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.

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.

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.

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.

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.

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.

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.

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.

A direct comparison of tumor angiogenesis with 68Ga-labeled NGR and RGD peptides in HT-1080 tumor xenografts using microPET imaging.

Peptides containing asparagine-glycine-arginine (NGR) and arginine-glycine-aspartic acid (RGD) sequence are being developed for tumor angiogenesis-targeted imaging and therapy. The aim of this study was to compare the efficacy of NGR- and RGD-based probes for imaging tumor angiogenesis in HT-1080 tumor xenografts. Two PET probes, (68)Ga-NOTA-G3-NGR2 and 68Ga-NOTA-G3-RGD2, were successfully prepared. In vitro stability, partition coefficient, tumor cell binding, as well as in vivo biodistribution properties were also analyzed for both PET probes. The results revealed that the two probes were both hydrophilic and stable in vitro and in vivo, and they were excreted predominately and rapidly through the kidneys. For both probes, the higher tumor uptake and lower accumulation in vital organs were determined. No significant difference between two probes was observed in terms of tumor uptake and the in vivo biodistribution properties. We concluded that these two probes are promising in tumor angiogenesis imaging. 68Ga-NOTA-G3-NGR2 has the potential as an alternative for PET imaging in patients with fibrosarcoma, and it may offer an opportunity to noninvasively monitor CD13-targeted therapy.

MicroPET imaging of CD13 expression using a (64)Cu-labeled dimeric NGR peptide based on sarcophagine cage.

CD13 receptor as a tumor vasculature biomarker has attracted great attention in cancer research. Through phage display screening, NGR-containing peptides have been characterized as specific ligands binding to CD13 receptor. In this study, a (64)Cu-labeled dimeric NGR peptide based on sarcophagine cage was synthesized and evaluated for micropositron emission tomography (PET) imaging of CD13 expression in vivo. Macrocyclic chelating agent (sarcophagine cage) was conjugated with two azide moieties, followed by mixing with an alkyne-containing NGR peptide to rapidly provide the Sar-NGR2 peptide by click chemistry. Radiolabeling of Sar-NGR2 with (64)Cu was achieved in >90% decay-corrected yield with radiochemical purity of >99%. The cell uptake study showed that (64)Cu-Sar-NGR2 binds to CD13-positive HT-1080 cells, but not to CD13-negative MCF-7 cells. MicroPET imaging results revealed that (64)Cu-Sar-NGR2 exhibits good tumor uptake in CD13-positive HT-1080 xenografts and significantly lower tumor uptake in CD13-negative MCF-7 xenografts. The CD13-specific binding of (64)Cu-Sar-NGR2 was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with coinjection of a nonradiolabeled NGR peptide. The biodistribution results demonstrated good tumor/muscle ratio (8.28 ± 0.37) of (64)Cu-Sar-NGR2 at 24 h pi in HT-1080 tumor xenografts, which is in agreement with the quantitative analysis of microPET imaging. In conclusion, sarcophagine cage has been successfully applied to the construction of a (64)Cu-labeled dimeric NGR-containing peptide. In vitro and in vivo studies demonstrated that (64)Cu-Sar-NGR2 is a promising PET probe for imaging CD13 expression in living mice.

68Ga-labeled cyclic NGR peptide for microPET imaging of CD13 receptor expression.

Peptides containing the asparagines-glycine-arginine (NGR) motif have been identified as specific ligands binding to CD13/aminopeptidase N (APN) receptor, a tumor neovascular biomarker. In this study, we synthesized a novel NGR-containing peptide (NOTA-G3-NGR), and labeled NOTA-G3-NGR with (68)Ga (t1/2 = 67.7 min). The resulting (68)Ga-NOTA-G3-NGR peptide was subject to in vitro and in vivo characterization. The microPET imaging results revealed that the (68)Ga-NOTA-G3-NGR peptide exhibits rapid and specific tumor uptake, and high tumor-to-background contrast in a subcutaneous HT-1080 fibrosarcoma mouse model. We concluded that the (68)Ga-NOTA-G3-NGR peptide has potential in the diagnosis of CD13-targeted tumor angiogenesis.

Effects of SARA on oxygen-glucose deprivation in PC12 cell line.

