Construction of a Cu2+-Responsive NIR Fluorescent Probe and the Preliminary Evaluation of its Multifunctional Application.

Cu2+ was deemed as toxic and the most common heavy metal pollution in the water and food. Meanwhile, endogenous Cu2+ was deeply involved in plenty of physiological and pathological processes of human. Cu2+ imbalance was related to multiple diseases. Here we developed a Cu2+-responsive NIR probe HX, which not only demonstrated obvious color change when subjected to Cu2+, but also showed linear-dependent NIR fluorescence emission to Cu2+ concentration for Cu2+ detection and quantification both in vitro and in vivo. When HX was applied to imaging Cu2+ in the cell or living animals, intracellular Cu2+ fluctuation and Cu2+ accumulation in the liver could be visualized to indicate the copper level in the cell or organs with low background signals. Meanwhile, by applying HX to monitor Cu2+ uptake in the tumor, copper transporter function could be evaluated to screen the patient who are sensitivity to platinum drug.

Hybrid-FHR: a multi-modal AI approach for automated fetal acidosis diagnosis.

BACKGROUND: In clinical medicine, fetal heart rate (FHR) monitoring using cardiotocography (CTG) is one of the most commonly used methods for assessing fetal acidosis. However, as the visual interpretation of CTG depends on the subjective judgment of the clinician, this has led to high inter-observer and intra-observer variability, making it necessary to introduce automated diagnostic techniques. METHODS: In this study, we propose a computer-aided diagnostic algorithm (Hybrid-FHR) for fetal acidosis to assist physicians in making objective decisions and taking timely interventions. Hybrid-FHR uses multi-modal features, including one-dimensional FHR signals and three types of expert features designed based on prior knowledge (morphological time domain, frequency domain, and nonlinear). To extract the spatiotemporal feature representation of one-dimensional FHR signals, we designed a multi-scale squeeze and excitation temporal convolutional network (SE-TCN) backbone model based on dilated causal convolution, which can effectively capture the long-term dependence of FHR signals by expanding the receptive field of each layer's convolution kernel while maintaining a relatively small parameter size. In addition, we proposed a cross-modal feature fusion (CMFF) method that uses multi-head attention mechanisms to explore the relationships between different modalities, obtaining more informative feature representations and improving diagnostic accuracy. RESULTS: Our ablation experiments show that the Hybrid-FHR outperforms traditional previous methods, with average accuracy, specificity, sensitivity, precision, and F1 score of 96.8, 97.5, 96, 97.5, and 96.7%, respectively. CONCLUSIONS: Our algorithm enables automated CTG analysis, assisting healthcare professionals in the early identification of fetal acidosis and the prompt implementation of interventions.

Development of a H2S-responsive NIR Fluorescent Probe for H2S Detection and H2S Releasing Monitoring From Prodrug.

H2S was deemed as a toxic gradient in the realm of food and environment but plays pivotal pathophysiological roles in organisms. H2S instabilities and disturbances are always responsible for multiple disorders. We fabricated a H2S-responsive NIR fluorescent probe (HT) for H2S detection and evaluation both in vitro and in vivo. HT exhibited rapid H2S response within 5 min, accompanied with visible color change and NIR fluorescence generation, and the fluorescent intensities were linearly correlated with corresponding H2S concentrations. When HT was incubated with A549 cells, the intracellular H2S and H2S fluctuations could be monitored ore rotundo via the responsive fluorescence. Meanwhile, when HT was co-administrated with H2S prodrug ADT-OH, the H2S release from ADT-OH could be visualized and monitored to evaluate its release efficacy.

DNA Zipper Mediated Membrane Fusion for Rapid Exosomal MiRNA Detection.

