Hydrogen-bonded cytosine-endowed supramolecular polymeric nanogels: Highly efficient cancer cell targeting and enhanced therapeutic efficacy.

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy-and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.

Development and application of a fully automatic multi-function cassette module Mortenon M1 for radiopharmaceutical synthesis.

INTRODUCTION: Functions of existing automatic module systems for synthesis of radiopharmaceuticals mainly focus on the radiolabeling of small molecules. There are few modules which have achieved full-automatic radiolabeling of non-metallic and metallic nuclides on small molecules, peptides, and antibody drugs. This study aimed to develop and test a full-automatic multifunctional module system for the safe, stable, and efficient production of radiopharmaceuticals. METHODS: According to characteristics of labeling process of radioactive drugs, using UG and Solidworks softwares, full-automatic cassette-based synthesis module system Mortenon M1 for synthesis of radiopharmaceuticals with various radionuclides, was designed and tested. Mortenon M1 has at least three significant highlights: the cassettes are disposable, and there is no need of manual cleaning; the synthesis method program is flexible and can be edited freely by users according to special needs; this module system is suitable for radiolabeling of both small-molecule and macromolecular drugs, with potentially various radionuclides including 18F, 64Cu, 68Ga, 89Zr, 177Lu, etc. By program control methods for certain drugs, Mortenon M1 was used for radiolabeling of both small-molecule drugs such as [68Ga]-FAPI-46 and macromolecular drugs such as [89Zr]-TROP2 antibody. Quality control assays for product purity were performed with radio-iTLC and radio-HPLC, and the radiotracers were confirmed for application in microPET imaging in xenograft tumor-bearing mouse models. RESULTS: Functional tests for Mortenon M1 module system were conducted, with [68Ga]-FAPI-46 and [89Zr]-TROP2 antibody as goal synthetic products, and it displayed that with the cassette modules, the preset goals could be achieved successfully. The radiolabeling synthesis yield was good ([68Ga]-FAPI-46, 70.63% ± 2.85%, n = 10; [89Zr]-TROP2, 82.31% ± 3.92%, n = 10), and the radiochemical purity via radio-iTLC assay of the radiolabeled products was above 99% after purification. MicroPET imaging results showed that the radiolabeled tracers had reasonable radioactive distribution in MDA-MB-231 and SNU-620 xenograft tumor-bearing mice, and the tumor targeted radiouptake was satisfactory for diagnosis. CONCLUSION: This study demonstrated that the full-automatic module system Mortenon M1 is efficient for radiolabeling synthesis of both small-molecule and macromolecular substrates. It may be helpful to reduce radiation exposure for safety, provide qualified radiolabeled products and reliable PET diagnosis, and ensure stable production and supply of radiopharmaceuticals.

The emergence of economic rationality of GPT.

As large language models (LLMs) like GPT become increasingly prevalent, it is essential that we assess their capabilities beyond language processing. This paper examines the economic rationality of GPT by instructing it to make budgetary decisions in four domains: risk, time, social, and food preferences. We measure economic rationality by assessing the consistency of GPT's decisions with utility maximization in classic revealed preference theory. We find that GPT's decisions are largely rational in each domain and demonstrate higher rationality score than those of human subjects in a parallel experiment and in the literature. Moreover, the estimated preference parameters of GPT are slightly different from human subjects and exhibit a lower degree of heterogeneity. We also find that the rationality scores are robust to the degree of randomness and demographic settings such as age and gender but are sensitive to contexts based on the language frames of the choice situations. These results suggest the potential of LLMs to make good decisions and the need to further understand their capabilities, limitations, and underlying mechanisms.

Antagonistic Activity and Mechanism of Bacillus subtilis XZ16-1 Suppression of Wheat Powdery Mildew and Growth Promotion of Wheat.

