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Both the gut microbiome and their host participate in arsenic (As) biotransformation, while their exact roles and mechanisms in vivoremain unclear and unquantified. In this study, as3mt–/–zebrafish were treated with tetracycline (TET, 100 mg/L) and arsenite (iAsIII) exposure for 30 days and treated with probiotic Lactobacillus rhamnosusGG(LGG, 1 × 108cfu/g) and iAsIIIexposure for 15 days, respectively. Structural equation modeling analysis revealed that the contribution rates of the intestinal microbiome to the total arsenic (tAs) and inorganic As (iAs) metabolism approached 44.0 and 18.4%, respectively. Compared with wild-type, in as3mt–/–zebrafish, microbial richness and structure were more significantly correlated with tAs and iAs, and more differential microbes and microbial metabolic pathways significantly correlated with arsenic metabolites (P< 0.05). LGG supplement influenced the microbial communities, significantly up-regulated the expressions of genes related to As biotransformation (gssand gst) in the liver, down-regulated the expressions of oxidative stress genes (sod1, sod2, and cat) in the intestine, and increased arsenobetaine concentration (P< 0.05). Therefore, gut microbiome promotes As transformation and relieves As accumulation, playing more active roles under iAs stress when the host lacks key arsenic detoxification enzymes. LGG can promote As biotransformation and relieve oxidative stress under As exposure.

Multi-modal services, integrating haptic modality into audio-visual applications, will further improve user's interactive and immersive experience. However, the quality of haptic signals in multi-modal services is very sensitive to transmission interference. Even in certain virtual scenarios, it is necessary to generate “virtual” haptic signals. Although several cross-modal reconstruction schemes are used to guarantee the quality of haptic signals, the weakly-supervised and weakly-paired issues still exist. To resolve this problem, a fine-grained audio-visual aided haptic signal reconstruction (FGHR) is proposed. Firstly, feature extraction with subcategory label exploration is designed by using the cross-modal transfer-based deep clustering network (CT-DCN). Then, the fusion features with shared semantic learning is performed under the triplet constraint. Finally, haptic signal reconstruction is realized by imposing the fine-grained semantic constraints. Experimental results show the effectiveness of the proposed scheme.

Introduction:Human enterovirus D68 (EV-D68), which belongs to enteroviruses of the small RNA family, is a type of enterovirus that can cause acute respiratory tract infection and central nervous system diseases. This study systematically analysed and summarized EV-D68 antibody studies in databases and identified the seropositivity rates of different regions, ages, and sexes. Methods:Meta-analysis was performed using STATA 16.0 software. I2 and Q tests were used to analyse the heterogeneity of the included studies. Meta-regression analysis was performed for different groups, and Egger’s linear regression analysis was used to evaluate publication bias. Results:The results of multiple studies indicated that the serological prevalence range of EV-D68 antibody was 17.78–96.69%. The results of the meta-analysis showed that the seropositivity rate of EV-D68 antibody was 76% (95% confidence interval [CI]: 67–84%), among which that of the Chinese population was 74% (95% CI: 61–86%) and that of other countries was 79% (95% CI: 65–91%). At the same time, a subgroup analysis was conducted. The seroprevalence of EV-D68 antibody was related to age but not sex or region. Conclusion:The seropositivity rate was lower in the below 5-year age group; however, it gradually increased with age. The results of this study showed that EV-D68 infection was widespread in the population, and the current clinical infection situation could not reflect the actual epidemic situation of the virus, among which children under 5 years old were vulnerable to infection, which should be given greater attention for epidemic prevention and control.

Pharmaceuticals have been developed for the treatment of a wide range of bone diseases and disorders, but suffer from problematic delivery to the bone marrow. Neutrophils are naturally trafficked to the bone marrow and can cross the bone marrow–blood barrier. Here we report the use of neutrophils for the targeted delivery of free drugs and drug nanoparticles to the bone marrow. We demonstrate how drug-loaded poly(lactic-co-glycolic acid) nanoparticles are taken up by neutrophils and are then transported across the bone marrow–blood barrier to boost drug concentrations in the bone marrow. We demonstrate application of this principle to two models. In a bone metastasis cancer model, neutrophil delivery is shown to deliver cabazitaxel and significantly inhibit tumour growth. In an induced osteoporosis model, neutrophil delivery of teriparatide is shown to significantly increase bone mineral density and alleviate osteoporosis indicators.

