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Abstract The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu2Cl(OH)3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overproduction H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.

Highlights The factors affecting electrophysiological recordings from active micro-nano-collaborative bioelectronic devices were discussed in terms of principle and fabrication. An overview of the applications of active micro-nano-collaborative bioelectronic devices in cardiomyocytes and neurons was further presented. The challenges faced by active micro-nano-collaborative bioelectronic devices in intracellular electrophysiological studies and their prospective biomedical applications are discussed.

AbstractDoublecortin-like kinase 1 (DCLK) is a microtubule-associated serine/threonine kinase that is upregulated in a wide range of cancers and is believed to be related to tumour growth and development. Upregulated DCLK1 has been used to identify patients at high risk of cancer progression and tumours with chemotherapy-resistance. Moreover, DCLK1 has been identified as a cancer stem cell (CSC) biomarker in various cancers, which has received considerable attention recently. Herein, a series of DCLK1 inhibitors were prepared based on the previously reported XMD8-92 structure. Among all the synthesised compounds, D1, D2, D6, D7, D8, D12, D14, and D15 showed higher DCLK1 inhibitory activities (IC50 40–74 nM) than XMD8-92 (IC50 161 nM). Compounds D1 and D2 were selective DCLK1 inhibitors as they showed a rather weak inhibitory effect on LRRK2. The antiproliferative activities of these compounds were also preliminarily evaluated. The structure-activity relationship revealed by our compounds provides useful guidance for the further development of DCLK1 inhibitors.

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

This paper proposes a high-sensitivity microstrip differential sensor for measuring the complex permittivity of liquids. The prototype of the differential sensor was formed by cascading two LC resonators on a microstrip transmission line based on stepped impedance. A strong electric field was found to be distributed in the circular patch of the LC resonator; therefore, a cylindrical micropore was set in the center of the circular LC resonator to measure the dielectric sample, which maximized the disturbance of the dielectric sample on the sensor. By optimizing the size of the circular LC resonator, a high-sensitivity sensor circuit was designed and manufactured. The complex permittivity of the test sample was calculated by measuring the transmission coefficient of different molar concentrations of ethanol–water solutions. The experimental results show that the designed differential sensor can accurately measure the complex permittivity of liquid materials with an average sensitivity of 0.76%.

Summary: The efficacy of COVID-19 vaccination relies on the induction of neutralizing antibodies, which can vary among vaccine recipients. In this study, we investigated the potential factors affecting the neutralizing antibody response by combining plasma and urine proteomics and gut microbiota analysis. We found that activation of the LXR/FXR pathway in plasma was associated with the production of ACE2-RBD-inhibiting antibodies, while urine proteins related to complement system, acute phase response signaling, LXR/FXR, and STAT3 pathways were correlated with neutralizing antibody production. Moreover, we observed a correlation between the gut microbiota and plasma and urine proteins, as well as the vaccination response. Based on the above data, we built a predictive model for vaccination response (AUC = 0.85). Our study provides insights into characteristic plasma and urine proteins and gut microbiota associated with the ACE2-RBD-inhibiting antibodies, which could benefit our understanding of the host response to COVID-19 vaccination.

Developing cost-effective cathode materials is conducive to accelerating the commercialization of sodium-ion batteries. Na4Fe3(PO4)2P2O7 (NFPP) has attracted extensive attention owning to its high theoretical capacity, stable structure, and low cost of raw materials. However, its inherent low conductivity hinders its further application. Herein, carbon-coated NFPP nanospheres are anchored to crumpled MXene nanosheets by an electrostatic self-assembly; this cross-linked structure induced by CTAB not only significantly expands the contact area between particles and improves the electronic conductivity, but also effectively reduces the aggregation of NFPP nanoparticles. The as-designed Na4Fe3(PO4)2(P2O7)@C/Ti3C2Tx (NFPP@MX) cathode exhibits a high discharge capacity (106.1 mAh g−1 g at 0.2 C), good rate capability (60.4 mAh g−1 at 10 C), and a long-life cyclic stability (85.2% capacity retention after 1000 cycles at 1 C). This study provides an effective strategy for the massive production of high-performance NFPP cathodes and broadens the application of MXene in the modification of other cathode materials.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Background As pregnant women are excluded from clinical trials of inactivated SARS-CoV-2 vaccines, it is important to assess the immune response in women receiving the vaccination while unknowingly pregnant. Methods In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 years. Serum antibody levels induced by inactivated vaccines were determined. Adverse events were collected by self-reported survey after vaccination. Logistic regression model and restricted cubic spline model were used to investigate the association of factors with antibody positivity. Results As the doses of the vaccine increase, neutralizing antibody (NAb) positivity was 98.3%, 39.5%, and 9.5% in pregnant women, respectively. The dose of vaccine and duration since vaccination were associated with NAb positivity. The OR of two and three doses of vaccines were 7.20 and 458.33 (P

