High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

Supramolecular nanomedicines based on host-guest interactions of cyclodextrins.

In the biomedical and pharmaceutical fields, cyclodextrin (CD) is undoubtedly one of the most frequently used macrocyclic compounds as the host molecule because it has good biocompatibility and can increase the solubility, bioavailability, and stability of hydrophobic drug guests. In this review, we generalized the unique properties of CDs, CD-related supramolecular nanocarriers, supramolecular controlled release systems, and targeting systems based on CDs, and introduced the paradigms of these nanomedicines. In addition, we also discussed the prospects and challenges of CD-based supramolecular nanomedicines to facilitate the development and clinical translation of these nanomedicines.

Research on image recognition of three Fritillaria cirrhosa species based on deep learning.

Based on the deep learning method, a network model that can quickly and accurately identify the species of Fritillaria cirrhosa species was constructed. The learning method based on deep residual convolutional neural network was used to input the unprocessed original image directly as input, and the features of the image were extracted through convolution and pooling operations. On this basis, the ResNet34 model was improved, and the additional fully connected layer was added in front of the Softmax classifier to improve the learning ability of the network model. Total of 3915 images of three kinds of Fritillaria cirrhosa were used as data sources for the experiments, among which 160 images of each type were randomly selected to form the validation set. The final training set recognition accuracy rate was 95.8%, the validation set accuracy rate reached 92.3%, and the test set accuracy rate was 88.7%. The image recognition method of Fritillaria cirrhosa based on deep learning proposed in this paper is effective and feasible, which can quickly and accurately identify the species of Fritillaria cirrhosa species, and provides a new idea for the intelligent recognition of Chinese medicinal materials.

Oxygen evolution from extremophilic cyanobacteria confined in hard biocoatings.

Biocoatings, in which viable bacteria are immobilized within a waterborne polymer coating for a wide range of potential applications, have garnered greater interest in recent years. In bioreactors, biocoatings can be ready-to-use alternatives for carbon capture or biofuel production that could be reused multiple times. Here, we have immobilized cyanobacteria in mechanically hard biocoatings, which were deposited from polymer colloids in water (i.e., latex). The biocoatings are formed upon heating to 37°C and fully dried before rehydrating. The viability and oxygen evolution of three cyanobacterial species within the biocoatings were compared. Synechococcus sp. PCC 7002 was non-viable inside the biocoatings immediately after drying, whereas Synechocystis sp. PCC 6803 survived the coating formation, as shown by an adenosine triphosphate (ATP) assay. Synechocystis sp. PCC 6803 consumed oxygen (by cell respiration) for up to 5 days, but was unable to perform photosynthesis, as indicated by a lack of oxygen evolution. However, Chroococcidiopsis cubana PCC 7433, a strain of desiccation-resistant extremophilic cyanobacteria, survived and performed photosynthesis and carbon capture within the biocoating, with specific rates of oxygen evolution up to 0.4 g of oxygen/g of biomass per day. Continuous measurements of dissolved oxygen were carried out over a month and showed no sign of decreasing activity. Extremophilic cyanobacteria are viable in a variety of environments, making them ideal candidates for use in biocoatings and other biotechnology. IMPORTANCE As water has become a precious resource, there is a growing need for less water-intensive use of microorganisms, while avoiding desiccation stress. Mechanically robust, ready-to-use biocoatings or "living paints" (a type of artificial biofilm consisting of a synthetic matrix containing functional bacteria) represent a novel way to address these issues. Here, we describe the revolutionary, first-ever use of an extremophilic cyanobacterium (Chroococcidiopsis cubana PCC 7433) in biocoatings, which were able to produce high levels of oxygen and carbon capture for at least 1 month despite complete desiccation and subsequent rehydration. Beyond culturing viable bacteria with reduced water resources, this pioneering use of extremophiles in biocoatings could be further developed for a variety of applications, including carbon capture, wastewater treatment and biofuel production.

Rosmarinic Acid-Crosslinked Supramolecular Nanoassembly with Self-Regulated Photodynamic and Anti-Metastasis Properties for Synergistic Photoimmunotherapy.