Swept-source optical coherence tomography angiography imaging of three patients before and after the onset of retinal pigment epithelium tears showed that choriocapillaris flow deficit measurements remained stable within the bed of the retinal pigment epithelium tears for at least 16 months after their onset.

Swept-source optical coherence tomography angiography imaging of undiagnosed relatives in a family with Sorsby macular dystrophy detected reticular pseudodrusen and abnormalities in Bruch membrane thickness, choriocapillaris thickness, and choriocapillaris perfusion only in family members shown to carry the Sorsby macular dystrophy mutation.

A deep learning algorithm was developed to automatically identify, segment, and quantify geographic atrophy (GA) based on optical attenuation coefficients (OACs) calculated from optical coherence tomography (OCT) datasets. Normal eyes and eyes with GA secondary to age-related macular degeneration were imaged with swept-source OCT using 6 × 6 mm scanning patterns. OACs calculated from OCT scans were used to generate customized composite en face OAC images. GA lesions were identified and measured using customized en face sub-retinal pigment epithelium (subRPE) OCT images. Two deep learning models with the same U-Net architecture were trained using OAC images and subRPE OCT images. Model performance was evaluated using DICE similarity coefficients (DSCs). The GA areas were calculated and compared with manual segmentations using Pearson’s correlation and Bland-Altman plots. In total, 80 GA eyes and 60 normal eyes were included in this study, out of which, 16 GA eyes and 12 normal eyes were used to test the models. Both models identified GA with 100% sensitivity and specificity on the subject level. With the GA eyes, the model trained with OAC images achieved significantly higher DSCs, stronger correlation to manual results and smaller mean bias than the model trained with subRPE OCT images (0.940 ± 0.032 vs 0.889 ± 0.056, p = 0.03, paired t-test, r = 0.995 vs r = 0.959, mean bias = 0.011 mm vs mean bias = 0.117 mm). In summary, the proposed deep learning model using composite OAC images effectively and accurately identified, segmented, and quantified GA using OCT scans.

Widefield swept-source optical coherence tomography imaging of eyes with proliferative diabetic retinopathy demonstrated that the diabetic choroid is abnormal throughout the macula. This approach can be applied to investigate choroidal dysfunction in other retinal diseases.

Mai-Luo-Shu-Tong pill is an effective traditional Chinese medicine formula for the treatment of superficial thrombophlebitis, but it was insufficiently chemically scrutinized. In this study, the mass spectral data of Mai-Luo-Shu-Tong pill were acquired by ultra-high performance liquid chromatography coupled with Q Exactive hybrid Quadrupole-Orbitrap high resolution mass spectrometry. Then, a data mining strategy combining multiple data processing methods was used to identify chemical constituents in Mai-Luo-Shu-Tong pill by constructing a database of precursor ions and summarizing the mass spectral fragmentation behaviors. As a result, a total of 211 compounds including 70 flavonoids, 56 terpenoids, 37 phenolic acids and 48 others were identified in positive and negative ion modes. Among them, 66 compounds have passed comparison verification with reference standards, 145 compounds were identified based on the data mining strategy combining the characteristic cleavage behaviour of homologous compounds and fragment ions and 4 compounds were potentially new compounds. This study provides a database for quality evaluation and further study of Mai-Luo-Shu-Tong pill in vivo. Moreover, it provides a reference for the characterization of the chemical constituents of other traditional Chinese medicine formulae.

To introduce a novel method for assessment of retinal vasculitis using swept-source OCT angiography (SS-OCTA).

To evaluate the prognostic significance of persistent choroidal hypertransmission defects (HyperTDs) detected on en face OCT imaging for predicting the progression of drusen to geographic atrophy (GA) by analyzing their association with the presence of nascent GA (nGA).

M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitroand in vivoexperiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.