Objective To explore the efficiency of hierarchical teaching model in advanced training of therapeutic blood component apheresis. Methods A total of 76 students who participated in the advanced training(≥3 months) of therapeutic blood component apheresis in Blood Transfusion Department of our hospital from January 2016 to December 2021 were taken as subjects. They were divided into observation group(hierarchical teaching mode, n=46) and control group (traditional teaching mode, n=30) using random number table method. The assessment scores of the two groups in terms of theoretical knowledge and experimental operation ability before and after the advanced traning were compared, and the satisfaction of students for the teaching models were collected by questionnaires. Results After training, the average score of the observation group and control group in terms of theoretical knowledge and experimental operation ability were 52.57±2.17 vs 51.00±2.73, 34.74±1.99 vs 33.40±2.42, respectively (P

Autologous ozonized blood transfusion(AOBT) is a therapy of re-transfusion of 100-200 mL of autologous blood after shaking and agitation with appropriate amount of oxygen-ozone in vitro. The oxidation of blood through the strong oxidation of ozone can enhance the non-specific immune response of the body, regulate the internal environment and promote health. This therapy has been increasingly applied in clinical practice, while no unified standard for the operation process in terms of ozone concentration, treatment frequency and treatment course had been established. This operation process of AOBT is primarily explored in order to standardize the operation process and ensure its safety and efficacy.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which B1-10J showed high degradative activity, with DC50 of 102 nM and cytotoxic IC50 of 2.2 μM against HCT116 cells. Moreover, B1-10J dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that B1-10J inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.

Abstract Extensive research have been devoted to the exploration of multifunctional theranostic agents for cancer, but the poor tumor specificity and unsatisfactory treatment efficacy are some of the critical obstacles for their clinical translations. Herein, ferrocene‐carbon dot‐crosslinked nanoparticles (Fc‐CD NPs) were designed and fabricated for achieving highly specific and photothermal‐augmented chemodynamic therapy (CDT). The Fc‐CD NPs were found not only to inherit the immanent fluorescence, photoacoustic, and photothermal properties of carbon dots (CDs), but also be endowed with CDT that could occur selectively in tumor microenvironment (TME) due to the presence of Fc for triggering Fenton reaction. Moreover, the enlarged particle size of Fc‐CD NPs facilitated their effective accumulation at tumor sites, thus realizing great improvement for antitumor treatment outcomes. Once docking at tumor and being exposed to 660 nm laser irradiation, significantly amplified CDT effect of Fc‐CD NPs was observed due to heat‐accelerating generation of reactive oxygen species (ROS). More interestingly, since the produced ROS could in turn alleviate the thermal‐resistance of photothermal therapy (PTT), the therapeutic efficiency of integrated PTT and CDT was synergized to the maximum extent. This study on the one hand provides a facile approach to fabricate CDs‐based multifunctional theranostic nanoplatform with enhanced tumor accumulation and specificity, on the other hand emphasizes the merits of synergizing mutually beneficial therapeutic modalities for more efficient cancer therapy.

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log2 ratio| >1 and p-value

Abstract It is significant to develop catalysts with high catalytic activity and durability to improve the electrochemical performances of lithium‐oxygen batteries (LOBs). While electronic metal‐support interaction (EMSI) between metal atoms and support has shown great potential in catalytic field. Hence, to effectively improve the electrochemical performance of LOBs, atomically dispersed Fe modified RuO2 nanoparticles are designed to be loaded on hierarchical porous carbon shells (FeSA‐RuO2/HPCS) based on EMSI criterion. It is revealed that the Ru‐O‐Fe1 structure is formed between the atomically dispersed Fe atoms and the surrounding Ru sites through electron interaction, and this structure could act as the ultra‐high activity driving force center of oxygen reduction/evolution reaction (ORR/OER). Specifically, the Ru‐O‐Fe1 structure enhances the reaction kinetics of ORR to a certain extent, and optimizes the morphology of discharge products by reducing the adsorption energy of catalyst for O2 and LiO2; while during the OER process, the Ru‐O‐Fe1 structure not only greatly enhances the reaction kinetics of OER, but also catalyzes the efficient decomposition of the discharge products Li2O2 by the favorable electron transfer between the active sites and the discharge products. Hence, LOBs based on FeSA‐RuO2/HPCS cathodes show an ultra‐low over‐potential, high discharge capacity and superior durability.

