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Abstract Background T cell-based immunotherapies are facing great challenges in the recruitment and activation of tumor-specific T cells against solid tumors. Among which, utilizing nanobody (Nb) or nanobodies (Nbs) to construct T cell engager has emerged as a more practical potential for enhancing the anti-tumor effectiveness of T cells. Here, we designed a new Nb-guided multifunctional T cell engager (Nb-MuTE) that not only recruited effector T cells into the tumor tissues, but also efficiently activated T cells anti-tumor immunity when synergies with photothermal effect. Results The Nb-MuTE, which was constructed based on an indocyanine green (ICG)-containing liposome with surface conjugation of CD105 and CD3 Nbs, and showed excellent targetability to both tumor and T cells, following enhancement of activation, proliferation and cytokine secretion of tumor-specific T cells. Notably, the immunological anti-tumor functions of Nb-MuTE-mediated T cells were further enhanced by the ICG-induced photothermal effect in vitro and in vivo. Conclusions Such a new platform Nb-MuTE provides a practical and “all-in-one” strategy to potentiate T cell responses for the treatment of solid tumor in clinic.

Abstract Background The adenoids act as a reservoir of bacterial pathogens and immune molecules, and they are significantly involved in children with otitis media with effusion (OME). As an essential carrier of intercellular substance transfer and signal transduction, exosomes with different biological functions can be secreted by various types of cells. There remains significant uncertainty regarding the clinical relevance of exosomes to OME, especially in its pathophysiologic development. In this study, we will seek to determine the biological functions of exosomes in children with adenoid hypertrophy accompanied by OME (AHOME). Methods The diagnostic criteria for OME in children aged 4–10 years include a disease duration of at least 3 months, type B or C acoustic immittance, and varying degrees of conductive hearing loss. Adenoidal hypertrophy is diagnosed when nasal endoscopy shows at least 60% adenoidal occlusion in the nostrils or when nasopharyngeal lateral X-ray shows A/N > 0.6. Children who meet the indications for adenoidectomy surgery undergo adenoidectomy. Peripheral blood, nasopharyngeal swab, and adenoid tissue will be collected from patients, and the exosomes will be isolated from the samples. Following the initial collection, patients will undergo adenoidectomy and peripheral blood and nasopharyngeal swabs will be collected again after 3 months. Expected results This study aims to identify differences in exosomes from preoperative adenoid tissue and peripheral blood samples between children with AHOME and those with adenoid hypertrophy alone. Additionally, it seeks to determine changes in microbial diversity in adenoid tissue between these groups. Conclusions The findings are expected to provide new insights into the diagnosis and treatment of OME, to identify novel biomarkers, and to enhance our understanding of the pathophysiology of OME, potentially leading to the development of innovative diagnostic and therapeutic approaches.

Abstract Endowing flexible and adaptable fiber devices with light-emitting capabilities has the potential to revolutionize the current design philosophy of intelligent, wearable interactive devices. However, significant challenges remain in developing fiber devices when it comes to achieving uniform and customizable light effects while utilizing lightweight hardware. Here, we introduce a mass-produced, wearable, and interactive photochromic fiber that provides uniform multicolored light control. We designed independent waveguides inside the fiber to maintain total internal reflection of light as it traverses the fiber. The impact of excessive light leakage on the overall illuminance can be reduced by utilizing the saturable absorption effect of fluorescent materials to ensure light emission uniformity along the transmission direction. In addition, we coupled various fluorescent composite materials inside the fiber to achieve artificially controllable spectral radiation of multiple color systems in a single fiber. We prepared fibers on mass-produced kilometer-long using the thermal drawing method. The fibers can be directly integrated into daily wearable devices or clothing in various patterns and combined with other signal input components to control and display patterns as needed. This work provides a new perspective and inspiration to the existing field of fiber display interaction, paving the way for future human–machine integration.

Abstract Background T cell engagers (TCEs) have been established as an emerging modality for hematologic malignancies, but solid tumors remain refractory. However, the upregulation of programmed cell death 1 (PD-1) is correlated with T cell dysfunction that confer tumor-mediated immunosuppression. Developing a novel nanobody-based trispecific T cell engager (Nb-TriTE) would be a potential strategy to improve therapeutic efficacy. Methods Given the therapeutic potential of nanobodies (Nbs), we first screened Nb targeting fibroblast activation protein (FAP) and successfully generated a Nb-based bispecific T cell engager (Nb-BiTE) targeting FAP. Then, we developed a Nb-TriTE by fusing an anti-PD-1 Nb to the Nb-BiTE. The biological activity and antitumor efficacy of the Nb-TriTE were evaluated in vitro and in both cell line-derived and patient-derived xenograft mouse models. Results We had for the first time successfully selected a FAP Nb for the generation of novel Nb-BiTE and Nb-TriTE, which showed good binding ability to their targets. Nb-TriTE not only induced robust tumor antigen-specific killing, potent T cell activation and enhanced T cell function in vitro, but also suppressed tumor growth, improved survival and mediated more T cell infiltration than Nb-BiTE in mouse models of different solid tumors without toxicity. Conclusions This novel Nb-TriTE provides a promising and universal platform to overcome tumor-mediated immunosuppression and improve patient outcomes in the future.

Two new compounds, macrolactin XY (1) and (5R, 9S, 10S)-5-(hydroxymethyl)-1,3,7-decatriene-9,10-diol (2), together with nine known compounds (3–11) were isolated from the marine Bacillus subtilis sp. 18 by the OSMAC strategy. These compounds were evaluated for antibacterial activity against six tested microorganisms. Compounds 1–5 and 7–10 showed varied antibacterial activity, with the minimum inhibitory concentration (MIC) ranging from 3 to 12 μg/mL. Macrolactin XY (1) was found to possess superior antibacterial activity, especially exhibiting significant effectiveness against Enterococcus faecalis. The antibacterial activity mechanism against E. faecalis was investigated. The mechanism may disrupt bacterial cell membrane integrity and permeability, and also inhibit the expression of genes associated with bacterial energy metabolism, as established by the experiments concerning cell membrane potential, SDS-PAGE electrophoresis, cell membrane integrity, and key gene expressions. This study offers valuable insights and serves as a theoretical foundation for the future development of macrolactins as antibacterial precursors.