Ischemic stroke is a major composition of cerebrovascular disease, seriously threatening to human health in the world. Activin A (ActA), belonging to transforming growth factor-beta (TGF-ß) super family, plays an important role in the hypoxic-ischemic brain injury through ActA/Smads pathway. While as an essential phosphorylation assistor in TGF-ß signaling, the functions and mechanisms of smad anchor for receptor activation (SARA) in ischemic brain injury remain poorly understood. To solve this problem and explore the pathological processes of ischemic stroke, we used an Oxygen-Glucose deprivation (OGD) model in nerve growth factor-induced differentiated rattus PC12 pheochromocytoma cells and down regulated the expressions of SARA by RNA interference technology. Our results showed that the repression of SARA before OGD exposure reduced the expressions of Smad2, 3, 4 mRNA and the phosphorylation rate of Smad2 protein, but it did not affect the mRNA expressions of Smad7. After OGD treatment, ActA/Smads pathway was activated and the expression of SARA in the SARA pre-repression group was significantly up-regulated. The pre-repression of SARA increased the sensitivities of nerve-like cells to OGD damage. Moreover, the mRNA expression of Smad7 which was supposed to participate in the negative feedback of ActA/Smads pathway was also elevated due to OGD injury. Taken together, these results suggest a positive role of SARA in assisting the phosphorylation of Smad2 and maintaining the neuron protective effect of ActA/Smads pathway.

Endogenous protection derived from activin A/Smads transduction loop stimulated via ischemic injury in PC12 cells.

Activin A (ActA), a member of transforming growth factor-beta (TGF-b) super- family, affects many cellular processes, including ischemic stroke. Though the neuroprotective effects of exogenous ActA on oxygen-glucose deprivation (OGD) injury have already been reported by us, the endogenous role of ActA remains poorly understood. To further define the role and mechanism of endogenous ActA and its signaling in response to acute ischemic damage, we used an OGD model in PC12 cells to simulate ischemic injury on neurons in vitro. Cells were pre-treated by monoclonal antibody against activin receptor type IIA (ActRII-Ab). We found that ActRII-Ab augments ischemic injury in PC12 cells. Further, the extracellular secretion of ActA as well as phosphorylation of smad3 in PC12 cells was also up-regulated by OGD, but suppressed by ActRII-Ab. Taken together, our results show that ActRII-Ab may augment ischemic injury via blocking of transmembrane signal transduction of ActA, which confirmed the existence of endogenous neuroprotective effects derived from the ActA/Smads pathway. ActRIIA plays an important role in transferring neuronal protective signals inside. It is highly possible that ActA transmembrance signaling is a part of the positive feed-back loop for extracellular ActA secretion.

[Damage of seminiferous tubules in mouse testis caused by active immunization of actin-like protein 7a].

OBJECTIVE: To obtain recombinant sperm-protein actin-like protein 7a (ACTL7a) and detect the damage seminiferous tubules in mouse testis caused by anti-sperm antibodies generated by purified ACTL7a active immunization. METHODS: The recombinant expression plasmid pET30a-ACTL7a was constructed and then transformed into E. coli Rosseta (DE3). The protein expression was induced by isopropyl ß-D-1-thiogalactopyranoside (IPTG), and the protein was purified by nickel ions chelating resin. Finally, the protein was separated by sodium dodecyl sulfate poly-acrylamide gel electrophoresis (SDS-PAGE) and harvested by excising the gel containing target. ICR (Institute of Cancer Research) mice were then immunized using purified ACTL7a protein. The antibody titers were determined by ELISA and the development of seminiferous tubules after active immunization was stained by PAS staining. RESULTS: Induced by IPTG, the target protein ACTL7a was expressed in E. coli. After purification, it was used to immunize the ICR mice. As shown by PAS staining, spermatid expulsion, pyknotic cells, absence of germ cells, and germ cells degenerated were seen in the seminiferous tubules in the immunized testes. CONCLUSIONS: The ACTL7a prokaryotic expression vector was successfully constructed. High-purity target protein was obtained after induction and purification. After the active immunization with the target protein, the seminiferous tubules in the mouse testes will be severely damaged.