In situ chemoimmunotherapy hydrogel elicits immunogenic cell death and evokes efficient antitumor immune response.

BACKGROUND: Chemoimmunotherapy has shown promising advantages of eliciting immunogenic cell death and activating anti-tumor immune responses. However, the systemic toxicity of chemotherapy and tumor immunosuppressive microenvironment limit the clinical application. METHODS: Here, an injectable sodium alginate hydrogel (ALG) loaded with nanoparticle albumin-bound-paclitaxel (Nab-PTX) and an immunostimulating agent R837 was developed for local administration. Two murine hepatocellular carcinoma and breast cancer models were established. The tumor-bearing mice received the peritumoral injection of R837/Nab-PTX/ALG once a week for two weeks. The antitumor efficacy, the immune response, and the tumor microenvironment were investigated. RESULTS: This chemoimmunotherapy hydrogel with sustained-release character was proven to have significant effects on killing tumor cells and inhibiting tumor growth. Peritumoral injection of our hydrogel caused little harm to normal organs and triggered a potent antitumor immune response against both hepatocellular carcinoma and breast cancer. In the tumor microenvironment, enhanced immunogenic cell death induced by the combination of Nab-PTX and R837 resulted in 3.30-fold infiltration of effector memory T cells and upregulation of 20 biological processes related to immune responses. CONCLUSIONS: Our strategy provides a novel insight into the combination of chemotherapy and immunotherapy and has the potential for clinical translation.

A Thermosensitive Bi-Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti-Tumor Efficacy of Frameshift Neoantigens.

Tumor-specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self-tolerance. Here, a thermosensitive hydrogel (FSP-RZ-BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn2+ (cGAS-STING agonist) is designed to promote the efficacy of FSPs on murine forestomach cancer (MFC). After peritumoral injection, FSP-RZ-BPH behaves as pH-responsive sustained drug release at sites near the tumor to effectively transform the immunosuppressive TME into an inflammatory type. FSP-RZ-BPH orchestrates innate and adaptive immunity to activate dendritic cells in tumor-draining lymph nodes and increase the number of FSPs-reactive effector memory T cells (TEM) in tumor by 2.9 folds. More importantly, these TEM also exhibit memory responses to nonvaccinated neoantigens on MFC. This epitope spreading effect contributes to reduce self-tolerance to maintain long-lasting anti-tumor immunity. In MFC suppressive model, FSP-RZ-BPH achieves 84.8% tumor inhibition rate and prolongs the survival of tumor-bearing mice with 57.1% complete response rate. As a preventive tumor vaccine, FSP-RZ-BPH can also significantly delay tumor growth. Overall, the work identifies frameshift MFC neoantigens for the first time and demonstrates the thermosensitive bi-adjuvant hydrogel as an effective strategy to boost bystander anti-tumor responses of frameshift neoantigens.

Engineered hydrochar from waste reed straw for peroxymonosulfate activation to degrade quinclorac and improve solanaceae plants growth.

Hydrochar from agricultural wastes is regarded as a prospective and low-cost material to activate peroxymonosulfate (PMS) for degrading pollutants. Herein, a novel in-situ N-doped hydrochar composite (RHCM4) was synthesized using montmorillonite and waste reed straw rich in nitrogen as pyrolysis catalyst and carbon source, respectively. The fabricated RHCM4 possessed excellent PMS activation performance for decomposing quinclorac (QC), a refractory herbicide, with a high removal efficiency of 100.0% and mineralization efficiency of 75.1%. The quenching experiments and electron spin resonance (ESR) detection disclosed free radicals (•OH, •SO4-, and •O2-) and non-radicals (1O2) took part in the QC degradation process. Additionally, the catalytic mechanisms were analyzed in depth with the aid of various characterizations. Moreover, the QC degradation intermediates and pathways were clarified by density functional theory calculations and HPLC-MS. Importantly, phytotoxicity experiments showed that RHCM4/PMS could efficaciously mitigate the injury of QC to Solanaceae crops (pepper, tomato, and tobacco). These findings give a new idea for enhancing the catalytic activity of hydrochar from agricultural wastes and broaden its application in the field of agricultural environment.

