Successful diagnosis of Mycobacterium marinum infection by mNGS in a patient with Human Immunodeficiency Virus: a case report.

INTRODUCTION: Mycobacterium marinum infection rarely occurs and has atypical symptoms. It is challenging to distinguish disseminated M. marinum infection from multifocal dermatosis caused by other factors clinically. CASE PRESENTATION: Herein, we reported a 68-year-old male patient with Human Immunodeficiency Virus (HIV) who presented redness and swelling in his left hand after being stabbed by marine fish for over 2 months. Mycobacterium tuberculosis infection was considered according to biochemical and pathological examinations, while empirical anti-infection treatment was ineffective. RESULTS: The metagenomic next-generation sequencing (mNGS) detected a large amount of M. marinum sequences, and the patient was finally diagnosed with M. marinum infection. After one month of combination therapy with ethambutol, rifabutin, moxifloxacin, and linezolid, the swelling disappeared significantly. In this case, the successful application of mNGS in diagnosing and treating M. marinum infection has improved the understanding of the microbe both in the laboratory and clinically, especially in patients with HIV. CONCLUSIONS: For diseases with atypical symptoms or difficulty in determining the pathogens, mNGS is suggested in clinical procedures for rapid and accurate diagnosis and treatment.

Material Engineering Strategies for Efficient Hydrogen Evolution Reaction Catalysts.

Water electrolysis, a key enabler of hydrogen energy production, presents significant potential as a strategy for achieving net-zero emissions. However, the widespread deployment of water electrolysis is currently limited by the high-cost and scarce noble metal electrocatalysts in hydrogen evolution reaction (HER). Given this challenge, design and synthesis of cost-effective and high-performance alternative catalysts have become a research focus, which necessitates insightful understandings of HER fundamentals and material engineering strategies. Distinct from typical reviews that concentrate only on the summary of recent catalyst materials, this review article shifts focus to material engineering strategies for developing efficient HER catalysts. In-depth analysis of key material design approaches for HER catalysts, such as doping, vacancy defect creation, phase engineering, and metal-support engineering, are illustrated along with typical research cases. A special emphasis is placed on designing noble metal-free catalysts with a brief discussion on recent advancements in electrocatalytic water-splitting technology. The article also delves into important descriptors, reliable evaluation parameters and characterization techniques, aiming to link the fundamental mechanisms of HER with its catalytic performance. In conclusion, it explores future trends in HER catalysts by integrating theoretical, experimental and industrial perspectives, while acknowledging the challenges that remain.

Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis.

BACKGROUND: Human epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). METHODS: Serum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th-75th percentile). RESULTS: Serum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15-139.08) vs 73.50 (59.88-82.00) vs 48.75 (43.38-52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child-Pugh class C patients compared with Child-Pugh class B patients and Child-Pugh class A patients [106.50 (83.46-151.25) vs 110.00 (73.83-166.75) vs 77.03 (72.35-83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412-54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146-0.946). CONCLUSIONS: Serum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

Effect of cellulase on dough structure and quality characteristics of tough biscuits enriched with potato whole flour.

Potato whole flour is a promising way to improve the nutrition of tough biscuits, while its gluten-free characteristic was difficult to form acceptable texture properties. In this study, cellulase was used to degrade the cellulose in dough enriched with potato whole flour, so as to mitigate the interference of cellulose with the gluten network, resulting in forming the potato whole flour biscuit with great characteristics. Results indicated that cellulase within 0.2% led to the gradually reduced G' and G'' values of dough from 5.50×104 to 4.00×104 and 2.66×104 to 1.35×104, respectively. Cellulase at 0.2% resulted in the significantly increased tensile properties of the dough compared to the control. The incorporation of cellulase within 0.2% also led to the tightly ordered and intact network structure base on the results of SEM, disulfide bonds determination and FTIR. Those results indicated that cellulase was beneficial to improve the baking quality of dough, which was conductive to form tough biscuit with great characteristics. The hardness, crunchiness, crispness and specific volume analysis results confirmed that 0.2% cellulase resulted in the significantly decreased hardness by 45.25% and the significantly increased specific volume, crunchiness and crispness by 24.74%, 121.20% and 156.47%, respectively. Overall, cellulase ultimately improved the quality of the biscuits by improving the properties and structure of the dough. It was of great significance for the utilization of potato whole flour resources and the industrial production of its tough biscuits. PRACTICAL APPLICATION: The results showed that inclusion of cellulase led to the reduced hardness and increased crunchiness, crispness, and specific volume of potato whole flour tough biscuits. Cellulase could be used as a potential improver of tough biscuits. This study will provide guidance for practical uses of cellulase in improving potato whole flour dough and tough biscuit quality.