A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self-regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6-conjugated ß-cyclodextrin (CD-Ce6) acts as the main PDT agent and ferrocene (Fc)-terminated phenylboronic acid-containing conjugates entering into the cavity of CD-Ce6, as well as rosmarinic acid (RA)-boronic acid crosslinked shell. Compared with non-crosslinked counterpart, CPR displays better stability and enhanced tumor accumulation. Under laser irradiation, CPR generates plenty of ROS to damage tumor cells and induce immunogenic cell death. Mildly acidic TME partly cleaves the crosslinkers to dissociate antioxidant RAs from micelles, which together with Fc in CPR scavenge PDT-induced ROS in the TME. By contrast, under acidic lysosomal conditions, Fc catalyzes abundant H2 O2 in tumor cells to produce highly cytotoxic •OH, while RA continuously reduces ferroptosis-generated Fc+ into Fc, both to augment the PDT efficacy in tumor cells. CPR also remarkably hinders the epithelial-mesenchymal transition to prevent the lung metastasis.

Research on Sparse Denoising of Strong Earthquakes Early Warning Based on MEMS Accelerometers.

In view of the fact that the noise in the same frequency band as the useful signal in the MEMS acceleration sensor observation data cannot be effectively removed by traditional filtering methods, a denoising method for strong earthquake signals based on the theory of sparse representation and compressive sensing is proposed in this paper. This skillfully realized the separation of strong earthquake signals from noise by adopting a fixed dictionary and utilizing sparse characteristics. Furthermore, considering the weakness of the sparse denoising method based on the fixed dictionary in the high signal-to-noise ratio, a spare denoising method based on learning an over-complete dictionary is proposed. Through the initial given seismic data, the ideal over-complete dictionary is trained to achieve seismic data denoising. In addition, for the interference waves of non-seismic events, this paper proposes an idea based on sparse representation classification to remove such non-seismic interference directly. Combining the ideas of noise reduction and non-seismic event elimination, we can obtain a standard sparse anti-interference denoising model for earthquake early warning. It's innovative that this model implements the sparse theory into the field of earthquake early warning. According to the experimental results, in the case of heavy noise, the denoising model based on sparse representation can reach average SNR of 8.73 and an average MSE of 29.53, and the denoising model based on compression perception can reach average SNR of 7.29 and an average MSE 41.34, and the denoising model based on learning dictionary can reach average SNR 11.07 and average MSE 17.32. The performance of these models is better than the traditional FIR filtering method (average SNR -0.73 and average MSE 260.37) or IIR filtering method (average SNR 4.73 and average MSE 73.95). On the other hand, the anti-interference method of the sparse classification proposed in this paper can accurately distinguish non-seismic interference events from natural earthquakes. The classification accuracy of the method based on the noise category of the selected test data set reaches 100% and achieves good results.

A sulfhydryl blocking reagent BT-4 sensitizes cisplatin-based micelle prodrugs for efficient treatment of breast cancer.

Detoxification of glutathione (GSH) and insufficient cellular uptake of cisplatin (CDDP) severely compromised the therapeutic efficacy of CDDP. Here, a nano-delivery system (BT-4@PtPPNPs) for CDDP prodrug (C16-Pt(Ⅳ)-PEG) based on a novel sulfhydryl blocking reagent methyl 2-(methylsulfonyl) benzothiazole-6-carboxylate (BT-4) was developed. On the one hand, BT-4 can deplete GSH in tumor cells by directly interacting with reactive sulfhydryl group on GSH, thereby increasing the cytotoxicity of CDDP. On the other hand, the CDDP prodrug carrier C16-Pt(IV)-PEG can promote the distribution of CDDP in tumors, reduce the probability of unexpected inactivation of CDDP, and reduce the content of GSH in tumor cells during the conversion to CDDP, thereby making CDDP more effective for treatment. The results showed that the optimized BT-4@PtPPNPs with a small particle size (130 nm) exhibited notable cytotoxicity and apoptosis of 4T1 cells. BT-4@PtPPNPs not only significantly improved the uptake of drugs by tumor cells, but also rapidly targeted and accumulated in the tumors for a long time. Moreover, in vivo efficacy studies showed that BT-4@PtPPNPs could effectively inhibit tumor growth, inhibiting 60.85 % of tumors in a 4T1 breast cancer mice model, showing superior antitumor activity, which can be attributed to GSH-triggered CDDP tolerance reversal. Overall, this study provides an attractive and simple strategy to combine novel sulfhydryl blockers and CDDP prodrugs to potentiate the efficacy of CDDP in breast cancer.