Environmental-friendly hydrochar-montmorillonite composite for efficient catalytic degradation of dicamba and alleviating its damage to crops.

In recent years, carbon-based materials catalyzing peroxymonosulfate (PMS) for green degradation of persistent organic pollutants have attracted increasing attention. However, PMS activation by hydrochar composite (e.g. hydrochar-montomorillonite) has rarely been investigated. Herein, a simple preparation, low-cost and eco-friendly catalyst of hydrochar-montmorillonite composite (HC-Mt) was prepared to firstly catalyze PMS for the degradation of dicamba (DIC). The as-prepared HC-Mt showed a remarkably better catalyzing performance for PMS than pure hydrochar (HC) due to its good physicochemical characteristics and abundant oxygen-containing groups. Furthermore, the electron spin resonance (ESR) and quenching tests revealed that active species such as SO4-, OH and O2- all participated in the degradation process. DIC sites on C6, Cl 10, and O15 exhibited higher reactivity according to the density functional theory (DFT) calculation, which were easily attacked by active species. The DIC degradation mainly occurred via hydroxyl substitution, decarboxylation, oxidation and ring-cleavage and finally most of the intermediates were mineralized into CO2 and H2O. Finally, the phytotoxicity assessment was measured by the germination growth situation of tobacco and mung beans in the presence of DIC (with or without treatment by HC-Mt/PMS). The result showed that HC-Mt/PMS could significantly reduce the phytotoxicity of DIC to crops, suggesting that catalyzing PMS using HC-Mt was environmentally friendly. Therefore, this work did not only provide a novel catalyzing PMS strategy using hydrochar composite for wastewater treatment, but also give a new idea for herbicide phytotoxicity management.

Versatile Protein Coronation Approach with Multiple Depleted Serum for Creating Biocompatible, Precision Nanomedicine.

The protein corona effect has long been treated as the evil source behind delivery efficacy issues. In this study, this concept is challenged by showcasing that the protein corona can serve as a versatile functionalization approach to improve the delivery efficacy or mitigate nanocytotoxicity. To this end, the depleted serum is introduced to create nanomaterials carrying functionally distinct protein corona, referred to as PCylated nanomaterials. It is confirmed that the passivation with depleted serum helps reduce the toxicity and pro-inflammatory response. Furthermore, the same method can be leveraged to enhance the capacity of nanomaterials to undergo endocytosis as well as their potential as an agonist for the NF-κB pathways. The comparable stability of protein corona created by late and early-stage serum reveals that the chanceless interaction with nanomaterials, rather than an inadequate binding strength, may be behind the failure of enriching certain components. The PCylation strategy is extended to cancer patient-derived fluid, creating a set of T1 and T3-stage cancer-specific nanotherapeutics to retard the metastasis of cancer cells, while leaving normal endothelial negligibly affected. It is hoped the novel PCylation approach validated here can shed light on the future development of precision nanomedicine with improved delivery efficacy.

Emerging High-Frequency Ultrasound Imaging in Medical Cosmetology.

Cosmetic skin diseases are a part of many dermatological concerns brought up by patients, which negatively affect mental health and quality of life. Imaging technology has an established role in the diagnosis of cosmetic skin diseases by recognizing information on deep skin lesions. Due to the complex physiological and pathological nature of cosmetic skin diseases, the diagnostic imaging performance varies greatly. Developing noninvasive technology models with wide applicability, particularly high-frequency ultrasound (HFUS), which is able to achieve high-resolution imaging of the skin from the stratum corneum down to the deep fascia, is of great significance to medical cosmetology. To explore the great potential of HFUS in cosmetic skin diseases, a narrative review of literature from PubMed and Web of Science published between 1985 and 2022 was conducted. This narrative review focuses on the progression of HFUS imaging in medical cosmetology, especially on its promising application in the quantitative evaluation and differential diagnosis of cutaneous pathological scar, port wine stain (PWS), acne, skin aging, and other cosmetic applications.