Enterovirus A71 (EV-A71) is an important pathogen of severe hand, foot, and mouth disease (HFMD) in young children. This study aimed to retrospectively analyze the molecular epidemiology and recombination of EV-A71 in mainland China during 1987–2017. Phylogenetic tree showed that besides the previously reported subgenotypes A, B5, C0, C2, C3, and C4, a new subgenotype C6 emerged in mainland China. Recombination analysis indicated that C4 EV-A71 was derived from a common ancestor as a “double-recombinant” virus by intertypic recombination between C EV-A71 and CVA4, CVA5, CVA14, and CVA16 strains in P3 region and intratypic recombination between C and B EV-A71 strains in P2 region. The B5 EV-A71 shared high similarity with C EV-A71 in P1 region while it contained an unidentified sequence in P2 and P3 regions with two possible recombination patterns: one occurred between C4 EV-A71 and CVA3, CVA5, CVA6, CVA10, and CVA12 stains with one breakpoint in 3C, and the other occurred between C1, C2, C3, and C5 EV-A71 and CVA4, CVA5, CVA14, and CVA16 strains with two breakpoints in the 2A/2B junction and 3C. The C2 EV-A71 was probably a recombinant virus between C4 EV-A71 and CVA8 strains with two breakpoints located in the 5′UTR and 2A/2B junction. Moreover, an incredible recombination of C6 EV-A71 occurred between C4 and C2 EV-A71 with multiple breakpoints. Thus, continuous studies on EV-A71 genome characteristics are still useful and essential for monitoring emergence of new viruses and preventing HFMD outbreaks.

The purpose of this study is to quantitatively assess correlations between local geographic atrophy (GA) growth rates and local optical coherence tomography angiography (OCTA)-measured choriocapillaris (CC) flow deficits. Thirty-eight eyes from 27 patients with GA secondary to age-related macular degeneration (AMD) were imaged with a commercial 1050 nm swept-source OCTA instrument at 3 visits, each separated by ∼6 months. Pearson correlations were computed between local GA growth rates, estimated using a biophysical GA growth model, and local OCTA CC flow deficit percentages measured along the GA margins of the baseline visits. The p-values associated with the null hypothesis of no Pearson correlation were estimated using a Monte Carlo permutation scheme that incorporates the effects of spatial autocorrelation. The null hypothesis (Pearson’s ρ = 0) was rejected at a Benjamini-Hochberg false discovery rate of 0.2 in 15 of the 114 visit pairs, 11 of which exhibited positive correlations; even amongst these 11 visit pairs, correlations were modest (r in [0.30, 0.53]). The presented framework appears well suited to evaluating other potential imaging biomarkers of local GA growth rates.

To determine if multiple intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors for unilateral exudative age-related macular degeneration (eAMD) are associated with thinning of the retinal nerve fiber layer (RNFL), we compared RNFL thickness measurements from the injected eye with that of the fellow eye with nonexudative age-related macular degeneration (neAMD).

Molybdenum sulfide (MoS2) has extensively attracted attention as a promising nonprecious metal catalyst for the electrochemical hydrogen evolution reaction (HER). Nevertheless, synergistically enhancing the intrinsic conductivity and active sites of MoS2is the pivotal challenge to build up its hydrogen production performance. Herein, a facile ionic liquid-assisted hydrothermal and subsequent annealing treatment strategy is first reported to synthesize W-doped MoS2nanosheets supported on carbon cloth (Mo1-xWxSy/CC). The experimental results prove that the substitutional W doping can effectively activate the catalytic activity of the inert basal plane of MoS2due to the generation of sulfur vacancies. Density functional theory calculations further confirm that W doping and S vacancies reduce the band gap of MoS2and promote the adsorption of H atoms, thereby greatly improving the HER performance. The synergistic effects of W doping and S vacancies endow this material remarkable HER performance with a low Tafel slope of 49.3 mV dec–1and an overpotenial of 165 mV for 10 mA cm–2in 0.5 M H2SO4solution. In short, our new strategy provides a simple and efficient pathway to synthesize Mo1-xWxSy/CC, and it can be applied to the design of other materials possessing multifarious merits.

