Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination.

Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.

Long noncoding RNA BMPR1B-AS1 stability regulated by IGF2BP2 affects the decidualization in endometriosis patients through the SMAD1/5/9 pathway.

Endometriosis (EMs)-related infertility commonly has decreased endometrial receptivity and normal decidualization is the basis for establishing and maintaining endometrial receptivity. However, the potential molecular regulatory mechanisms of impaired endometrial decidualization in patients with EMs have not been fully clarified. We confirmed the existence of reduced endometrial receptivity in patients with EMs by scanning electron microscopy and quantitative real-time PCR. Here we identified an lncRNA, named BMPR1B-AS1, which is significantly downregulated in eutopic endometrium in EMs patients and plays an essential role in decidual formation. Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and rescue analyses revealed that BMPR1B-AS1 positively regulates decidual formation through interaction with the RNA-binding protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Downregulation of IGF2BP2 led to a decreased stability of BMPR1B-AS1 and inhibition of activation of the SMAD1/5/9 pathway, an inhibitory effect which diminished decidualization in human endometrial stromal cells (hESCs) decidualization. In conclusion, our identified a novel regulatory mechanism in which the IGF2BP2-BMPR1B-AS1-SMAD1/5/9 axis plays a key role in the regulation of decidualization, providing insights into the potential link between abnormal decidualization and infertility in patients with EMs, which will be of clinical significance for the management and treatment of infertility in patients with EMs.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS: Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. RESULTS: We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Efficacy of OFD with EMD for treatment of periodontal defects: A systematic review and meta-analysis.

OBJECTIVES: In order to enhance clinical improvement of periodontal defects, the addition of enamel matrix derivatives (EMD) to open flap debridement (OFD) has been investigated. The aim of this systematic review is to figure out whether such a combination, in comparison to the treatment with OFD alone has some effects on the following outcomes: clinical attachment level gain, probing depth reduction, and gingival recessions increase. METHODS: Electronic databases (PubMed, Embase, Web of Science, and Cochrane) were searched for randomized controlled trials in humans addressing the use of a combination of OFD and EMD versus a control group with OFD alone for the treatment of periodontal defects, with a minimum of 6 months of follow-up; meta-analysis and trial sequential analysis were then performed. RESULTS: From a total of 204 records screened by title and abstract, 13 studies were read full-text and eight out of them included in the meta-analysis. Some significant differences have been demonstrated both for clinical attachment level gain and probing depth reduction between test and control groups. CONCLUSIONS: In the treatment of periodontal defects, the addition of EMD to OFD seems to be beneficial in terms of clinical attachment level gain, probing depth reduction, promoting periodontal regeneration. However, such results should be considered with caution because of the small number of studies included in the meta-analysis and their heterogeneity.

Establishing reference sequences for each clade of SARS-CoV-2 to provide a basis for virus variation and function research.

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As the COVID-19 pandemic continues, mutations of SARS-CoV-2 accumulate. These mutations may not only make the virus spread faster, but also render current vaccines less effective. In this study, we established a reference sequence for each clade defined using the GISAID typing method. Homology analysis of each reference sequence confirmed a low mutation rate for SARS-CoV-2, with the latest clade GRY having the lowest homology with other clades (99.89%-99.93%), and the homology between other clade being greater than or equal to 99.95%. Variation analyses showed that the earliest genotypes S, V, and G had 2, 3, and 3 characterizing mutations in the genome respectively. The G-derived clades GR, GH, and GV had 5, 6, and 13 characterizing mutations in the genome respectively. A total of 28 characterizing mutations existed in the genome of the latest clades GRY. In addition, we found differences in the geographic distribution of different clades. G, GH, and GR are popular in the USA, while GV and GRY are common in the UK. Our work may facilitate the custom design of antiviral strategies depending on the molecular characteristics of SARS-CoV-2.

Impaired intestinal stem cell activity in ETEC infection: enterotoxins, cyclic nucleotides, and Wnt signaling.