Determining the inherent selectivity for carbon radical hydroxylation versus halogenation with high-spin oxoiron(iv)-halide complexes: a concerted rebound step.

A synthetic iron model can process both halogenation and hydroxylation with vague selectivity, which is different from halogenase even though these structures are used for the simulation of halogenase. The key factor of the synthetic oxo-iron model mediated hydroxylation or the halogenation is still under debate. Herein density functional theory calculation is used to investigate the hydroxylation versus halogenation of propylene by the complex [FeIV(O)(TQA)(X)]+ (X = F, Cl, Br). Our results suggest that a concerted rebound mechanism (between the -X and the hydroxyl ligands after the hydrogen abstraction) leads to the formation of two different kinds of products.

Lymph node-targeted neoantigen nanovaccines potentiate anti-tumor immune responses of post-surgical melanoma.

BACKGROUND: Neoantigens are considered ideal targets for immunotherapy, especially tumor vaccine, because of their strong specificity and immunogenicity. Here, we developed a neoantigen nanovaccine used liposomes with lymph-node targeting characteristic. METHODS: Our nanovaccine was composed of neoantigens, an amphiphilic liposome and an adjuvant Montanide™ ISA 51. Small animal imaging system and immunofluorescence staining were used to identify the distribution of nanovaccines. A subcutaneous-tumor-resection mouse model of melanoma was established to evaluate the anti-tumor efficacy. Flow cytometry was performed to assay the immune responses initiated by nanovaccines. RESULTS: Nanovaccines could traffic to lymph nodes, be uptaken by CD11c+ DCs and promote DCs maturity. After the treatment of our neoantigen nanovaccines, the average recurrence time was extended from 11 to 16 days and the median survival time was even prolonged 7.5 days relative to the control group (NS group). Nanovaccines increased neoantigen-specific T cells to 10-fold of free vaccines, and upregulated Th1 cytokines, such as IFN-γ and TNF-α. The anti-tumor activity of spleen lymphocytes in the nanovaccine group was significantly stronger than that of other groups. However, some immune-inhibitory cells or molecules in tumor microenvironment have been detected upregulated under the immune pressure of neoantigen nanovaccines, such as Tregs and PD-L1. The efficacy of the neoantigen nanovaccine combined with anti-PD1 antibody or Treg inhibiting peptide P60 was better than that of the single treatment. CONCLUSIONS: We developed a general vaccine strategy, triggering specific T cell responses, and provided feasible combination strategies for better anti-tumor efficacy.

Exploring the relationship between the "ON-OFF" mechanism of fluorescent probes and intramolecular charge transfer properties.

In this study, the excited state charge distribution characteristics and fluorescence mechanism of HClO detection probes HN-ClO (weak fluorescence) and HN-ClO-F (strong fluorescence) probes were investigated based on density functional theory (DFT) and time-dependent density functional theory (TDDFT). The results of electrostatic potential (ESP) map and hole-electron analysis show that the HN-ClO and HN-ClO-F probes have obvious charge separation characteristics in the excited state. The excited state energy decomposition and Merz-Kollman charge analysis demonstrate the existence of distinct planar intramolecular charge transfer (PICT) features in HN-ClO and HN-ClO-F. Due to the strong charge coupling caused by the planar structure, the fluorescence of HN-ClO-F could occur. Furthermore, the weak fluorescence of HN-ClO is caused by inter-system crossing (ISC) between S1 and T1 state. Our result proves that the ICT process could exist in HN-ClO-F, but the PICT process does not cause fluorescence quenching, which have provided an excellent supplement to the mechanism of fluorescent probes. The conclusion is consistent with the fluorescence phenomenon observed in the experiment.