Glioma is a malignant brain tumor. There is growing evidence that its progression involves altered metabolism. This study’s objective was to understand how those metabolic perturbations were manifested in plasma and urine. Metabolic signatures in blood and urine were characterized by liquid chromatography–tandem mass spectrometry. The results were linked to gene expression using data from the Gene Expression Omnibus database. Genes and pathways associated with the disease were thus identified. Forty metabolites were identified, which were differentially expressed in the plasma of glioma patients, and 61 were identified in their urine. Twenty-two metabolites and five disturbed pathways were found both in plasma and urine. Twelve metabolites in plasma and three in urine exhibited good diagnostic potential for glioma. Transcriptomic analyses revealed specific changes in the expression of 1437 genes associated with glioma. Seventeen differentially expressed genes were found to be correlated with four of the metabolites. Enrichment analysis indicated that dysregulation of glutamatergic synapse pathway might affect the pathology of glioma. Integration of metabolomics with transcriptomics can provide both a broad picture of novel cancer signatures and preliminary information about the molecular perturbations underlying glioma. These results may suggest promising targets for developing effective therapies.

The efficacy and safety of mRNA vaccines both rely on a fine-tuning of specific humoral and cellular immune responses. Instead of adjustments in vaccine component, we proposed a concept of chronological management of adjuvant effect to modulate the adaptive immune potency and preference inspired by natural virus infection. By simulating type I interferon expression dynamics during viral infection, three vaccine strategies employing distinct exposure sequences of adjuvant and mRNA have been developed, namely Precede, Coincide, and Follow. Follow, the strategy of adjuvant administration following mRNA, effectively suppressed tumor progression, which was attributed to enhanced mRNA translation, augmented p-MHC I expression, and elevated CD8+T cell response. Meanwhile, Followexhibited improved biosafety, characterized by reduced incidences of cardiac and liver toxicity, owing to its alteration to the vaccination microenvironment between successive injections. Our strategy highlights the importance of fine-tuning adjuvant effect dynamics in optimizing mRNA vaccines for clinical application.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer’s disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer’s disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer’s diseases.

Structural OCT images from eyes with nonexudative age-related macular degeneration (AMD) were graded for the presence of a double-layer sign to determine if the double-layer sign predicted subclinical macular neovascularization (MNV).

Designing and constructing supramolecular photosensitizer nanosystems with highly efficient photodynamic therapy (PDT) is vital in the nanomedical field. Despite recent advances in forming well-defined superstructures, the relationship between molecular arrangement in nanostructures and photodynamic properties has rarely been involved, which is crucial for developing stable photosensitizers for highly efficient PDT. In this work, through a microemulsion-assisted self-assembly approach, indium porphyrin (InTPP) was used to fabricate a series of morphology-controlled self-assemblies, including nanorods, nanospheres, nanoplates, and nanoparticles. They possessed structure-dependent 1O2generation efficiency. Compared with the other three nanostructures, InTPP nanorods featuring strong π–πstacking, J-aggregation, and high crystallinity proved to be much more efficient at singlet oxygen (1O2) production. Also, theoretical modeling and photophysical experiments verified that the intermolecular π–πstacking in the nanorods could cause a decreased singlet–triplet energy gap (ΔEST) compared with the monomer. This played a key role in enhancing intersystem crossing and facilitating 1O2generation. Both in vitroand in vivoexperiments demonstrated that the InTPP nanorods could trigger cell apoptosis and tumor ablation upon laser irradiation (635 nm, 0.1 W/cm2) and exhibited negligible dark toxicity and high phototoxicity. Thus, the supramolecular self-assembly strategy provides an avenue for designing high-performance photosensitizer nanosystems for photodynamic therapy and beyond.

Direct intercellular communication is an important prerequisite for the development of multicellular organisms, the regeneration of tissue, and the maintenance of various physiological activities. Tunnel nanotubes (TNTs), which have diameters of approximately 50–1500 nm and lengths of up to several cell diameters, can connect cells over long distances and have emerged as one of the most important recently discovered types of efficient communication between cells. Moreover, TNTs can also directly transfer organelles, vehicles, proteins, genetic material, ions, and small molecules from one cell to adjacent and even distant cells. However, the mechanism of intercellular communication between various immune cells within the complex immune system has not been fully elucidated. Studies in the past decades have confirmed the existence of TNTs in many types of cells, especially in various kinds of immune cells. TNTs display different structural and functional characteristics between and within different immunocytes, playing a major role in the transmission of signals across various kinds of immune cells. In this review, we introduce the discovery and structure of TNTs, as well as their different functional properties within different immune cells. We also discuss the roles of TNTs in potentiating the immune response and their potential therapeutic applications.