Abstract The first carbon dot (CD)-based organic long persistent luminescence (OLPL) system exhibiting more than 1 h of duration was developed. In contrast to the established OLPL systems, herein, the reported CDs-based system (named m-CDs@CA) can be facilely and effectively fabricated using a household microwave oven, and more impressively, its LPL can be observed under ambient conditions and even in aqueous media. XRD and TEM characterizations, afterglow decay, time-resolved spectroscopy, and ESR analysis were performed, showing the successful composition of CDs and CA, the formation of exciplexes and long-lived charged-separated states. Further studies suggest that the production of covalent bonds between CA and CDs plays pivotal roles in activating LPL and preventing its quenching from oxygen and water. To the best of our knowledge, this is a very rare example of an OLPL system that exhibits hour-level afterglow under ambient conditions. Finally, applications of m-CDs@CA in glow-in-the-dark paints for emergency signs and multicolored luminous pearls were preliminarily demonstrated. This work may provide new insights for the development of rare-earth-free and robust OLPL materials.

Nanomedicines are considered one of the promising strategies for anticancer therapy; however, the low targeting efficiency of nanomedicines in vivo is a great obstacle to their clinical applications. Camouflaging nanomedicines with either platelet membrane (PM) or platelet would significantly prolong the retention time of nanomedicines in the bloodstream, enhance the targeting ability of nanomedicines to tumor cells, and reduce the off-target effect of nanomedicines in major organs during the anticancer treatment. In the current review, the advantages of using PM or platelet as smart carriers for delivering nanomedicines to inhibit tumor growth, metastasis, and recurrence were summarized. The opportunities and challenges of this camouflaging strategy for anticancer treatment were also discussed.

Sustaining proliferative signaling and enabling replicative immortality are two important hallmarks of cancer. The complex of cyclin-dependent kinase (CDK) and its cyclin plays a decisive role in the transformation of the cell cycle and is also critical in the initiation and progression of cancer. CRIF1, a multifunctional factor, plays a pivotal role in a series of cell biological progresses such as cell cycle, cell proliferation, and energy metabolism. CRIF1 is best known as a negative regulator of the cell cycle, on account of directly binding to Gadd45 family proteins or CDK2. In addition, CRIF1 acts as a regulator of several transcription factors such as Nur77 and STAT3 and partly determines the proliferation of cancer cells. Many studies showed that the expression of CRIF1 is significantly altered in cancers and potentially regarded as a tumor suppressor. This suggests that targeting CRIF1 would enhance the selectivity and sensitivity of cancer treatment. Moreover, CRIF1 might be an indispensable part of mitoribosome and is involved in the regulation of OXPHOS capacity. Further, CRIF1 is thought to be a novel target for the underlying mechanism of diseases with mitochondrial dysfunctions. In summary, this review would conclude the latest aspects of studies about CRIF1 in cancers and mitochondria-related diseases, shed new light on targeted therapy, and provide a more comprehensive holistic view.

Abstract Near-infrared (NIR), particularly NIR-containing dual-/multi-mode afterglow, is very attractive in many fields of application, but it is still a great challenge to achieve such property of materials. Herein, we report a facile method to prepare green and NIR dual-mode afterglow of carbon dots (CDs) through in situ embedding o-CDs (being prepared from o-phenylenediamine) into cyanuric acid (CA) matrix (named o-CDs@CA). Further studies reveal that the green and NIR afterglows of o-CDs@CA originate from thermal activated delayed fluorescence (TADF) and room temperature phosphorescence (RTP) of o-CDs, respectively. In addition, the formation of covalent bonds between o-CDs and CA, and the presence of multiple fixation and rigid effects to the triplet states of o-CDs are confirmed to be critical for activating the observed dual-mode afterglow. Due to the shorter lifetime and insensitiveness to human vision of the NIR RTP of o-CDs@CA, it is completely covered by the green TADF during directly observing. The NIR RTP signal, however, can be readily captured if an optical filter (cut-off wavelength of 600 nm) being used. By utilizing these unique features, the applications of o-CDs@CA in anti-counterfeiting and information encryption have been demonstrated with great confidentiality. Finally, the as-developed method was confirmed to be applicable to many other kinds of CDs for achieving or enhancing their afterglow performances.

Cancer is still a leading cause of death worldwide and liquid biopsy is a powerful tool that can be applied to different stages of cancer screening and treatment. However, as the second most abundant cell type in the bloodstream, platelets are isolated through well-established and fast methods in clinic but their value as a BioSource of cancer biomarkers is relatively recent. Many studies demonstrated the bidirectional interaction between cancer cells and platelets. Platelets transfer various proteins (e.g., growth factors, cytokine, chemokines) and RNAs (e.g., mRNA, lncRNA, miRNA, circRNA) into the tumor cells and microenvironment, leading the stimulation of tumor growth and metastasis. In turn, the platelet clinical characteristics (e.g., count and volume) and contents (e.g., RNA and protein) are altered by the interactions with cancer cells and this enables the early cancer detection using these features of platelets. In addition, platelet-derived microparticles also demonstrate the prediction power of being cancer biomarkers. In this review, we focus on the clinical applications of platelet detection using the platelet count, mean platelet volume, platelet RNA and protein profiles for human cancers and discuss the gap in bringing these implementations into the clinic.