New plant polyphenol-derived tannic acid-based chromium-free tanning agent for sustainable and clean leather production.

This study aimed to prepare a new bio-based chromium-free tanning agent. The green epoxide monocase ethylene glycol diglycidyl ether (EGDE) was grafted with tannic acid (TA) derived from natural plant using the one-pot method to synthesize new plant polyphenol-derived tannic acid-based chromium-free tanning agents (TA-EGDE) with abundant terminal epoxides. FTIR, 1H NMR, XPS, GPC, SEM, and other analytical techniques were used to characterize tanning agents. These consequences manifested that EGDE was successfully grafted with the phenol hydroxyl group of TA. The epoxide value of TA-EGDE showed a tendency to increase and then decrease with increasing EGDE dosage, and the epoxide value of TA-EGDE-2 attained a maximum of 0.262 mol/100 g. GPC analysis showed that the formula weight of the prepared TA-EGDE was partially distributed above 5000 Da. The tanning experiment demonstrated that the shrinkage temperatures (Ts) of the TA-EGDE-tanned leathers were all higher than 81.5 °C. Compared with the traditional commercial chromium-free tanning agent (F-90, TWS), TA-EGDE-tanned leathers exhibited higher Ts and better mechanical properties. The TA-EGDE prepared in this study not only has ecological environmental protection but also provides finished leather with good moisture, heat resistance, and mechanical properties.

The LISA-PPV Formula: An Ensemble Artificial Intelligence-Based Thick Intraocular Lens Calculation Formula for Vitrectomized Eyes.

PURPOSE: To investigate the relationship between effective lens position (ELP) and patient characteristics, and to further develop a new intraocular lens (IOL) calculation formula for cataract patients with previous pars plana vitrectomy (PPV). DESIGN: Cross-sectional study. METHODS: A total of 2793 age-related cataract patients (group 1) and 915 post-PPV cataract patients (group 2) who underwent phacoemulsification with IOL implantation were included. The ELP of 2 groups was compared and the association between ELP and patient characteristics was further evaluated using standardized multivariate regression coefficients. An ensemble artificial intelligence-based ELP prediction model was developed using a training set of 810 vitrectomized eyes, and a thick-lens IOL formula (LISA-PPV) was constructed and compared with 7 existing formulas on an external multi-center testing set of 105 eyes. RESULTS: Compared to eyes with age-related cataract, vitrectomized eyes showed a similar ELP distribution (P = .19), but different standardized coefficients of preoperative biometry for ELP. The standardized coefficients also varied with the type of vitreous tamponade, history of scleral buckling, and ciliary sulcus IOL implantation. The LISA-PPV formula showed the lowest mean and median absolute prediction error (MAE: 0.63 D; MedAE: 0.44 D), and the highest percentages of eyes within ±0.5 D of prediction error (57.14%) in the testing dataset. CONCLUSIONS: The ELP prediction required optimization specifically for vitrectomized eyes based on their biometric and surgical characteristics. The LISA-PPV formula is a useful and accurate tool for determining IOL power in cataract patients with previous PPV (available at http://ppv-iolcalculator.com/).

Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner.

