Operation-friendly and accurate naked-eye observation assay for fast zoonotic echinococcosis and pulmonary tuberculosis monitoring in clinics.

Echinococcosis and tuberculosis are two common zoonotic diseases that can cause severe pulmonary infections. Early screening and treatment monitoring are of great significance, especially in areas with limited medical resources. Herein, we designed an operation-friendly and rapid magnetic enrichment-silver acetylene chromogenic immunoassay (Me-Sacia) to monitor the antibody. The main components included secondary antibody-modified magnetic nanoparticles (MNP-Ab2) as capture nanoparticles, specific peptide (EG95 or CFP10)-modified silver nanoparticles (AgNP-PTs) as detection nanoparticles, and alkyne-modified gold nanoflowers as chromogenic nanoparticles. Based on the magnetic separation and plasma luminescence techniques, Me-Sacia could completely replace the colorimetric assay of biological enzymes. It reduced the detection time to approximately 1 h and simplified the labor-intensive and equipment-intensive processes associated with conventional ELISA. Meanwhile, the Me-Sacia showed universality for various blood samples and intuitive observation with the naked eye. Compared to conventional ELISA, Me-Sacia lowered the detection limit by approximately 96.8 %, increased the overall speed by approximately 15 times, and improved sensitivity by approximately 7.2 %, with a 100 % specificity and a coefficient of variation (CV) of less than 15 %.

Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.

The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC50 = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC50 values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs.

Molecular fingerprint and machine learning enhance high-performance MOFs for mustard gas removal.

Chemical warfare agents (CWAs), epitomized by the notoriously used mustard gas (HD), represent a class of exceptionally toxic chemicals whose airborne removal is paramount for battlefield safety. This study integrates high-throughput computational screening (HTCS) with advanced machine learning (ML) techniques to investigate the efficacy of metal-organic frameworks (MOFs) in adsorbing and capturing trace amounts of HD present in the air. Our approach commenced with a comprehensive univariate analysis, scrutinizing the impact of six distinct descriptors on the adsorption efficiency of MOFs. This analysis elucidated a pronounced correlation between MOF density and the Henry coefficient in the effective capture of HD. Then, four ML algorithms were employed to train and predict the performance of MOFs. The Random Forest (RF) algorithm demonstrates strong model learning and good generalization, achieving the best prediction result of 98.3%. In a novel exploratory stride, we incorporated a 166-bit MACCS molecular fingerprinting (MF) to identify critical functional groups within adsorbents. From the top 100 MOFs analyzed, 22 optimal functional groups were identified. Leveraging these insights, we designed three innovative substructures, grounded in these key functional groups, to enhance HD adsorption efficiency. In this work, the combination of MF and ML could provide a new direction for efficient screening of MOFs for the capture of HD in the air. The outcomes of this study offer substantial potential to revolutionize the domain of CWA capture. This represents a significant stride toward developing practical solutions that enhance both environmental protection and battlefield security.

Lysophosphatidylcholine acyltransferase 1 suppresses nanoclustering and function of KRAS.

KRAS is frequently mutated in cancer, contributing to 20% of all human cancer especially pancreatic, colorectal and lung cancer. Signaling of the constitutively active KRAS oncogenic mutants is mostly compartmentalized to proteolipid nanoclusters on the plasma membrane (PM). Signaling nanoclusters of many KRAS mutants selectively enrich phosphatidylserine (PS) lipids with unsaturated sn-2 acyl chains, but not the fully saturated PS species. Thus, remodeling PS acyl chains may suppress KRAS oncogenesis. Lysophosphatidylcholine acyltransferases (LPCATs) remodel sn-2 acyl chains of phospholipids, with LPCAT1 preferentially generating the fully saturated lipids. Here, we show that stable expression of LPCAT1 depletes major PS species with unsaturated sn-2 chains while decreasing minor phosphatidylcholine (PC) species with the corresponding acyl chains. LPCAT1 expression more effectively disrupts the nanoclustering of oncogenic GFP-KRASG12V, which is restored by acute addback of exogenous unsaturated PS. LPCAT1 expression compromises signaling and oncogenic activities of the KRAS-dependent pancreatic tumor lines. LPCAT1 expression sensitizes human pancreatic tumor MiaPaCa-2 cells to KRASG12C specific inhibitor, Sotorasib. Statistical analyses of patient data further reveal that pancreatic cancer patients with KRAS mutations express less LPCAT1. Higher LPCAT1 expression also improves survival probability of pancreatic and lung adenocarcinoma patients with KRAS mutations. Thus, PS acyl chain remodeling selectively suppresses KRAS oncogenesis.