Erratum: Author correction to "A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease" [Acta Pharmaceutica Sinica B 12, (2021) 4032-4044].

[This corrects the article DOI: 10.1016/j.apsb.2021.04.022.].

A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease.

Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aß deposition or TAU protein need to be resolved urgently. Herein, a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD]. DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions, and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma. Then exposed KLVFF can capture and carry Aß to microglia, attenuating Aß-induced neurotoxicity. Strikingly, rapamycin, an autophagy promoter, is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aß degradation and normalize inflammatory condition. This design altogether accelerates Aß degradation and alleviates oxidative stress and excessive inflammatory response. Collectively, our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment, to achieve efficient AD therapy.

GSH-responsive SN38 dimer-loaded shape-transformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy.

Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92 ± 1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor. In vitro, co-administering iRGD with d-SN38@NPs+laser showed higher cellular uptake, apoptosis ratio and multicellular spheroid penetration. In vivo, d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor, leading to 60.89% of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile. Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting, penetrating and retention, and empowers anticancer efficacy.

Introducing Porosity in Colloidal Biocoatings to Increase Bacterial Viability.

A biocoating confines nongrowing, metabolically active bacteria within a synthetic colloidal polymer (i.e., latex) film. Bacteria encapsulated inside biocoatings can perform useful functions, such as a biocatalyst in wastewater treatment. A biocoating needs to have a high permeability to allow a high rate of mass transfer for rehydration and the transport of both nutrients and metabolic products. It therefore requires an interconnected porous structure. Tuning the porosity architecture is a challenge. Here, we exploited rigid tubular nanoclays (halloysite) and nontoxic latex particles (with a relatively high glass transition temperature) as the colloidal "building blocks" to tailor the porosity inside biocoatings containing Escherichia coli bacteria as a model organism. Electron microscope images revealed inefficient packing of the rigid nanotubes and proved the existence of nanovoids along the halloysite/polymer interfaces. Single-cell observations using confocal laser scanning microscopy provided evidence for metabolic activity of the E. coli within the biocoatings through the expression of a yellow fluorescent protein. A custom-built apparatus was used to measure the permeability of a fluorescein sodium salt in the biocoatings. Whereas there was no measurable permeability in a coating made from only latex particles, the permeability coefficient of the composite biocoatings increased with increasing halloysite content up to a value of 1 × 10-4 m h-1. The effects of this increase in permeability was demonstrated through a specially developed resazurin reduction assay. Bacteria encapsulated in halloysite composite biocoatings had statistically significant higher metabolic activities in comparison to bacteria encapsulated in a nonoptimized coating made from latex particles alone.

Internet Hospitals Help Prevent and Control the Epidemic of COVID-19 in China: Multicenter User Profiling Study.