Accurate and reliable detection of exosomal miRNA can serve as a promising method for early diagnosis of disease and evaluation of therapeutic effects. However, current exosomal miRNA detection methods commonly involve exosome enrichment, containing RNA extraction, and qRT-PCR based quantification, which are expensive and time-consuming. Herein, we develop a DNA zipper-mediated membrane fusion approach for rapid exosomal miRNA detection and cancer diagnosis. First, a lipid vesicle probe containing miR21-targeting molecular beacons (MBs) is constructed and further loaded with zipper DNA constructs (ZDCs) on its surface. Meanwhile, complementary zipper DNA constructs (cZDCs) are introduced on the exosome of interest. Upon mixing them together, zipping between ZDC and cZDC induces the membrane fusion of exosomes and vesicle probes, triggering the recognition of exosomal miR21 by contained MBs and fluorescence emission that can be conveniently detected within 30 min. Importantly, with the assistance of flow cytometry, miR21-overexpressed tumor exosomes derived from either cell culture medium or clinical patient serums can be distinguished from exosomes secreted from normal cells. This approach provides a convenient way to accurately detect the exosomal miRNA, which may hold great potential in liquid biopsy for early cancer diagnosis and monitoring the therapeutic effects during the treatments.

Development and preliminary evaluation of an integrin α2ß1-targeted PET probe as a supplement and alternative of PSMA imaging for prostate cancer.

An integrin α2ß1-targeted PET probe (68Ga-IABtP) was developed to serve as a supplement and alternative of PSMA imaging for prostate cancer. 68Ga-IABtP was synthesized by labeling the precursor peptide with 68Ga with 93% labeling yield and 4.14 MBq/µg specific radioactivity. 68Ga-IABtP showed no specific uptake in LNCaP prostate cancer cell with low integrin α2ß1 expression but significantly increased uptake in PC-3 prostate cancer cell with high integrin α2ß1 expression, which could be specifically blocked by the integrin α2ß1 monoclonal antibody. The efflux experiments demonstrated that 68Ga-IABtP could rapidly penetrate into PC-3 cell after cell binding, thereby prolonging the residence time in the tumor and allow enough time for probe clearance from the circulation and non-specific organs. The biodistribution study indicated that 68Ga-IABtP showed no specific accumulation in non-target organs and was quickly cleared from the kidney. The in vivo PET-CT imaging demonstrated that 68Ga-IABtP showed no specific uptake in LNCaP tumor but could specifically accumulate in the PC-3 tumor, and was rapidly cleared from spleen, intestine, kidney and liver, resulting in excellent contrast effect with low background signal and high target to non-target ratios.

Ratiometric nanoprobe for circulating tumor cell detection and intracellular hydrogen peroxide evaluation in colorectal cancer patients.

The application of intensity-based H2O2-responsive fluorescence nanoprobe for circulating tumor cell detection was limited by the complex background and the nanoprobe uptake in each CTC. In this context, we developed a ratiometric fluorescence nanoprobe, on which a H2O2-responsive subunit and a stable subunit grafted working as a H2O2 detector and a reference, respectively. When responding to intracellular H2O2, the reference fluorescence (580 nm) maintained as a correction background while the detector fluorescence (450 nm) was turned on to conduct CTC enumeration and intracellular H2O2 evaluation. Two normal cells and three colon cancer cells were examined to evaluate their endogenous H2O2 with the ratiometric nanoprobe by flow cytometry and confocal laser scanning microscopy. CTC sample from colorectal cancer patients was used to validate the performance of the nanoprobe for CTC enumeration and H2O2 evaluation. The results indicated that not only CTC could be effectively identified based on the "turn on" fluorescence, but also the viability of the identified CTCs could be assessed with the intensity of the reference fluorescence to avoid the false-positive number. Moreover, the clinical results demonstrated that the viability CTC count combined with intracellular H2O2 content (described as I450/580)were related to the tumor TNM stage, which might provide significant guidance for clinical treatments.

In situ localization of alkaline phosphatase activity in tumor cells by an aggregation-induced emission fluorophore-based probes.