Engineering a biomimicking strategy for discovering nonivamide-based quorum-sensing inhibitors for controlling bacterial infection.

The overuse of antibiotics over an extended period has led to increasing antibiotic resistance in pathogenic bacteria, culminating in what is now considered a global health crisis. To tackle the escalating disaster caused by multidrug-resistant pathogens, the development of new bactericides with new action mechanism is highly necessary. In this study, using a biomimicking strategy, a series of new nonivamide derivatives that feature an isopropanolamine moiety [the structurally similar to the diffusible signal factor (DSF) of Xanthomonas spp.] were prepared for serving as potential quorum-sensing inhibitors (QSIs). After screening and investigation of their rationalizing structure-activity relationships (SARs), compound A26 was discovered as the most optimal active molecule, with EC50 values of 9.91 and 7.04 µg mL-1 against Xanthomonas oryzae pv oryzae (Xoo) and Xanthomonas axonopodis pv. citri (Xac). A docking study showed that compound A26 exhibited robust interactions with Glu A: 161 of RpfF, which was strongly evidenced by fluorescence titration assay (KA value for Xoo RpfF-A26 = 104.8709 M-1). Furthermore, various bioassays showed that compound A26 could inhibit various bacterial virulence factors, including biofilm formation, extracellular polysaccharides (EPS), extracellular enzyme activity, DSF production, and swimming motility. In addition, in vivo anti-Xoo results showed that compound A26 had excellent control efficiency (curative activity: 43.55 %; protective activity: 42.56 %), surpassing that of bismerthiazol and thiodiazole copper by approximately 8.0%-37.3 %. Overall, our findings highlight a new paradigm wherein nonivamide derivatives exhibit potential in combating pathogen resistance issues by inhibiting bacterial quorum sensing systems though attributing to their new molecular skeleton, novel mechanisms of action, and non-toxic features.

Comparison of conventional MRI analysis versus MRI-based radiomics to predict the circumferential margin resection involvement of rectal cancer.

BACKGROUND: To compare the application of conventional MRI analysis and MRI-based radiomics to identify the circumferential resection margin (CRM) status of rectal cancer (RC). METHODS: A cohort of 301 RC patients with 66 CRM invloved status and 235 CRM non-involved status were enrolled in this retrospective study between September 2017 and August 2022. Conventional MRI characteristics included gender, age, diameter, distance to anus, MRI-based T/N phase, CEA, and CA 19 - 9, then the relevant logistic model (Logistic-cMRI) was built. MRI-based radiomics of rectal cancer and mesorectal fascia were calculated after volume of interest segmentation, and the logistic model of rectal cancer radiomics (Logistic-rcRadio) and mesorectal fascia radiomics (Logistic-mfRadio) were constructed. And the combined nomogram (nomo-cMRI/rcRadio/mfRadio) containing conventional MRI characteristics, radiomics of rectal cancer and mesorectal fascia was developed. The receiver operator characteristic curve (ROC) was delineated and the area under curve (AUC) was calculated the efficiency of models. RESULTS: The AUC of Logistic-cMRI was 0.864 (95%CI, 0.820 to 0.901). The AUC of Logistic-rcRadio was 0.883 (95%CI, 0.832 to 0.928) in the training set and 0.725 (95%CI, 0.616 to 0.826) in the testing set. The AUCs of Logistic-mfRadio was 0.891 (95%CI, 0.838 to 0.936) in the training set and 0.820 (95%CI, 0.725 to 0.905) in the testing set. The AUCs of nomo-cMRI/rcRadio/mfRadio were the highest in both the training set of 0.942 (95%CI, 0.901 to 0.969) and the testing set of 0.909 (95%CI, 0.830 to 0.959). CONCLUSION: MRI-based radiomics of rectal cancer and mesorectal fascia showed similar efficacy in predicting the CRM status of RC. The combined nomogram performed better in assessment.

CRISPR-Cas9 for selective targeting of somatic mutations in pancreatic cancers.

