Tumor Microenvironment-Activatable Phototheranostic: Leveraging Nitric Oxide and Weak Acidity as Dual Biomarkers for Ratiometric Fluorescence, Photoacoustic Imaging, and Photothermal Therapy.

Tumor microenvironment-responsive phototheranostic agents are highly sought after for their ability to improve diagnostic accuracy and treatment specificity. Here, we introduce a novel single-molecule probe, POZ-NO, which is activated by nitric oxide (NO) and weak acidity, enabling dual-mode imaging and photothermal therapy (PTT) of tumors. In acidic environments with elevated NO levels, POZ-NO exhibits a distinctive ratiometric fluorescence signal shift from the red to near-infrared, accompanied by a 700 nm photoacoustic signal. Additionally, POZ-NO demonstrated potent photothermal effects upon NO and acidity activation, achieving an impressive conversion efficiency of 74.3% under 735 nm laser irradiation. In vivo studies confirm POZ-NO's ability to accurately image tumors through ratiometric fluorescence and photoacoustic modes while selectively treating tumors with PTT.

Carbon Monoxide: A Second Biomarker to Couple with Viscosity for the Construction of "Dual-Locked" Near-Infrared Fluorescent Probes for Accurately Diagnosing Non-Alcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) can progress to cirrhosis and liver cancer if left untreated. Therefore, it is of great importance to develop useful tools for the noninvasive and accurate diagnosis of NAFLD. Increased microenvironmental viscosity was considered as a biomarker of NAFLD, but the occurrence of increased viscosity in other liver diseases highly reduces the diagnosis accuracy of NAFLD by a single detection of viscosity. Hence, it is very necessary to seek a second biomarker of NAFLD. It has been innovatively proposed that the overexpressed heme oxygenase-1 enzyme in NAFLD would produce abnormally high concentrations of CO in hepatocytes and that CO could serve as a potential biomarker. In this work, we screened nine lactam Changsha dyes (HCO-1-HCO-9) with delicate structures to obtain near-infrared (NIR), metal-free, and "dual-locked" fluorescent probes for the simultaneous detection of CO and viscosity. Changsha dyes with a 2-pyridinyl hydrazone substituent could sense CO, and the 5-position substituents on the 2-pyridinyl moiety had a great electron effect on the reaction rate. The double bond in these dyes served as the sensing group for viscosity. Probe HCO-9 was utilized for precise diagnosis of NAFLD by simultaneous detection of CO and viscosity. Upon reacting with CO in a high-viscosity microenvironment, strong fluorescence at 745 nm of probe HCO-9 was turned on with NIR excitation at 700 nm. Probe HCO-9 was proven to be an effective tool for imaging CO and viscosity. Due to the advantages of NIR absorption and low toxicity, probe HCO-9 was successfully applied to image NAFLD in a mouse model.

ZIF-8 induced hydroxyapatite-like crystals enabled superior osteogenic ability of MEW printing PCL scaffolds.

ZIF-8 may experience ion-responsive degradation in ionic solutions, which will change its initial architecture and restrict its direct biological use. Herein, we report an abnormal phenomenon in which ZIF-8 induces large hydroxyapatite-like crystals when soaked directly in simulated body fluid. These crystals grew rapidly continuously for two weeks, with the volume increasing by over 10 folds. According to Zn2+ release and novel XRD diffraction peak presence, ZIF-8 particles can probably show gradual collapse and became congregate through re-nucleation and competitive coordination. The phenomenon could be found on ZIF-8/PCL composite surface and printed ZIF-8/PCL scaffold surface. ZIF-8 enhanced PCL roughness through changing the surface topography, while obviously improving the in-vivo and in-vitro osteoinductivity and biocompatibility. The pro-biomineralization property can make ZIF-8 also applicable in polylactic acid-based biomaterials. In summary, this study demonstrates that ZIF-8 may play the role of a bioactive additive enabling the surface modification of synthetic polymers, indicating that it can be applied in in-situ bone regeneration.

A Novel Glycolysis-Related Signature for Predicting the Prognosis and Immune Infiltration of Uveal Melanoma.