Two-dimensional (2D) materials have been a research hot topic in the passed decades due to their unique and fascinating properties. Among them, mechanical properties play an important role in their application. However, there lacks an effective tool for high-throughput calculating, analyzing and visualizing the mechanical properties of 2D materials. In this work, we present the mech2d package, a highly automated toolkit for calculating and analyzing the second-order elastic constants (SOECs) tensor and relevant properties of 2D materials by considering their symmetry. In the mech2d, the SOECs can be fitted by both the strain–energy and stress–strain approaches, where the energy or strain can be calculated by a first-principles engine, such as VASP. As a key feature, the mech2d package can automatically submit and collect the tasks from a local or remote machine with robust fault-tolerant ability, making it suitable for high-throughput calculation. The present code has been validated by several common 2D materials, including graphene, black phosphorene, GeSe2 and so on.

Abstract Li‐CO2 battery has attracted extensive attention and research due to its super high theoretical energy density and its ability to fix greenhouse gas CO2. However, the slow reaction kinetics during discharge/charge seriously limits its development. Hence, a simple cation exchange strategy is developed to introduce Ru atoms onto a Co3O4 nanosheet array grown on carbon cloth (SA Ru‐Co3O4/CC) to prepare a single atom site catalyst (SASC) and successfully used in Li‐CO2 battery. Li‐CO2 batteries based on SA Ru‐Co3O4/CC cathode exhibit enhanced electrochemical performances including low overpotential, ultra high capacity, and long cycle life. Density functional theory calculations reveal that single atom Ru as the driving force center can significantly enhance the intrinsic affinity for key intermediates, thus enhancing the reaction kinetics of CO2 reduction reaction in Li‐CO2 batteries, and ultimately optimizing the growth pathway of discharge products. In addition, the Bader charge analysis indicates that Ru atoms as electron‐deficient centers can enhance the catalytic activity of SA Ru‐Co3O4/CC cathode for the CO2 evolution reaction. It is believed that this work has important implications for the development of new SASCs and the design of efficient catalyst for Li‐CO2 batteries.

PurposeRepairing the irradiation-induced osteogenic differentiation injury of bone marrow mesenchymal stem cells (BM-MSCs) is beneficial to recovering haematopoiesis injury in radiotherapy; however, its mechanism is elusive. Our study aimed to help meet the needs of understanding the effects of radiotherapy on BM-MSC osteogenic potential.Methods and MaterialsBalb/c mice and the BM-MSCs were used to evaluate the irradiation-induced osteogenic differentiation injury in vivo. The cellular and molecular characterization were applied to determine the mechanism for recovery of irradiation-derived haematopoiesis injuries.ResultsWe report a functional role of IL-12 in acute irradiation hematopoietic injury recovery and intend to dissect the possible mechanisms through BM-MSC, other than the direct effect of IL-12 on hematopoietic stem and progenitor cells (HSPCs). Specifically, we show that early use of IL-12 enhanced the osteogenic differentiation of BM-MSCs through IL-12Rβ1/TYK2/STAT3 signaling; furthermore, IL-12 induced osteogenesis facilitated bone formation and irradiation hematopoiesis recovery when transplanted BM-MSCs in the femur of Balb/c mice. For the mechanism of action, we found that IL-12 receptor beta 1 (IL-12Rβ1) expression of irradiated BM-MSCs was upregulated rapidly, coincidentally consistent with early use of IL-12 induced osteogenic differentiation enhancement. IL-12Rβ1 and tyrosine kinase 2 gene (Tyk2) silencing experiments and phosphotyrosine of signal transducer and activator of transcription 3 (p-STAT3) suppression experiments indicated the IL-12Rβ1/TYK2/STAT3 signaling was essential in IL-12-induced osteogenic differentiation enhancement of BM-MSCs.ConclusionThese findings suggested that IL-12 may exert BM-MSCs-based hematopoietic recovery by repairing osteogenic differentiation abilities damages through IL-12Rβ1/TYK2/STAT3 signaling pathway post-irradiation.

Abstract Multifunctional nanocarrier-based theranostics is supposed to overcome some key problems in cancer treatment. In this work, a novel method for the preparation of a fluorescent mesoporous silica–carbon dot nanohybrid was developed. Carbon dots (CDs), from folic acid as the raw material, were prepared in situ and anchored on the surface of amino-modified mesoporous silica nanoparticles (MSNs–NH2) via a microwave-assisted solvothermal reaction. The as-prepared nanohybrid (designated MSNs–CDs) not only exhibited strong and stable yellow emission but also preserved the unique features of MSNs (e.g., mesoporous structure, large specific surface area, and good biocompatibility), demonstrating a potential capability for fluorescence imaging-guided drug delivery. More interestingly, the MSNs–CDs nanohybrid was able to selectively target folate receptor-overexpressing cancer cells (e.g., HeLa), indicating that folic acid still retained its function even after undergoing the solvothermal reaction. Benefited by these excellent properties, the fluorescent MSNs–CDs nanohybrid can be employed as a fluorescence-guided nanocarrier for the targeted delivery of anticancer drugs (e.g., doxorubicin), thereby enhancing chemotherapeutic efficacy and reducing side effects. Our studies may provide a facile strategy for the fabrication of multifunctional MSN-based theranostic platforms, which is beneficial in the diagnosis and therapy of cancers in future.

