High-performance etchless lithium niobate layer electro-optic modulator enabled by quasi-BICs.

A facile strategy is proposed for a high-performance electro-optic modulator with an etchless lithium niobate (LN) layer assisted by the silicon resonator metasurface, which pioneers the way to engineer an ultra-sharp spectral line shape via the excitation of quasi-bound states in the continuum (BICs). Meanwhile, strong out-of-plane electric/magnetic fields within the proximity area to the electro-optic layer lead to ultra-sensitive modulations. As a result, only a slight voltage change of 0.2 V is needed to fully shift the resonances and then realize switching modulation between the "off" and "on" states. The findings pave new, to the best of our knowledge, insights in reconfiguration of spatial optical fields and offer prospects for functional optoelectronic devices.

Electromagnetic heating-assisted metasurface for stably tunable, fast-responding chiroptics.

Herein, a graphene-dielectric metasurface with the function of stably tunable and fast responding on the chiroptics is theoretically investigated and numerically demonstrated. Via utilizing the intrinsic thermo-optical effect of the silicon, the circular dichroism (CD) peak position can be linearly scaled with a spectral sensitivity of up to 0.06 nm/K by artificially adjusting the temperature. Moreover, a perfectly adjusting manipulation with a wavelength shift of full width at half maximum for the resonant spectrum and the simultaneously maintained CD values can be realized by a slight temperature variation of ∼0.8 K. Additionally, we take a graphene layer as the heating source to actually demonstrate the ultra-fast thermal generation. Applying an input voltage of 2 V to the graphene with only 10 µs can rapidly increase the metasurface temperature of up to 550 K. Such performances hold the platform with wide applications in functional chiroptics and optoelectronics.

Gradient-assisted metasurface absorber with dual-band chiral switching and quasi-linearly tunable circular dichroism.

Chiral metasurfaces with tunable or switchable circular dichroism (CD) responses hold great potential for advanced optical devices. In this work, we theoretically propose and numerically demonstrate a chiral metasurface absorber composed of periodically serrated Ge2Sb2Te5 (GST) resonators. By harnessing strong plasmonic resonance using the gradient geometry, we achieve a strongly enhanced chiral response with a CD value of 0.98 at λ2 = 2359 nm and a CD value of 0.7 at λ1 = 2274 nm. Additionally, by controlling the gradient difference in the serrated GST resonator, we can modify the CD intensity in multiple dimensions and near-perfectly optimize the chiral properties. Furthermore, it is worth noting that the CD value can be strongly varied by adjusting the phase transition characteristics of GST in the range of 0.007 to 0.7 at λ1 and 0.002 to 0.98 at λ2, corresponding to a switch between "on" and "off" states. The findings give new insight into multi-functional chiroptics and hold wide applications.

Near-perfect quantitatively tunable Q factors of quasi-bound states in the continuum via material-based thermal-optic perturbations.

We successfully achieved high-Q dual-band quasi-bound states in the continuum (BICs) by introducing geometrical perturbations and thermally induced material perturbations into silicon half-disk nanodimers. Importantly, it is found that the Q factor obtained from the thermally induced material perturbations fits better with the inverse quadratic function of the asymmetry relation than that of the geometrical-perturbations-based system. Notably, we demonstrated that changes occurring at the sub-K scale can enable the simultaneous realization of the full width at half maximum offset distance for quasi-BICs and a maximum contrast ratio exceeding 44 dB. Our research provides novel, to the best of our knowledge, insights for potential applications in nano-lasers, temperature sensors, and infrared imaging.

A Simple Kit Formulation for Preparation and Exploratory Human Studies of a Novel 99mTc-Labeled Fibroblast Activation Protein Inhibitor Tracer for Imaging of the Fibroblast Activation Protein in Cancers.

Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment because it is selectively expressed on the cell membrane of cancer-associated fibroblasts in most solid tumor stroma. The aim of this study was to develop a 99mTc-labeled fibroblast activation protein inhibitor (FAPI) tracer, evaluate its imaging efficacy in nude mice, and further explore its biodistribution in healthy volunteers and uptake in tumor patients. An FAPI-derived ligand (DP-FAPI) containing d-proline was designed and synthesized as a linker, and a stable hydrophilic 99mTc-labeled complex ([99mTc]Tc-DP-FAPI) was obtained by kit formulation. In vitro cellular uptake and saturation binding assays were performed in FAP-transfected HT-1080 cells (FAP-HT-1080). The biodistribution was characterized, and micro-single-photon emission computed tomography (SPECT) imaging was performed in BALB/c nude mice bearing U87 MG tumors. Furthermore, a first-in-man application was performed in four healthy volunteers and three patients with gastrointestinal tumors. In vitro, the nanomolar Kd values of [99mTc]Tc-DP-FAPI indicated that it had significantly high target affinity for FAP. Biodistribution and micro-SPECT imaging studies showed that [99mTc]Tc-DP-FAPI exhibited high uptake and high tumor-to-nontargeted ratios. The calculated effective dose for [99mTc]Tc-DP-FAPI was approximately <5 mSv in four healthy volunteers. In three patients with gastrointestinal tumors, [99mTc]Tc-DP-FAPI quantitative SPECT/CT revealed high and reliable uptake. [99mTc]Tc-DP-FAPI exhibited high selectivity and affinity for FAP in vitro. The safety and effectiveness of [99mTc]Tc-DP-FAPI in primary tumor imaging have been confirmed by animal and clinical studies, revealing the potential clinical application value of this tracer.

Central GLP-1 Resistance Induced by Severe Traumatic Brain Injury Was Associated with Persistent Hyperglycemia in Humans.

INTRODUCTION: Whether central glucagon-like peptide 1 (GLP-1)/GLP-1 receptor system mediated peripheral glucose homeostasis in patients with traumatic brain injury (TBI) is not clear. We aim to determine if plasma GLP-1 level could distinguish the non-survivors from the survivors during the first 14 days after TBI that could prognose 6 months mortality. METHODS: Metabolic, inflammatory, and hematologic profiles were examined in 73 patients with TBI in neurological intensive care unit. Factors that discriminate non-survivors from survivors were determined by two-way ANOVA. Biomarkers associated with mortality were determined by binary logistic regression and Cox proportional hazard regression. RESULTS: The non-survivors had higher infectious SOFA scores (p < 0.001), lower first 3 days' body temperature (p = 0.017), greater chance of cerebral hernia (p = 0.048), and decompressive craniectomy (p = 0.001) than the survivors. Higher 14-day plasma GLP-1 (p < 0.0001), glucose (p = 0.002), and IL-6 (p = 0.005) levels, in contrast with lower insulin level at days 4-7 (p = 0.020) were found in non-survivors than in survivors. Except the survivors who had an increased 14-day platelet number (p < 0.001), the two groups did not differ in hematological profile and intestinal barrier function. Although GLP-1 correlated closely with IL-6 in both the groups, it correlated with neither insulin nor glucose in each group. GLP-1 on days 8-10 and IL-6 on days 1-3 were positively, while insulin on days 4-7 was negatively associated with mortality. CONCLUSION: Persistent higher GLP-1 level in non-survivors over the survivors may present more severe central resistance to endogenous GLP-1 in non-survivors, which may be associated with progressive hyperglycemia with increased mortality in TBI.

Prognostic Significance of Plasma Insulin Level for Deep Venous Thrombosis in Patients with Severe Traumatic Brain Injury in Critical Care.