Sulfonated carbon is a ‘green,’ solid-acid catalyst. For applications purposes, its surface area needs to be improved and its preparation needs to be made environmentally friendly. The objective of the present study was to provide a green and economical method of preparing a sulfonated carbon catalyst by using palygorskite (Plg) fiber as a support for sulfonated carbon. Sulfonated carbon/palygorskite solid-acid catalyst (SC-Plg) was synthesized via one-step carbonization-sulfonation by mixing palygorskite with sucrose as the carbon source and p-toluenesulfonic acid as the sulfonating agent. The catalyst was characterized by SEM, EDX, TEM, FTIR, and nitrogen adsorption-desorption isotherms. The results indicated that sucrose-derived carbon was loaded uniformly on the surface of Plg fibers and formed the SC-Plg catalyst. The inexpensive Plg fibers could replace sucrose-derived carbon and increase the surface area of the resulting catalyst. The SC-Plg shows significant catalytic performance and excellent stability when used in the esterification of oleic acid with methanol. The conversion of oleic acid reached 68.09%, even after five cycles. This work paves the way for the development of highly active, carbon-based, solid-acid composite catalysts using a natural Plg nanofiber template.

The hallmark of proliferative diabetic retinopathy (PDR) is retinal neovascularization. Tortuous intraretinal vascular segments known as intraretinal microvascular abnormalities (IRMAs) are a known risk factor for neovascularization (NV), but whether IRMA represents a biomarker or a vascular precursor lesion to NV has not been demonstrated. The purpose of this study was to determine whether IRMA may evolve directly into NV.

Copper-based materials have been extensively developed as electrocatalysts for water oxidation due to their promising efficiency and large abundance. Among them, copper telluride could be a potential electrocatalyst but is rarely reported compared with other copper chalcogenides. In this work, rationally designed copper telluride nanosheet arrays on copper foil are fabricated via a facile ionic liquid (1-butyl-3-methylimidazole chloride, [Bmim]Cl) assisted hydrothermal process. The ionic liquid serves as the solvent and etching agent, promoting the progress of reaction and affecting the morphology of products and the corresponding oxygen evolution reaction (OER) performance. The resulting layer-structure electrocatalysts provide a larger specific surface area and more exposed surface atoms as well as a tight interface with good adhesion to the substrate, thereby accelerating charge transfer and mass diffusion. Based on the above-mentioned advantages, the copper telluride electrode exhibits favorable catalytic OER activity and long-term stability in alkaline media. This work not only expands the variety of OER electrocatalysts but also provides a practicable approach to developing active and stable non-noble materials toward electrochemical water-splitting systems.

Ultraviolet photodissociation (UVPD) experiments of protonated tryptamine ([Tryp+H]+) have been implemented by a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer combined with a wavelength-tunable optical parametric oscillator (OPO) laser. UVPD mass spectra under different laser wavelengths have been obtained, in which the dependence of the yield of fragment ions on the laser wavelength was observed. The UVPD spectrum of [Tryp+H]+has been obtained in the range of 210–310 nm. Besides the previously reported two competitive channels of H loss and NH3loss, two important channels of losing CH2NH and CH2NH2units were observed and further studied by UV–UV tandem mass spectrometry and theoretical calculations. Interestingly, results show that the pair of competitive channels of CH2NH loss and CH2NH2loss are both from the McLafferty-type rearrangement caused by ππ* electronic excited states. After the excitation, the two different dissociation pathways produce two different ion–neutral complexes, respectively. The wavelength-dependent dissociation and the existing competitive channels shown in this study reflect the diversity of UVPD processes of such organic molecules.