In situ detection of certain specific enzyme activities in cells is deeply attached to tumor diagnosis. Conventional enzyme-responsive fluorescent probes have difficulty detecting targeted enzymes in situ in cells due to the low detection accuracy caused by the spread of fluorescence probes. In order to solve this problem, we have designed and synthesized an enzyme-responsive, water-soluble fluorescent probe with AIE characteristics, which could aggregate and precipitate to produce in situ fluorescence when reacting with the targeted enzyme in cells. The AIE fluorophore (TPEQH) was utilized to design the enzyme-responsive, fluorescent probe (TPEQHA) by introducing a phosphate group on to it, which could be specifically decomposed by the targeted enzyme, namely alkaline phosphatase (ALP). In tumor cells, TPEQH was highly produced due to the interaction of phosphate on the TPEQHA and the overexpressed ALP. Water-insoluble TPEQH then precipitated and release fluorescence in situ, thereby successfully detecting the ALP. Furthermore, the expression level of ALP could be determined by the fluorescence intensity of TPEQH with higher accuracy due to the inhibition of TPEQH leak, which demonstrated a potential application of in suit ALP detection in both clinical diagnosis and scientific research of tumor.

Synthesis and preliminary evaluation of 18F-icotinib for EGFR-targeted PET imaging of lung cancer.

Epidermal growth factor receptor (EGFR) has emerged as an attracting target in the field of imaging and treatment for non-small cell lung cancer (NSCLC). Radiolabeled EGFR-tyrosine kinase inhibitors (EGFR-TKIs) specifically targeting EGFR are deemed as promising probes for the imaging of NSCLC. This study aimed to label icotinib (one kind of EGFR-TKI) with 18F through click reaction to develop a new EGFR-targeting PET probe-18F-icotinib. 18F-icotinib was obtained in 44.81% decay-corrected yield in 100 min synthesis time with 34 GBq/µmol specific activity and >99% radiochemical purity at the end of synthesis. The identity of the product was confirmed by co-injection with 18F-icotinib and 19F-icotinib. The Log P was 1.28 ±â€¯0.04 (n = 6). The tracer displayed excellent stability after incubation for 4 h in vitro. 18F-icotinib showed satisfying binding ability to A549 NSCLC cells, which could be inhibited by icotinib. PET imaging studies demonstrated a specific uptake of the radiotracer (0.90 ±â€¯0.24% ID/g) in A549 tumor-bearing mice, while lower uptake was observed in heart, lung and spleen at 1.5 h post injection. Inmunohistochemical staining confirmed that the A549 tumor was EGFR-positive. Therefore, we considered that 18F-icotinib was a highly promising compound for EGFR-based tumor PET imaging.

Development of a Supermolecular Radionuclide-Drug Conjugate System for Integrated Radiotheranostics for Non-small Cell Lung Cancer.

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.

Relationship between human activities and environmental changes in the southern Tibetan Plateau since the Little Ice Age.

The Tibetan Plateau (TP) is one of the most challenging areas for human long-term settlement due to its extreme living environment. Understanding the relationship between human activities and environmental changes in this extreme environment is important and can provide a historical reference for adapting to future climate change. In this study, we took the Angren Basin in the southern TP as a case study to elucidate the relationship since Little Ice Age (LIA). Using fecal stanol in feces, lake and river surface sediments, surface soils, and sediment core, we found that specific indices S1 and S2 from the composition of coprostanol, epicoprostanol, 5ß-ethylcoprostanol and 5ß-ethylepicoprostanol can reflect changes in human population and herbivores, respectively. Through the comparison between environmental changes determined by grain size, elements, sedimentation rate, and other climate records, the relationship between human activities and environmental changes was interpreted. Our results indicate that: (i) during 1480-1820 CE, the fecal stanols in lake sediments mainly originated from livestock, and the human population was low. In contrast, during 1820-2021 CE, the proportion and flux of S1 have been continuously increasing, indicating significant population growth. (ii) During the middle LIA, the cold-dry climate inhibited the development of agriculture and farming. However, the increased precipitation during the late LIA promoted that development, resulting in an increase in human population and livestock in a short term. (iii) Since 1951, people have reclaimed wasteland and developed husbandry, leading to increased soil erosion. (iv) Over the past 40 years, with a warm-humid climate and good policy support, human activities, such as agriculture and husbandry, have rapidly increased, but soil erosion has declined in the recent 20 years due to good soil-water conservation efforts. This study sheds light on the relationship between human activities and environmental changes and provides insights into future climate change responses.

