions.

[Characteristics of Soil NO Emissions in the Yangtze River Delta Region for Year 2018].

Soil NO emissions represent an important source of atmospheric nitric oxide (NO) and play an important role in atmospheric chemistry. Based on the latest BDSNP algorithm, this study estimated the soil NO emissions over the Yangtze River Delta region for the year 2018 and further analyzed the associated temporal and spatial variations and uncertainties. The results showed that the annual soil NO emissions in 2018 over the YRD region was 213.6 kt, accounting for 7.3% of the total anthropogenic NOx emissions. Areas with high emissions were mainly concentrated in northern Anhui Province and most parts of Jiangsu Province. In terms of monthly variations, soil NO emissions peaked in June, accounting for 19.9% of the annual emissions and 19.7% of anthropogenic NOx emissions in June. In terms of daily variations, soil NO emissions peaked around 16:00 and accounted for 5.5% of daily emissions. Soil NO emissions came from three components:soil background, nitrogen fertilizer application, and nitrogen deposition. Nitrogen fertilizer application was the main source of soil NO emissions, accounting for up to 77.8%. With the in-depth reduction in NOx emissions from motor vehicles and industries, the importance of soil NO emissions will become increasingly prominent.

Masseteric-to-facial nerve transfer combined with static suspension: Evaluation and validation of facial symmetry in patients with different levels of asymmetry.

One-stage combined dynamic reanimation with static suspension has obvious advantages of improving facial symmetry. In clinical observation, patients with different levels of oral commissure drooping achieve different symmetry outcomes, despite undergoing the same surgical procedure. Patients with slight asymmetry obtain better outcomes than those with severe asymmetry. The mechanisms influencing postoperative outcomes have not been systematically explored. We retrospectively analyzed 44 patients performed with masseteric-to-facial nerve transfer combined with static suspension. Patients were divided into two groups according to the level of oral commissure drooping: slight-asymmetry group (n = 24) and severe-asymmetry group (n = 20). Static and dynamic symmetry were assessed with FACE-gram software pre and postoperatively. The symmetry of the oral commissures at rest and during smiling significantly improved postoperatively in all patients. The differences of the bilateral oral commissure positions were significantly smaller in slight-asymmetry group than that in severe-asymmetry group (p<0.001), indicating that slight-asymmetry group achieved better symmetry. Furthermore, these differences were caused by the oral commissures position on the unaffected side, both pre and postoperatively (p<0.001), but not the paralyzed side's (p>0.05). In conclusion, masseteric-to-facial nerve transfer combined with static suspension achieved dynamic and static symmetry in patients with different levels of asymmetry. Patients with slight asymmetry obtained better postoperative symmetry than those with severe asymmetry. Postoperative facial asymmetry might be influenced by the hypertonicity of facial muscles on the unaffected side.

Facial reanimation with interposition nerve graft or masseter nerve transfer: a comparative retrospective study.

Both interposition nerve grafts and masseter nerve transfers have been successfully used for facial reanimation after irreversible injuries to the cranial portion of the facial nerve. However, no comparative study of these two procedures has yet been reported. In this two-site, two-arm, retrospective case review study, 32 patients were included. Of these, 17 patients (eight men and nine women, mean age 42.1 years) underwent interposition nerve graft after tumor extirpation or trauma between 2003 and 2006 in the Ear Institute, School of Medicine, Shanghai Jiao Tong University, China, and 15 patients (six men and nine women, mean age 40.6 years) underwent masseter-to-facial nerve transfer after tumor extirpation or trauma between November 2010 and February 2016 in Shanghai Ninth People's Hospital, China. More patients achieved House-Brackmann III recovery after masseter nerve repair than interposition nerve graft repair (15/15 vs. 12/17). The mean oral commissure excursion ratio was also higher in patients who underwent masseter nerve transfer than in patients subjected to an interposition nerve graft. These findings suggest that masseter nerve transfer results in strong oral commissure excursion, avoiding obvious synkinesis, while an interposition nerve graft provides better resting symmetry. This study was approved by the Institutional Ethics Committee, Shanghai Ninth People's Hospital, China (approval No. SH9H-2019-T332-1) on December 12, 2019.

A Carbonic Anhydrase IX (CAIX)-Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti-Tumor Immunity.

An ideal cancer treatment should not only destroy primary tumors but also improve the immunogenicity of the tumor microenvironment to achieve a satisfactory anti-tumor immune effect. We designed a carbonic anhydrase IX (CAIX)-anchored rhenium(I) photosensitizer, named CA-Re, that not only performs type-I and type-II photodynamic therapy (PDT) with high efficiency under hypoxia (nanomolar-level phototoxicity), but also evokes gasdermin D (GSDMD) mediated pyroptotic cell death to effectively stimulate tumor immunogenicity. CA-Re could disrupt and self-report the loss of membrane integrity simultaneously. This promoted the maturation and antigen-presenting ability of dendritic cells (DCs), and fully activated T cells dependent adaptive immune response in vivo, eventually eliminating distant tumors at the same time as destroying primary tumors. To the best of our knowledge, CA-Re is the first metal complex-based pyroptosis inducer.

Ferroptosis-Enhanced Cancer Immunity by a Ferrocene-Appended Iridium(III) Diphosphine Complex.

Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis-inducing agents have great potential as new antitumor candidates. Here, we report a IrIII complex (Ir1) containing a ferrocene-modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton-like reaction, produce hydroxyl radicals, induce lipid peroxidation, down-regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis-inducing capabilities for effective cancer immunotherapy.

