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Metabolic reprogramming is a common phenomenon in cancer, with aerobic glycolysis being one of its important characteristics. Hypoxia-inducible factor-1α ( HIF1Α) is thought to play an important role in aerobic glycolysis. Meanwhile, naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits. In this work, we identified glycolytic genes related to HIF1Α by analyzing the colon cancer database. The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Α overexpression on glycolysis, and the proliferation and migration of colon cancer cells. Moreover, naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Α function. The results showed that the HIF1Α and enolase 2 ( ENO2) levels in colon cancer tissues were highly correlated, and their high expression indicated a poor prognosis for colon cancer patients. Mechanistically, HIF1Α directly binds to the DNA promoter region and upregulates the transcription of ENO2; ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells. Most importantly, we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α, which in turn decreased aerobic glycolysis in colon cancer cells. Generally, naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Α and the proliferation and invasion of colon cancer cells. This study helps to elucidate the relationship between colon cancer progression and glucose metabolism, and demonstrates the efficacy of naringin in the treatment of colon cancer.

Background We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1–2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. Methods This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18–59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. Findings Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744–2746) for the low-dose group, 2269 (1792–2873) for the medium-dose group, and 2895 (2294–3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85–135) in the low-dose group, 110 (87–140) in the medium-dose group, and 141 (111–179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836–11 815) in the low-dose group, 2338 (593–9226) in the medium-dose group, and 7069 (1361–36 725) in the high-dose group. Interpretation Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. Funding Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

BackgroundCOVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern.MethodsWe conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged ≥18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 μg of ancestral (D614) and 5 μg of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 ≥14 days after the second injection (post-dose 2 [PD2]).ResultsBetween 19 Oct 2021 and 15 Feb 2022, 12,924 participants received ≥1 study injection. 75% of participants were SARS-CoV-2 non-naïve. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) ≥14 days PD2 with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naïve and 30.9% (95% CI -39.3; 66.7%) in naïve participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile.ConclusionsA bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naïve adults 18–59 years of age.ClinicalTrials.govNCT04904549

In this work, rare-earth single atoms (La, Er) were decorated on the surface of 2D-TiO2 nanosheets by an impregnation-calcination strategy. The formation of rare-earth single atoms was certified by AC HAADF-STEM and XAS. TiO2 decorated with rare-earth single atoms (La1-TiO2 and Er1-TiO2) exhibited outstanding photocatalytic activity than pure 2D-TiO2 nanosheets (2D-TiO2) towards gas-phase degradation of O-xylene. Compared with 2D-TiO2, the rare-earth single atoms greatly improved the adsorption capacity of O-xylene without increasing their specific surface area. This is because rare-earth single atoms provide additional adsorption sites and reduce the adsorption energy of O-xylene. In addition, the hybrid orbital formed by the combination of rare-earth single atom and oxygen atom is beneficial to the rapid transmission and separation of photo-induced electrons, thereby improving the performance of photocatalytic degradation. In addition, in-situ DRIFTS and GC-MS were used to reveal the photocatalytic oxidation mechanism. Interestingly, the results showed that the La1-TiO2 and Er1-TiO2 samples can reduce the types of intermediates and simplify the reaction route, implying that the single atoms play an important role in the modulation and thorough mineralization of intermediate products. This work shows that the rare-earth single atom decorated 2D-TiO2 nanosheets have great potential in photocatalytic air pollution control.

Mutations in P/Q type voltage gated calcium channel (VGCC) lead severe human neurological diseases such as episodic ataxia 2, familial hemiplegic migraine 1, absence epilepsy, progressive ataxia and spinocerebellar ataxia 6. The pathogenesis of these diseases remains unclear. Mice with spontaneous mutation in the Cacna1a gene encoding the pore-forming subunit of P/Q type VGCC also exhibit ataxia, epilepsy and neurodegeneration. Based on the previous work showing that the P/Q type VGCC in neurons regulates lysosomal fusion through its calcium channel activity on lysosomes, we utilized CACNA1A mutant mice to further investigate the mechanism by which P/Q-type VGCCs regulate lysosomal function and neuronal homeostasis. We found CACNA1A mutant neurons have reduced lysosomal calcium storage without changing the resting calcium concentration in cytoplasm and the acidification of lysosomes. Immunohistochemistry and transmission electron microscopy reveal axonal degeneration due to lysosome dysfunction in the CACNA1A mutant cerebella. The calcium modulating drug thapsigargin, by depleting the ER calcium store, which locally increases the calcium concentration can alleviate the defective lysosomal fusion in mutant neurons. We propose a model that in cerebellar neurons, P/Q-type VGCC maintains the integrity of the nervous system by regulating lysosomal calcium homeostasis to affect lysosomal fusion, which in turn regulates multiple important cellular processes such as autophagy and endocytosis. This study helps us to better understand the pathogenesis of P/Q-type VGCC related neurodegenerative diseases and provides a feasible direction for future pharmacological treatment.