INTRODUCTION: As the most common aggressive intraocular cancer in adults, uveal melanoma (UVM) threatens the survival and vision of many people. Glycolysis is a novel hallmark of cancer, but the role of glycolysis-related genes in UVM prognosis remains unknown. The purpose of the study was to establish a glycolysis-related gene signature (GRGS) to predict UVM prognosis. METHODS: Raw data were obtained from TCGA-UVM and GSE22138 datasets. The GRGS was established by univariate, LASSO, and multivariate Cox regression analyses. Kaplan-Meier survival and time-dependent receiver operating characteristic curves were used to evaluate the predictive ability of the GRGS. The relationships of the GRGS with infiltrating immune cell levels and mutations were analyzed with CIBERSORT and maftools. RESULTS: A novel GRGS (risk score = 0.690861*ISG20 + 0.070991*MET - 0.227520*SDC2 + 0.690223*FBP1 + 0.048008*CLN6 - 0.128520*SDC3) was developed for predicting UVM prognosis. The GRGS had robust predictive stability in UVM. Enrichment annotation suggested that the high-risk group had stronger adaptive immune responses and that the low-risk group had more innate immune cell infiltration. Moreover, BAP1 mutation was related to high risk, and SF3B1 mutation was related to low risk. CONCLUSIONS: This study developed and validated a novel GRGS to predict UVM prognosis and immune infiltration. The signature revealed an association between glycolysis-related genes and the tumor microenvironment, providing new insights into the role of glycolysis in UVM.

Transcriptomic and Physiological Responses of Chlorella pyrenoidosa during Exposure to 17α-Ethinylestradiol.

17α-ethinylestradiol (17α-EE2) is frequently detected in water bodies due to its use being widespread in the treatment of prostate and breast cancer and in the control of alopecia, posing a threat to humans and aquatic organisms. However, studies on its toxicity to Chlorella pyrenoidosa have been limited to date. This study investigated the effects of 17α-EE2 on the growth, photosynthetic activity, and antioxidant system of C. pyrenoidosa and revealed related molecular changes using transcriptomic analysis. The cell density of algae was inhibited in the presence of 17α-EE2, and cell morphology was also altered. Photosynthetics were damaged, while reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) content increased. Further transcriptomic analysis revealed that the pathways of photosynthesis and DNA replication were affected at three concentrations of 17α-EE2, but several specific pathways exhibited various behaviors at different concentrations. Significant changes in differentially expressed genes and their enrichment pathways showed that the low-concentration group was predominantly impaired in photosynthesis, while the higher-concentration groups were biased towards oxidative and DNA damage. This study provides a better understanding of the cellular and molecular variations of microalgae under 17α-EE2 exposure, contributing to the environmental risk assessment of such hazardous pollutants on aquatic organisms.

A simple and rapid immunochromatography test based on readily available filter paper modified with chitosan to screen for 13 sulfonamides in milk.

In this study, we developed a novel, simple, rapid, and low-cost colloidal gold-based immunochromatography method, with filter paper replacing nitrocellulose membrane as the substrate. To obtain adequately immobilized protein, chitosan was used to functionalize the filter paper. After conditions and parameters were optimized, the novel immunochromatography method was applied for detection of sulfonamide residues in milk. Quantitative detection was accomplished using a smartphone and Photoshop software (Adobe Inc., San Jose, CA), allowing us to screen 13 sulfonamides with a limit of detection ranging from 0.42 to 8.64 µg/L and recovery ranging from 88.2 to 116.9% in milk. The proposed novel method performed similarly to the conventional method that uses a nitrocellulose membrane as the transport medium, and it had lower cost and better usability because of the inexpensive and easily available filter paper.

Highly sensitive chromatographic time-resolved fluoroimmunoassay for rapid onsite detection of streptomycin in milk.

Antibiotic residues are major contaminants in milk because of their use in agriculture and animal husbandry. In particular, streptomycin, an aminoglycoside antibiotic, is a potential risk to consumers because of its ototoxicity, anaphylaxis, and growth inhibition. Herein, monoclonal antibodies for streptomycin were conjugated with europium microspheres to serve as detection probes for the development of a chromatographic time-resolved fluoroimmunoassay to detect streptomycin residues in milk. The method had a low detection limit of 0.58 µg/kg, a linear range of 0.8 to 6.25 µg/kg, and substantial recovery, from 85.6 to 108.3%. It showed slight cross-reactivity with another aminoglycoside analog. Strong correlations between the results of established chromatographic time-resolved fluoroimmunoassay and ultra-performance liquid chromatography-tandem mass spectrometry indicated that the established fluoroimmunoassay is a reliable method for rapid onsite detection of streptomycin in milk and it has great potential in food safety monitoring.

Immunochromatographic fluorometric determination of clenbuterol with enhanced sensitivity.