Somatic mutations are desirable targets for selective elimination of cancer, yet most are found within noncoding regions. We have adapted the CRISPR-Cas9 gene editing tool as a novel, cancer-specific killing strategy by targeting the subset of somatic mutations that create protospacer adjacent motifs (PAMs), which have evolutionally allowed bacterial cells to distinguish between self and non-self DNA for Cas9-induced double strand breaks. Whole genome sequencing (WGS) of paired tumor minus normal (T-N) samples from three pancreatic cancer patients (Panc480, Panc504, and Panc1002) showed an average of 417 somatic PAMs per tumor produced from single base substitutions. Further analyses of 591 paired T-N samples from The International Cancer Genome Consortium found medians of ∼455 somatic PAMs per tumor in pancreatic, ∼2800 in lung, and ∼3200 in esophageal cancer cohorts. Finally, we demonstrated 69-99% selective cell death of three targeted pancreatic cancer cell lines using 4-9 sgRNAs designed using the somatic PAM discovery approach. We also showed no off-target activity from these tumor-specific sgRNAs in either the patient's normal cells or an irrelevant cancer using WGS. This study demonstrates the potential of CRISPR-Cas9 as a novel and selective anti-cancer strategy, and supports the genetic targeting of adult cancers.

The Role of Placental DNA Methylation at Reproduction-Related Genes in Associations between Prenatal Bisphenol Analogues Exposure and the Digit Ratio in Children at Age 4: A Birth Cohort Study.

Placental DNA methylation (DNAm) may be a potential mechanism underlying the effects of prenatal bisphenol analogues (BPs) exposure on reproductive health. Based on the Shanghai-Minhang Birth Cohort Study (S-MBCS), this study investigated associations of placental DNAm at reproduction-related genes with prenatal BPs exposure and children's digit ratios at age 4 using multiple linear regression models, and mediation analysis was further used to examine the mediating role of placental DNAm in the associations between prenatal BPs exposure and digit ratios among 345 mother-child pairs. Prenatal exposure to bisphenol A (BPA) was associated with hypermethylation at Protocadherin 8 (PCDH8), RBMX Like 2 (RBMXL2), and Sperm Acrosome Associated 1 (SPACA1), while bisphenol F (BPF) exposure was associated with higher methylation levels of Fibroblast Growth Factor 13 (FGF13). Consistent patterns were found in associations between higher DNAm at the 4 genes and increased digit ratios. Further mediation analysis showed that about 15% of the effect of BPF exposure on increased digit ratios was mediated by placental FGF13 methylation. In conclusion, the altered placental DNAm status might be a mediator underlying the feminizing effect of prenatal BPs exposure.

Perfluorooctane sulfonate promotes the migration of colorectal cancer cells by inducing epithelial-mesenchymal transition.

The potential association between colorectal cancer (CRC) and environmental pollutants is worrisome. Previous studies have found that some perfluoroalkyl acids, including perfluorooctane sulfonate (PFOS), induced colorectal tumors in experimental animals and promoted the migration of and invasion by CRC cells in vitro, but the underlying mechanism is unclear. Here, we investigated the effects of PFOS on the proliferation and migration of CRC cells and the potential mechanisms involving activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition (EMT). It was found that PFOS promoted the growth and migration of HCT116 cells at non-cytotoxic concentrations and increased the mRNA expression of the migration-related angiogenic cytokines vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In a mechanistic investigation, the up-stream signal pathway PI3K/Akt-NF-κB was activated by PFOS, and the process was suppressed by LY294002 (PI3K/Akt inhibitor) and BAY11-7082 (NF-κB inhibitor) respectively, leading to less proliferation of HCT116 cells. Furthermore, matrix metalloproteinases (MMP) and EMT-related markers were up-regulated after PFOS exposure, and were also suppressed respectively by LY294002 and BAY11-7082. Moreover, the up-regulation of EMT markers was suppressed by a MMP inhibitor GM6001. Taken together, our results indicated that PFOS promotes colorectal cancer cell migration and proliferation by activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition. This could be a potential toxicological mechanism of PFOS-induced malignant development of colorectal cancer.

Cu(II) complex that synergistically potentiates cytotoxicity and an antitumor immune response by targeting cellular redox homeostasis.

Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.

Rapid enrichment of AnAOB with a novel vermiculite/tourmaline modification technology for enhanced DEAMOX process.