The aberrant expression of methyltransferase Set7/9 plays a role in various diseases. However, the contribution of Set7/9 in ischemic stroke remains unclear. Here, we show ischemic injury results in a rapid elevation of Set7/9, which is accompanied by the downregulation of Sirt5, a deacetylase reported to protect against injury. Proteomic analysis identifies the decrease of chromobox homolog 1 (Cbx1) in knockdown Set7/9 neurons. Mechanistically, Set7/9 promotes the binding of Cbx1 to H3K9me2/3 and forms a transcription repressor complex at the Sirt5 promoter, ultimately repressing Sirt5 transcription. Thus, the deacetylation of Sirt5 substrate, glutaminase, which catalyzes the hydrolysis of glutamine to glutamate and ammonia, is decreased, promoting glutaminase expression and triggering excitotoxicity. Blocking Set7/9 eliminates H3K9me2/3 from the Sirt5 promoter and normalizes Sirt5 expression and Set7/9 knockout efficiently ameliorates brain ischemic injury by reducing the accumulation of ammonia and glutamate in a Sirt5-dependent manner. Collectively, the Set7/9-Sirt5 axis may be a promising epigenetic therapeutic target.

All-in-one strategy for the nano-engineering of paper-based bifunctional fluorescent platform for robustly-integrated real-time monitoring of food and drinking-water safety.

Cu2+ contamination and food spoilage raise food and drinking water safety issues, posing a serious threat to human health. Besides, Cu2+ and H2S levels indicate excess Cu2+-caused diseases and protein-containing food spoilage. Herein, a coumarin-containing bifunctional paper-based fluorescent platform integrated with a straightforward smartphone color recognition app is developed by an all-in-one strategy. The proposed fluorescent materials can simultaneously detect Cu2+ and H2S for on-demand food and drinking water safety monitoring at home. Specifically, a coumarin-derived fluorescence sensor (referred to as CMIA) with a low detection limit (0.430 µM) and high-selectivity/-sensitivity for Cu2+ is synthesized through a simple one-step route and then loaded onto commercially used cellulose fiber filter paper to engineer a biomass-based fluorescent material (CMIA-FP). The CMIA-FP offers user-friendly, high-precision, fast-responsive, and real-time visual monitoring of Cu2+. Moreover, CMIA forms a chemically stable complex with Cu2+, loaded onto filter paper to prepare another biomass-based fluorescent platform (CMIA-CU-FP) for visual real-time monitoring of H2S. Based on the exquisite composition design, the proposed dual-function paper-based fluorescent materials equipped with a smartphone color recognition program concurrently realize fast, accurate, and easy real-time monitoring of Cu2+ in drinking water and H2S in chicken breast-/shrimp-spoilage, demonstrating an effective detection strategy for the Cu2+ and H2S monitoring and presenting the new type of biomass-based platforms for concentrated reflection of drinking water and food safety.

Müller cells under hydrostatic pressure modulate retinal cell survival via TRPV1/PLCγ1 complex-mediated calcium influx in experimental glaucoma.

Glaucoma, an irreversible blinding eye disease, is currently unclear whose pathological mechanism is. This study investigated how transient receptor potential cation channel subfamily V member 1 (TRPV1), 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCγ1), and P2X purinoceptor 7 (P2X7) modulate the levels of intracellular calcium ions (Ca2+ ) and adenosine triphosphate (ATP) in Müller cells and retinal ganglion cells (RGCs) under conditions of elevated intraocular pressure (IOP). Müller cells were maintained at hydrostatic pressure (HP). TRPV1- and PLCG1-silenced Müller cells and P2X7-silenced RGCs were constructed by transfection with short interfering RNA (siRNAs). RGCs were cultured with the conditioned media of Müller cells under HP. A mouse model of chronic ocular hypertension (COH) was established and used to investigate the role of TRPV1 in RGCs in vivo. Müller cells and RGCs were analyzed by ATP release assays, intracellular calcium assays, CCK-8 assays, EdU (5-ethynyl-2'-deoxyuridine) staining, TUNEL staining, flow cytometry, and transmission electron microscopy. In vivo changes in inner retinal function were evaluated by hematoxylin and eosin (H&E) staining and TUNEL staining. Western blot analyses were performed to measure the levels of related proteins. Our data showed that HP increased the levels of ATP and Ca2+ influx in Müller cells, and those increases were accompanied by the upregulation of TRPV1 and p-PLCγ1 expression. Suppression of TRPV1 or PLCG1 expression in Müller cells significantly decreased the ATP levels and intracellular Ca2+ accumulation induced by HP. Knockdown of TRPV1, PLCG1, or P2X7 significantly decreased apoptosis and autophagy in RGCs cultured in the conditioned media of HP-treated Müller cells. Moreover, TRPV1 silencing decreased RGC apoptosis and autophagy in the in vivo model of COH. Collectively, inhibition of TRPV1/PLCγ1 and P2X7 expression may be a useful therapeutic strategy for managing RGC death in glaucoma.