A method is described to enhance the sensitivity of an immunochromatographic assay for clenbuterol (CLE) by making use of dually-labeled gold nanoparticles (GNPs), background fluorescence blocking, and immunomagnetic separation. The GNPs were labeled with biotinylated antibody and streptavidin, respectively, and dually labeled GNPs were obtained via the biotin-streptavidin interaction to amplify the detection signal. The fluorescent signal was blocked by dually labeled GNPs and decreased as the dually labeled GNPs aggregation increases on nitrocellulose membrane, which derived from fluorescent polyvinylchloride card. However, fluorescence (measured at excitation/emission wavelengths of 518/580 nm) recovers when CLE reacts with dually labeled GNPs. Immunomagnetic separation was first applied for sample pretreatment. This can offset the matrix effect and improves the sensitivity and accuracy of the assay. Under the optimal conditions, the limits of detection of CLE visually were 0.25 µg·L-1. In addition, clenbuterol can be quantified in swine urine with a 0.03 µg·L-1 detection limit. This is 60-fold lower than current immunochromatography. Response is linear in the 0.06-0.59 µg·L-1 concentration range, and the recoveries from spiked swine urine range from 81 to 115%." Graphical abstract Schematic presentation of the strategies for improving sensitivity of immunochromatographic assay. It includes immunomagnetic separations, dually-labeled gold nanoparticles and background fluorescence blocking. The assay was applied to detect clenbuterol (CLE) in swine urine with an excellent performance.

Engineered nanovesicles from stromal vascular fraction promote angiogenesis and adipogenesis inside decellularized adipose tissue through encapsulating growth factors.

Acellular matrix is a commonly used biomaterial in the field of biomedical engineering and revascularization is the key process to affect the effect of acellular matrix on tissue regeneration. The application of bioactive factors related to angiogenesis has been popular in the regulation of revascularization, but the immune system clearance, uncontrollable systemic reactions, and other factors make this method face challenges. Recent reports showed that engineered cells into nanovesicles can reorganize cell membranes and encapsulate cellular active factors, extending the in vitro preservation of cytokines. However, the problems of exogenous biological contamination and tumorigenicity restricted the clinical transformation and wide application of this method. Here, we for the first time engineer stromal vascular fraction (SVF) which is extracted from fat into nanovesicles (SVF-EVs) for angiogenesis in the acellular matrix. SVF-EVs not only promote the migration of vascular endothelial cells in vitro, but also facilitate the lipogenic differentiation of mesenchymal stem cells. In vivo, SVF-EVs enhanced the retention of decellularized adipose tissue after transplanting to the subcutaneous area of nude mice. Immunofluorescence staining further showed that SVF-EVs promoted the formation of vascular networks with large lumen diameter in the grafted acellular matrix, accompanied by adipocyte regeneration peripherally. These findings reveal that SVF-EVs can be a viable method for accelerating revascularization in acellular matrix, and this process of squeezing tissue into nanovesicles shows the potential for rapid clinical transformation.

Characterization and genome analysis of Acinetobacter oleivorans S4 as an efficient hydrocarbon-degrading and plant-growth-promoting rhizobacterium.

Plant-growth-promoting rhizobacteria (PGPR) have received increasing attention for assisting phytoremediation. However, the effect of PGPR on total petroleum hydrocarbon (TPH) degradation and plant growth promotion and its underlying mechanism is not well understood. In this study, phenotypic analysis and whole genome sequencing were conducted to comprehensively characterize a newly isolated rhizobacterium strain S4, which was identified as Acinetobacter oleivorans, from a TPH-contaminated soil. The strain degraded 62.5% of initially spiked diesel (1%) in minimal media within six days and utilized n-alkanes with a wide range of chain length (i.e., C12 to C40). In addition, the strain showed phenotypic traits beneficial to plant growth, including siderophore production, indole-3-acetic acid synthesis and phosphate solubilization. Potential metabolic pathways and genes encoding proteins responsible for the phenotypic traits were identified. In a real TPH-contaminated soil, inoculation of Acinetobacter oleivorans S4 significantly enhanced the growth of tall fescue relative to the soil without inoculation. In contrast, inoculation of Bacillus sp. Z7, a hydrocarbon-degrading strain, showed a negligible effect on the growth of tall fescue. The removal efficiency of TPH with inoculation of Acinetobacter oleivorans S4 was significantly higher than those without inoculation or inoculation of Bacillus sp. Z7. These results suggested that traits of PGPR beneficial to plant growth are critical to assist phytoremediation. Furthermore, heavy metal resistance genes and benzoate and phenol degradation genes were found in the genome of Acinetobacter oleivorans S4, suggesting its application potential in broad scenarios.