Maternal endocrine disrupting chemicals (EDCs) exposure, the common environmental pollutants, was capable of involving in adverse pregnancy outcomes. However, the evidence of their connection is not consistent. Our goal was to comprehensively explore the risk of EDCs related to adverse pregnancy outcomes. One hundred and one studies were included from two databases before 2023 to explore the association between EDCs and adverse pregnancy outcomes including miscarriage, small for gestational age (SGA), low birth weight (LBW) and preterm birth (PTB). We found that maternal PFASs exposure was positively correlated with PTB (OR:1.13, 95% CI:1.04–1.23), SGA (OR:1.10, 95% CI:1.04–1.16) and miscarriage (OR:1.09, 95% CI:1.00–1.19). The pooled estimates also showed maternal PAEs exposure was linked with PTB (OR:1.16, 95% CI:1.11–1.21), SGA (OR:1.20, 95% CI:1.07–1.35) and miscarriage (OR:1.55, 95% CI:1.33–1.81). In addition, maternal exposure to some specific class of EDCs including PFOS, MBP, MEHP, DEHP, and BPA was associated with PTB. Maternal exposure to PFOS, PFOA, PFHpA was associated with SGA. Maternal exposure to BPA was associated with LBW. Maternal exposure to MMP, MEHP, MEHHP, MEOHP, BPA was associated with miscarriage. Maternal PFASs, PAEs and BPA exposure may increase adverse pregnancy outcomes risk according to our study. However, the limited number of studies on dose-response hampered further explanation for causal association.

Cisplatin (CDDP) stands as a highly effective chemotherapeutic agent; however, its ototoxicity remains a perplexing challenge in the field. Formononetin (FMNT), a potent flavonoid isolated from Astragalus membranaceus, displays a diverse range of promising pharmacological activities, encompassing antioxidant, anti-apoptotic, and anti-inflammatory effects. Nonetheless, the advantageous effects of FMNT on cisplatin-induced cochlear hair cell injury demand further investigation. This study aimed to assess the protective properties of FMNT against cisplatin-induced hair cell damage by conducting in vitro assays on explant-cultured cochlear hair cells. The findings revealed that FMNT exhibited a notable reduction in cisplatin-induced hair cell apoptosis. Also, FMNT effectively mitigated the accumulation of reactive oxygen species and mitochondrial damage in cochlear explants exposed to cisplatin, while also restoring the turnover of the reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio. Furthermore, our study demonstrated that FMNT protects hair cells against CDDP injury through the activation of the PI3K/AKT-Nrf2 signaling pathway. Consequently, formononetin emerges as a potential therapeutic agent for the treatment of cisplatin-induced ototoxicity.

In this manuscript, we present a comprehensive fabrication protocol for high-performance graphene oxide (GO) sensor concepts. It is suitable for a variety of biosensing applications and contains the essential process steps, starting with vapor phase evaporation for siloxane monolayers, followed by spin-coating of GO as a nanometer-thin transducer with exceptional homogeneity and micromechanical surface methods which enable seamless transformation of GO transducers to be desired micro and nano dimensions.In addition to linking basic research and innovative sensor concepts with an outlook for commercial applications of point-of-care systems for early-stage diagnostics, the authors consider it necessary to take a closer look at the manufacturing processes to create more transparency and clarity, to manufacture such specific sensor concepts systematically. The detailed manufacturing approaches are intended to motivate practitioner to explore and improve this GO-based key technology.This process development is illustrated below using the manufacturing methods for three types of sensors, namely sensors based on i) surface plasmon resonance spectroscopy (SPR), ii) impedance spectroscopy and iii) bio-field effect transistors (ISFETs).The obtained results in this work prove successful GO sensor productions by achieving: • Uniform and stable immobilization of GO thin films, • High yield of sensor units on a wafer scale, here up to 96 %, • Promising integration potential for various biomedical sensor concepts to early-stage diagnostic.

Pseudomonas aeruginosa is known to generate bacterial biofilms that increase antibiotic resistance. With the increase of multi-drug resistance in recent years, the formulation of a new therapeutic strategy has seemed urgent. Preliminary findings show that Prodigiosin (PG), derived from chromium-resistant Serratia marcescens, exhibited efficient anti-biofilm activity against Staphylococcus aureus. However, its anti-biofilm activity against P. aeruginosa remains largely unexplored. The anti-biofilm activity of PG against three clinical single drug-resistant P. aeruginosa was evaluated using crystal violet staining, and the viability of biofilms and planktonic cells were also assessed. A model of chronic lung infection was constructed to test the in vivo antibiofilm activity of PG. The results showed that PG inhibited biofilm formation and effectively inhibited the production of pyocyanin and extracellular polysaccharides in vitro, as well as moderated the expression of interleukins (IL-1β, IL-6, IL-10) and tumor necrosis factor (TNF-α) in vivo, which might be attributed to the downregulation of biofilm-related genes such as algA, pelA, and pslM. These findings suggest that PG could be a potential treatment for drug-resistant P aeruginosa and chronic biofilm infections.

In this work, the electromagnetic properties of Ni0.22Cu0.31Zn0.47Fe2O4 (NiCuZn) ferrites doped with 0.3 wt% Bi2O3 + xCuO flux (x = 0.2, 0.4, 0.6, and 0.8 wt%) were studied. Doping resulted in a reduction in the sintering temperature to 900 °C. The doped ferrites were synthesized via the solid-state method. XRD patterns revealed that the prepared ferrites had a cubic spinel structure; thus, a moderate addition of flux did not change the crystal structure. The SEM images, as well as the density and grain size distribution of the samples, showed that the NiCuZn ferrites had densified, homogenized, and contained fully grown grains for x = 0.6 wt%. The sample exhibited good soft magnetic properties, with μ′ reaching the maximum value of 245.4 for x = 0.6 wt% and ε′, Ms, and Hc reaching the maximum values of 23.1, 28.06 emu/g, and 45.86 Oe for x = 0.8 wt%, respectively. Furthermore, the ferrites exhibited good gyromagnetic properties, with 4πMs reaching the maximum value of 1744 Gauss for x = 0.8 wt% and ΔH reaching the minimum value of 228 Oe for x = 0.6 wt%. NiCuZn ferrites were successfully sintered at a lower temperature (900 °C) by adding Bi2O3–CuO flux through LTCC technology and exhibited good soft magnetic properties and gyromagnetic properties. We envisage that these ferrites could be used in multilayer devices.

Desert areas of China have important ecological functions, so analyzing changing characteristics of ecosystem service values in this region is important for sustainable development. Using land use change data for desert areas from 1978 to 2022, this paper combined the equivalent factor method and the actual situation of the study area to revise value coefficients of ecosystem services and study characteristics of land use and ecosystem service value changes after reform and opening up. The results showed that after reform and opening up, the area of plow, water, and other lands in the study area decreased, while grassland, forest, construction land, and sandy land increased. The conversion of a land use type mainly occurred as conversion of grassland and other lands to other land use types. The value of ecosystem services increased, increasing by 19.63 × 108 CNY. From the perspective of land use type in 2022, the ecosystem service value of grassland was the highest, reaching 12.19 × 108 CNY, an increase of 11.73 × 108 CNY compared with the early stage of reform and opening up. From the perspective of ecosystem service types in 2022, the value of maintaining soil ecological services was the highest, reaching 3.07 × 108 CNY, an increase of 2.97 × 108 CNY compared with the beginning of reform and opening up. From the perspective of the ecological sensitivity index, the sensitivity index results for the ecosystem service value in the study area were all