Solvent effect on the excited-state intramolecular double proton transfer of 1,3-bis(2-pyridylimino)-4,7-dihydroxyisoindole.

Density functional theory (DFT) and time-dependent density functional theory (TDDFT) are used to study the solvatochromic effect and the excited-state intramolecular double proton transfer (ESIDPT) of 1,3-Bis(2-pyridylimino)-4,7-dihydroxyisoindole (BPI-OH) in different kinds of solvents. The hydrogen bonding parameters and IR spectra reveal that in the excited state, the strength of excited hydrogen bond increase with the decrease of solvent polarity. Furthermore, the reduction density gradient (RDG) analysis confirms the corresponding conclusion. Frontier molecular orbitals (FMOs) are analyzed, illuminating that the smaller the polarity of solvent, the smaller the energy gap between the HOMO and LUMO. The structures of BPI-OH (N) (normal), BPI-OH (T1) (single), and BPI-OH (T2) (double) were optimized. Previous reports found the double protons in BPI-OH molecule are transferred step-by-step process BPI-OH(N)→BPI-OH(T1)→BPI-OH(T2) in the ground state (S0) and the first excited singlet state (S1). Here, the potential energy curves of O1-H2 and O4-H5 in the S0 and S1 states were scanned in four kinds of solvents, respectively. It was found that in S1 state, BPI-OH(N)→BPI-OH(T1) was more prone to proton transfer than BPI-OH(T1)→BPI-OH(T2). In addition, by comparing the reaction energy barriers of the four kinds of solvents, it can be found that ESIPT is difficult to occur with the increase of solvent polarity. Meanwhile, it was also studied that MeOH as an explicit solvent was more likely to promote the ESIPT process than other implicit solvents.

Solvation effect on the ESIPT mechanism of nitrile-substituted ortho-hydroxy-2-phenyl-oxazolines.

In this study, density functional theory (DFT) and time-dependent density functional theory (TD-DFT) were used to unveil the solvation effects on the excited-state intramolecular proton transfer (ESIPT) of nitrile-substituted ortho-hydroxy-2-phenyl-oxazoline (NOHPO) molecules in three different solvents. According to the functional analysis of the reduced density gradient, hydrogen bond in low-polar solvents is stronger compared to that in high-polar solvents, indicating that proton transfer (PT) can be influenced by the polarity of the solvent. Moreover, the geometric parameters and infrared vibration spectrum of NOHPO in different types of solvents in the S0 and S1 state were compared, which confirmed the above results. By analyzing electronic spectra and frontier molecular orbitals, it was found that the spectral properties were affected by different polar solvents. Molecular electrostatic potential surface calculations proved that PT took place between the H2 atom and N3 atom, and the natural population analysis and Hirshfeld charge reveal the charge distribution after photoexcitation. To investigate the ESIPT progress intensively, the potential energy curves of NOHPO in three types of solvents were established. The findings revealed that NOHPO could transform from enol to keto form in the S1 state spontaneously, and ESIPT progress was promoted with the decrease in polarity.

Relevant Work Factors Associated with Voice Disorders in Early Childhood Teachers: A Comparison between Kindergarten and Elementary School Teachers in Yancheng, China.