Soft, miniaturized, wireless olfactory interface for virtual reality.

Recent advances in virtual reality (VR) technologies accelerate the creation of a flawless 3D virtual world to provide frontier social platform for human. Equally important to traditional visual, auditory and tactile sensations, olfaction exerts both physiological and psychological influences on humans. Here, we report a concept of skin-interfaced olfactory feedback systems with wirelessly, programmable capabilities based on arrays of flexible and miniaturized odor generators (OGs) for olfactory VR applications. By optimizing the materials selection, design layout, and power management, the OGs exhibit outstanding device performance in various aspects, from response rate, to odor concentration control, to long-term continuous operation, to high mechanical/electrical stability and to low power consumption. Representative demonstrations in 4D movie watching, smell message delivery, medical treatment, human emotion control and VR/AR based online teaching prove the great potential of the soft olfaction interface in various practical applications, including entertainment, education, human machine interfaces and so on.

Intelligent Soft Sweat Sensors for the Simultaneous Healthcare Monitoring and Safety Warning.

Intelligent monitoring human physiological information in real time raises the demand for skin-integrated electronics, as which is a flexible format and can be mounted onto the curved human skin for noninvasive healthcare monitoring. The biofluid such as sweat from skin contains abundant biomarkers reflecting body health conditions. Here, a skin-integrated sweat monitor with six biosensors embedded for the detection of NH4 + , Na+ , glucose, pH, skin impedance, and surface temperature is described, which could decode the information in the fresh sweat generated during exercising. Furthermore, the system also includes an innovative safety warning mechanism, which is based on a miniaturized actuator to provide mechanical stimuli, and coupled with six changeable colors light emitting diodes corresponding to the six biosensors for providing simultaneous safety alarming to users. The self-developed microfluidics system with a hydrophilic surface allows to enhance the sweat collection rate. Meanwhile, microfluidic filters can reduce the interruption of skin debris during biosignal monitoring. These state-of-art biosensors can real-time monitor health related signals with excellent linearity and specificity. The skin-integrated sweat monitor system exhibits a great potential in human healthcare monitoring and medical treatment.

Identification of Diagnostic Biomarkers and Their Correlation with Immune Infiltration in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of the central retina, with no suitable biomarkers for early diagnosis and treatment. This study aimed to find potential diagnostic biomarker candidates for AMD and investigate their immune-related roles in this pathology. Weight gene correlation analysis was first performed based on data from the Gene Expression Omnibus database and 20 hub genes were identified. The functional enrichment analyses showed that the innate immune response, inflammatory response, and complement activation were key pathways associated with AMD. Complement C1s (C1S), adrenomedullin (ADM), and immediate early response 5 like (IER5L) were identified as the crucial genes with favorable diagnostic values for AMD by using LASSO analysis and multiple logistic regression. Furthermore, a 3-gene model was constructed and proved to be of good diagnostic and predictive performance for AMD (AUC = 0.785, 0.840, and 0.810 in training, test, and validation set, respectively). Finally, CIBERSORT was used to evaluate the infiltration of immune cells in AMD tissues. The results showed that the NK cells, CD4 memory T cell activation, and macrophage polarization may be involved in the AMD process. C1S, ADM, and IER5L were correlated with the infiltration of the above immune cells. In conclusion, our study suggests that C1S, ADM, and IER5L are promising diagnostic biomarker candidates for AMD and may regulate the infiltration of immune cells in the occurrence and progression of AMD.

Simple application of adipose-derived stem cell-derived extracellular vesicles coating enhances cytocompatibility and osteoinductivity of titanium implant.

Surface modification using bioactive molecules is frequently performed to improve the biological properties of medical metal biomaterial titanium (Ti) implants. Developmental evidence suggests that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) served as potent bioactive component. As a subset of MSC-EV, adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) could be obtained from abundant adipose tissue. Meanwhile, it possesses multiple regenerative properties and might be used to endow biological activities to medical Ti implant. Here, we present a simple ADSC-EV coating strategy based on physisorption of fibronectin. This ADSC-EV functionalized Ti implants (EV-Ti) revealed enhanced osteoblast compatibility and osteoinductive activity. Cell spreading area of EV-Ti group was 1.62- and 1.48-fold larger than that of Ti group after 6 and 12 h of cell seeding, respectively. Moreover, EV-Ti promoted alkaline phosphatase, collagen 1 and osteocalcin gene expression in osteoblast by 1.51-, 1.68- and 1.82-fold compared with pristine Ti, respectively. Thus, the MSC-EVs modification method reported here provide a clinically translatable strategy to promote the bioactivity of Ti implants.