Abstract Background Bone marrow stromal cells (BMSCs) are extensively used in regeneration therapy and cytology experiments simulate how BMSCs respond to radiation. Due to the small number and the heterogeneity of primary isolated BMSCs, extensive in vitro expansion is usually required before application, which affects the cellular characteristics and gene expression of BMSCs. However, whether the radiation response of BMSCs changes during in vitro expansion is unclear. Methods In this study, BMSCs were passaged in vitro and irradiated at passage 6 (P6) and passage 10 (P10). Then, apoptosis, the cell cycle, senescence, the cytokine secretion and the gene expression profile were analysed for the P6, P10, and non-irradiated (control) BMSCs at different post-irradiation time points. Results The P6 BMSCs had a lower percentage of apoptotic cells than the P10 BMSCs at 24 and 48 h post-irradiation but not compared to that of the controls at 2 and 8 h post-irradiation. The P6 BMSCs had a lower percentage of cells in S phase and a higher percentage in G1 phase than the P10 BMSCs at 2 and 8 h post-irradiation. The radiation had similar effects on the senescent cell level and impaired immunomodulation capacity of the P6 and P10 BMSCs. Regardless of whether they were irradiated, the P6 and P10 BMSCs always expressed a distinctive set of genes. The upregulated genes were enriched in pathways including the cell cycle, DNA replication and oocyte meiosis. Then, a subset of conserved irradiation response genes across the BMSCs was identified, comprising 12 differentially upregulated genes and 5 differentially downregulated genes. These genes were especially associated with the p53 signaling pathway, DNA damage and DNA repair. Furthermore, validation experiments revealed that the mRNA and protein levels of these conserved genes were different between the P6 and P10 BMSCs after irradiation. Weighted gene co-expression network analysis supported these findings and further revealed the effects of cell passage on the irradiation response in BMSCs. Conclusion The results indicated that cell passage in vitro affected the irradiation response of BMSCs via molecular mechanisms that mediated differences in apoptosis, the cell cycle, senescence and the cytokine secretion. Thus, accurate cell passage information is not only important for transplantation therapy but also for future studies on the radiation response in BMSCs.

Thrombocytopenia 2 (THC2) is a major type of inherited thrombocytopenia caused by the persistent ANKRD26 expression during the late stage of megakaryocytopoiesis. For the first time, we generated a human induced pluripotent stem cell (hiPSC) line SHAMUi001-A from the bone marrow hematopoietic progenitor cells of a THC2 patient, who has a heterozygous mutation (c.-128G>T) in the 5′-UTR of ANKRD26 gene. SHAMUi001-A cells retain the mutation, display pluripotent stem cell characteristics, and have a normal female karyotype. This disease-specific hiPSC line will be a useful model for THC2 research.

Thrombocytopenia 2 (THC2) is one of the most prevalent forms of inherited thrombocytopenia. It is caused by a heterogeneous group of ANKRD26 gene mutation and shows a heterogeneous clinical and laboratory characteristics. We present a big Chinese family with 10 THC2 patients carrying c.-128G > T heterozygous substitution in the 5-untranslated region of the ANKRD26 gene. Although the platelets are fewer than 50 × 109/L in 8 THC2 family members, only the proband and her son show a higher WHO bleeding score. The proband and her son are also beta-thalassemia carriers with heterozygous c.52A > T mutation of HBB, which might not be associated with the increased bleeding tendency since 3 other family members with low bleeding tendency also carried both ANKRD26 c.-128G > T and HBB c.52A > T mutations. However, the proband and her son also show hypofibrinogenaemia, which is likely the cause of their more severe clinical manifestation. HID1 c.442G > T mutation was detected not only in these two hypofibrinogenaemia family members but also in the other 8 family members with normal blood fibrinogen levels. Our study suggests that the co-occurrence of other inherited genetic conditions associated with blood coagulation might contribute to the heterogeneity of clinical and laboratory characteristics in THC2 patients. Considering the hematologic and myeloid malignancy predisposition of THC2 patients and a large population of immune thrombocytopenia in China, we urge more attention to be paid to the diagnosis of THC2 patients to avoid misdiagnosis and mistreatment.