Biomimetic Exogenous "Tissue Batteries" as Artificial Power Sources for Implantable Bioelectronic Devices Manufacturing.

Implantable bioelectronic devices (IBDs) have gained attention for their capacity to conformably detect physiological and pathological signals and further provide internal therapy. However, traditional power sources integrated into these IBDs possess intricate limitations such as bulkiness, rigidity, and biotoxicity. Recently, artificial "tissue batteries" (ATBs) have diffusely developed as artificial power sources for IBDs manufacturing, enabling comprehensive biological-activity monitoring, diagnosis, and therapy. ATBs are on-demand and designed to accommodate the soft and confining curved placement space of organisms, minimizing interface discrepancies, and providing ample power for clinical applications. This review presents the near-term advancements in ATBs, with a focus on their miniaturization, flexibility, biodegradability, and power density. Furthermore, it delves into material-screening, structural-design, and energy density across three distinct categories of TBs, distinguished by power supply strategies. These types encompass innovative energy storage devices (chemical batteries and supercapacitors), power conversion devices that harness power from human-body (biofuel cells, thermoelectric nanogenerators, bio-potential devices, piezoelectric harvesters, and triboelectric devices), and energy transfer devices that receive and utilize external energy (radiofrequency-ultrasound energy harvesters, ultrasound-induced energy harvesters, and photovoltaic devices). Ultimately, future challenges and prospects emphasize ATBs with the indispensability of bio-safety, flexibility, and high-volume energy density as crucial components in long-term implantable bioelectronic devices.

Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis.

Endothelial injury and dysfunction in the artery wall fuel the process of atherosclerosis. As a key epigenetic regulator, Ash2l (Absent, small, or homeotic-Like 2) is involved in regulating vascular injury and its complications. However, the role of Ash2l in atherosclerosis has not yet been fully elucidated. Here, we found increased Ash2l expression in high-cholesterol diet-fed ApoE-/- mice and oxidized LDL (oxLDL) treated endothelial cells (ECs). Furthermore, Ash2l promoted the scavenger receptors transcription by catalyzing histone H3 lysine 4 (H3K4) trimethylation at the promoter region of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) and triggered the activation of the pro-inflammatory nuclear factor-kappa B (NF-κB) by enhancing interaction between CD36 and toll-like receptor 4 (TLR4). Meanwhile, enhanced expression of scavenger receptors drove more oxLDL uptake by ECs. In vivo studies revealed that ECs-specific Ash2l knockdown reduced atherosclerotic lesion formation and promoted fibrous cap stability in the aorta of ApoE-/- mice, which was partly associated with a reduced endothelial activation by suppressing scavenger receptors and the uptake of lipids by ECs. Collectively, our findings identify Ash2l as a novel regulator that mediates endothelial injury and atherosclerosis. Targeting Ash2l may provide valuable insights for developing novel therapeutic candidates for atherosclerosis.

Robustness of open source community multi-project knowledge collaboration network based on structural hole theory.

Nodes in the structural hole position play a key role in the multi-project network of the open source community (OSC). This paper studies the robustness of this network based on structural hole theory. First, a semantic-based multi-project KCN is constructed, and four node types are identified: knowledge contribution nodes, knowledge dissemination nodes, structural hole nodes (SHNs) and opinion leader nodes. Second, a robustness analysis model of the edge failures of these four key nodes is constructed. Third, a simulation test is conducted on the proposed model using empirical data from the Local Motors multi-project OSC. The results show that the KCN has the lowest robustness when facing the edge failure of opinion leader nodes, followed by knowledge dissemination nodes, knowledge contribution nodes, SHNs and random nodes. The edge failure of opinion leader nodes causes the lowest network robustness because of the propagation effect of these nodes. Additionally, SHN failure has only a small initial impact on connectivity, whereas knowledge collaboration efficiency decreases rapidly (i.e., the edge failure of SHNs causes the network to enter a state of high connectivity and low efficiency). The proposed model can be used to provide comprehensive and targeted management guidance for OSC development.