BACKGROUND: Whether insulin resistance underlies deep venous thrombosis (DVT) development in patients with severe traumatic brain injury (TBI) is unclear. In this study, the association between plasma insulin levels and DVT was analyzed in patients with severe TBI. METHODS: A prospective observational study of 73 patients measured insulin, glucose, glucagon-like peptide 1 (GLP-1), inflammatory factors, and hematological profiles within four preset times during the first 14 days after TBI. Ultrasonic surveillance of DVT was tracked. Two-way analysis of variance was used to determine the factors that discriminated between patients with and without DVT or with and without insulin therapy. Partial correlations of insulin level with all the variables were conducted separately in patients with DVT or patients without DVT. Factors associated with DVT were analyzed by multivariable logistic regression. Neurological outcomes 6 months after TBI were assessed. RESULTS: Among patients with a mean (± standard deviation) age of 53 (± 16 years), DVT developed in 20 patients (27%) on median 10.4 days (range 4-22), with higher Acute Physiology and Chronic Health Evaluation II scores but similar Sequential Organ Failure Assessment scores and TBI severity. Patients with DVT were more likely to receive insulin therapy than patients without DVT (60% vs. 28%; P = 0.012); hence, they had higher 14-day insulin levels. However, insulin levels were comparable between patients with DVT and patients without DVT in the subgroups of patients with insulin therapy (n = 27) and patients without insulin therapy (n = 46). The platelet profile significantly discriminated between patients with and without DVT. Surprisingly, none of the coagulation profiles, blood cell counts, or inflammatory mediators differed between the two groups. Patients with insulin therapy had significantly higher insulin (P = 0.006), glucose (P < 0.001), and GLP-1 (P = 0.01) levels and were more likely to develop DVT (60% vs. 15%; P < 0.001) along with concomitant platelet depletion. Insulin levels correlated with glucose, GLP-1 levels, and platelet count exclusively in patients without DVT. Conversely, in patients with DVT, insulin correlated negatively with GLP-1 levels (P = 0.016). Age (P = 0.01) and elevated insulin levels at days 4-7 (P = 0.04) were independently associated with DVT. Patients with insulin therapy also showed worse Glasgow Outcome Scale scores (P = 0.001). CONCLUSIONS: Elevated insulin levels in the first 14 days after TBI may indicate insulin resistance, which is associated with platelet hyperactivity, and thus increasing the risk of DVT.

Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg-1·d-1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ß-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.

Dynamically electrical/thermal-tunable perfect absorber for a high-performance terahertz modulation.

We present a high-performance functional perfect absorber in a wide range of terahertz (THz) wave based on a hybrid structure of graphene and vanadium dioxide (VO2) resonators. Dynamically electrical and thermal tunable absorption is achieved due to the management on the resonant properties via the external surroundings. Multifunctional manipulations can be further realized within such absorber platform. For instance, a wide-frequency terahertz perfect absorber with the operation frequency range covering from 1.594 THz to 3.272 THz can be realized when the conductivity of VO2 is set to 100000 S/m (metal phase) and the Fermi level of graphene is 0.01 eV. The absorption can be dynamically changed from 0 to 99.98% and in verse by adjusting the conductivity of VO2. The impedance matching theory is introduced to analyze and elucidate the wideband absorption rate. In addition, the absorber can be changed from wideband absorption to dual-band absorption by adjusting the Fermi level of graphene from 0.01 eV to 0.7 eV when the conductivity of VO2 is fixed at 100000 S/m. Besides, the analysis of the chiral characteristics of the helical structure shows that the extinction cross-section has a circular dichroic response under the excitation of two different circularly polarized lights (CPL). Our study proposes approaches to manipulate the wide-band terahertz wave with multiple ways, paving the way for the development of technologies in the fields of switches, modulators, and imaging devices.

Multiple resonant modes coupling enabled strong CD response in a chiral metasurface.

The chiral structures with strong circular dichroism (CD) response and narrow linewidth are desirable in chiral sensing, circularly-polarized light detection, and polarization imaging. Here, we theoretically proposed a hybrid chiral metasurface for differential absorption of circularly polarized light. Based on the multiple resonant modes coupling effect in a two-dimensional dielectric slab, it is realizable then to achieve a nearly perfect absorption for right circularly polarized light and simultaneously reflects 90% of left circularly polarized light, suggesting the generation of strong CD of 0.886 within a narrowly spectral linewidth of 4.53 nm. The multipole analysis reveals that the electric dipole, the magnetic dipole, and the electric quadrupole make dominant contributions to chiral absorption and the high CD response in this metsurface. The excitation of guided mode resonance enhances the ability of this metasurface to absorb electric field. Moreover, the optical chirality response can be further manipulated through the geometry features. These findings pave a powerful way to realize the narrowing and strong CD platform for single-band and multiband chirality behaviors.