Enterotoxigenic Escherichia coli (ETEC) in humans and animals colonizes the intestine and thereafter secrets heat-stable enterotoxin (ST) with or without heat-labile enterotoxin (LT), which triggers massive fluid and electrolyte secretion into the gut lumen. The crosstalk between the cyclic nucleotide-dependent protein kinase/cystic fibrosis transmembrane conductance regulator (cAMP or cGMP/CFTR) pathway involved in ETEC-induced diarrhea channels, and the canonical Wnt/ß-catenin signaling pathway leads to changes in intestinal stem cell (ISC) fates, which are strongly associated with developmental disorders caused by diarrhea. We review how alterations in enterotoxin-activated ion channel pathways and the canonical Wnt/ß-catenin signaling pathway can explain inhibited intestinal epithelial activity, characterize alterations in the crosstalk of cyclic nucleotides, and predict harmful effects on ISCs in targeted therapy. Besides, we discuss current deficits in the understanding of enterotoxin-intestinal epithelial cell activity relationships that should be considered when interpreting sequelae of diarrhea.

Roles of Al2O3@ZrO2 Particles in Modulating Crystalline Morphology and Electrical Properties of P(VDF-HFP) Nanocomposites.

Polymer materials with excellent physicochemical and electrical properties are desirable for energy storage applications in advanced electronics and power systems. Here, Al2O3@ZrO2 nanoparticles (A@Z) with a core-shell structure are synthesized and introduced to a P(VDF-HFP) matrix to fabricate P(VDF-HFP)/A@Z nanocomposite films. Experimental and simulation results confirm that A@Z nanoparticles increase the crystallinity and crystallization temperature owing to the effect of the refined crystal size. The incorporation of A@Z nanoparticles leads to conformational changes of molecular chains of P(VDF-HFP), which influences the dielectric relaxation and trap parameters of the nanocomposites. The calculated total trapped charges increase from 13.63 µC of the neat P(VDF-HFP) to 47.55 µC of P(VDF-HFP)/5 vol%-A@Z nanocomposite, indicating a substantial improvement in trap density. The modulated crystalline characteristic and interfaces between nanoparticles and polymer matrix are effective in inhibiting charge motion and impeding the electric conduction channels, which contributes to an improved electrical property and energy density of the nanocomposites. Specifically, a ~200% and ~31% enhancement in discharged energy density and breakdown strength are achieved in the P(VDF-HFP)/5 vol%-A@Z nanocomposite.

Dynamic Covalent Nanoparticles for Acid-Responsive Nonaqueous Pickering Emulsions.

Acid-responsive nonaqueous (glycerol in n-decane) Pickering emulsions were prepared using preferentially oil-wetted dynamic covalent silica (SiO2-pDB) nanoparticles as the Pickering emulsifiers. The acid-responsive Pickering emulsifier SiO2-pDB was prepared based on a Schiff base reaction between amino silica (SiO2-NH2) and p-decanoxybenzaldehyde (pDBA). The formation of SiO2-pDB was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, and elemental analysis. The preferentially oil-wetted character of SiO2-pDB was indicated by contact angle measurement. Stable nonaqueous Pickering emulsions were prepared using preferentially oil-wetted SiO2-pDB as the Pickering emulsifier. However, after adjusting the nonaqueous Pickering emulsions to an acidic environment, complete phase separation occurred. In the acidic environment, preferentially oil-wetted SiO2-pDB decomposed into hydrophilic SiO2-NH2 and hydrophobic pDBA due to the decomposition of the dynamic imine bond in the SiO2-pDB. Then, the hydrophilic SiO2-NH2 and hydrophobic pDBA desorbed from the two-phase interface, resulting in complete phase separation of the initially stable nonaqueous Pickering emulsions. The acid-responsive nonaqueous Pickering emulsions show great potential in application in water sensitive systems, such as oil-based drilling fluids.

Identification and Characterization of MIKCc-Type MADS-Box Genes in the Flower Organs of Adonis amurensis.