Development of a NIR fluorescent probe for fluorescence-assisted EGFR-TKI applicable patients screening and drug resistance monitoring.

EGFR tyrosine kinase inhibitor exerts significant benefits to non-small cell lung cancer patient, but was also limited by the applicable patient screening and drug resistance. Here we presented with an EGFR-targeted and reactive oxygen species-responsive NIR probe (LX) to achieve both patient screening and drug resistance monitoring for EGFR-tyrosine kinase inhibitor. LX inherited EGFR selectivity and preference from EGFR-tyrosine kinase inhibitor, which only showed specificity to tumor with EGFR mutation. Meanwhile, the near-infrared fluorescence of LX was initially inhibited and could be turned on by intratumoral reactive oxygen species. When LX could bind to tumor EGFR, reactive oxygen species-responsive specific fluorescence was generated to indicate the applicability of tumors to EGFR-tyrosine kinase inhibitor. However, no specific LX fluorescence could be observed in inapplicable tumors due to the lack of specificity between tumor EGFR and LX. Meanwhile, when drug resistance was developed during treatments, obvious intratumoral reactive species oxygen decrease happened, which was also deemed as a significant signal of the drug resistance. By visualizing intratumoral reactive oxygen species fluctuation by responsive fluorescence, drug resistance could be monitored and reported.

Electrochemical Control over the Optical Properties of II-VI Colloidal Nanoplatelets by Tailoring the Station of Extra Charge Carriers.

An electrochemical (EC) method has been successfully applied to regulate the optical properties of nanocrystals, such as reducing their gain threshold by EC doping and enhancing their photoluminescence intensity by EC filling of trap states. However, the processes of EC doping and filling are rarely reported simultaneously in a single study, hindering the understanding of their underlying interactions. Here, we report the spectroelectrochemical (SEC) studies of quasi-two-dimensional nanoplatelets (NPLs), intending to clarify the above issues. EC doping is successfully achieved in CdSe/CdZnS core/shell NPLs, with red-shifted photoluminescence and a reversal of the emission intensity trend. The injection of extra electrons (holes) into the conduction (valence) band edges needs high bias voltages, while the passivation/activation process of trap states with the shift of Fermi level starts at lower EC potentials. Then, we explore the role of excitation light conditions in these processes, different from existing SEC research studies. Interestingly, increasing the laser power density can hinder EC electron injection, whereas decreasing the excitation energy evades the passivation process of trap states. Moreover, we demonstrate that EC control strategies can be used to realize color display and anti-counterfeiting applications via simultaneously tailoring the photoluminescence intensity of red- and green-emitting NPLs.

Synthesis and preliminary exploration of a NIR fluorescent probe for the evaluation of androgen dependence of prostate cancer.

PURPOSE: Castration resistance prostate cancer patients showing resistance to the androgen deprivation therapy always have low five-year survival rate and worse prognosis. A responsive NIR fluorescent probe was designed to report the androgen dependence and monitor the development of castration resistance for prostate cancer. METHODS: Intratumoral H2S in prostate cancer was closely related to castration resistance. A H2S-responsive NIR probe (HM) was developed as a dependent indicator to report the androgen dependence of prostate cancer. The specificity of HM to H2S and the influence of normal intracellular substrates to the response between H2S and HM were determined. Cell/in vivo animal imaging were performed on PC-3 and LnCAP cell/tumor bearing mice, which presented with androgen independence and androgen dependence, respectively. RESULTS: When HM responded to H2S, strong fluorescence at 770 nm could be rapidly turned on in 5 min with the stokes shift as large as 200 nm. The recognition between HM and H2S showed high specificity. Neither other common substrates showed capacity to turn on HM's fluorescence, nor their existence demonstrated competition. The fluorescence intensity was linearly dependent to the H2S concentration and the limited of detection was 0.15 µM. When HM was applied to PC-3/LNCaP prostate cancer cell and tumor, the intracellular and intratumoral H2S could be clearly imaged and monitored. CONCLUSION: HM showing obvious fluorescent behaviors in androgen dependence and independence prostate tumor, which could work as an indicator to reported the androgen dependence of prostate cancer and monitor the development of castration resistance.