Multiple dipolar resonant silicon-based metamaterials for high-performance optical switching and sensing.

Dielectric nanostructures reinforcing light-matter interactions by manipulating geometric parameters have a sound momentum in optoelectronic applications. Here, we construct and numerically demonstrate a new platform with multiple dipolar resonant behaviors or impressive switching operation and optical sensing with a high sensitivity and figure of merit (FOM) via the graphene-silicon combined metamaterials. Ultra-sharp resonances are excited by introducing broken symmetry in such all-dielectric metamaterials (ADMs) consisting of two silicon trapezoidal bodies on a silica substrate. By analyzing the distributions of the electromagnetic fields and current densities, we find that two types of multipole modes have been excited to support multiple ultra-narrowband resonances in the near-infrared range. The influence of geometers, such as period, thickness, asymmetry parameters, and polarization angle of the incident light, has also been studied. In addition, by adjusting the Fermi levels of graphene, we realize a 95% amplitude modulation efficiency, which manifests perfect capacity for an optical switch. According to the calculated results, the highest sensitivity can reach 447.5 nm/RIU and a large FOM is also up to 1173 RIU-1. This platform not only introduces new insight onto the achievement of high-quality ultra-sharp resonant responses but also offers a distinct possibility for the further development of high-quality related applications in optical sensors, notch filtering, strong light-matter interactions including the nonlinear optics, and multispectral optoelectronics.

[Changes of Inflammasome in Children with Immune Thrombocytopenia before and after Treatment].

OBJECTIVE: To clarify the significance of inflammasome NLRP3 in children with immune thrombocytopenia (ITP) by detecting its changes before and after treatment. METHODS: Twenty children with ITP diagnosed and treated in Xuzhou Children's Hospital were enrolled as observation group, and 10 healthy children as control group. The mRNA levels of NLRP3, ASC, and Caspase-1 were measured by real-time quantitative PCR (RT-qPCR), the serum levels of IL-18, IL-1ß, and high mobility group protein B1 (HMGB1) were detected by ELISA, and the protein level of NLRP3 was detected by Western blot. RESULTS: In newly diagnosed ITP children, the serum levels of IL-18, IL-1ß and HMGB1 significantly decreased after treatment (P<0.05). After treatment, NLRP3, ASC, and Caspase-1 mRNA levels in peripheral blood mononuclear cells were significantly lower than those before treatment (P<0.05). NLRP3 protein expression decreased significantly after treatment. CONCLUSION: Expression of NLRP3 inflammasome and downstream inflammatory factors are decrease after treatment in children with ITP, which may be used as effective prognostic markers.

The screening and identification of internalized nanobody against EpCAM / 药学学报

Epithelial cell adhesion molecule (EpCAM) is a popular target for cancer therapy. In this research, 3 nanobodies with high specificity and endocytosis activity against EpCAM were developed, which provides a basis for the study of immunotoxin based on EpCAM. In our preliminary experiments, we have immunized a camel with EpCAM-Fc antigen and constructed a high-quality phage display library. Seventeen nanobodies with different complementarity determining region (CDR) 3 sequences have been screened after 3 rounds of biopanning by phage display technology. The animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Fudan University School of Pharmacy. After purification, 7 nanobodies showed high cell binding activity by fluorescent activated cell sorting (FACS) identification. Furthermore, 3 nanobodies presented high endocytosis activity based on FACS and laser confocal microscopy, which also showed high affinity to EpCAM measured by ForteBio. According to this study, we aimed to provide a novel alternative approach to the EpCAM-targeted therapy and to provide guidance for the study of nanobody based immunotoxins for other targets.

A Hybrid Ensemble Model Based on ELM and Improved AdaBoost.RT Algorithm for Predicting the Iron Ore Sintering Characters.