Adonis amurensis is a perennial herbaceous flower that blooms in early spring in northeast China, where the night temperature can drop to -15 °C. To understand flowering time regulation and floral organogenesis of A. amurensis, the MIKCc-type MADS (Mcm1/Agamous/ Deficiens/Srf)-box genes were identified and characterized from the transcriptomes of the flower organs. In this study, 43 non-redundant MADS-box genes (38 MIKCc, 3 MIKC*, and 2 Mα) were identified. Phylogenetic and conserved motif analysis divided the 38 MIKCc-type genes into three major classes: ABCDE model (including AP1/FUL, AP3/PI, AG, STK, and SEPs/AGL6), suppressor of overexpression of constans1 (SOC1), and short vegetative phase (SVP). qPCR analysis showed that the ABCDE model genes were highly expressed mainly in flowers and differentially expressed in the different tissues of flower organs, suggesting that they may be involved in the flower organ identity of A. amurensis. Subcellular localization revealed that 17 full-length MADSs were mainly localized in the nucleus: in Arabidopsis, the heterologous expression of three full-length SOC1-type genes caused early flowering and altered the expression of endogenous flowering time genes. Our analyses provide an overall insight into MIKCc genes in A. amurensis and their potential roles in floral organogenesis and flowering time regulation.

Profiling the pattern of human TRB/IGH-CDR3 repertoire in liver transplantation patients via high-throughput sequencing analysis.

Immune processes in liver transplantation remain poorly understood. Acute allograft rejection in liver transplantation is a kind of T cell-mediated inflammatory disease accompanied by inflammatory cell infiltration. However, the effect of acute allograft rejection on the immunological characteristics of TCRs in peripheral blood mononuclear cell is unknown. In this study, we characterized the pattern of the human T cell receptor beta chain (TRB) and immunoglobulin heavy chain (IGH) complementarity-determining region 3 (CDR3) repertoires via high-throughput sequencing in 11 acute allograft rejection (AG) cases, 23 patients with stable allograft liver function (ST) who had liver transplantation performed and 20 healthy controls (HC). The diversity of TRB-CDR3 was significantly reduced in the AG group compared with the ST group and healthy controls (HC). The CDR3 and N-addition length distribution were not significantly different between the AG and ST groups. However, N-addition length distribution was significantly changed compared to HC. It seemed that AG used more short N-additions and healthy people used more long N-additions in TRB-CDR3 repertoire. Our findings suggested that the TRB-CDR3 region of AG had distinctive V gene use compared with that of HC. The characteristics of ST seemed to be in between those of AG and HC although the difference is not significant. Cluster analysis showed that the TRB repertoire could not effectively distinguish AG from ST. This research might give to a better understanding of the immune process of liver transplantation.

Vitamin D supplementation rescues simvastatin induced myopathy in mice via improving mitochondrial cristae shape.

Statin induced myopathy (SIM) is a main deleterious effect leading to the poor treatment compliance, while the preventive or therapeutic treatments are absent. Mounting evidences demonstrated that vitamin D plays a vital role in muscle as a direct modulator. The deficiency of vitamin D was considered as a cause of muscle dysfunction, whereas the supplementation resulted in a remission. However, there is no causal proof that vitamin D supplementation rescues SIM. Here, using the mice model of simvastatin-induced myopathy, we investigated the role of vitamin D supplementation and the mechanisms associated with mitochondria. Results indicated that simvastatin administration (80 mg/kg) impaired skeletal muscle with the increased serum creatine kinase (CK) level and the declined grip strength, which were alleviated by vitamin D supplementation. Moreover, vitamin D supplementation rescued the energy metabolism dysfunction in simvastatin-treated mice gastrocnemius by reducing the abnormal aggregation of muscular glycogen and lactic acid. Mitochondrial homeostasis plays a key role in the process of energy metabolism. Thus, the mitochondrial dysfunction is a mortal damage for the highly energy-requiring tissue. In our study, the mitochondrial cristae observed under transmission electron microscope (TEM) were lytic in simvastatin-treated gastrocnemius. Interestingly, vitamin D supplementation improved the mitochondrial cristae shape by regulating the expression of mitofusin-1/2 (MFN1/2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (Drp1). As expected, the mitochondrial dysfunction and oxidative stress was mitigated by vitamin D supplementation. In conclusion, these findings suggested that moderate vitamin D supplementation rescued simvastatin induced myopathy via improving the mitochondrial cristae shape and function.

Differential expression of microRNA in exosomes derived from endometrial stromal cells of women with endometriosis-associated infertility.