Abstract Background Neonatal alloimmune thrombocytopenia (NAIT), caused by maternal antibodies raised against alloantigens carried on foetal platelets, is a very common haematological abnormality in newborns worldwide. However, baseline data on NAIT in China are lacking. Therefore, this study seeks to explore the incidence of alloantibody against the human platelet antigen (HPA) in pregnant women and its associations with NAIT in China. Methods A multicentre, prospective cohort study design will be used, and 55,497 pregnant women will be recruited for the first screening of the anti-HPA antibody at 12 to 28 weeks of gestational age. Subjects who are positive in the first screening for the anti-HPA antibody will be included in the exposure group. Re-tests of the antibody titre, antigen-specificity and genotyping of HPA and HLA will be conducted during admission. A ratio of 1:1 paired individuals with the same ethnicity and parity but testing negative for the anti-HPA antibody will be randomly selected to be included in the non-exposure group. NAIT will be diagnosed in the newborns on day one of the birth. The HPA of the neonates in the exposure group will also be genotyped by sequencing. Associations of maternal HLA with the occurrence of the anti-HPA antibody and correlation of the severity of NAIT with the titre of the anti-HPA antibody will be further analysed. Discussion The study is expected to provide baseline data on NAIT in China. Besides, we hope to find out a population who expresses particular HLA molecules has significant higher risk of HPA alloimmunization in Chinese individuals. We also hope to find a Chinese-specific cut-off antibody titre for the prediction of the severity of NAIT and to provide a means to evaluate the necessity of antenatal treatment. Trial registration ClinicalTrials.gov: NCT02934906 (date registered: 13.10.2016).

Nanomaterials with localized surface plasmon resonance (LSPR) have exquisite optical properties, which allow a wide range of applications. Non-stoichiometric copper sulfides with active LSPR have drawn great attention, because its LSPR peak falls in the NIR region that is suitable for deep bioimaging and photothermal therapy (PTT). Despite numerous biomedical applications, the biocompatibility and toxicity of copper sulfides have not been studied systematically. In this contribution, we synthesized the ultrasmall biocompatible copper sulfide nanoparticle encapsulated within bovine serum albumin (BSA), CuS@BSA. The physical features of CuS@BSA were characterized. The MTT and flow cytometry assays were performed. The in vitro PTT was also investigated. The results indicated that such CuS@BSA nanoparticle had an average TEM size of 8 nm, and an average DLS size of 15 nm. A lower concentration of CuS@BSA was not toxic to HeLa cells, but the critical apoptotic events occurred in HeLa cells after co-incubation with 45 μg/mL CuS@BSA for 48 h. The photothermal effect of the CuS@BSA in aqueous medium were concentration-dependent and time-dependent, which were also verified by flow cytometry and microscopy, while the CuS@BSA were co-cultured with HeLa cells and treated with laser. This work designed an ultrasmall potential biocompatible nanoparticle, CuS@BSA, for cancer photothermal therapy, and provided the toxic information to safely guide its biomedical applications.

RGD tripeptide is a specific, high-affinity ligand for integrin, which is highly expressed in cancer cells. We previously reported that cRGD chemically modified AAV2 (AAV2N587+1/azido+RGD) showed significantly enhanced infectivity compared to RGD genetically inserted AAV2 (AAV2N587+RGD) (10.1016/j.biomaterials.2015.11.066) [1]. Herein we provide the binding ability analysis of RGD modified AAV2 and U87 cell by flow cytometry and the theoretical working model of RGD–αvβ3 integrin interaction. Keywords: Adeno-associated virus, Viral modification, Targeted gene delivery

Carbon dots (CDs) with a room temperature phosphorescent (RTP) feature have attracted considerable interest in recent years due to their fundamental importance and promising applications. However, the reported matrix-free RTP CDs only show short-wavelength (green to yellow) emissions and have to be triggered by ultraviolet (UV) light (below 400 nm), limiting their applications in certain fields. Herein, visible-light-excited matrix-free RTP CDs (named AA-CDs) with a long-wavelength (orange) emission are reported for the first time. The AA-CDs can be facilely prepared via a microwave heating treatment of L-aspartic acid (AA) in the presence of ammonia and they emit unique orange RTP in the solid state with visible light (420 nm) excitation just being switched off. Through the studies of the carbonization process, the C=O and C=N containing moieties in the AA-CDs are confirmed to be responsible for the observed RTP emission. Finally, the applications of AA-CDs in information encryption and anti-counterfeiting were preliminarily demonstrated.

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation.