Background: Early childhood teachers consist of kindergarten and elementary school teachers in the lower grades. Young children at school may increase the vocal load of these teachers. Therefore, the objectives of this study were to determine the prevalence of voice disorders and the associated factors in early childhood teachers, and to determine if differences exist between kindergarten and elementary school teachers. Method: A cross-sectional survey was performed in July 2019 as a network questionnaire. Through cluster sampling, teachers (n = 414) from all five public kindergartens (n = 211) in the urban area of Yancheng, China, and four public elementary schools (n = 203) in the same school district participated in this study. Multivariate logistic regression models were used to analyze the associations among the prevalence of voice disorders in the teachers, school type, and relevant factors. Results: Our results indicated, based on the Voice Handicap Index scale (VHI-10, China), that the prevalence of voice disorders in early childhood teachers was 59.7%, while that in elementary school teachers (65.5%) was significantly higher than that in kindergarten teachers (54.0%) during the previous semester. Contributing factors included daily class hours, classroom air humidity, and speaking loudly during teaching. Additionally, certain types of voice usage in teaching such as falsetto speak, speaking more than other teachers, not using vocal techniques, and habitual voice clearing, were significantly associated with voice disorders. Conclusion: Most early childhood teachers have voice disorders. Compared with the kindergarten teachers, the elementary school teachers experienced a significantly higher prevalence of voice disorders. Several factors among work organization, work environment, and types of voice usage in teaching were associated with the voice disorders in early childhood teachers. The finding suggests that voice training should be provided for early childhood teachers, classroom teaching time should be decreased, and the number of teachers in basic subjects should be increased in the lower grades of elementary schools.

The molecular structure, spectroscopic features and electronic properties of tioxolone under the external electric field.

It is very helpful to understand the properties of molecules by studying a series of physical and chemical changes in molecules under an external electric field (EEF). Tioxolone is an important bioactive compound for its wide applications in the medical field. In this work, density function theory calculations combined with EEF were used to investigate the structure, spectra and electronic properties of tioxolone. The calculated results indicate that the bond lengths, bond angles, total energy, dipole moment, charge and aromaticity of tioxolone change under EEF. As EEF increases, the energy gap of tioxolone gradually reduces and makes it easier to participate in chemical reactions. Under the effect of EEF, the infrared and UV-Vis spectra show vibrational stark effect, which causes a redshift or blueshift of the frequency. These results help to understand the effect of EEF on structures and electronic properties for tioxolone, which will further provide effective guidance for the various application of tioxolone.

A first-principles study of nitrogene with monovacancy and light-atom substituted doping.

Recent studies have shown that group V monolayer, called nitrogene, remain stable in a free-standing buckled honeycomb structure with a two-dimensional hexagonal lattice. It is predicted to be a nonmagnetic, wide band gap semiconductor. In this paper, three allotropes of nitrogen single layers are firstly investigated and it is determined that the buckled honeycomb structure of nitrogene (denoted as b-N) is the lowest energetically. Then taking b-N as an example, the geometrical structures and the electronic properties of it with monovacancy and substituted doping with heterogeneous atoms, such as B, C, O, Al, Si, and P, are studied. It is found that the single vacancy in b-N is in P3m symmetry and it is polarized stable with a local magnetic moment of 3.0 µ B for each monovacancy. The substituted heterogeneous atom has little impact on the geometrical structures, while for Al, Si, and P, they move upward of the nitrogene plane due to the larger atomic radius compared to N. It is also found that C-, Si-, and O-doped nitrogene are spin-polarized stable, bringing a magnetic moment of about 1.0 µ B for each doped atom. Doping of multiple carbon atoms in one hexagonal ring of nitrogene, which prefers forming the polymer and the nitrogene with the doping of an odd number of carbon atoms, is magnetic stable, arising about 1.0 µ B magnetic moment in each supercell.

Aqueous Dual-Ion Battery Based on a Hematite Anode with Exposed {1 0 4} Facets.

The aqueous rechargeable lithium battery (ARLB) is one of the most promising devices for large-scale grid applications. Currently, a key issue for ARLBs is to develop promising anode materials with favorable electrochemical performances. Here, for the first time, we demonstrate an aqueous battery that utilizes the reversible redox reaction with hydroxide ions (OH- ) in the hematite (Fe2 O3 ) anode and a commercial Li ion intercalation compound in neutral solution as the cathode. The fabricated aqueous battery displays a reversible capacity of 92 mAh g-1 . The morphology of the used Fe2 O3 anode with exposed {1 0 4} facets for this aqueous battery is unique and attractive. Importantly, with the dual-pH neutral-alkaline hybrid electrolyte, many excellent anode materials that previously could only work in alkaline electrolytes can now be successfully combined with commercial cathodes in neutral solutions, which may significantly enrich the range of anode materials for ARLBs. In addition, the reported battery configuration can be extended to other aqueous batteries beyond Li-ion ones with lower cost.