Wheat powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) is one of the most serious wheat diseases in the world. Biological control is considered an environmentally safe approach to control plant diseases. Here, to develop effective biocontrol agents for controlling wheat powdery mildew, antagonistic strain XZ16-1 was isolated and identified as Bacillus subtilis based on the morphological, biochemical, and physiological characteristics and 16S rDNA sequence. The culture filtrate of B. subtilis XZ16-1 and its extracts had a significant inhibitory effect on the spore germination of Bgt. Moreover, the therapeutic and prevention efficacy of the 100% culture filtrate on wheat powdery mildew reached 81.18 and 83.72%, respectively, which was better than that of chemical fungicide triadimefon. Further antimicrobial mechanism analysis showed that the XZ16-1 culture filtrate could inhibit the development of powdery mildew spores by disrupting the cell membrane integrity, causing reductions in the mitochondrial membrane potential, and inducing the accumulation of reactive oxygen species in the spores. Biochemical detection indicated that XZ16-1 could solubilize phosphate, fix nitrogen, and produce hydrolases, lipopeptides, siderophores, and indole-3-acetic acid. Defense-related enzymes activated in wheat seedlings treated with the culture filtrate indicated that disease resistance was induced in wheat to resist pathogens. Furthermore, a 106 CFU/ml suspension of XZ16-1 increased the height, root length, fresh weight, and dry weight of wheat seedlings by 77.13, 63.46, 76.73, and 19.16%, respectively, and showed good growth-promotion properties. This study investigates the antagonistic activity and reveals the action mechanism of XZ16-1, which can provide an effective microbial agent for controlling wheat powdery mildew.

Curcumin attenuates intracerebral hemorrhage-induced neuronal apoptosis and neuroinflammation by suppressing JAK1/STAT1 pathway.

Intracerebral hemorrhage (ICH) is a kind of fatal stroke with the highest mortality and morbidity in the world. To date, there is no effective treatment strategy for ICH. Curcumin, a major active ingredient of Curcuma longa L., possesses a potential anti-inflammatory activity in many types of disease. In the current study, the mechanism underlying curcumin attenuated ICH-induced neuronal apoptosis and neuroinflammation was explored. Herein, we studied that curcumin decreased brain edema and improved neurological function by using brain edema measurement, assessment of neurological-deficient score, immunofluorescence, and Western blotting analyses after ICH. The results showed that curcumin improved ICH-induced neuronal apoptosis and neuroinflammation. Functionally, the polarization of microglia was assessed by immunofluorescence and Western blotting analyses after ICH in the absence or presence of curcumin. The results suggested that the M1-type microglia were activated after ICH, while the effect was blocked by curcumin treatment, suggesting that curcumin alleviates the neuroinflammation and apoptosis of neurons by suppressing the M1-type polarization of microglia. Mechanically, M1 polarization of microglia was regulated by JAK1/STAT1, and the activation of JAK1/STAT1 was blocked by curcumin. Meanwhile, the protective function of curcumin can be blocked by RO8191, an activator of JAK1. Taken together, our study suggested that curcumin improved the ICH-induced brain injury through alleviating M1 polarization of microglia/macrophage and neuroinflammation via suppressing the JAK1/STAT1 pathway.

Crocin Alleviates Intracerebral Hemorrhage-Induced Neuronal Ferroptosis by Facilitating Nrf2 Nuclear Translocation.

Intracerebral hemorrhage (ICH) is the deadliest type of stroke. Oxidative stress was considered to play an important role in ICH-induced secondary injury. Crocin, the main compound isolated from Crocus sativus L., possesses a potential anti-oxidative function in many types of diseases including ICH. In the current study, the protective role of crocin in ICH-induced brain injury was investigated in the ICH model. The ICH-induced brain edema and neurological deficits were analyzed by brain edema measurement and neurological testing. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity and the content of malondialdehyde (MDA) were assessed by a total superoxide dismutase assay kit. The expressions of ferroptosis-related genes were verified by quantitative real-time PCR (qPCR) and western blotting. The ICH-induced brain edema and neurological deficits were significantly decreased after treatment with crocin. Moreover, the SOD and GSH-px activities were obviously increased in the ICH with crocin-treated group compared with the ICH group, while the content of MDA was markedly decreased after treatment with crocin. Crocin inhibited ferroptosis of neuron cells, as evidenced by increased Fe2+ concentration and the expression of GPX4, FTH1, and SLC7A11. Mechanistically, crocin treatment increased the expression and nuclear translocation of Nrf2. Our data suggest that crocin alleviates intracerebral hemorrhage-induced neuronal ferroptosis by facilitating Nrf2 nuclear translocation.