The DEnitrifying AMmonium OXidation (DEAMOX) has been proven to be a promising process treating contaminated surface water containing ammonia and nitrate, while the enrichment of the slow-growing anammox bacteria (AnAOB) remains a challenge. In this study, a novel polyurethane-adhesion vermiculite/tourmaline (VTP) modified carrier was developed to achieve effective enrichment of AnAOB. The results demonstrated that the VTP-1 (vermiculite: tourmaline = 1:1) system exhibited the greatest performance with the total nitrogen removal efficiency reaching 87.6% and anammox contributing 63% to nitrogen removal. Scanning electron microscope analysis revealed the superior biofilm structure of the VTP-1 carrier, providing attachment for AnAOB. The addition of VTP-1 promoted the secretion of EPS (extracellular polymeric substances) by microorganisms, which increased to 85.34 mg/g VSS, contributing to the aggregation of anammox cells. The favorable substrate microenvironment created by NH4+ adsorption and NO2- supply via partial denitrification process facilitated the growth of AnAOB. The relative abundance of Candidatus Brocadia and Thauera increased from 0.04% to 0.3%-1.03% and 2.06% in the VTP-1 system, respectively. This study sheds new light on the anammox biofilm formation and provides a valid approach to initiate the DEAMOX process for low nitrogen polluted water treatment.

Addressing Hospital Overwhelm During the COVID-19 Pandemic by Using a Primary Health Care-Based Integrated Health System: Modeling Study.

Background: After strict COVID-19-related restrictions were lifted, health systems globally were overwhelmed. Much has been discussed about how health systems could better prepare for future pandemics; however, primary health care (PHC) has been largely ignored. Objective: We aimed to investigate what combined policies PHC could apply to strengthen the health care system via a bottom-up approach, so as to better respond to a public health emergency. Methods: We developed a system dynamics model to replicate Shanghai's response when COVID-19-related restrictions were lifted. We then simulated an alternative PHC-based integrated health system and tested the following three interventions: first contact in PHC with telemedicine services, recommendation to secondary care, and return to PHC for recovery. Results: The simulation results showed that each selected intervention could alleviate hospital overwhelm. Increasing the rate of first contact in PHC with telemedicine increased hospital bed availability by 6% to 12% and reduced the cumulative number of deaths by 35%. More precise recommendations had a limited impact on hospital overwhelm (<1%), but the simulation results showed that underrecommendation (rate: 80%) would result in a 19% increase in cumulative deaths. Increasing the rate of return to PHC from 5% to 20% improved hospital bed availability by 6% to 16% and reduced the cumulative number of deaths by 46%. Moreover, combining all 3 interventions had a multiplier effect; bed availability increased by 683%, and the cumulative number of deaths dropped by 75%. Conclusions: Rather than focusing on the allocation of medical resources in secondary care, we determined that an optimal PHC-based integrated strategy would be to have a 60% rate of first contact in PHC, a 110% recommendation rate, and a 20% rate of return to PHC. This could increase health system resilience during public health emergencies.

Intrinsic Stress Field for Liquid Surfaces.

The microscopic stress field inhomogeneity in the interfacial region adjacent to the liquid surface is the fundamental origin of the liquid surface tension, but because of broadening due to capillary fluctuations, a detailed molecular level understanding of the stress field remains elusive. In this work, we deconvolute the capillary fluctuations to reveal the intrinsic stress field and show that the atomic-level contributions to the surface tension are similar in functional form across a variety of monatomic systems. These contributions are confined to an interfacial region approximately 1.5±0.1 times the particle diameter for all systems studied. In addition, the intrinsic density and stress profiles show a strong spatial correlation that should be useful in the development of a statistical mechanical theory for the prediction of surface stress and surface tension.

Cevanine-type steroidal alkaloids from the bulbs of Fritillaria cirrhosa D. Don.

Eight previously undescribed cevanine-type steroidal alkaloids, cirrhosinones I-N and cirrhosinols A-B, along with five known analogs, were isolated from the bulbs of Fritillaria cirrhosa D. Don. Their structures were elucidated on the basis of comprehensive analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and single-crystal X-ray diffraction analyses. All compounds revealed weak NO inhibitory activities in the LPS-stimulated NR8383 cells at the concentration of 20 µM, with inhibition ratios ranging from 5.1% to 14.3%.

Picrachinentins A-F, 14-Membered Cyclopeptide Alkaloid-Type Burpitides with Uncommon N-Terminal Modifications from Picrasma chinensis and Their Neuroprotective Activity.

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways.

Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)(III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphosphine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1-H-XR4), namely [Rh(XR1)2(TPP)Cl]·(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a-YNU-1d in Hep-G2 and HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity and selectivity in HCC1806 cells (IC50 = 0.13 ± 0.06 µM, selectivity factor (SF) = 384.6). The compounds YNU-1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and downregulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly, hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic characteristics. YNU-1a-YNU-1d compounds are promising drug candidates that can be used to overcome cisplatin resistance.

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations.

Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge. To date, no effective drugs have been approved to simultaneously overcome clinical resistance caused by these two mutants. Thus, a series of pyrazinamide macrocyclic compounds were first designed and evaluated to overcome the secondary mutations of FLT3. The representative 8v exhibited potent inhibitory activities against FLT3D835Y and FLT3D835Y/F691L with IC50 values of 1.5 and 9.7 nM, respectively. 8v also strongly suppressed the proliferation against Ba/F3 cells transfected with FLT3-ITD, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-D835Y-F691L, and MV4-11 acute myeloid leukemia (AML) cell lines with IC50 values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, 8v demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that 8v can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.

Does a GP service package matter in addressing the absence of health management by the occupational population? A modelling study.

OBJECTIVE: To assess the influence of supply and demand factors on the contract behavior of occupational populations with general practitioner (GP) teams. METHODS: We employed a system dynamics approach to assess and predict the effect of the general practitioner service package (GPSP) and complementary incentive policies on the contract rate for 2015-2030. First, the GPSP is designed to address the unique needs of occupational populations, enhancing the attractiveness of GP contracting services, including three personalized service contents tailored to demand-side considerations: work-related disease prevention (WDP), health education & counseling (HEC), and health-care service (HCS). Second, the complementary incentive policies on the supply-side included income incentives (II), job title promotion (JTP), and education & training (ET). Considering the team collaboration, the income distribution ratio (IDR) was also incorporated into supply-side factors. FINDINGS: The contract rate is predicted to increase to 57.8% by 2030 after the GPSP intervention, representing a 15.4% increase on the non-intervention scenario. WDP and HEC have a slightly higher (by 2%) impact on the contract rate than that from HCS. Regarding the supply-side policies, II have a more significant impact on the contract rate than JTP and ET by 3-5%. The maximum predicted contract rate of 75.2% is expected by 2030 when the IDR is 0.5, i.e., the GP receives 50% of the contract income and other members share 50%. CONCLUSION: The GP service package favorably increased the contract rate among occupational population, particularly after integrating the incentive policies. Specifically, for a given demand level, the targeted content of the package enhanced the attractiveness of contract services. On the supply side, the incentive policies boost GPs' motivation, and the income distribution motivated other team members.

Acidity-responsive polyphenol-coordinated nanovaccines for improving tumor immunotherapy via bidirectional reshaping of the immunosuppressive microenvironment and controllable release of antigens.

The tumor immunosuppressive microenvironment (TIME) and uncontrollable release of antigens can lower the efficacy of nanovaccine-based immunotherapy (NBI). Therefore, it is necessary to develop a new strategy for TIME reshaping and controllable release of antigens to improve the NBI efficacy. Herein, an acidity-responsive Schiff base-conjugated polyphenol-coordinated nanovaccine was constructed for the first time to realize bidirectional TIME reshaping and controllable release of antigens for activating T cells. In particular, an acidity-responsive tannic acid-ovalbumin (TA-OVA) nanoconjugate was prepared via a Schiff base reaction. FeIII was coordinated with TA-OVA to produce a FeIII-TA-OVA nanosystem, and 1-methyltryptophan (1-MT) as an indoleamine 2,3-dioxygenase inhibitor was loaded to form a polyphenol-coordinated nanovaccine. The coordination between FeIII and TA could cause photothermal ablation of primary tumors, and the acidity-triggered Schiff base dissociation of TA-OVA could controllably release OVA to realize lysosome escape, initiating the body's immune response. More importantly, oxidative stress generated by a tumor-specific Fenton reaction of Fe ions could promote the polarization of tumor-associated macrophages from the M2 to M1 phenotype, resulting in the upregulation of cytotoxic T cells and helper T cells. Meanwhile, 1-MT could downregulate immunosuppressive regulatory T cells. Overall, such skillful combination of bidirectional TIME reshaping and controllable antigen release into one coordination nanosystem could effectively enhance the NBI efficacy of tumors.

Intramolecular Hydrogen Bonding Rigidifying Flexible Bridge for Solution- and Vacuum-Processed TSCT-TADF Emitters.

To realize strong donor-acceptor face-to-face stacking for efficient through-space charge transfer-type thermally activated delayed fluorescence, a conceptually new design strategy is proposed to couple flexible bridges with adequate rigidity via built-in intramolecular hydrogen bonds (IHBs). The resulting emitter ACE-CN has a planarized benzyl methyl ether bridge self-anchored by the C-H···O IHB and shows a high photoluminescence quantum efficiency of 93%. The solution- and vacuum-processed devices exhibited high external quantum efficiencies of 11.8% and 24.7%, respectively.