Drug discovery and optimization based on the co-crystal structure of natural product with target.

Due to their structural diversities and prevalent biological activities, natural products (NPs) are momentous resources for drug discovery. Although NPs have a wide range of biological activities, many exhibit structural complexity that leads to synthetic difficulties, which combines with inefficient biological activity, toxicity, and unfavorable pharmacokinetic characteristics and ultimately imparts poor safety and efficacy outcomes. Progress in crystallization and computational techniques allow crystallography to have a seasonable influences on drug discovery. By co-crystallizing with proteins, therapeutic targets of NPs in specific diseases can be identified. By analyzing the co-crystal information, the structure-activity relationships (SARs) of NPs targeting specific proteins can be grasped. Under the guidance of co-crystal information, directional structural modification and simplification are powerful strategies for overcoming limitations of NPs, improving the success rate of NP-based drug discovery, and obtaining NP-based drugs with high selectivity, low toxicity and favorable pharmacokinetic characteristics. Here, we review the co-crystal information of a selection of NPs, focusing on the SARs of NPs reflected by co-crystal information and the modification and simplification strategies of NPs, and discuss how to apply co-crystal information in the optimization of NP-based lead compound.

ASH2L upregulation contributes to diabetic endothelial dysfunction in mice through STEAP4-mediated copper uptake.

Endothelial dysfunction is a common complication of diabetes mellitus (DM) and contributes to the high incidence and mortality of cardiovascular and cerebrovascular diseases. Aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs) play key roles in the initiation and progression of diabetic vascular complications. ASH2L, a H3K4me3 regulator, triggers genetic transcription, which is critical for physiological and pathogenic processes. In this study we investigated the role of ASH2L in mediating diabetic endothelial dysfunction. We showed that ASH2L expression was significantly elevated in vascular tissues from diabetic db/db mice and in rat aortic endothelial cells (RAECs) treated with high glucose medium (11 and 22 mM). Knockdown of ASH2L in RAECs markedly inhibited the deteriorating effects of high glucose, characterized by reduced oxidative stress and inflammatory responses. Deletion of endothelial ASH2L in db/db mice by injection of an adeno-associated virus (AAV)-endothelial specific system carrying shRNA against Ash2l (AAV-shAsh2l) restored the impaired endothelium-dependent relaxations, and ameliorated DM-induced vascular dysfunction. We revealed that ASH2L expression activated reductase STEAP4 transcription in vitro and in vivo, which consequently elevated Cu(I) transportation into ECs by the copper transporter CTR1. Excess copper produced by STEAP4-mediated copper uptake triggered oxidative stress and inflammatory responses, resulting in endothelial dysfunction. Our results demonstrate that hyperglycemia triggered ASH2L-STEAP4 axis contributes to diabetic endothelial dysfunction by modulating copper uptake into ECs and highlight the therapeutic potential of blocking the endothelial ASH2L in the pathogenesis of diabetic vascular complications.

Engineering cancer cell membranes with endogenously upregulated HSP70 as a reinforced antigenic repertoire for the construction of material-free prophylactic cancer vaccines.