Abstract Nanobodies (Nbs) are the variable domain of heavy‐chain antibodies derived from the blood of camelids or sharks. Nanobodies are the smallest antibody fragment with intact antigen‐binding ability. Compared to conventional antibodies, nanobodies have unique properties such as small size, excellent stability and solubility, low immunogenicity, ability to recognize hidden epitopes, high tissue penetration, and industrialized production. More excitingly, the camelid‐specific amino acid sequences in the framework are mutated to their human heavy‐chain variable domain equivalent, which is humanized, to a wide range of applications. These superior characteristics make nanobody an ideal alternative to conventional antibody, showing excellent prospects for various applications in structural biology, molecular imaging, disease diagnosis and therapy, agricultural products, and environmental chemicals detection. With the continuous updating of theories and the rapid development of technology, the screening and expression methods of nanobodies are increasingly mature. Consequently, several technologies to identify and express nanobodies have been established, and various use cases have been described. In this review, we summarize recent advances in the discovery and production of novel nanobodies, and their use in detection and diagnosis platforms.

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin–Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7−/− mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.

Anxiety and depression are important risk factors for chronic obstructive pulmonary disease (COPD). The aim of this study was to develop a prediction model to predict anxiety or depression in COPD patients. The retrospective study was conducted in COPD patients receiving stable treatment between 2018 and 2020 to develop prediction model. The variables, were readily available in clinical practice, were analysed. After data preprocessing, model training and performance evaluation were performed. Validity of the prediction model was verified in 3 comparative model training. Between 2018 and 2020, 375 eligible patients were analysed. Thirteen variables were included into the final model: gender, age, marital status, education level, long-term residence, per capita annual household income, payment method of medical expenses, direct economic costs of treating COPD in the past year, smoking, COPD progression, number of acute exacerbation of COPD in the last year, regular treatment with inhalants and family oxygen therapy. Risk score threshold in each sample in the training set was 1.414. The area under the curve value was respectively 0.763 and 0.702 in the training set and test set, which were higher than three comparative models. The simple prediction model to predict anxiety or depression in patients with COPD has been developed. Based on 13 available data in clinical indicators, the model may serve as an instrument for clinical decision-making for COPD patients who may have anxiety or depression.Key messagesThirteen variables were included into the prediction model.The AUC value was, respectively, 0.763 and 0.702 in the training set and test set, which were higher than three comparative models.The simple prediction model to predict anxiety or depression in patients with COPD has been developed.

Abstract Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.

When measuring plant functional traits across geomorphologies, 5–10 healthy individuals of a plant species are commonly sampled. However, whether more individuals should be sampled in habitat-heterogeneous karst vegetation remains unknown. In this study, two dominant tree species (Clausena dunniana and Platycarya strobilacea) in karst evergreen and broadleaved mixed forests in Southwestern China were selected. On the basis of a large quantity of individuals of the two species grown in different peak clumps and slope positions, variations of 10 morphological traits in the two species were statistically analyzed. The suggested sampling number of individuals, which could mostly represent the common trait characteristics, was further explored. All traits showed significant differences between the two species (p

The Arctic-derived fungus Eutypella sp. D-1 can produce numerous secondary metabolites, and some compounds exhibit excellent biological activity. Seven pimarane-type diterpenes, including three new compounds eutypellenone F (1), libertellenone Y (2), and libertellenone Z (3), and four known compounds (4–7), were isolated from fermentation broth of Eutypella sp. D-1 by the OSMAC strategy of adding ethanol as a promoter in the culture medium. Compound 2 has a rare tetrahydrofuran-fused pimarane diterpene skeleton. The anti-inflammatory activity of all compounds was evaluated. Compounds 3–6 showed a significant inhibitory effect on cell NO release at 10 μmol/L by in vitro experiments, of which 3–5 had inhibitory rates over 60% on nitric oxide (NO) release. Subsequently, the anti-inflammatory activity of 3–5 was evaluated based on a zebrafish model, and the results showed that 3 had a significant inhibitory effect on inflammatory cells migration at 40 μmol/L, while 4 and 5 had a significant inhibitory effect at 20 μmol/L. Moreover, compounds 3–5 have the same conjugated double bond structure, which may be an important group for these compounds to exert anti-inflammatory activity.

The limit sets of zeros of the partition function for $\lambda $ -state Potts models on diamond-like hierarchical lattice are the Julia sets of functions in a family of rational functions. In this paper, the consensus problem of Julia sets generated by $\lambda $ -state Potts models on diamond-like hierarchical lattice is studied. Two types of the consensus problem of Julia sets are considered, one is with a leader and the other is with no leaders. Based on these two types, two different control protocols are proposed respectively to make systems achieve consensus of Julia sets. The simulations confirm the efficacy of control protocols.

Abstract Objective To evaluate the diagnostic performance of short state homeobox 2 (SHOX2) promoter methylation as biomarker for lung cancer identification through aggregating the open published data. Methods We did an electronic search in Pubmed, EMBASE, Ovid, Web of Science, Google Scholar, and the China National Knowledge Infrastructure (CNKI) to identify the publications related to SHOX2 promoter methylation and lung cancer. The diagnostic performance of sensitivity (SEN), specificity (SPE), odds ratio (DOR), and summary receiver operating characteristic (SROC) cure were aggregated by fixed or random effect model. Fagan's nomogram was used to investigate the post‐test diagnostic probability. Deek's funnel plot and line regression test was applied to evaluate the publication bias. Results In total, 18 clinical studies about SHOX2 promoter methylation and lung cancer were included in the meta‐analysis. The combined diagnostic SEN, SPE, DOR were 0.63 (95% CI = 0.54–0.70), 0.91 (95% CI = 0.87–0.94), and 16.84 (95% CI = 11.18–25.36) in random effect model respectively. The pooled area under the curve (AUC) of SROC was 0.88 (95% CI = 0.84–0.90). The post‐test probability of lung cancer was 88% and 29% when SHOX2 methylated and unmethylated in humoral components given a pre‐test probability of 50%. Deek's funnel plot and regression test indicated no publication bias (p = 0.62). Conclusion SHOX2 promoter methylation in humoral components may be a potential biomarker for lung cancer diagnosis with relative high diagnostic specificity.