Correlation between Traditional Chinese Medicine Syndromes and Type 2 Myocardial Infarction in Critically Ill Patients with Pulmonary Disease.

Background: Treatment based on syndrome differentiation under the traditional Chinese medicine (TCM) framework has been shown to be helpful in patients with coronary artery disease. We hypothesized that syndrome types could predict the risk of type 2 myocardial infarction (T2MI) caused by imbalance between myocardial oxygen supply and demand in critically ill patients with pulmonary disease. Methods: This retrospective study included consecutive critically ill patients with pulmonary disease admitted to the ICU at Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences from January 1, 2017, to July 1, 2019. Diagnosis of T2MI was based on the fourth universal definition of myocardial infarction. Risk factors associated with T2MI were identified using multivariate regression analysis. Results: A total of 244 patients were included in the study: 78 who developed T2MI and the remaining 166 who did not develop T2MI during hospitalization. The incidence of phlegm syndrome and deficiency syndrome was 61.9% and 38.1%, respectively. In comparison with the patients with phlegm syndrome, the incidence of T2MI in patients with deficiency syndrome is significantly higher (40.9% vs. 26.5%, P=0.019). In multivariate logistic regression, T2MI was independently associated with the baseline troponin level (OR 12.682, 95% CI 1.397∼115.121; P=0.024), hemoglobin < 55 g/L (OR 12.76, 95% CI 2.359∼69.021; P=0.003), mechanical ventilation (OR 2.244, 95% CI 1.029∼4.892; P=0.042), and TCM deficiency syndrome (OR 2.214, 95% CI 1.032∼4.749; P=0.041). After adjusting for confounding factors in Cox regression models, the hazard ratio (95% confidence interval) of qi deficiency syndrome groups was 1.183 (95% CI 1.053∼3.123, P=0.032). Conclusions: Patients with deficiency syndrome are at high risk of T2MI, especially those combined with qi deficiency syndrome.

Hypoxia/reoxygenation-induced upregulation of miRNA-542-5p aggravated cardiomyocyte injury by repressing autophagy.

MicroRNAs (miRNAs) and autophagy exert an important role in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury. The current study aimed to explore the role of miRNA and autophagy in H/R-induced cardiomyocyte injury. Cardiomyocyte H9c2 was exposed to H/R to simulate H/R injury in vitro. The differentially expressed miRNAs were identified using quantitative RT-PCR (qPCR). Lactate dehydrogenase (LDH) activity was assayed to assess H/R injury. The role of miRNA and autophagy in regulating the viability and cell apoptosis was evaluated using cell counting kit-8 (CCK-8) assay, flow cytometry (FCM), and western blot. The autophagy activation was assessed through testing the number of light chain 3 (LC3) puncta and LC3-II expression using western blot and immunofluorescence analysis. In the present study, we found that the miR-542-5p expression and the autophagy activation were significantly increased in H9c2 cells after H/R injury. Functionally, forced expression of miR-542-5p further aggravated H/R injury in H9c2 cells, whereas miR-542-5p inhibition alleviated H/R injury as measured by the cell viability, LDH activity and cell apoptosis. miR-542-5p repressed autophagy activation, whereas miR-542-5p inhibition facilitated autophagy activation in H9c2 cells exposed to H/R as measured by the LC3 puncta number, LC3II, and p62 protein level. Especially, autophagy inhibition by specific inhibitor partially lessened the role of miR-542-5p inhibitor in alleviating H/R injury. Finally, the autophagy-related 7 (ATG7) was identified as a novel target gene of miR-542-5p in H9c2 cells. The current data suggest that miR-542-5p/autophagy pathway might be a potential target for the treatment of H/R-related heart diseases.