As energy efficiency becomes increasingly important to the steel industry, the iron ore sintering process is attracting more attention since it consumes the second large amount of energy in the iron and steel making processes. The present work aims to propose a prediction model for the iron ore sintering characters. A hybrid ensemble model combined the extreme learning machine (ELM) with an improved AdaBoost.RT algorithm is developed for regression problem. First, the factors that affect solid fuel consumption, gas fuel consumption, burn-through point (BTP), and tumbler index (TI) are ranked according to the attributes weightiness sequence by applying the RReliefF method. Second, the ELM network is selected as an ensemble predictor due to its fast learning speed and good generalization performance. Third, an improved AdaBoost.RT is established to overcome the limitation of conventional AdaBoost.RT by dynamically self-adjusting the threshold value. Then, an ensemble ELM is employed by using the improved AdaBoost.RT for better precision than individual predictor. Finally, this hybrid ensemble model is applied to predict the iron ore sintering characters by production data from No. 4 sintering machine in Baosteel. The results obtained show that the proposed model is effective and feasible for the practical sintering process. In addition, through analyzing the first superior factors, the energy efficiency and sinter quality could be obviously improved.

Safety, pharmacokinetics, and biomarkers of F-652, a recombinant human interleukin-22 dimer, in healthy subjects.

F-652 is a recombinant fusion protein consisting of two human interleukin-22 (IL-22) molecules linked to an immunoglobulin constant region (IgG2-Fc). IL-22 plays critical roles in promoting tissue repair and suppressing bacterial infection. The safety, pharmacokinetics (PK), tolerability, and biomarkers of F-652 were evaluated following a single dose in healthy male volunteers in a randomized, double-blind, placebo-controlled study. Following single-dose subcutaneous (SC) injection of F-652 at 2.0 µg/kg into healthy subjects, six out of six subjects experienced delayed injection site reactions, which presented as erythematous and/or discoid eczematous lesions 10 to 17 days post-dosing. F-652 was then administered to the healthy subjects via an intravenous (IV) infusion at 2.0, 10, 30, and 45 µg/kg. No severe adverse event (SAE) was observed during the study. Among the IV-dosed cohorts, eye and skin treatment emergent adverse events (TEAEs) were observed in the 30 and 45 µg/kg cohorts. F-652 IV dosing resulted in linear increases in Cmax and AUC(0-t), and the T1/2 ranged from 39.4 to 206 h in the cohorts. An IV injection of F-652 induced dose-dependent increases in serum marker serum amyloid A, C-reactive protein, and FIB, and decreased serum triglycerides. The serum levels of 36 common pro-inflammatory cytokines/chemokines were not altered by the treatment of F-652 at 45 µg/kg. In conclusion, IV administration of F-652 to healthy male volunteers is safe and well-tolerated and demonstrates favorable PK and pharmacodynamic properties. These results warrant further clinical development of F-652 to treat inflammatory diseases.

Selenium-lentinan inhibits tumor progression by regulating epithelial-mesenchymal transition.

BACKGROUND: Selenium supplementation can be used to treat tumors. However, inorganic selenium is highly toxic, and natural organic selenium is extremely rare. Polysaccharides can improve drug bioavailability and targeting. Lentinan is a polysaccharide that has been approved as an anti-cancer drug in Japan and China. METHODS: Lentinan, an antitumor polysaccharide extracted from Lentinus edodes, was conjugated with seleninic acid to be transformed into ester (Se-lentinan) and utilized as drug carrier. The enhancement of the anti-tumor effects of Se-lentinan was evaluated by cell viability, cell cycle, migration, and transwell assays and animal xenograft models. The effects of Se-lentinan on the expression levels of epithelial-mesenchymal transition (EMT) markers were determined through immunofluorescence, Western blot, and immunohistochemistry analyses. RESULTS: Se-lentinan inhibited the invasiveness of B16-BL6 and HCT-8 cells by suppressing EMT. In vivo, Se-lentinan significantly inhibited tumor growth and metastasis of the transplanted melanoma and colon cancer cells and showed less toxicity than sodium selenite. Moreover, Se-lentinan reduced the accumulation of selenium in the liver and kidney tissues of mice and exhibited low organ toxicity. CONCLUSION: The antitumor activity of selenium was enhanced greatly, and its side effects were reduced with the use of lentinan as drug carrier.

Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction.

Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI). Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling. Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival. Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.

Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters.

Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.