RESEARCH QUESTION: What is the expression pattern of microRNA (miRNA) in exosomes isolated from eutopic endometrial stromal cells (EuESC) of women with endometriosis-associated infertility? DESIGN: Small RNA sequencing was conducted in exosomes isolated from EuESC of women with endometriosis-associated infertility (n = 3) and normal endometrial stromal cells (NESC) of fertile women without endometriosis (n = 3). The differentially expressed miRNA in exosomes derived from EuESC and NESC were identified. The functions of the differentially expressed miRNA were analysed by gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: Small RNA sequencing showed that the percentages of exosomal miRNA in the total small RNA isolated from EuESC and NESC were not significantly different (P = 0.7804). A total of 49 differentially expressed miRNA (fold change >1.5 and P < 0.05) were identified, including 26 up-regulated and 23 down-regulated in EuESC exosomes as compared with NESC exosomes. Functional analysis revealed that 12 miRNA were predicted to target homeobox A10 (HOXA10) and/or the leukaemia inhibitory factor (LIF) 3' untranslated region (UTR). Both HOXA10 and LIF mRNA expression levels were significantly decreased in EuESC compared with NESC (P = 0.0222 and 0.0395, respectively). In addition, the predicated target genes of these differentially expressed exosomal miRNA were significantly (P < 0.05) enriched in 76 pathways, including the MAPK and Wnt signalling pathways. CONCLUSIONS: The differential expression patterns of exosomal miRNA were identified. Many exosomal miRNA may be involved in regulating the endometrial receptivity of women with endometriosis-associated infertility.

Cytomegalovirus Infection Is a Risk Factor in Gastrointestinal Cancer: A Cross-Sectional and Meta-Analysis Study.

BACKGROUND: This study was planned to investigate the association betweenhuman cytomegalovirus (HCMV) infection and gastrointestinal cancer (GIC) risk, by undertaking a meta-analysis and case-control cross-sectional study. SUMMARY: A cross-sectional study analysis of 160 GIC patients and 100 control subjects indicated significantly higher HCMV prevalence in GIC patients based on the HCMV IgM test. However, a similar analysis based on an IgG test revealed no significant relationship. Further meta-analysis of 11 studies, including 1,044 patients and 991 healthy subjects, displayed HCMV infection as an important risk factor for not only colorectal cancer occurrence and development based on a HCMV DNA test, but also for GIC based on a HCMV IgM test. However, the IgG test again displayed no significant relationship between HCMV infection and GIC occurrence. Key Message: Overall, our study revealed that HCMV infection is associated with an increased GIC risk. However, additional studies are warranted to elucidate the molecular mechanism underlying this association.

Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium.

BACKGROUND: Ceramide, a bioactive lipid, plays an essential role in the development of several pulmonary inflammatory diseases. Matrix metallopeptidase 9 (MMP-9) regulates the synthesis and degradation of extracellular matrix, and is associated with airway remodeling and tissue injury. This study was conducted to investigate the effects and underlying mechanisms of ceramide on MMP-9 expression in airway epithelium. METHODS: BEAS-2B cells, normal human bronchial epithelium cell lines, were pretreated with AG490, a selective janus tyrosine kinase 2 (JAK2) inhibitor, or Stattic, a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. The cells were then stimulated with C6-ceramide. The levels of MMP-9 were determined by ELISA and real-time quantitative PCR (RT-qPCR). JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) expression was examined by Western blotting. BALB/c mice were pretreated with AG490 or Stattic before intratracheally instillated with C6-ceramide. Pathological changes in lung tissues were examined by Hematoxylin and Eosin staining, Periodic-acid Schiff staining, and Masson's trichrome staining. MMP-9, JAK2, p-JAK2, STAT3, and p-STAT3 expression in the lung tissues was examined by Western blotting. RESULTS: The expression of MMP-9, p-JAK2 and p-STAT3 in BEAS-2B cells was significantly increased after the treatment of C6-ceramide. Furthermore, the increased expression of MMP-9 induced by C6-ceramide was inhibited by AG490 and Stattic. Similar results were obtained in the lung tissues of C6-ceramide-exposed mice which were treated with AG490 or Stattic. CONCLUSIONS: Ceramide could up-regulate MMP-9 expression through the activation of the JAK2/STAT3 pathway in airway epithelium. Targeted modulation of the ceramide signaling pathway may offer a potential therapeutic approach for inhibiting MMP-9 expression. This study points to a potentially novel approach to alleviating airway remodeling in inflammatory airway diseases.