Abstract Background The aim of this study was to quantitatively analysis the diagnostic performance of adenomatous polyposis coli (APC) gene promoter methylation in serum or sputum/bronchoalveolar lavage fluid (BLAF) as a biomarker for lung cancer identification through pooling of open published data. Methods The relevant electronic MEDLINE, EMBASE, Ovid, web of science and CNKI databases were systematically searched to identify the studies related to APC gene promoter methylation for lung cancer diagnosis. Data of true positive (tp), false positive (fp), false negative (fn) and true negative (tn) were extracted from the publications included in the study. The pooled diagnostic sensitivity, specificity and area under summary receiver operating characteristic (SROC) curve (AUC‐SROC) of APC gene promoter methylation were calculated. Publication bias was evaluated by Begg's funnel plot and Egger's line regression test. Results Fourteen studies associated with APC gene promoter methylation and lung cancer were identified in the databases and finally included in the meta‐analysis. The data was pooled using a random effect model due to significant statistical heterogeneity across the 14 studies (p

Chimeric antigen receptor (CAR) T-cell immunotherapy has become one of the research hotspots in the treatment of malignant tumors nowadays. However, the available tumor surface antigens are limited in number. Most tumor-associated antigens are intracellular molecules that can’t be targeted by conventional CAR T cells. As the major histocompatibility complex (MHC)/peptide complex is a presentation form of intracellular proteins on the surface of tumor cells, here, we chose the Glypican-3 (GPC3) oncoprotein and Wilms tumor 1 (WT1) oncoprotein as examples to explore whether nanobody (Nb)-based T cell receptor (TCR)-like CAR T cells could kill tumor cells by targeting the MHC/peptide complexes. Using the immune nanobody phage display library, we developed human leukocyte antigen (HLA)-A2/GPC3- and HLA-A2/WT1-specific nanobodies for the first time and then incorporated these nanobodies in two TCR-like CARs, targeting HLA-A2/GPC3 and HLA-A2/WT1 respectively. These TCR-like Nb CAR-redirected T cells could selectively recognize and lyse MHC/peptide complex-expressing tumor cells in vitro assays and subcutaneous mouse tumor models. This study offers a possible strategy for targeting intracellular antigens and widening the application of CAR T-cell therapy.

Abstract Background The inner ear organ is a delicate tissue consisting of hair cells (HCs) and supporting cells (SCs).The mammalian inner ear HCs are terminally differentiated cells that cannot spontaneously regenerate in adults. Epithelial non‐hair cells (ENHCs) in the utricle include HC progenitors and SCs, and the progenitors share similar characteristics with SCs in the neonatal inner ear. Methods We applied single‐cell sequencing to whole mouse utricles from the neonatal period to adulthood, including samples from postnatal day (P)2, P7 and P30 mice. Furthermore, using transgenic mice and immunostaining, we traced the source of new HC generation. Results We identified several sensory epithelial cell clusters and further found that new HCs arose mainly through differentiation from Sox9+ progenitor cells and that only a few cells were produced by mitotic proliferation in both neonatal and adult mouse utricles. In addition, we identified the proliferative cells using the marker UbcH10 and demonstrated that in adulthood the mitotically generated HCs were primarily found in the extrastriola. Moreover, we observed that not only Type II, but also Type I HCs could be regenerated by either mitotic cell proliferation or progenitor cell differentiation. Conclusions Overall, our findings expand our understanding of ENHC cell fate and the characteristics of the vestibular organs in mammals over the course of development.

Abstract Background Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells,we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36. Methods Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, wetested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. Results After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice. Conclusions Ourfindings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential totreatmalignant tumors through in vivo adoptive therapy.

(Reduced) graphene oxides as promising 2D materials have been explored extensively to improve the performance characteristics of SPR sensors. Herein, we demonstrate the tuning optical properties of SPR biochips by the combination of two strategies: (i) using gold/reduced graphene oxide (Au/rGO) interfaces prepared by thermal annealing of Au/GO, and (ii) applying external electrical bias via the solid-liquid interface during SPR measurements. We investigated this novel approach by studying a model biological interaction of prostate-specific antigen (PSA) with lectin Concanavalin A (Con A) based on glycan recognition, as the glycan motifs detection is increasingly requested due to the growing knowledge of the importance of glycans in various biological processes and their use as biomarkers. The thermally annealed Au/rGO as a functional layer of SPR chips provides higher signals and 10 times better LOD (limit of detection) compared to Au/GO case. This experimental finding was cross-verified by SPR simulations based on a model combining the optical indices (dielectric parameters) and thicknesses of the GO and rGO thin films obtained from ellipsometry characterizations. In addition, the unique optoelectrical properties of rGO thin films allowed for efficient tuning of the plasmonic intensities by applying an electrical bias at the Au/rGO interface, exploited here to improve the Con A LOD down to 10 ng/ml, what is by 1 order of magnitude better compared to the classic Au chip. The electrical SPR biosensor approach presents a proof-of-concept for future ultrasensitive SPR biosensor platforms.

The aim of this study was to investigate the effect of LLY-283, a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), on a noise-induced hearing loss (NIHL) mouse model and to identify a potential target for a therapeutic intervention against NIHL. Eight-week-old male C57BL/6 mice were used. The auditory brainstem response was measured 2 days after noise exposure. The apoptosis of hair cells (HCs) was detected by caspase-3/7 staining, whereas the accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. We demonstrated that the death of HCs and loss of cochlear synaptic ribbons induced by noise exposure could be significantly reduced by the presence of LLY-283. LLY-283 pretreatment before noise exposure notably decreased 4-HNE and caspase-3/7 levels in the cochlear HCs. We also noticed that the number of spiral ganglion neurons (SGNs) was notably increased after LLY-283 pretreatment. Furthermore, we showed that LLY-283 could increase the expression level of p-AKT in the SGNs. The underlying mechanism involves alleviation of ROS accumulation and activation of the PI3K/AKT pathway, indicating that LLY-283 might be a potential candidate for therapeutic intervention against NIHL.

Automated, effective and efficient sleep‐stage monitoring and structure analysis is an essential enabling procedure for healthcare automation. Sleep diagnosis by polysomnography is a golden standard but expensive procedure involving huge effort from patients. There remain challenges for smart devices to precisely identify sleep stage and minimize intrusive effect on sleep progression. Herein, a novel noncontact sleep structure prediction system (NSSPS) using a single radar sensor is presented to analyze sleep structure without any tethered unit. The NSSPS is realized through training a convolutional recurrent neural network and neural conditional random fields using reflected radio frequency (RF) waves acquired by radar antennas. By capturing implicit temporal information in RF signals and transitions of sleep progression, high accuracy of sleep‐stage prediction is achieved and characteristics of sleep structure are extracted. The performance of the NSSPS is validated by transfer learning between radar signals with different frequency bands and crossvalidation among different subjects. Moreover, the NSSPS is demonstrated to estimate overnight parameters that are critical for sleep diagnosis. Benefiting from its low cost, convenient setup, and accurate prediction capability of sleep‐stage identification, the NSSPS can be widely deployed in “smart” homes and exploited to conduct daily sleep structure analysis.