Electrochemical control of emission enhancement in solid-state nitrogen-doped carbon quantum dots.

Because of their excellent optical and electrical properties, doped carbon quantum dots (CQDs) are expected to be used in novel film optoelectronic devices such as light-emitting diodes and solar cells. However, these device advancements are currently hindered by the elusive photophysical process of doped CQDs in solid-state films. Here, the optical properties of nitrogen-doped CQD (N-CQD) films are studied using spectro-electrochemical (SEC) methods. A distinctive photoluminescence (PL) enhancement phenomenon is observed, in which the PL intensity of the N-CQD film can be increased in both positive and negative electrochemical potential sweeps. The effect of positive potential on PL enhancement is greater (∼340% at +1.4 V), while that of negative potential is slightly weaker (∼10% at -1.4 V). To the best of our knowledge, no similar brightening process has been reported in all previous SEC studies on a variety of QDs, wherein the emission intensity can only exhibit enhancement under positive or negative potential at most. We propose that the above PL brightening is related to the weakened π-π stacking effect after electrochemical charge injection and nitrogen doping plays a crucial role in it. Finally, a low hysteresis reversible electrochemistry regulation of the PL spectrum can be achieved by increasing electrolyte fluidity with argon gas bubbling to reduce local charge aggregation.

Development of a NIR fluorescent probe for the detection of intracellular cysteine and glutathione and the monitoring of the drug resistance.

Intracellular cysteine and glutathione was deemed as the most important reductants in the cell and played significant roles in the cellular homeostasis and redox adjustment. Here we developed a NIR fluorescent probe (HI) to detect and report the intracellular cysteine and glutathione, and monitor the development of the drug resistance of tumor. HI with both excited wavelength and emitting wavelength located within near infrared area showed no fluorescence in the normal physiological environment. However, when HI responded to cysteine and glutathione, strong NIR fluorescence could be turned on, which was linear dependent to the cysteine concentrations and the limited of detection was 0.18 µM. The response between HI and cysteine/glutathione demonstrated high specificity and no other amino acids showed influence or competition. The HPLC identification of the recognition results confirmed the response of acryloyloxy on the HI and active sulfhydryl on the cysteine/glutathione. DFT calculation of the HOMO and LUMO energy before and after response revealed the intramolecular charge transfer mechanism that induced the generation of the fluorescence. When HI was incubated with PATU-8988 and PATU-8988/Fu cell, the intracellular cysteine and glutathione could be clearly imaged and monitored by the enhanced fluorescence. Meanwhile, when HI was applied to the tumor-bearing mice, the drug resistance of tumor could be monitored and reported.

Evaluation of a new magnetic bead as an integrated platform for systematic CTC recognition, capture and clinical analysis.

A novel form of magnetic bead, namely antibody-coated magnetic lipid nano-vehicle (AMLV), was synthesized by embedding Fe3O4 nanoparticles into an amphiphilic antibody-modified liposome as a high-performance circulating tumor cell (CTC) hunter. The CTC capture performance of AMLV was validated based on an enlarged patient sample (including 318 colorectal, 78 breast, 77 lung and 55 liver cancer patients) with high detection rate. The preliminary comparison with Cellsearch was also conducted, indicating that the cell membrane-semblance AMLVEpCAM showed higher capture performance for different kinds of EpCAM-expressed circulating tumor cells in the peripheral blood (4.4 ± 1.2-fold for AMLVEpCAM vs CellsearchTM, n=5, P<0.001). Moreover, the AMLVEpCAM-isolated CTCs could be used as a functional material to provide various clinical information for tumor patients and work as an alternative of tumor tissue to conduct gene analysis after conventional PCR amplification.