Positive Rate of Serology and RT-PCR for COVID-19 among Community Residents and Healthcare Workers in Wuhan, China.

This study aimed to evaluate the infection rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among different populations in Wuhan, China. This cross-sectional survey-based study examined the results of SARS-CoV-2-specific serological tests and RT-PCR tests for 4,454 community residents and 4,614 healthcare workers performed from May 15 to May 29, 2020. The healthcare workers were classified as administrative and logistical staff (n = 1,378), non-first-line healthcare workers (n = 2,630), or first-line healthcare workers (n = 606) according to their frequency of contact with coronavirus disease (COVID-19) patients. The positive rates of SARS-CoV-2-specific IgG, IgM, and RNA were 2.9%, 0.4%, and 0.1% for the community residents and 3.3%, 0.6%, and 0.2% for the healthcare workers, respectively. There were no statistically significant differences between the rates of the two groups. Spearman's correlation analysis showed that the frequency of contact with COVID-19 patients negatively correlated with the positive rates of RT-PCR (rs = -0.036, P = 0.016), but did not significantly correlate with the positive rates of IgM (rs = -0.006, P = 0.698) or IgG (rs = 0.017, P = 0.239). There was no statistically significant difference between the SARS-CoV-2-specific IgG, IgM, or RNA positive rates of the community residents and those of the healthcare workers. The positive rate of SARS-CoV-2 RNA was lower for the first-line healthcare workers than for the non-first-line healthcare workers and the administrative and logistical staff.

Presence of SARS-CoV-2 RNA in isolation ward environment 28 days after exposure.

Recent studies have reported that surfaces and objects in the rooms of infected patients that are frequently touched by both medical staff and patients could be contaminated with SARS-CoV-2. In December 2019, Wuhan China suffered the earliest from this COVID-19 pandemic, and we took that opportunity to investigate whether the SARS-CoV-2 RNA exists in the ward environment after a long time from exposure. We found that on the 28th day following the discharge of COVID-19 patients, SARS-CoV-2 RNA could still be detected on the surfaces of pagers and in drawers in the isolation wards. Thorough disinfection of the ward environment was subsequently performed, after which these surfaces in the isolation wards tested negative for the presence of SARS-CoV-2 RNA. The findings remind us that the contaminated environment in the wards may become potential infectious resources and that despite a long time from exposure, the thorough disinfection in the COVID-10 units after is still necessary.

Clinicopathological and prognostic significance of caveolin-1 and ATG4C expression in the epithelial ovarian cancer.

OBJECTIVE: Altered expression of caveolin-1 (CAV1) and autophagy marker ATG4C is observed in various types of human cancers. However, the clinical significance of CAV1 and ATG4C expression in epithelial ovarian cancer (EOC) remains largely unknown. The present study aims to explore the clinicopathological value and prognostic significance of CAV1 and ATG4C expression in EOC. METHODS: The expression pattern and prognostic value of CAV1 and ATG4C mRNA in EOC were analyzed using data from the Cancer Genome Atlas (TCGA) database (N = 373). In addition, immunohistochemistry analysis was performed to detect and assay the expression of CAV1 and ATG4C proteins in tissue microarray of EOC. RESULTS: Based on TCGA data, Kaplan-Meier analysis indicated that patients with low CAV1 mRNA (p = 0.021) and high ATG4C mRNA (p = 0.018) expression had a significantly shorter overall survival (OS). Cox regression analysis demonstrated that the expression levels of CAV1 (p = 0.023) and ATG4C mRNA (p = 0.040) were independent prognostic factors for OS in EOC. In addition, the Concordance Index of the nomogram for OS prediction was 0.660. Immunohistochemical analysis showed the expression levels of stromal CAV1 and cancerous ATG4C proteins, and high expression of both CAV1 and ATG4C protein in the stroma were found to significantly correlate with the histologic subtypes of EOC, especially with serous subtype. CONCLUSIONS: Decreased expression of CAV1 mRNA and increased expression of ATG4C mRNA in EOC can predict poor overall survival. The expression levels of CAV1 protein in stromal cells and ATG4C protein in cancer cells are significantly associated with histologic subtypes of EOC. These findings suggest that CAV1 and ATG4C serve as useful prognostic biomarkers and candidate therapeutic targets in EOC.