Arctic-derived fungus Eutypella sp. D-1 has attracted wide attention due to its huge ability to synthesize secondary metabolites. However, current studies only focus on stimulating its production of new secondary metabolites by OSMAC strategies, and the relationship between secondary metabolites and biosynthetic gene clusters (BGCs) has not been explored. In this study, the preparation and regeneration conditions of Eutypella sp. D-1 protoplasts were explored to lay a foundation for the study of genetic transformation of this fungus. Orthogonal experiment showed that the optimal preparation conditions were 0.75 M NaCl, 20 g/L of lysing enzyme, and 20 g/L of driselase, 28°C for 6 h. The maximum yield of Eutypella sp. D-1 protoplasts could reach 6.15 × 106 cells·ml−1, and the concentration of osmotic stabilizer NaCl was the most important factor for Eutypella sp. D-1 protoplasts. The results of FDA staining showed that the prepared protoplasts had good activity. Besides, the best protoplasts regeneration medium was YEPS, whose maximum regeneration rate is 36%. The mediums with nitrogen sources, such as SR and RM, also had good effects on the Eutypella sp. D-1 protoplast regeneration, indicating that nitrogen sources played an important role on the Eutypella sp. D-1 protoplast regeneration. Subsequent transformation experiments showed that hygromycin resistance genes (hrg) could be successfully transferred into the genome of Eutypella sp. D-1, indicating that the prepared protoplasts could meet the needs of subsequent gene manipulation and research. This study lays a foundation for the genetic transformation of Eutypella sp. D-1.

Abstract Chimeric antigen receptor-based T-cell immunotherapy is a promising strategy for treatment of hematological malignant tumors; however, its efficacy towards solid cancer remains challenging. We therefore focused on developing nanobody-based CAR-T cells that treat the solid tumor. CD105 expression is upregulated on neoangiogenic endothelial and cancer cells. CD105 has been developed as a drug target. Here we show the generation of a CD105-specific nanobody, an anti-human CD105 CAR-T cells, by inserting the sequences for anti-CD105 nanobody-linked standard cassette genes into AAVS1 site using CRISPR/Cas9 technology. Co-culture with CD105+ target cells led to the activation of anti-CD105 CAR-T cells that displayed the typically activated cytotoxic T-cell characters, ability to proliferate, the production of pro-inflammatory cytokines, and the specific killing efficacy against CD105+ target cells in vitro. The in vivo treatment with anti-CD105 CAR-T cells significantly inhibited the growth of implanted CD105+ tumors, reduced tumor weight, and prolonged the survival time of tumor-bearing NOD/SCID mice. Nanobody-based CAR-T cells can therefore function as an antitumor agent in human tumor xenograft models. Our findings determined that the strategy of nanobody-based CAR-T cells engineered by CRISPR/Cas9 system has a certain potential to treat solid tumor through targeting CD105 antigen.

Our objective was to study the characteristics of patients with subjective tinnitus and normal hearing and to investigate whether the features correlated to different shapes on audiograms. In this retrospective study, 313 patients with subjective tinnitus and clinically normal hearing were enrolled from the tinnitus outpatient department of the Eye and ENT Hospital of Fudan University. The following phenotypic variables were collected: age, dominant tinnitus pitch (TP), tinnitus loudness, tinnitus duration, tinnitus severity, sex, education, hearing thresholds, tinnitus position, and tinnitus condition. The dominant TPs of patients with normal hearing were mostly high-pitched, with a mean of 4866.8 ± 2579.6 Hz; thus, we speculated that the condition is related to high-frequency hearing threshold elevations. We further divided the patients into four subgroups based on the matched TP: (i) TP ≤ 500 Hz (n = 34), (ii) 500 Hz < TP ≤ 3,000 Hz (n = 15), (iii) 3,000 Hz < TP ≤ 8,000 Hz (n = 259), and (iv) TP > 8,000 Hz (n = 5). We studied the phenotypic profiling of different audiograms and found that the group with TP of ≤500 Hz had an average “inverted-U” shaped audiogram, and the group with TP between 500 and 3,000 Hz had a slowly ascending slope audiogram below 2,000 Hz, followed by a drastically descending slope audiogram ranging from 2,000 to 8,000 Hz; further, the high-frequency (3,000–8,000 Hz) and ultra-high-frequency (>8,000 Hz) groups had flat curves below 2,000 Hz and steeper slope audiograms over 2,000 Hz. Our findings confirmed a consistency ratio between the distributions of dominant TPs and the frequencies of maximum hearing thresholds in both ears. The dominant TP was positively correlated with the maximum hearing threshold elevation frequency (left ear: r = 0.277, p < 0.05; right ear: r = 0.367, p < 0.001). Hearing threshold elevations, especially in high frequency, might explain the appearance of dominant high-frequency TP in patients without clinically defined hearing loss. This is consistent with the causal role of high-frequency coding in the generation of tinnitus.

Objective This study was conducted to explore the appropriate radical radiation dose in concurrent chemoradiotherapy (CCRT) for patients with inoperable stage II–III esophageal squamous cell carcinoma (ESCC). Methods This retrospective study included patients with esophageal cancer (EC) from the database of patients treated at the Affiliated Zhangjiagang Hospital of Soochow University (1/2015–12/2019). Overall survival (OS), progression-free survival (PFS), objective remission rate (ORR), first failure pattern, and toxicities were collected. Results 112 patients treated with intensity-modulated radiation therapy (IMRT) combined with concurrent chemotherapy of nedaplatin-based regimens were included. Fifty-eight (51.8%) and 54 (48.2%) patients received 60 (HD) and 50.4 (LD) Gy of radiotherapy, respectively. The HD group showed superior OS and a trend for longer PFS compared with the LD group (median OS: 25.5 vs 17.5 months, P = .021; median PFS: 14.0 vs 10.5 months, P = .076). There were more patients with a complete remission (CR) in the HD group than in the LD group (P=.016). The treatment-related toxicities were generally acceptable, but HD radiotherapy would increase the incidence of grade ≥3 late radiotoxicity (22.4% vs 5.6%, P = .011). Conclusion In nedaplatin-based CCRT for stage II–III ESCC, the radiotherapy dose of 60 Gy achieved a better prognosis. Strengths and limitations of this study A comparative study of 50.4 Gy and 60 Gy was conducted to evaluate whether 50.4 Gy can be used as a radical radiotherapy dose for inoperable stage II–III esophageal squamous cell carcinoma from a real-world perspective. The highly consistent selection criteria in our study make analysis results highly reliable and scientific. The existing research results support that nedaplatin can be used in concurrent chemoradiotherapy for esophageal squamous cell carcinoma, and this study focuses on the discovery of a better nedaplatin-based combination regimen. The findings of this study are limited to a single-center study with a non-large sample size. Inevitably, recall bias may exist in this retrospective study. Surgery was not involved in the follow-up treatment after concurrent chemoradiotherapy, which may worsen the prognosis of some patients.