Late Holocene vegetation responses to climate change and human impact on the central Tibetan Plateau.

Understanding long-term environmental changes under natural and anthropic forces is helpful for facilitating sustainable development. Here we present a sedimentary record from the central Tibetan Plateau to investigate the impacts of climate and human activities on alpine vegetation during the late Holocene, based on a 162-cm-long lacustrine sediment core collected from Tangra Yumco. Palynology, charcoal and minerogenic input reveal variations of climate and human activity during the past 3400 cal yr BP. Our results show that alpine steppe dominated by Artemisia, Cyperaceae and Poaceae was present in the Tangra Yumco area during the entire covered period. Only minor human activities are visible between 3400 and 2300 as well as from 1700 to 400 cal yr BP, when vegetation was mainly influenced by climate. Although human activities (presence/grazing) became more intensive between 2300 and 1700 cal yr BP corresponding to the Zhang Zhung Kingdom, vegetation change is still mainly affected by a more arid climate. Strongest human influence on vegetation was found after 400 cal yr BP, when vegetation composition was altered by farming and grazing activities. Our records indicate human activities did not have significant impacts on alpine environment until the past few centuries at Tangra Yumco on the central Tibetan Plateau.

Hydrogen peroxide-response nanoprobe for CD44-targeted circulating tumor cell detection and H2O2 analysis.

Circulating tumor cells (CTCs) represent the most common way of tumor metastasis and has been considered as a significant index for tumor diagnosis, staging and prognosis. However, CTC detection and analysis are always limited by the scarcity of CTC in the peripheral blood and the interference of blood cells. Therefore, here we presented with a hydrogen peroxide (H2O2)-response nanoprobes with CD44-targeted ability to reduce the interference of blood cells and improve the detection efficiency and accuracy and the pancreatic cancer cell was used to evaluate the feasibility of our probe. Shortly, hydrophobic H2O2-response naphthalimide-borate fluorophore was introduced onto the hydrophilic hyaluronic acid to form an amphiphilic complex, which could self-assemble into fluorescent nanoprobes in water. Our studies demonstrated that the nanoprobes were not only able to specifically recognize the pancreatic cancer cells with overexpressed CD44 proteins and reduce the influence of white blood cells in the peripheral blood, but also capable of semi-quantifying H2O2 content in CTCs, Which could be further used as a significant index for tumor clinical evaluation and therapy.

Climate change on the Tibetan Plateau in response to shifting atmospheric circulation since the LGM.

The Tibetan Plateau (TP) is primarily influenced by the northern hemispheric middle latitude Westerlies and the Indian summer monsoon (ISM). The extent, long-distance effects and potential long-term changes of these two atmospheric circulations are not yet fully understood. Here, we analyse modern airborne pollen in a transition zone of seasonally alternating dominance of the Westerlies and the ISM to develop a pollen discrimination index (PDI) that allows us to distinguish between the intensities of the two circulation systems. This index is applied to interpret a continuous lacustrine sedimentary record from Lake Nam Co covering the past 24 cal kyr BP to investigate long-term variations in the atmospheric circulation systems. Climatic variations on the central TP widely correspond to those of the North Atlantic (NA) realm, but are controlled through different mechanisms resulting from the changing climatic conditions since the Last Glacial Maximum (LGM). During the LGM, until 16.5 cal kyr BP, the TP was dominated by the Westerlies. After 16.5 cal kyr BP, the climatic conditions were mainly controlled by the ISM. From 11.6 to 9 cal kyr BP, the TP was exposed to enhanced solar radiation at the low latitudes, resulting in greater water availability.

Diversified bioactivities of four types of naturally occurring quinochalcones.

Quinochalcones, quinone-containing chalcones, belong to the flavonoid family and have attracted increasing popularity in Western countries in the last decade due to their pharmacological activities. This review describes four types of naturally occurring quinochalcones and summarizes their different pharmacological activities, including anti-cerebral ischemia, anti-tumor, and anti-infection activities. In addition, the pharmacological activities and relevant structure-activity relationships of synthetic quinochalcones are also reviewed.