Immune cells distinguish cancer cells mainly relying on their membrane-membrane communication. The major challenge of cancer vaccines exists in difficult identification of cancer neoantigens and poor understanding over immune recognition mechanisms against cancer cells, particularly the combination among multiple antigens and the cooperation between antigens and immune-associated proteins. We exploit cancer cell membranes as the whole cancer antigen repertoire and reinforce its immunogenicity by cellular engineering to modulate the cytomembrane's immune-associated functions. This study reports a vaccine platform based on radiation-engineered cancer cells, of which the membrane HSP70 protein as the immune chaperon/traitor is endogenously upregulated. The resulting positive influences are shown to cover immunogenic steps occurring in antigen-presenting cells, including the uptake and the cross-presentation of the cancer antigens, thus amplifying cancer-specific immunogenicity. Membrane vaccines offer chances to introduce desired metal ions through membrane-metal complexation. Using Mn2+ ion as the costimulatory interferon genes agonist, immune activity is enhanced to further boost adaptive cancer immunogenicity. Results have evidenced that this artificially engineered membrane vaccine with favorable bio-safety could considerably reduce tumorigenicity and inhibit tumor growth. This study provides a universally applicable and facilely available cancer vaccine platform by artificial engineering of cancer cells to inherit and amplify the natural merits of cancer cell membranes. STATEMENT OF SIGNIFICANCE: The major challenge of cancer vaccines exists in difficult identification of cancer neoantigens and poor understanding over immune recognition mechanisms against cancer cells, particularly the combination among multiple antigens and the cooperation between antigens and immune-associated proteins. Cancer cell membrane presents superior advantages as the whole cancer antigen repertoire, including the reported and the unidentified antigens, but its immunogenicity is far from satisfactory. Cellular engineering approaches offer chances to endogenously modulate the immune-associated functions of cell membranes. Such a reinforced vaccine based on the engineered cancer cell membranes matches better the natural immune recognition pathway than the conventional vaccines.

ASH2L-mediated H3K4me3 drives diabetic nephropathy through HIPK2 and Notch1 pathway.

Diabetic nephropathy (DN) is one of the complications of diabetes. Long-term hyperglycemia in the kidney results in renal insufficiency, and eventually leads to end-stage renal disease. Epigenetic factor ASH2L has long been identified as a transcriptional activator, and we previously indicated that ASH2L aggravated fibrosis and inflammation in high glucose-induced glomerular mesangial cells, but the pathophysiological relevance and the mechanism of ASH2L-mediated H3K4me3 in DN is not well understood. Here we demonstrated that ASH2L is upregulated in glomeruli isolated from db/db mice. Loss of ASH2L protected glomerular injury caused by hyperglycemia, as evidenced by reduced albuminuria, preserved structure, decreased glomerular extracellular matrix deposition, and lowered renal glomerular expression of proinflammatory and profibrotic markers in db/db mice. Furthermore, we demonstrated that enrichment of ASH2L-mediated H3K4me3 on the promoter regions of ADAM17 and HIPK2 triggered their transcription, leading to aberrant activation of Notch1 signaling pathway, thereby contributing to fibrosis and inflammation in DN. The findings of this study provide compelling evidence for targeting ASH2L as a potential therapeutic strategy to prevent or slow down the progression of DN.

Immunoadjuvant-Modified Rhodobacter sphaeroides Potentiate Cancer Photothermal Immunotherapy.

Photothermal immunotherapy has become a promising strategy for tumor treatment. However, the intrinsic drawbacks like light instability, poor immunoadjuvant effect, and poor accumulation of conventional inorganic or organic photothermal agents limit their further applications. Based on the superior carrying capacity and active tumor targeting property of living bacteria, an immunoadjuvant-intensified and engineered tumor-targeting bacterium was constructed to achieve effective photothermal immunotherapy. Specifically, immunoadjuvant imiquimod (R837)-loaded thermosensitive liposomes (R837@TSL) were covalently decorated onto Rhodobacter sphaeroides (R.S) to obtain nanoimmunoadjuvant-armed bacteria (R.S-R837@TSL). The intrinsic photothermal property of R.S combined R837@TSL to achieve in situ near-infrared (NIR) laser-controlled release of R837. Meanwhile, tumor immunogenic cell death (ICD) caused by photothermal effect of R.S-R837@TSL, synergizes with released immunoadjuvants to promote maturation of dendritic cells (DCs), which enhance cytotoxic T lymphocytes (CTLs) infiltration for further tumor eradication. The photosynthetic bacteria armed with immunoadjuvant-loaded liposomes provide a strategy for immunoadjuvant-enhanced cancer photothermal immunotherapy.

The intramolecular SN2 reaction tautomeric ent-Kauranoids isolated from the aerial parts of Isodon amethystoides.