Abstract Background Inner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages. Methods Here, we used Sox2 GFP/+ mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis. Results Consistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration. Conclusions In our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

The in-depth study of fungal secondary metabolites (SMs) over the past few years has led to the discovery of a vast number of novel fungal SMs, some of which possess good biological activity. However, because of the limitations of the traditional natural product mining methods, the discovery of new SMs has become increasingly difficult. In recent years, with the rapid development of gene sequencing technology and bioinformatics, new breakthroughs have been made in the study of fungal SMs, and more fungal biosynthetic gene clusters of SMs have been discovered, which shows that the fungi still have a considerable potential to produce SMs. How to study these gene clusters to obtain a large number of unknown SMs has been a research hotspot. With the continuous breakthrough of molecular biology technology, gene manipulation has reached a mature stage. Methods such as gene knockout and heterologous expression techniques have been widely used in the study of fungal SM biosynthesis and have achieved good effects. In this review, the representative studies on the biosynthesis of fungal SMs by gene knockout and heterologous expression under the fungal genome mining in the last three years were summarized. The techniques and methods used in these studies were also briefly discussed. In addition, the prospect of synthetic biology in the future under this research background was proposed.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an infectious disease that has become a serious burden on global public health. This study screened and yielded specific nanobodies (Nbs) against SARS-CoV-2 spike protein receptor binding domain (RBD), following testing its basic characteristics. A nanobody phage library was established by immunizing a camel with RBD protein. After three rounds of panning, the positive colonies were screened by enzyme-linked immunosorbent assay (ELISA). By sequencing, four different sequences of nanobody gene fragments were selected. The four nanobody fusion proteins were expressed and purified, respectively. The specificity and affinity of the four nanobodies were identified by ELISA. Our results showed that an immune phage display library against SARS-CoV-2 has been successfully constructed with a library capacity of which was 4.7 × 108 CFU. The four purified nanobodies showed specific high-affinity binding SARS-CoV-2 S-RBD. Among these, the antigen binding affinity of Nb61 was more comparable to that of commercial rabbit anti-SARS-CoV-2 S-RBD antibodies. In sum, our study has obtained four nanobody strains against SARS-CoV-2 S-RBD with significant affinity and specificity, therefore laying an essential foundation for further research as well as the applications of diagnostic and therapeutic tools of SARS-CoV-2.

The present study is to explore the anticancer effect of loonamycin (LM) in vitro and in vivo, and investigate the underlying mechanism with combined multi-omics. LM exhibited anticancer activity in human triple negative breast cancer cells by promoting cell apoptosis. LM administration inhibited the growth of MDA-MB-468 tumors in a murine xenograft model of breast cancer. Mechanistic studies suggested that LM could inhibit the topoisomerase I in a dose-dependent manner in vitro experiments. Combined with the transcriptomics and proteomic analysis, LM has a significant effect on O-glycan, p53-related signal pathway and EGFR/PI3K/AKT/mTOR signal pathway in enrichment of the KEGG pathway. The GSEA data also suggests that the TNBC cells treated with LM may be regulated by p53, O-glycan and EGFR/PI3K/AKT/mTOR signaling pathway. Taken together, our findings predicted that LM may target p53 and EGFR/PI3K/AKT/mTOR signaling pathway, inhibiting topoisomerase to exhibit its anticancer effect.

Aggregated eutectic intermetallic phases in a casting Mg-Ag-Al alloy were characterized using transmission electron microscopy. Three kinds of intermetallic phases, namely ε-Mg3Ag (or ε-Mg26−xAg7+x), β′-Mg2(Al,Ag)3, and γ-Mg17Al12, were observed to aggregate together following certain crystallographic orientation relationships (ORs) as: (001)ε//(11¯2)γ and [100]ε//[110]γ (OR1), (001)ε//(110)γ and [001]ε//[110]γ (OR2), (011¯)β′//(1¯10)γ and [100]β′//[110]γ, and (001)β′//(010)ε and [100]β′//[100]ε. TEM observations combined with the corresponding phase diagrams reveal that the ε phase firstly formed during solidification, then the γ phase nucleated on the ε phase, and finally, the β′ phase nucleated on the γ phase. This special intermetallic phase composition which owns numerous fine particles and many semi-coherent interphase boundaries results in high-strength and high-ductility for the casting QA61 alloy. Keywords: Magnesium alloys, Transmission electron microscopy (TEM), Intermetallic phase, Orientation relationship, Formation mechanism

The utricle is one of the five sensory organs in the mammalian vestibular system, and while the utricle has a limited ability to repair itself, this is not sufficient for the recovery of vestibular function after hair cell (HC) loss induced by ototoxic drugs. In order to further explore the possible self-recovery mechanism of the adult mouse vestibular system, we established a reliable utricle epithelium injury model for studying the regeneration of HCs and examined the toxic effects of 3,3′-iminodiproprionitrile (IDPN) on the utricle in vivo in C57BL/6J mice, which is one of the most commonly used strains in inner ear research. This work focused on the epithelial cell loss, vestibular dysfunction, and spontaneous cell regeneration after IDPN administration. HC loss and supporting cell (SC) loss after IDPN treatment was dose-dependent and resulted in dysfunction of the vestibular system, as indicated by the swim test and the rotating vestibular ocular reflex (VOR) test. EdU-positive SCs were observed only in severely injured utricles wherein above 47% SCs were dead. No EdU-positive HCs were observed in either control or injured utricles. RT-qPCR showed transient upregulation of Hes5 and Hey1 and fluctuating upregulation of Axin2 and β-catenin after IDPN administration. We conclude that a single intraperitoneal injection of IDPN is a practical way to establish an injured utricle model in adult C57BL/6J mice in vivo. We observed activation of Notch and Wnt signaling during the limited spontaneous HC regeneration after vestibular sensory epithelium damage, and such signaling might act as the promoting factors for tissue self-repair in the inner ear.

The aim of this study was to investigate the diagnostic performance of serum 1,3-β-D-gluan as biomarker for invasive fungal infection through meta-analysis.

Proximal sensing offers a novel means for determination of the heavy metal concentration in soil, facilitating low cost and rapid analysis over large areas. In this respect, spectral data and model variables play an important role. Thus far, no attempts have been made to estimate soil heavy metal content using continuum-removal (CR), different preprocessing and statistical methods, and different modeling variables. Considering the adsorption and retention of heavy metals in spectrally active constituents in soil, this study proposes a method for determining low heavy metal concentrations in soil using spectral bands associated with soil organic matter (SOM) and visible–near-infrared (Vis–NIR). To rapidly determine the concentration of heavy metals using hyperspectral data, partial least squares regression (PLSR), principal component regression (PCR), and support vector machine regression (SVMR) statistical methods and 16 preprocessing combinations were developed and explored to determine an optimal combination. The results showed that the multiplicative scatter correction and standard normal variate preprocessing methods evaluated with the second derivative spectral transformation method could accurately determine soil Cr and Ni concentrations. The root-mean-square error (RMSE) values of Vis–NIR model combinations with PLSR, PCR, and SVMR were 0.34, 3.42, and 2.15 for Cr, and 0.07, 1.78, and 1.14 for Ni, respectively. Soil Cr and Ni showed strong spectral responses to the Vis–NIR spectral band. The R2 value of the Vis–NIR-based PLSR model was higher than 0.99, and the RMSE value was 0.07–0.34, suggesting higher stability and accuracy. The results were more accurate for Ni than Cr, and PLSR showed the best performance, followed by SVMR and PCR. This perspective has critical implications for guiding quantitative biogeochemical analysis using proximal sensing data.