Determinants of gefitinib pharmacokinetics in healthy Chinese male subjects: A pharmacogenomic study of cytochrome p450 enzymes and transporters.

WHAT IS KNOWN AND OBJECTIVE: Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, exhibited a wide interindividual variability in pharmacokinetics. In the present study, we aimed to evaluate the impact of single-nucleotide polymorphisms in the metabolizing enzymes and transporters on gefitinib disposition in healthy Chinese subjects. METHODS: Fourteen single-nucleotide polymorphisms, including polymorphisms of ATP-binding cassette (ABC) transporters and cytochrome P450 enzymes, were genotyped by Sanger sequencing, and the concentration of gefitinib was measured by ultrafast liquid chromatography-tandem mass spectrometry. The association between the pharmacokinetic parameters (peak plasma concentration [Cmax ], time to reach Cmax , plasma half-life, area under the concentration-time curve from 0 to 168 hours [AUC(0-168h) ], AUC(0-∞) and plasma clearance [CL/F]) and genotypes was evaluated using unpaired t test or Mann-Whitney U test. A stepwise multiple linear regression analysis was applied to assess the relationships between multiple factors and gefitinib pharmacokinetics. Thirty-nine healthy Chinese male subjects were enrolled in the pharmacokinetic study. RESULTS AND DISCUSSION: Subjects carrying an ABCG2 A allele (c.421CA + c.421AA genotypes) exhibited 33 and 37% increases in the mean gefitinib AUC(0-168h) and AUC(0-∞) values (P < .05), respectively, compared to that of subjects carrying wild-type ABCG2 (c.421CC). Additionally, the mean CL/F of the c.421A allele carriers was 32% less than that of the c.421CC carriers (P < .05). No associations were found between polymorphisms in other metabolic enzymes or ABC transporters and gefitinib pharmacokinetics. WHAT IS NEW AND CONCLUSION: Our results suggested that a single-nucleotide polymorphism in ABCG2 (c.421C>A) significantly affected the pharmacokinetics of gefitinib. Further studies are required to evaluate the effects of single-nucleotide polymorphism on the pharmacokinetics, pharmacodynamics and toxicity of gefitinib.

Association between chronic obstructive pulmonary disease and serum lipid levels: a meta-analysis.

BACKGROUND: Metabolic syndrome is a common extrapulmonary comorbidity in patients with chronic obstructive pulmonary disease (COPD). However, the reported relationship of COPD with dyslipidemia, an important component of metabolic syndrome, is ambiguous. The aim of this meta-analysis is to investigate the association between COPD and the serum levels of high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and triglyceride (TG). METHODS: The PubMed and Embase databases were searched to find potential studies using the search terms of ("dyslipidemia" or "HDL" or "LDL" or "cholesterol" or "triglyceride") and COPD. We also performed subgroup analysis enrolling patients who were not receiving treatment for dyslipidemia. Mean differences (MD) with 95% confidence intervals (CI) were estimated with random effects models. RESULTS: A total of 11 studies comprising 615 cases and 471 controls were included in the study. No significant differences were found in the HDL (MD = -2.55, 95% CI [-6.03, 0.93], P = 0.15), LDL (MD = -2.25, 95% CI [-13.36, 8.86], P = 0.69), TC (MD = -2.69, 95% CI [-13.30, 7.92], P = 0.62), and TG (MD = 6.90, 95% CI [-2.81, 16.60], P = 0.16) levels of the 2 groups. However, subgroup analysis enrolling patients who were not receiving treatment for dyslipidemia showed that TG levels were higher in patients with stable COPD than in healthy individuals (MD = 16.35, 95% CI [5.90, 26.80], P = 0.002). CONCLUSIONS: Excluding the impact of hypolipidemic treatment on serum lipid profile, TG levels were higher in patients with COPD than in healthy individuals. This meta-analysis suggested that physicians should screen COPD patients for elevated TG levels to reduce the risk of cardiovascular morbidity and mortality.

Enhanced anodic electrochemiluminescence of CdTe quantum dots based on electrocatalytic oxidation of a co-reactant by dendrimer-encapsulated Pt nanoparticles and its application for sandwiched immunoassays.