FLASH Binds p53 and Enhances its Transcriptional Activity / 中国生物化学与分子生物学报

As an important transcription factor, the tumor suppressor protein p53 is involved in multiple biological processes such as cell cycle regulation, cell division, cell senescence and DNA repair The functional roles of p53 under various physiological conditions are inseparable from the assistance of many cofactors, which can regulate the protein modification, cellular sub-localization, and protein stability of p53 Therefore, the identification of p53-binding protein(s) has important biological significance for further understanding the signal transduction network of p53 in vivo. In the present study, a novel p53-binding protein, FADD-like interleukin-1β-converting enzyme associated huge protein (FLASH) was identified through a yeast two-hybrid screen The protein-protein interaction and the structural basis of the interaction between FLASH and p53 was also confirmed by co-immunoprecipitation analysis These studies have shown that p53 can simultaneously interact with both FLASH-N1 (aa 1 ~ 200) and FLASH-C1 (aa 1 534 ~ 1 780) In addition, both of FLASH-N and FLASH-C can interact with the same region of p53 (aa 293 ~ 393) Transcription analysis has revealed that the full length of FLASH and FLASH-M (aa 921 ~ 1533) can enhance the transcription activity of p53 In summary, FLASH can bind to p53 and enhance its transcriptional activity

Spontaneous Self-Assembly of Single-Chain Amphiphilic Polymeric Nanoparticles in Water.

Single-chain polymeric nanoparticles (SCPNs) have great potential as functional nanocarriers for drug delivery and bioimaging, but synthetic challenges in terms of final yield and purification procedures limit their use. A new concept to modify and improve the synthetic procedures used to generate water-soluble SCPNs through amphiphilic interactions has been successfully exploited. We developed a new ultrahigh molecular weight amphiphilic polymer containing a hydrophobic poly(epichlorohydrin) backbone and hydrophilic poly(ethylene glycol) side chains. The polymer spontaneously self-assembles into SCPNs in aqueous solution and does not require subsequent purification. The resulting SCPNs possess a number of distinct physical properties, including a uniform hydrodynamic nanoparticle diameter of 10-15 nm, extremely low viscosity and a desirable spherical-like morphology. Concentration-dependent studies demonstrated that stable SCPNs were formed at high concentrations up to 10 mg/mL in aqueous solution, with no significant increase in solution viscosity. Importantly, the SCPNs exhibited high structural stability in media containing serum or phosphate-buffered saline and showed almost no change in hydrodynamic diameter. The combination of these characteristics within a water-soluble SCPN is highly desirable and could potentially be applied in a wide range of biomedical fields. Thus, these findings provide a path towards a new, innovative route for the development of water-soluble SCPNs.

Type 1 myocardial infarction rapid screening scale for emergency triage in patients with non-traumatic chest pain: A study of 1928 cases with coronary angiography.

INTRODUCTION: The effectiveness of treatment and prognosis of patients with type 1 myocardial infarction are highly correlated with time of diagnosis. This study aimed to develop a type 1 MI rapid screening scale (T1MIrs scale) suitable for emergency pre-diagnosis. METHODS: A total of 1928 patients who underwent coronary angiography were enrolled. Multivariate regression analysis was used to identify the independent risk factors of type 1 MI. And the T1MIrs scale was developed and evaluated according to the multivariate regression result. RESULTS: The incidence of type 1 MI was 23.3% in the population with suspected acute coronary syndrome. After 5 adjusting for relevant factors, MEWS score (OR = 1.809, 95%CI 1.623-2.016, P < .001), typical symptoms (OR = 9.826, 95%CI 7.379-13.084, P < .001), male (OR = 2.184, 95%CI 1.602-2.979, P < .001), age (OR = 1.021, 95%CI 1.009-1.033, P = .001), history of diabetes (OR = 2.174, 95%CI 1.594-2.963, P < .001) and current smoker (OR = 2.498, 95%CI 1.550-4.026, P < .001) were the independent risk factors for type 1 MI. The T1MIrs scale is established based on risk factors, with a range of 0-8 points. The incidence of type 1 MI is ascending with the scale (0.3% vs. 3.7% vs. 14.3% vs. 34.9% vs. 57% vs. 76.4% vs. 84.2% vs. 87.5% vs. 100%, P for trend <0.001). CONCLUSIONS: Type 1 MI is common in patients with suspected acute coronary syndrome in emergency department. The T1MIrs scale could act as a rapid pre-examination triage of suspected population in emergency department, which is meaningful to screen out type 1 MI patients as soon as possible.