Abstract Tuberculosis, caused by Mycobacterium tuberculosis, affects the functions of the lung and causes high morbidity and mortality rates worldwide. MASP-2 is an executioner enzyme, which plays an essential role in the activation of lectin pathway. In our previous studies, the MASP-2 played a dual role in promoting the progress of lesions in BCG-infected rabbit skin models. However, the really effects of MASP-2 on tuberculosis are unknown. The aim of this study was to investigate the effects of MASP-2 in granuloma formation with BCG-infected mice. Compared to the control group, rAd-hMASP-2 treated group showed increasing in survival rate of BCG-infected mice (P = 0.042), and decreasing of bacteria loads (P = 0.005) in the lung tissue. MASP-2 displayed a protective efficacy in BCG-infected mice, which promoted the activation and recruitment of macrophages and lymphocytes to the granuloma. Moreover, the data obtained from the ELISA and RT-PCR demonstrated that mRNA expression for IL-6, CCL12, CCL2 and cytokines of IFN-γ, TNF-α in lung were significantly elevated by treatment of rAd-hMASP-2. Those findings provided an evidence that MASP-2 may be as a newly immunomodulatory in targeting granuloma formation, which displayed a potential protective role in control of tuberculosis.

Bike-sharing systems (BSS) have widely spread over many cities in the world as an environmentally friendly means to reduce air pollution and traffic congestion. This paper focuses on the bike-sharing rebalancing problem (BRP), which consists of two aspects: determining desired demands at each station and designing routes to redistribute bikes among stations. For the first task, we firstly apply the random forest, a very efficient machine learning algorithm, to forecast desired demands for each station, which can be easily implemented with distributed computing. For the second task, it belongs to the broad class of the vehicle routing problem with pickup and delivery (VRPPD). In most existing settings, all of the demands being strictly satisfied can lead to longer routes and add operational costs. In this paper, we propose a new model with unserved demands by relaxing demands satisfying constraints. Then, we design a distributed ant colony optimization (ACO) based algorithm with some specific modifications to increase its efficiency for the proposed model. We propose to use the percentage of average cost saving per bike as a metric to evaluate the performance of our method on cost-reducing and compare with existing methods and best-known values. Computational results on benchmarks show the advantage of our approach. Finally, we provide a real case study of BSS in Hangzhou, China, with insightful elaborations.

Libertellenone H (LH), a marine-derived pimarane diterpenoid isolated from arctic fungus Eutypella sp. D-1, has shown effective cytotoxicity on a range of cancer cells. The present study is to explore the anticancer effect of LH on human pancreatic cancer cells and to investigate the intracellular molecular target and underlying mechanism. As shown, LH exhibited anticancer activity in human pancreatic cancer cells by promoting cell apoptosis. Mechanistic studies suggested that LH-induced reactive oxygen species (ROS) accumulation was responsible for apoptosis as antioxidant N-acetylcysteine (NAC) and antioxidant enzyme superoxide dismutase (SOD) antagonized the inhibitory effect of LH. Zymologic testing demonstrated that LH inhibited Trx system but had little effect on the glutathione reductase and glutaredoxin. Mass spectrometry (MS) analysis revealed that the mechanism of action was based on the direct conjugation of LH to the Cys32/Cys35 residue of Trx1 and Sec498 of TrxR, leading to a decrease in the cellular level of glutathione (GSH) and activation of downstream ASK1/JNK signaling pathway. Taken together, our findings revealed LH was a marine derived inhibitor of Trx system and an anticancer candidate.

The choice and configuration of the ferroelectric (FE) substrate and the ferromagnetic (FM) layer in FM/FE heterostructures play an important role in magnetism modification with regard to amplitude and efficiency. In this study, we fabricated FeSi films on low crystalline (011) [Pb(Mg1/3Nb2/3)O3]0.7-[PbTiO3]0.3 (PMN-0.32PT) using radio frequency magnetron sputtering. In the annealed FeSi/(011) PMN-0.32PT heterostructures, the FeSi film presented with a (011) preferred orientated polycrystalline structure and low magnetocrystalline anisotropy. Both loop-like and butterfly-like magnetism modifications were observed by applying bipolar electric fields, and the weak and abnormal electrically mediated magnetism behaviors were significantly different from the prominent magnetic anisotropy transition in FeSi/(011) PMN-0.3PT. The comparative analyses suggest that the resulting high-quality single-crystalline PMN-xPT and FM films with low coercivity are of great significance for exploring giant, reversible, and non-volatile magnetism regulation.

Background: L-Arabinose is a non-caloric sugar, which could affect glucose and lipid metabolism and suppress obesity. However, few reports have described the effect of L-arabinose in metabolic syndrome, a combination of medical disorders that increase the risk of diabetes and cardiovascular disease. Objective: This study was conducted to explore the effects of L-arabinose in rats with metabolic syndrome induced by a high-carbohydrate, high-fat (HCHF) diet. Methods: After the rat model for metabolic syndrome was successfully established, L-arabinose was administrated by oral gavage for 6 weeks. The biochemical index and histological analysis were measured, and the expression levels of genes related to fatty acid metabolism were analyzed using real-time PCR. Results: Following treatment with L-arabinose, metabolic syndrome rats had an obvious reduction in body weight, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, total cholesterol, serum insulin, TNF-α, and leptin. Further study showed that treatment with L-arabinose significantly increased the expression of mRNA for hepatic CPT-1α and PDK4, but the expression of mRNA for hepatic ACCα was reduced. Conclusions: This work suggests that L-arabinose could lower body weight, Lee's index, and visceral index and improve dyslipidemia, insulin resistance, inflammation, and viscera function, which indicate that it might be a promising candidate for therapies combating metabolic syndrome.