Aim: The aim of this study was to investigate the mechanisms of Cr6+-induced red blood cells (RBCs) damage. Methods: The effect of Cr6+ exposure on RBCs was evaluated by hemolytic rate and blood gas assays. After exposure to 20 μM Cr6+, the percentage of phosphatidylserine (PS)-exposing cells, intracellular Ca2+, reactive oxygen species (ROS), and ATP levels were evaluated, and cell morphology was observed. RBCs were exposed to Cr6+ in different Ringer solutions to investigate the role of changes of Ca2+, ROS, and ATP levels in eryptosis and morphology. Results: The Cr6+-induced damage of RBCs was dose-dependent. After a 6 h incubation with Cr6+, RBCs exhibited significant Ca2+ influx, ROS increase, ATP depletion, and PS exposure, but displayed no obvious change in morphology at this time point. After 24 h Cr6+ exposure, the RBCs decreased in size, appeared to be spike-like, and had decreased forward scatter. Inhibition of Ca2+ influx attenuated PS-exposure caused by 6 h Cr6+ exposure, but did not prevent 24 h Cr6+ exposure-induced morphological change in RBCs. Inhibition of rapid ATP consumption using adenine significantly ameliorated Cr6+-caused PS-exposure at 12 h, 24 h and 48 h, and prevented 24 h Cr6+ incubation-induced morphological change in RBCs. Conclusion: Cr6+ can lead to eryptosis. Ca2+ influx, increased ROS levels, and rapid ATP consumption are closely related to Cr6+-induced RBCs damage. Ca2+ influx plays an extremely important role in Cr6+-mediated toxicity.

A series of N-mustards, which was conjugated to mono- or bis-naphthalimides with a flexible amine link, were synthesized and evaluated for cytotoxicity against five cancer cell lines (HCT-116, PC-3, U87 MG, Hep G2 and SK-OV-3). Several compounds displayed better activities than the control compound amonafide. Further evaluations by fluorescence spectroscopy studies and DNA-interstrand cross-linking assays revealed that the derivatives showed both alkylating and intercalating properties. Among the derivatives, the bis-naphthalimide N-mustard derivative 11b was found to exhibit the highest cytotoxic activity and DNA cross-linking ability. Both 11b and 7b induce HCT-116 cell apoptosis by S phase arrest.

The achievements of multicolor photoluminescent (PL)-emissive carbon dots (CDs), particularly red to near infrared (NIR), are critical for their applications in optoelectronic devices and bioimaging, but it still faces great challenges to date. In this study, PL emission red-shifts were observed when tartaric acid (TA) was added into m-phenylenediamine (mPD) or o-phenylenediamine (oPD) solutions as carbon sources to prepare CDs, i.e., from blue to green for mPD and from yellow-green to red for oPD. Morphology and structure analyses revealed that the increased surface oxidation and carboxylation were responsible for the red-shifts of emission, indicating that TA played a key role in tuning the surface state of CDs. These factors could be employed as effective strategies to adjust PL emissions of CDs. Consequently, multicolor PL CDs (i.e., blue-, green-, yellow-green- and red-emissive CDs) can be facilely prepared using mPD and oPD in the absence and presence of TA. Particularly, the obtained red-emissive CDs showed a high PL quantum yield up to 22.0% and an emission covering red to NIR regions, demonstrating great potentials in optoelectronic devices and bioimaging. Moreover, multicolor phosphors were further prepared by mixing corresponding CDs with polyvinylpyrrolidone (PVP), among which the blue, green, and red ones could serve as three primary color phosphors for fabricating multicolor and white light-emitting diodes (LEDs). The white LED was measured to show a Commission Internationale de L’Eclairage (CIE) 1931 chromaticity coordinate of (0.34, 0.32), a high color rendering index (CRI) of 89, and a correlated color temperature (CCT) of 5850 K, representing one of the best performances of white LEDs based on CDs.

A new natural product named longanlactone was isolated from Dimocarpus longan Lour. seeds. Its structure was determined as 3-(2-acetyl-1H-pyrrol-1-yl)-5-(prop-2-yn-1-yl)dihydrofuran-2(3H)-one by spectroscopic methods and HRESIMS.

Pirfenidone, a pyridone compound, is an effective and novel antifibrotic agent. In this article, we describe the design, synthesis and activity evaluation of novel antifibrotic agents, 1-(substituted aryl)-5-trifluoromethyl-2(1H) pyridones modified with carbohydrate. Most of the title compounds exhibited comparable or better inhibitory activity than fluorofenidone. Notably, compound 19a demonstrated the highest cell-based inhibitory activity against NIH 3T3 (IC50 = 0.17 mM).

The CD44 protein, as a predominant receptor for hyaluronan (HA), is highly expressed on the surface of multiple tumor cells. HA, as a targeting molecule for a CD44-contained delivery system, increases intracellular drug concentration in tumor tissue. However, due to the weak binding ability of hyaluronan oligosaccharide to CD44, targeting for tumor drug delivery has been restricted. In this study, we first use a HA tetrasaccharide cluster as the target ligand to enhance the binding ability to CD44. A polyamidoamine (PAMAM) dendrimer was modified by a HA tetrasaccharide cluster as a nonviral vector for small interfering RNA (siRNA) delivery. The dendrimer/siRNA nanocomplexes increased the cellular uptake capacity of siRNA through the CD44 receptor-mediated endocytosis pathway, allowing the siRNA to successfully escape the endosome/lysosome. Compared with the control group, nanocomplexes effectively reduced the expression of GFP protein and mRNA in MDA-MB-231-GFP cells. This delivery system provides a foundation to increase the clinical applications of PAMAM nanomaterials.