[Role of Land Use Changes on Ammonia Emissions from Agricultural Ecosystems in the Yangtze River Delta Region from 2000 to 2018].

Based on Landsat satellite remote sensing images, this study interprets land use changes in the Yangtze River Delta (YRD) region from 2000 to 2018. Combined with changes in nitrogen fertilizer application, the changes in ammonia emissions from farmland ecosystem due changes in land use and nitrogen fertilizer application were further investigated. The results show that along with the rapid urbanization process, the area of cultivated land in the YRD region has gradually decreased from 276269 km2 (49% of total land area) in 2000 to 244001 km2 (44%) in 2018. The effects of changes in land use and nitrogen fertilizer application on ammonia emissions from farmland ecosystems mainly include emissions from soil background and nitrogen fertilizer application. From 2000 to 2018, ammonia emissions due to the application of nitrogen fertilizer decreased from 690 kt·a-1 to 541 kt·a-1 (relative decrease by 22%), while the ammonia emissions from the soil background reduced from 32 kt·a-1 to 29 kt·a-1 (decrease by 9%). During the past 20 years, urbanization in the YRD region has accelerated, and the area of cultivated land and the total amount of nitrogen fertilizer application have significantly reduced, thus resulting in reductions in ammonia emissions from the farmland ecosystem.

Induction and Monitoring of DNA Phase Separation in Living Cells by a Light-Switching Ruthenium Complex.

Phase separation of DNA is involved in chromatin packing for the regulation of gene transcription. Visualization and manipulation of DNA phase separation in living cells present great challenges. Herein, we present a Ru(II) complex (Ru1) with high DNA binding affinity and DNA "light-switch" behavior that can induce and monitor DNA phase separation both in vitro and in living cells. Molecular dynamics simulations indicate that the two phen-PPh3 ligands with positively charged lipophilic triphenylphosphine substituents and flexible long alkyl chains in Ru1 play essential roles in the formation of multivalent binding forces between DNA molecules to induce DNA phase separation. Importantly, the unique environmental sensitive emission property of Ru1 enables direct visualization of the dynamic process of DNA phase separation in living cells by two-photon phosphorescent lifetime imaging. Moreover, Ru1 can change the gene expression pattern by modulating chromatin accessibility as demonstrated by integrating RNA-sequencing and transposase-accessible chromatin with high-throughput sequencing. In all, we present here the first small-molecule-based tracer and modulator of DNA phase separation in living cells and elucidate its impact on the chromatin state and transcriptome.

[Influence of mandibulotomy approaches on oral function following radical resection of tongue carcinoma].

OBJECTIVE: This study aimed to compare the influences of postoperative oral function in patients with median or paramedian mandibulotomy during the radical resection of tongue carcinoma and to provide evidence for the choice of osteotomy location for mandibulotomy. METHODS: The clinical data of 126 patients who underwent combined radical neck dissection with mandibulectomy and glossectomy followed by simultaneous reconstruction were analyzed retrospectively. The patients were divided into two groups according to the position of mandibulotomy: median mandibulotomy group (median group, n=60) and paramedian mandibulotomy group (paramedian group, n=66). The fourth edition of the University of Washington Quality of Life Questionnaire (UW-QOL) was used to compare the differences in oral functions, such as swallowing, mastication, and speech, between the two groups during regular follow-up. SPSS 24.0 software package was used for statistical analysis, and P<0.05 was considered statistically significant. RESULTS: Six months after the operation, no significant differences in swallowing, mastication, and speech functions were found between the median and paramedian groups. However, the swallowing and speech functions in the paramedian group were better than those in the median group 1 year after the operation (P<0.05), whereas no statistical difference in mastication function was observed between the two groups. CONCLUSIONS: Evaluation of the postoperative oral function results showed that paramedian mandibulotomy was a better surgical approach than median mandibulotomy. Paramedian mandibulotomy is worth prioritizing in the radical resection of tongue carcinoma.

[Trend in the prevalence of prostate cancer in Shihezi, Xinjiang from 2009 to 2017].

OBJECTIVE: To analyze the trend in the prevalence and mortality of prostate cancer in Shihezi, Xinjiang from 2009 to 2017 and provide some evidence for the prevention and control of the malignance. METHODS: We collected the data on the cancer registries in the Shihezi area between 2009 and 2017, calculated the incidence and mortality rates of prostate cancer, and analyzed the annual percent change (APC) and prevalence trend of the disease. RESULTS: The crude incidence rate, age-standardized incidence rate by Chinese standard population (ASIRC), age-standardized incidence rate by world standard population (ASIRW) and cumulative incidence rate of prostate cancer (in 0－74-year-olds) in Shihezi between 2009 and 2017 were 16.94, 10.33, 8.98 and 2.29 per 100 000, respectively. The crude mortality rate, age-standardized mortality rate by Chinese standard population (ASMRC), age-standardized mortality rate by world standard population (ASMRW) and cumulative incidence rate (in 0－74-year-olds) were 9.03, 5.39 and 4.72 and 0.49 per 100 000, respectively. Both the incidence and mortality rates showed an increasing trend from 2009 to 2017, with an APC of 16.69% (P < 0.05) and 19.71% (P < 0.05), respectively. From 2011 to 2017, the increase rates of incidence and mortality of prostate cancer in the >60-year-olds were 86.20% and 89.30%, with the peak values shifted from the 70－74 to the 80－84 years old males. CONCLUSIONS: The incidence and mortality of prostate cancer in Shihezi showed an increasing trend from 2009 to 2017, chiefly in the males aged over 60 years, with the peak value moving towards an older age.