Self-Assembled Supramolecular Micelles with pH-Responsive Properties for More Effective Cancer Chemotherapy.

pH-Responsive hydrogen-bonded supramolecular micelles, composed of a water-soluble poly(ethylene glycol) polymer with two terminal sextuple hydrogen bonding groups, can spontaneously organize in aqueous media to give well-defined, uniformly sized spherical micelles. The supramolecular micelles exhibit a number of unique physical characteristics, such as interesting amphiphilic behavior, desirable micellar size and nanospherical morphology, excellent biocompatibility, tailorable drug-loading capacities, and high structural stability in media containing serum or red blood cells. In addition, the drug release kinetics of drug-loaded micelles can be easily manipulated to achieve the desired release profile by regulating the environmental pH, thus these micelles are highly attractive candidates as an intelligent drug carrier system for cancer therapy. Cytotoxicity assays showed that the drug-loaded micelles induced pH-dependent intracellular drug release and exerted strong antiproliferative and cytotoxic activities toward cancer cells. Importantly, cellular uptake and flow cytometric analyses confirmed that a mildly acidic intracellular environment significantly increased cellular internalization of the drug-loaded micelles and subsequent drug release in the cytoplasm and nucleus of cancer cells, resulting in more effective induction of apoptotic cell death. Thus, this system may provide an efficient route toward achieving the fundamental properties and practical realization of pH-sensitive drug-delivery systems for chemotherapy.

Type 2 myocardial infarction among critically ill elderly patients in the Intensive Care Unit: the clinical features and in-hospital prognosis.

BACKGROUND: Type 2 myocardial infarction (T2MI) refers to myocardial ischemic necrosis as a result of myocardial oxygen supply/demand mismatch, which are common comorbidities of critically ill patients. The purpose of this study was to investigate the incidence rate and risks of T2MI in critically ill elderly patients and further elucidate in-hospital prognostic factors. METHODS: A total of 223 critically ill elderly patients admitted to our hospital from October 2016 to September 2018 were recruited. The clinical data and the in-hospital mortality rate were compared between the T2MI and non-T2MI groups. Multivariate linear regression analysis was used to identify independent factors related to T2MI. The clinical data and incidence of T2MI were also compared between patients who survived and those who died; multivariate regression analysis was used to identify independent risk factors for in-hospital death and survival analysis was conducted. RESULTS: In this study, the incidence of T2MI was 24.2% (54/223), and the mortality rate of critically ill elderly patients was 39.0% (87/223). Multivariate linear regression analysis showed that severe hypoxemia, arrhythmia, shock, and multiple organ dysfunction syndrome (MODS) were independent risk factors of T2MI. Compared to the survival patients, the use of mechanical ventilation, the incidence of T2MI, APACHE II score, troponin T, high-sensitivity C-reactive protein, and procalcitonin levels were significantly higher in patients who died, while the estimated glomerular filtration rate (eGFR) was significantly decreased (all P < 0.05). In-hospital mortality was significantly increased in patients with T2MI (59.3% vs. 32.5%, P < 0.001). After adjustment for relevant factors, the incidence of T2MI, mechanical ventilation required, and eGFR reduction were independent and significant predictors of in-hospital death. CONCLUSIONS: Critically, ill elderly patients have a high incidence of T2MI. In addition to severe hypoxia, shock, and arrhythmia, MODS is also associated with T2MI. At the same time, the risk of in-hospital death is increased in patients with type 2 MI.

The use of DNA barcodes to estimate phylogenetic diversity in forest communities of southern China.