A series of novel 3-N-sugar-substituted quinazolinediones were synthesizedthrough the cyclization of the intermediate 2-aminobenzamides using triphosgene as the condensing reagent. Their anti-angiogenesis activities were investigated. The compound 3-(2'-aminoglucosyl)-2,4-(1H,3H)-quinazolinedione, (5d) showed good anti-angiogenesis activity.

A series of benzo[d]imidazole analogues of thiabenzole were synthesized and their antiinflammatory activities toward NLRP3 (nucleotide‐binding domain leucine‐rich repeat containing protein family，pyrin domain‐containing 3，also known as cryopyrin or NALP3) inflammasome were evaluated in vitro. Two lead compounds, TBZ‐09 and TBZ‐21, were identified by antiproduction of IL‐1β. In the second round of biological evaluation, based on the lead, 34 more compounds were synthesized and their in vitro anti‐inflammatory activities were investigated. Several compounds were identified as anti‐inflammatory agents that can reduce IL‐1β expression in a dosedependent manner. A preliminary structure–activity relationship is also summarized here.

BACKGROUND: High mobility group box 1(HMGB1) was first recognized as a nuclear protein that increased the chromatin remodeling and regulates transcription of many genes. In recent years, HMGB1 has been identified as a critical "late" pro-inflammatory mediator due to its unique secretion pattern and lethal effects in sepsis. Therefore, preventing the active release and inhibiting the pro-inflammatory activity of HMGB1 become promising strategies for the treatment of sepsis. Here, we reported the therapeutic effects of Gu-4, a lactosyl derivative, on sepsis and the underlying molecular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: In an experimental rat model of sepsis caused by cecal ligation and puncture (CLP), Gu-4 administration prominently attenuated lung injury and improved the survival of the septic animals, which was positively correlated with the decrease of the serum HMGB1 level. Using RAW264.7 macrophage cell line, we further showed that Gu-4 significantly suppressed the lipopolysaccharide (LPS)-induced release and cytoplasmic translocation of HMGB1. Moreover, Gu-4 not only dose-dependently attenuated recombinant human (rhHMGB1)-induced production of TNF-α, IL-6, and IL-1β in THP-1 cells, but also greatly inhibited the adhesion of rhHMGB1-challenged THP-1 cells to HUVECs. Analyses of flow cytometry demonstrated that Gu-4 could effectively reduce the activation of CD11b elicited by rhHMGB1. Western blot analyses revealed that Gu-4 treatment could partially block the rhHMGB1-induced activation of ERK and NF-κB signalings. Meanwhile, CD11b knockdown also obviously attenuated the rhHMGB1-induced phosphorylations of ERK and IKKα/β. CONCLUSIONS/SIGNIFICANCE: Taken together, our results suggest that Gu-4 possesses a therapeutic potential in the treatment of sepsis probably via inhibiting the LPS-induced release of HMGB1 from macrophages and via suppressing the pro-inflammatory activity of HMGB1.

To evaluate the expression of ALDH1A1 in lung adenoma stem cells (LASCs) and maintenance of their stemness through the Notch pathway.LASCs (A549s) were isolated from lung adenoma cells (A549) and identified by their coexpression of CD133 and CD326 and their capacity formulti-directional differentiation. Expression of ALDH1A1 in A549 and A549s cells were evaluated by Real-time PCR. Effects of ALDH1A1 upregulation in A549 cells and its downregulation in A549s cells on the clonogenicity and cell cycle were assessed by colony-forming unit assay. Moreover, the effects of ALDH1A1 on the Notch pathway, and thus on the cell cycle, were studied.A549s cells were successfully isolated and identified.ALDH1A1expression was significantly higher in A549s than in A549 cells. Clonogenicity was significantly decreased in A549s cells treated with ALDH1A1 siRNA. Duration of the G1 stage of the cell cycle increased after ALDH1A1 was overexpressed, or decreased with ALDH1A1 siRNA. ALDH1A1, Notch1, -2, and -3, CDK2, and CCNE1 expression levels were higher in A549s cells than in A549 cells. Expression of Notch1, -2, and -3, CDK2, and CCNE1 was significantly decreased by upregulation of ALDH1A1 in A549 cells, but increased by its interruption in A549s cells. When Notch3 or CDK2 expression was downregulated, the expression levels of ALDH1A1, Notch1, -2, and -3, CDK2, and CCNE1 were reduced in all cell types.ALDH1A1 expression improved clonogenicity and inhibited the cell cycle, maintaining the stemness of the A549s cells; this may involve suppression of the Notch/CDK2/Cyclin pathway.