Herein, we synthesized Pt dendrimer-encapsulated nanoparticles (Pt DENs) using amine-terminated sixth-generation polyamidoamine dendrimers. The enhanced and stable anodic electrochemiluminescence (ECL) of 3-mercaptopropionic acid-capped CdTe quantum dots (QDs) in a tripropylamine solution was achieved owing to Pt DENs. The reason may be that Pt DENs exhibit high catalytic electrochemical oxidation in the presence of tripropylamine and excellent conductive property. Inspired by this, Pt DENs were conjugated with Fe3O4@SiO2 nanoparticles and served as nano-carriers. The capture antibodies were immobilized on the Fe3O4@SiO2-Pt DEN nanocomposites, which possess many attractive advantages such as the ease of bioconjugation, large specific surface area, and convenience of magnetic separation. Fluorescence microscopy images and UV-vis spectra were used to verify the immobilization of capture antibodies on the nanocomposites. The CdTe QDs were applied as signal labels for conjugation of nanocomposites with detection antibodies, which were characterized by agarose gel electrophoresis. Electrochemical impedance spectroscopy and cyclic voltammetry demonstrated the successful preparation of an ECL immunosensor. Under the optimal conditions, the proposed immunosensor provided a wide linear range from 0.005 ng mL-1 to 150 ng mL-1 with a detection limit of 0.2 pg mL-1 (S/N = 3) for the detection of carcinoembryonic antigen. Moreover, the immunosensor showed good performance for the detection of carcinoembryonic antigen in serum samples as well as great potential in clinical bioassay.

Formaldehyde aggravates airway inflammation through induction of glycolysis in an experimental model of asthma exacerbated by lipopolysaccharide.

Formaldehyde (FA) exposure has been reported to induce or aggravate allergic asthma. Infection is also a potential risk factor for the onset and aggravation of asthma. However, no study has addressed the effects of FA exposure on asthmatic patients with respiratory infection. FA is ubiquitous in environment and respiratory infections are common in clinics. Therefore, it is necessary to explore whether FA exposure leads to the further worsening of symptoms in asthma patients with existing respiratory infection. In the present study, ovalbumin (OVA) was used to establish the murine asthma model. Lipopolysaccharide (LPS) was intratracheal administrated to mimic asthma with respiratory infection. The mice were exposed to 0.5 mg/m3 FA. FA exposure did not induce a significant aggravation on OVA induced allergic asthma. However, the lung function of specific airway resistance (sRaw), histological changes and cytokines production were greatly aggravated by FA exposure in OVA/LPS induced murine asthma model. Monocyte-derived macrophages (MDMs) were isolated from asthmatic patients. Exposure of MDMs to FA and LPS resulted in increased TNF-α, IL-6, IL-1ß, and nitric oxide (NO) production. Lactate produciton and lactate dehydrogenase A (LDHA) expression were found to be upregulated by FA in OVA/LPS induced asthmatic mice and LPS stimulated MDMs. Furthermore, glycolysis inhibitor 2-Deoxy-d-glucose attenuated FA and LPS induced TNF-α, IL-6, IL-1ß, and NO production. We conclude that FA exposure can lead to the aggravation of allergic asthma with infection through induction of glycolysis. This study could offer some new insight into how FA promotes asthma development.

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity.

Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.

An Amino Acid-Enabled Separator for Effective Stabilization of Li Anodes.

Fundamentally suppressing Li dendrite growth is known to be critical for realizing the potential high energy density for Li-metal batteries (LMBs). Inspired by the ionic transport function of proteins, we previously discovered that utilizing natural proteins was able to stabilize the Li anode but have not demonstrated how a specific amino acid of the protein enabled the function. In this study, we decorate the separator with Leucine (Leu) amino acid assisted by poly(acrylic acid) (PAA) for effectively stabilizing the Li-metal anode, so as to dramatically improve the cycling performance of LMBs. The decorated separator improves electrolyte wettability and effectively suppresses Li dendrite growth. As a result, the amino acid-enabled separator prolongs the cycle life of the symmetrical Li|Li cells, exhibits higher Coulombic efficiency in the Li|Cu cells, and improves the cycling performance in LMBs with the LiFePO4 cathode. This work is an initial study on applying a specific amino acid of proteins to enhance the performance of batteries, providing a new strategy on guiding Li+ deposition, and laying an important foundation for functional separator design of high-energy-density batteries.