To elucidate potential ecological and evolutionary processes associated with the assembly of plant communities, there is now widespread use of estimates of phylogenetic diversity that are based on a variety of DNA barcode regions and phylogenetic construction methods. However, relatively few studies consider how estimates of phylogenetic diversity may be influenced by single DNA barcodes incorporated into a sequence matrix (conservative regions vs. hypervariable regions) and the use of a backbone family-level phylogeny. Here, we use general linear mixed-effects models to examine the influence of different combinations of core DNA barcodes (rbcL, matK, ITS, and ITS2) and phylogeny construction methods on a series of estimates of community phylogenetic diversity for two subtropical forest plots in Guangdong, southern China. We ask: (a) What are the relative influences of single DNA barcodes on estimates phylogenetic diversity metrics? and (b) What is the effect of using a backbone family-level phylogeny to estimate topology-based phylogenetic diversity metrics? The combination of more than one barcode (i.e., rbcL + matK + ITS) and the use of a backbone family-level phylogeny provided the most parsimonious explanation of variation in estimates of phylogenetic diversity. The use of a backbone family-level phylogeny showed a stronger effect on phylogenetic diversity metrics that are based on tree topology compared to those that are based on branch lengths. In addition, the variation in the estimates of phylogenetic diversity that was explained by the top-rank models ranged from 0.1% to 31% and was dependent on the type of phylogenetic community structure metric. Our study underscores the importance of incorporating a multilocus DNA barcode and the use of a backbone family-level phylogeny to infer phylogenetic diversity, where the type of DNA barcode employed and the phylogenetic construction method used can serve as a significant source of variation in estimates of phylogenetic community structure.

Dual stimuli-responsive supramolecular boron nitride with tunable physical properties for controlled drug delivery.

The new concept of modifying and tailoring the properties of existing two-dimensional (2D) nanomaterials by invoking the assembly of supramolecular networks upon association with a adenine-functionalized macromer (A-PPG) has significant potential to facilitate the development of highly water-dispersible few-layered 2D nanosheets. In this study, we propose that water-soluble A-PPG directly self-assembles into a long-period stacking-ordered lamellar structure over the surface of hexagonal boron nitride (BN) in aqueous solution, due to the efficient non-covalent interactions between A-PPG and BN nanosheets. The layer number of BN nanosheets can be easily tuned by altering the mass ratio of the A-PPG and BN blend, and the resulting exfoliated nanosheets also exhibit excellent temperature/pH-responsive behavior, biocompatibility and extremely high drug-loading capacity (up to 36.2%), features that are highly desirable yet exceedingly rare in traditional 2D nanomaterials. Importantly, in vitro drug release studies showed the drug-loaded nanosheets function as a stable nanocarrier with excellent stability and drug entrapment under normal physiological conditions. Increasing the environmental temperature to 40 °C or decreasing the pH to 5.5 triggered rapid release of the encapsulated drug from the drug-loaded nanosheets, suggesting this newly developed material has potential as a novel multi-responsive 2D nanocarrier to safely deliver drugs and effectively facilitate controlled drug release under specific microenvironmental conditions. This study provides new insight towards the promising application of this system in controlled release drug delivery systems.

Entrapment of an adenine derivative by a photo-irradiated uracil-functionalized micelle confers controlled self-assembly behavior.

HYPOTHESIS: Invoking cooperative assembly of the uracil-functionalized supramolecular polymer BU-PPG [uracil end-capped poly(propylene glycol)] upon association with the nucleobase adenine derivative A-MA [methyl 3-(6-amino-9H-purin-9-yl)propanoate] as a model drug provides a new concept to control and tune the properties of supramolecular complexes and holds significant potential for the development of safer, more effective drug delivery systems. EXPERIMENTS: BU-PPG and A-MA were successfully developed and exhibited specific recognition and high affinity, which enabled reversible complementary adenine-uracil (A-U) hydrogen bonding-induced formation of spherical micelles in aqueous solution. The self-assembly and controllable A-MA release behavior of BU-PPG/A-MA micelles were studied using morphological analysis and optical and light scattering techniques to investigate the effect of photoirradiation and temperature on the complementary hydrogen bond interactions between BU-PPG and A-MA. FINDINGS: The resulting micelles possess unusual physical properties, including controlled photoreactivity kinetics, controllable self-assembled morphology and low cytotoxicity in vitro, as well as reversible temperature-responsive behavior. Importantly, irradiated micelles exhibited excellent long-term structural stability under normal physiological conditions and serum disturbance. Increasing the temperature triggered rapid release of A-MA by disrupting A-U complexes. These findings represent an entirely new, promising strategy for the development of multi-controlled release drug delivery nanocarriers based on complementary hydrogen bonding interactions.

Highly Effective Photocontrollable Drug Delivery Systems Based on Ultrasensitive Light-Responsive Self-Assembled Polymeric Micelles: An in Vitro Therapeutic Evaluation.