Experimental and theoretical studies on the vibrational spectra of trans-3-phenylacryloyl chloride.

The infrared and Raman spectra of trans-3-phenylacryloyl chloride (TPC) were reported and compared with the theoretical results calculating at B3LYP/6-311++G (d, p) level. Both wavenumbers and intensities obtained from the experimental and theoretical spectra were in good agreement. A complete spectral assignment was made with the aid of potential energy distribution (PED) based on the scaled quantum mechanical (SQM) force field method. This study provided valuable insight for understanding the observed spectral features of TPC. Additionally, the HOMO-LUMO gap, molecular electrostatic potential (MEP) atomic charge distribution, and natural bond orbitals (NBO) were studied theoretically on the same basis set.

A combined experimental and theoretical analysis on molecular structure and vibrational spectra of 2,4-dihydroxybenzoic acid.

The FT-IR and FT-Raman spectra of 2,4-dihydroxybenzoic acid (2,4-DHBA) in the solid phase have been recorded in the regions 4000-400 cm(-1) and 3700-100 cm(-1), respectively. The total energies of sixteen stable conformers for 2,4-DHBA have been calculated by density functional theory (DFT) using the B3LYP method with 6-311++G (d, p) basis set, and the C1 conformer with the lowest energy was obtained, the geometrical parameters between X-ray experiment diffraction and DFT calculation show good consistency. Furthermore, the vibrational frequencies of 2,4-DHBA were computed, and the detailed analysis of vibrational spectra was made on the basis of the potential energy distribution (PED) by combining experimental with theoretical data. In addition, frontier molecular orbitals, atomic charge distribution and molecular electrostatic potential (MEP) were also given.

[Raman, FTIR spectra and normal mode analysis of acetanilide].

The Raman and FTIR spectra of acetanilide (ACN) were measured experimentally in the regions of 3 500-50 and 3 500-600 cm(-1) respectively. The equilibrium geometry and vibration frequencies of ACN were calculated based on density functional theory (DFT) method (B3LYP/6-311G(d, p)). The results showed that the theoretical calculation of molecular structure parameters are in good agreement with previous report and better than the ones calculated based on 6-31G(d), and the calculated frequencies agree well with the experimental ones. Potential energy distribution of each frequency was worked out by normal mode analysis, and based on this, a detailed and accurate vibration frequency assignment of ACN was obtained.

[Study on the vibrational spectra of 3,5-dimethoxybenzyl alcohol].

3,5-dimethoxybenzyl alcohol (L1 OH) is a kind of important pharmaceutical intermediate and it is also the starting material of a family of dendrimer LnOH (integer n means the layers of "branch"). A number of articles reported the structure and properties of the L1 OH. However, its molecular vibrational spectra have not been reported up to date. Study of vibrational spectra on L1 OH at the molecular level can provide new information, which is significant for the in-depth study of related molecules of drug and the dendrimer. Recent studies indicated a morphology effect on the light-harvesting functions of dendritic macromolecules. In the present report, the Raman and FTIR spectra of 3,5-dimethoxybenzyl alcohol were measured experimentally. And the density functional theory (DFT) method (B3LYP/6-311G(d,p)) were used to calculate the equilibrium geometry and vibration frequencies of L1 OH. The results showed that the calculated frequencies agree well with the experimental ones. Potential energy distribution of each frequency was worked out by normal mode analysis. Thereafter the authors got a detail assignment of the vibrational frequencies for L1 OH for the first time. Also, the results showed that the DFT is really a useful method in the study of molecular vibrational spectra.