Gene vectors play a critical role in gene therapy. To achieve efficient transfection, we developed a novel nonvirus cationic liposome (Lipo-Par), which was bound covalently with the cationic polypeptide pardaxin (Par). Interestingly, the Lipo-Pars exhibited highly enhanced gene transfection efficiency in various cell lines compared to that of the non-Par-bonded liposomes (Lipo-Nons). As a result, the internalization and intracellular transport mechanisms of the Lipo-Pars were investigated, and the findings indicated their ability to actively target the endoplasmic reticulum (ER) by moving along the cell cytoskeleton after undergoing caveolin-mediated endocytosis. This intracellular transport process is similar to that of some viruses. It was also found that ER stress and calcium level disturbances can affect the Lipo-Par-mediated expression of certain exogenous genes. A possible, yet non-negligible explanation for the high transfection efficiency of the Lipo-Par is its virus-like intracellular behavior and the intimate relationship between the ER membrane and the nuclear envelope.

To determine age-related changes in choroidal thickness and the volume of choroidal vessels and stroma using automated algorithms based on structural swept-source OCT (SS-OCT) scans.

Local hypoxia in solid malignancies often results in resistance to radiotherapy (RT) and chemotherapy (CT), which may be one of the main reasons for their failure in clinical application. Especially, oxygen is an essential element for enhancing DNA damage caused by ionizing radiation in radiotherapy. Here, two biomimetic oxygen delivery systems were designed by encapsulating hemoglobin (Hb) alone into a liposome (Hb-Lipo) or co-encapsulating Hb and doxorubicin (DOX) into a liposome (DOX-Hb-Lipo). Our data indicated that both Hb-Lipo and DOX-Hb-Lipo could effectively alleviate hypoxia in tumors. We demonstrated that RT plus tumor-targeting delivery of oxygen mediated by Hb-Lipo could significantly overcome the tolerance of hypoxic cancer cells to RT, showing significantly enhanced cancer-cell killing and tumor growth inhibition ability, mainly attributing to hypoxia alleviation and increased reactive oxygen species production under RT in cancer cells. Furthermore, a melanoma model that was quite insensitive to both RT and CT was used to test the efficacy of chemoradiotherapy combined with hypoxia alleviation. RT plus Hb-Lipo only caused a limited increase in antitumor activity. However, extremely strong tumor inhibition could be obtained by RT combined with DOX-Hb-Lipo-mediated CT, attributed to radio-triggered DOX release and enhanced immunogenic cell death induced by RT under an oxygen supplement. Our study provided a valuable reference for overcoming hypoxia-induced radioresistance and a useful therapeutic strategy for cancers that are extremely insensitive to chemo- or radiotherapy.

Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extraterminal family. BRD4 inhibitors can regulate acetylated lysine and form protein complexes that initiate transcriptional programs as an epigenetic regulator of the histone code. BRD4 was initially considered to be one of the most promising targets for combating malignant tumors. However, many recent studies have shown that BRD4 plays a crucial role in various kinds of diseases, including cancer, coronary heart disease, neurological disorder, and obesity. Currently, several BRD4 inhibitors are undergoing clinical trials. A search for new BRD4 inhibitors appears to be of great utility for developing novel drugs. In this mini-review, we highlight the inhibitors of BRD4 from natural products and synthesized sources, as well as their applications in cancer, glucolipid metabolism, inflammation, neuronal stimulation activation, human immunodeficiency virus and renal fibrosis.

Negative ion mass spectrometry can serve as an effective and easy way to find new candidates of superhalogen species. In order to investigate superhalogen properties of polytitanium clusters, the laser ablation mass spectrum of TiO2was obtained with a Fourier transform ion cyclotron resonance mass spectrometer. Density functional theory calculations were also performed in this study. Species of [(TiO2)x(H2O)yOH]−(x= 1–8, y= 1–3) were observed in the mass spectrum. Among them, the intensities of [(TiO2)4(H2O)OH]−, [(TiO2)4(H2O)2OH]−, [(TiO2)3(H2O)2OH]−, and [(TiO2)5(H2O)2OH]−are remarkable. The structures of these species and their neutral counterparts are studied on the level of B3LYP/Lanl2dz/6-311++G(2d, 2p). Results show that the electron affinities (EAs) of the neutral clusters are all higher than that of the chlorine atom and (TiO2)4(H2O)2OH has the highest electron affinity value at 6.23 eV. This series of polytitanium superhalogens not only indicate that the OH might be applied as an effective superhalogen ligand but also show the potential of metal titanium in the design of novel superhalogen compounds.