As our ongoing searching for the bioactive natural terpenoids, nine ent-kauranoids (1-9), including three previously undescribed ones (1, 2, and 9), were isolated from the aerial parts of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic data analysis, including NMR, MS, and ECD. Compounds 1 and 2 were a pair of tautomeric compounds, which was confirmed by the HPLC analysis and low temperature NMR testing. The underlying mechanism of the tautomer was proposed as an intramolecular SN2 reaction, which was explained by quantum chemical calculation. The HOMO-LUMO gap and the free energy revealed the spontaneous of the tautomeric of the 1 and 2. Additionally, the similar phenomena were also found in the two groups of known compounds 3 and 4 and 6 and 7, respectively. Apart from the tautomer, compounds 3 and 4 can be hydrolyzed into 5 through ester hydrolysis in CDCl3, while compounds 6, 7 can be hydrolyzed into 8 through ester hydrolysis. These phenomena were also confirmed through HPLC analysis and low temperature nuclear magnetic resonance tests and the mechanism was studied using quantum chemical calculation.

Internet appointment has more advantages than traditional appointment in the nursing service of dry eye patients.

Dry eye disease is one of the most common eye diseases. Clinical studies have found that meibomian gland expression can effectively improve the function of meibomian glands in patients with meibomian gland dysfunction. Compared with traditional appointments, Internet appointment has advantages in treating dry eye disease. A cross-sectional study was conducted to collect 300 patients with dry eye disease through an online questionnaire. Using Pearson chi-squared test, associations between the clinical parameters and appointment mode were analyzed. Spearman-rho test was executed to compare clinical data and appointment mode for correlation analysis and relationship between score of advantages of Internet booking (SOAIB), evaluation of the effectiveness of the Internet booking (EEIB), waiting in line for medical treatment (WMT). Univariate logistic regression analysis calculated the odds ratio (OR) of appointment mode for potential correlation factors. By using Pearson chi-squared test, SOAIB (P = .005), EEIB (P = .029) and WMT (P = .041) was significantly correlated with the appointment mode. Spearman correlation coefficient displayed that appointment mode was significantly correlated with EEIB (ρ = -0.126, P = .029) and WMT (ρ = 0.118, P = .041). Univariate logistic regression and concludes that EEIB (OR = 0.183, 95%CI: 0.033-1.004, P = .05), WMT (OR = 2.543, 95%CI: 1.013-6.384, P = .047) have a clear correlation with appointment mode. Spearman correlation coefficient displayed that SOAIB was significantly correlated with EEIB (ρ = -0.247, P < .001) and WMT (ρ = 0.157, P = .006). Internet appointment can effectively reduce the waiting time for dry eye disease treatment by meibomian gland expression. Effectiveness evaluation of Internet appointments is significantly higher than traditional appointments.

Dendritic Cell-Based In Situ Nanovaccine for Reprogramming Lipid Metabolism to Boost Tumor Immunotherapy.

Cancer vaccines have been considered to be an alternative therapeutic strategy for tumor therapy in the past decade. However, the popularity and efficacy of cancer vaccines were hampered by tumor antigen heterogeneity and the impaired function of cross-presentation in the tumor-infiltrating dendritic cells (TIDCs). To overcome these challenges, we engineered an in situ nanovaccine (named as TPOP) based on lipid metabolism-regulating and innate immune-stimulated nanoparticles. TPOP could capture tumor antigens and induce specific recognition by TIDCs to be taken up. Meanwhile, TPOP could manipulate TIDC lipid metabolism and inhibit de novo synthesis of fatty acids, thus improving the ability of TIDCs to cross-present by reducing their lipid accumulation. Significantly, intratumoral injection of TPOP combined with pretreatment with doxorubicin showed a considerable therapeutic effect in the subcutaneous mouse colorectal cancer model and melanoma model. Moreover, in combination with immune checkpoint inhibitors, such TPOP could markedly inhibit the growth of distant tumors by systemic antitumor immune responses. This work provides a safe and promising strategy for improving the function of immune cells by manipulating their metabolism and activating the immune system effectively for in situ cancer vaccines.