Hair cell (HC) loss is irreversible because only very limited HC regeneration has been observed in the adult mammalian cochlea. Wnt/β-catenin signaling regulates prosensory cell proliferation and differentiation during cochlear development, and Wnt activation promotes the proliferation of Lgr5+ cochlear HC progenitors in newborn mice. Similar to Lgr5, Lgr6 is also a Wnt downstream target gene. Lgr6 is reported to be present in adult stem cells in the skin, nail, tongue, lung, and mammary gland, and this protein is very important for adult stem cell maintenance in rapidly proliferating organs. Our previous studies showed that Lgr6+ cells are a subpopulation of Lgr5+ progenitor cells and that both Lgr6+ and Lgr5+ progenitors can generate Myosin7a+ HCs in vitro. Thus we hypothesized that Lgr6+ cells are an enriched population of cochlear progenitor cells. However, the detailed distinctions between the Lgr5+ and Lgr6+ progenitors are unclear. Here, we systematically compared the proliferation, HC differentiation, and detailed transcriptome expression profiles of these two progenitor populations. We found that the same number of isolated Lgr6+ progenitors generated significantly more Myosin7a+ HCs compared to Lgr5+ progenitors; however, Lgr5+ progenitors formed more epithelial colonies and more spheres than Lgr6+ progenitors in vitro. Using RNA-Seq, we compared the transcriptome differences between Lgr5+ and Lgr6+ progenitors and identified a list of significantly differential expressed genes that might regulate the proliferation and differentiation of these HC progenitors, including 4 cell cycle genes, 9 cell signaling pathway genes, and 54 transcription factors. In conclusion, we demonstrate that Lgr6+ progenitors are an enriched population of inner ear progenitors that generate more HCs compared to Lgr5+ progenitors in the newborn mouse cochlea, and the our research provides a series of genes that might regulate the proliferation of progenitors and HC generation.

The emerging Bicycle Sharing System (BSS) provides a new social microscope that allows us to "photograph" the main aspects of the society and to create a comprehensive picture of human mobility behavior in this new medium. BSS has been deployed in many major cities around the world as a short-distance trip supplement for public transportations and private vehicles. A unique value of the bike flow data generated by these BSSs is to understand the human mobility in a short-distance trip. This understanding of the population on short-distance trip is lacking, limiting our capacity in management and operation of BSSs. Many existing operations research and management methods for BSS impose assumptions that emphasize statistical simplicity and homogeneity. Therefore, a deep understanding of the statistical patterns embedded in the bike flow data is an urgent and overriding issue to inform decision-makings for a variety of problems including traffic prediction, station placement, bike reallocation, and anomaly detection. In this paper, we aim to conduct a comprehensive analysis of the bike flow data using two large datasets collected in Chicago and Hangzhou over months. Our analysis reveals intrinsic structures of the bike flow data and regularities in both spatial and temporal scales such as a community structure and a taxonomy of the eigen-bike-flows.

Hair cell (HC) loss is the major cause of permanent sensorineural hearing loss in mammals. Unlike lower vertebrates, mammalian cochlear HCs cannot regenerate spontaneously after damage, although the vestibular system does maintain limited HC regeneration capacity. Thus HC regeneration from the damaged sensory epithelium has been one of the main areas of research in the field of hearing restoration. Hedgehog signaling plays important roles during the embryonic development of the inner ear, and it is involved in progenitor cell proliferation and differentiation as well as the cell fate decision. In this study, we show that recombinant Sonic Hedgehog (Shh) protein effectively promotes sphere formation, proliferation, and differentiation of Lgr5+ progenitor cells isolated from the neonatal mouse cochlea. To further explore this, we determined the effect of Hedgehog signaling on cell proliferation and HC regeneration in cultured cochlear explant from transgenic R26-SmoM2 mice that constitutively activate Hedgehog signaling in the supporting cells of the cochlea. Without neomycin treatment, up-regulation of Hedgehog signaling did not significantly promote cell proliferation or new HC formation. However, after injury to the sensory epithelium by neomycin treatment, the over-activation of Hedgehog signaling led to significant supporting cell proliferation and HC regeneration in the cochlear epithelium explants. RNA sequencing and real-time PCR were used to compare the transcripts of the cochleae from control mice and R26-SmoM2 mice, and multiple genes involved in the proliferation and differentiation processes were identified. This study has important implications for the treatment of sensorineural hearing loss by manipulating the Hedgehog signaling pathway.

Low fusion efficiency and nominal activity of fusion cells (FCs) restrict the clinical application of dendritic cell (DC)/tumor fusion cells. Collagen I (Col I) is an interstitial collagen with a closely-knit structure used to repair damaged cell membranes. This study evaluated whether Col I could improve the fusion efficiency of polyethylene glycol (PEG)-induction and enhance the immunogenicity of fusion vaccine. DC/B16 melanoma and controlled DC/H22 hepatoma cell fusions were induced by PEG with or without Col I. Col I/PEG treatment increased the levels of DC surface molecules and the secretion of lactate, pro- and anti-inflammatory cytokines in fusion cells. Col I/PEG-treated FCs enhanced T-cell proliferation and cytotoxic T lymphocyte activity. The Col I-prepared fusion vaccine obviously suppressed tumor growth and prolonged mice survival time. Thus Col I treatment could significantly improve the efficiency of PEG-induced DC/tumor fusion and enhance the anticancer activity of the fusion vaccine. This novel fusion strategy might promote the clinical application of DC/tumor fusion immunotherapy.

As a source of potent anti-inflammatory traditional medicines, the quantitative chromatographic fingerprints of sea urchin shell polysaccharides were well established via pre-column derivatization high performance liquid chromatography (HPLC) analysis. Based on the quantitative results, the content of fucose and glucose could be used as preliminary distinguishing indicators among three sea urchin shell species. Besides, the anti-inflammatory activities of the polysaccharides from sea urchin shells and their gonads were also determined. The gonad polysaccharide of Anthocidaris crassispina showed the most potent anti-inflammatory activity among all samples tested.

Background: Anthocyanins have been proven to be beneficial to the eyes. However, information is scarce about the effects of purple sweet potato (Ipomoea batatas, L.) anthocyanin (PSPA), a class of anthocyanins derived from purple sweet potato roots, on visual health. Objective: The aim of this study was to investigate whether PSPA could have influences on the growth characteristics (cellular morphology, survival, and proliferation) of human retinal pigment epithelial (RPE) cells, which perform essential functions for the visual process. Methods: The RPE cell line D407 was used in the present study. The cytotoxicity of PSPA was assessed by MTT assay. Then, cellular morphology, viability, cell cycle, Ki67expression, and PI3K/MAPK activation of RPE cells treated with PSPA were determined. Results: PSPA exhibited dose-dependent promotion of RPE cell proliferation at concentrations ranging from 10 to 1,000 µg/ml. RPE cells treated with PSPA demonstrated a predominantly polygonal morphology in a mosaic arrangement, and colony-like cells displayed numerous short apical microvilli and typical ultrastructure. PSPA treatment also resulted in a better platform growing status, statistically higher viability, an increase in the S-phase, and more Ki67+ cells. However, neither pAkt nor pERK were detected in either group. Conclusions: We found that PSPA maintained high cell viability, boosted DNA synthesis, and preserved a high percentage of continuously cycling cells to promote cell survival and division without changing cell morphology. This paper lays the foundation for further research about the damage-protective activities of PSPA on RPE cells or human vision.