An ultrasensitive light-responsive block copolymer, a combination of a multiarmed poly(ethylene glycol)-b-poly(caprolactone) polymer as a water-soluble element and maleimide-anthracene linkers as a photosensitive group, was successfully synthesized and rapidly self-assembled to form spherical micellar nanoparticles in aqueous media and phosphate-buffered saline. Their unique characteristics, such as extremely low critical micelle concentration, desirable micellar stability, well-controlled light-responsiveness, tailorable drug-loading content, and ultrasensitive light-induced drug release, make these micelles potential candidates for development of a more effective, safer drug delivery platform for cancer treatment. In vitro studies revealed that the drug-loaded micelles exhibited high structural stability in serum-containing media and very low toxicity toward normal and cancer cells under physiological conditions. Irradiation of cancer cells incubated with the drug-loaded micelles with ultraviolet light at 254 nm for only 10 s triggered rapid and complete release of the drug in the intracellular environment and induced strong antiproliferative/cytotoxic activity. Importantly, real-time cytotoxic assays and fluorescence imaging analysis further demonstrated that the drug-loaded micelles were rapidly taken up into the cytosol or nuclei of the cells, and subsequent ultraviolet exposure induced drug release and apoptotic cell death. Given their simplicity of design, high reliability, and performance, this new light-sensitive micelle may provide a promising route for developing a multifunctional therapeutic nanocarrier system.

Early increase of neutrophil-to-lymphocyte ratio predicts 30-day mortality in patients with spontaneous intracerebral hemorrhage.

AIMS: To examine whether early rise of neutrophil-to-lymphocyte ratio (NLR) after patient hospitalization correlates with 30-day mortality in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: This retrospective study included all patients receiving treatment for spontaneous ICH between January 2015 and September 2016 at the Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences in Shanghai, China. NLR was determined at admission (T1), at 24-48 hours (T2) and 5-7 days (T3). NLR and clinicopathologic features were compared between those who survived for >30 days vs not. Multivariate regression was used to identify risk factors for 30-day mortality. RESULTS: A total of 275 subjects were included in the analysis: 235 survived for at least 30 days; the remaining 40 subjects died within 30 days. The patients who died within 30 days had higher ICH score, larger ICH volume, and lower GCS score (all P < 0.05). In comparison with the baseline (NLRT1 ), NLR at 24-48 hours (NLRT2 ) and 5-7 days (NLRT3 ) was significantly higher in patients who died within 30 days (P < 0.05), but not in patients surviving for >30 days. In the multivariate analysis, the 30-day mortality was associated with both NLRT2 (OR 1.112, 95%CI 1.032-1.199, P = 0.006) and NLRT3 (OR 1.163, 95%CI 1.067-1.268, P = 0.001). Spearman correlation analysis showed that both NLRT2 and NLRT3 correlated inversely with GCS score and positively with ICH score and ICH volume at the baseline. CONCLUSIONS: Early rise of NLR predicts 30-day mortality in patients with spontaneous ICH.

Serum iron levels are an independent predictor of in-hospital mortality of critically ill patients: a retrospective, single-institution study.

OBJECTIVE: This study aimed to examine the relationship between serum iron levels and in-hospital mortality in critically ill patients. METHODS: We retrospectively studied 250 critically ill patients who received treatment at the intensive care unit between June 2015 and May 2017. Blood chemistry and hepatic and renal function were measured. Kaplan-Meier survival curves were plotted according to serum iron levels. Correlations between serum iron levels and other variables were analyzed. RESULTS: A total of 165 (66.0%) patients had abnormally low serum iron levels (<10.6 µmol/L). Patients who died during hospitalization had markedly higher Acute Physiology and Chronic Health Evaluation II scores and significantly lower serum iron levels compared with those who survived. Cumulative survival was significantly lower in patients with low serum iron levels than in those with normal serum iron levels in subgroup analysis of older patients (n = 192). Multivariate regression analysis showed that, after adjusting for relevant factors, low serum iron levels remained an independent risk for in-hospital mortality (odds ratio 2.014; 95% confidence interval 1.089, 3.725). CONCLUSIONS: Low serum iron levels are present in a significant proportion of critically ill patients and are associated with higher in-hospital mortality, particularly in older patients.