BACKGROUND: During the spread of the novel coronavirus disease (COVID-19), internet hospitals in China were engaged with epidemic prevention and control, offering epidemic-related online services and medical support to the public. OBJECTIVE: The aim of this study is to explore the role of internet hospitals during the prevention and control of the COVID-19 outbreak in China. METHODS: Online epidemic-related consultations from multicenter internet hospitals in China during the COVID-19 epidemic were collected. The counselees were described and classified into seven type groups. Symptoms were recorded and compared with reported patients with COVID-19. Hypochondriacal suspicion and offline visit motivation were detected within each counselees' group to evaluate the social panic of the epidemic along with the consequent medical-seeking behaviors. The counselees' motivation and the doctors' recommendation for an offline visit were compared. Risk factors affecting the counselees' tendency of hypochondriacal suspicion and offline visit motivation were explored by logistic regression models. The epidemic prevention and control measures based on internet hospitals were listed, and the corresponding effects were discussed. RESULTS: A total of 4913 consultations were enrolled for analysis with the median age of the counselees at 28 years (IQR 22-33 years). There were 104 (2.12%) healthy counselees, 147 (2.99%) hypochondriacal counselees, 34 (0.69%) exposed counselees, 853 (17.36%) mildly suspicious counselees, 42 (0.85%) moderately suspicious counselees, 3550 (72.26%) highly suspicious counselees, and 183 (3.72%) severely suspicious counselees. A total of 94.20% (n=4628) of counselees had epidemic-related symptoms with a distribution similar to those of COVID-19. The hypochondriacal suspicion (n=2167, 44.11%) was common. The counselees' motivation and the doctors' recommendation for offline visits were inconsistent (P<.001) with a Cohen kappa score of 0.039, indicating improper medical-seeking behaviors. Adult counselees (odds ratio [OR]=1.816, P<.001) with epidemiological exposure (OR 7.568, P<.001), shortness of breath (OR 1.440, P=.001), diarrhea (OR 1.272, P=.04), and unrelated symptoms (OR 1.509, P<.001) were more likely to have hypochondriacal suspicion. Counselees with severe illnesses (OR 2.303, P<.001), fever (OR 1.660, P<.001), epidemiological exposure history (OR 1.440, P=.01), and hypochondriacal suspicion (OR 4.826, P<.001) were more likely to attempt an offline visit. Reattending counselees (OR 0.545, P=.002) were less motivated to go to the offline clinic. CONCLUSIONS: Internet hospitals can serve different types of epidemic counselees, offer essential medical supports to the public during the COVID-19 outbreak, reduce the social panic, promote social distancing, enhance the public's ability of self-protection, correct improper medical-seeking behaviors, reduce the chance of nosocomial cross-infection, and facilitate epidemiological screening, thus, playing an important role on preventing and controlling COVID-19.

Visualising nanoscale restructuring of a cellular membrane triggered by polyelectrolyte microcapsules.

Polymer-based multilayer microencapsulation technology represents one of the promising strategies for intracellular drug delivery, however, membrane processes involved in vehicle internalisation are not fully understood. Here we employed a scanning probe microscopy technique called Scanning Ion Conductance Microscopy (SICM) to study these complex processes at nanoscale resolution in real time. We were able to image topography simultaneously with local elastic modulus throughout the whole course of microcapsule internalisation in A549 cell culture without disrupting the internalisation process. The imaging revealed that capsules triggered the formation of membrane protrusions in their vicinity, which is an important but not a sufficient step towards full capsule internalisation. A crucial aspect appeared to be nanoscale restructuring of these protrusions into smooth thin layers extending over the surface of capsules. Simultaneous mapping of elastic modulus during capsule internalisation allowed monitoring the structural changes during extension of the membrane sheets over the surface of the capsule and the subsequent post-internalisation phenomenon of capsule buckling. To our knowledge these are the first experimental data capturing the interactions between the cellular membrane and microcapsules in their whole complexity with nanoscale resolution. The methodology established here has the potential to provide new insights into interactions at the interface between the nanostructured materials and cellular membrane under physiological conditions.

An Empirical Study of the Impact of the Air Transportation Industry Energy Conservation and Emission Reduction Projects on the Local Economy in China.

Green development has been of particular interest to a range of industries worldwide, one of which being the air transportation industry (ATI). The energy conservation and emission reduction (ECER) projects of the ATI have a huge impact on the local economy. In this study, the input-output method was used to analyze the indirect economic impact of the implementation of the ECER projects of the ATI on the local economy of the Beijing-Tianjin-Hebei (BTH) region. We examined the direct benefits, backward spread effects, forward spread effects, and consumption multiplier effects. The final results showed that the comprehensive economic income from 2011⁻2013 in the BTH region reached RMB 4.74 billion. The results revealed that the ECER projects commissioned by the ATI were worth investing from both the economic and social benefits perspectives. To increase the green development effects and promote the sustainable development of the ATI, the special funds provided by the Civil Aviation Administration of China should be invested intensively in basic green technology research and setting green regulating and governance rules.