The effect of crystallization of y-Y2Si2O7 (Y-c and Y2S-c2)/Y4.67(SiO4)3O (Y2S-c1) single crystal or simultaneously y-Y2Si2O7, Al6Si2O13 and SiO2 crystals (YMS-c) on the hardness and thermal expansion coefficient (TEC) of Y2O3–Al2O3–SiO2 (YAS) glass is studied. Crystallization activation energy is 591, 650 and 282 kJ/mol for Y, Y2S and YMS glasses, crystallization mechanisms of glasses Y and Y2S (Tc1) are surface crystallization and one-dimensional crystal growth, while YMS glass is two- and one-dimensional growth of crystals. The volume fraction of crystalline phases in Y-c (91.45%), Y2S-c1 (83.00%) and -c2 (92.55%) glass ceramics are larger than that of YMS-c (71.11%), precipitated y-Y2Si2O7 single crystal decrease the TEC ( × 10−6 °C−1/30–1000 °C) of Y and Y2S parent glasses to 3.95 (Y-c) and 5.09 (Y2S-c2) while Y4.67(SiO4)3O single crystal increase the TEC of Y2S-c1 to 7.15, YMS-c has the smallest TEC (3.34) among studied glass ceramics, the enhancing effect of Y4.67(SiO4)3O on the hardness of Y2S glass is more than that of y-Y2Si2O7. Y and YMS glasses could be used as coating, sealing and jointing materials for SiC ceramics used in the high temperature fields.

Efficient propagation of spin waves in a magnetically coupled vortex is crucial to the development of future magnonic devices. Thus far, only a double vortex can serve as spin-wave emitter or oscillator; the propagation of spin waves in the higher-order vortex is still lacking. Here, we experimentally realize a higher-order vortex (2D vortex network) by a designed nanostructure, containing four cross-type chiral substructures. We employ this vortex network as a waveguide to propagate short-wavelength spin waves (∼100 nm) and demonstrate the possibility of guiding spin waves from one vortex to the network. It is observed that the spin waves can propagate into the network through the nanochannels formed by the Bloch-Néel-type domain walls, with a propagation decay length of several micrometers. This technique paves the way for the development of low-energy, reprogrammable, and miniaturized magnonic devices.

An effective method for controlling the corrosion rate of Mg-based implants must be urgently developed to meet the requirements of clinical applications. As a naturally occurring osteoid material, nacre offers a strategy to endow biomedical Mg alloys with excellent biocompatibility, and corrosion resistance. In this study, pearl powder and NaH2PO4 were used as precursors to deposit coatings on AZ91D alloy substrates hydrothermally based on Na2EDTA-assisted induction. Na2EDTA-induced nacre coatings were fabricated at various pH values, and its chemical composition and microstructure were analyzed via energy-dispersive X-ray, scanning electron microscopy, and X-ray diffraction spectroscopy. The corrosion-resistant performance and cytocompatibility of the samples were evaluated via electrochemical measurements and in vitro cell experiments. Results showed that the samples hydrothermally treated under faint acid conditions present excellent corrosion resistance, whereas the samples treated under slight alkaline conditions demonstrate improved biocompatibility due to high Ca and P content and large Ca/P atomic ratio. This study provides substantial evidence of the potential value of nacre coatings in expanding the biological applications of implanted biomaterials.

SummaryBackgroundThis study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM.MethodsThis Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18–59/≥60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5μg, 10μg or 15μg of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (NAbs) against the D614G variant are presented (primary objectives).FindingsOf 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received ≥1 injections (5μg, n=240; 10μg, n=239; 15μg, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 naïve participants at D36, 96·9%, 97.0% and 97·6% of participants had ≥4-fold-rise in NAb titres from baseline in the 5μg-, 10μg- and 15μg-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5μg-, 10μg- and 15μg-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-naïve adults after one injection were higher than titres after two injections in naïve adults.InterpretationTwo injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 naïve and non-naïve adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.

In this work, rare-earth single atoms (La, Er) were decorated on the surface of 2D-TiO

Mutations in P/Q type voltage gated calcium channel (VGCC) lead severe human neurological diseases such as episodic ataxia 2, familial hemiplegic migraine 1, absence epilepsy, progressive ataxia and spinocerebellar ataxia 6. The pathogenesis of these diseases remains unclear. Mice with spontaneous mutation in the Cacna1a gene encoding the pore-forming subunit of P/Q type VGCC also exhibit ataxia, epilepsy and neurodegeneration. Based on the previous work showing that the P/Q type VGCC in neurons regulates lysosomal fusion through its calcium channel activity on lysosomes, we utilized CACNA1A mutant mice to further investigate the mechanism by which P/Q-type VGCCs regulate lysosomal function and neuronal homeostasis. We found CACNA1A mutant neurons have reduced lysosomal calcium storage without changing the resting calcium concentration in cytoplasm and the acidification of lysosomes. Immunohistochemistry and transmission electron microscopy reveal axonal degeneration due to lysosome dysfunction in the CACNA1A mutant cerebella. The calcium modulating drug thapsigargin, by depleting the ER calcium store, which locally increases the calcium concentration can alleviate the defective lysosomal fusion in mutant neurons. We propose a model that in cerebellar neurons, P/Q-type VGCC maintains the integrity of the nervous system by regulating lysosomal calcium homeostasis to affect lysosomal fusion, which in turn regulates multiple important cellular processes such as autophagy and endocytosis. This study helps us to better understand the pathogenesis of P/Q-type VGCC related neurodegenerative diseases and provides a feasible direction for future pharmacological treatment.

Background Herpes simplex virus 2 (HSV2) causes genital herpes in >400 million persons worldwide. Methods We conducted a randomized, double-blinded, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults were enrolled in each of 3 serogroups of individuals: those negative for both HSV1 and HSV2 (HSV1−/HSV2−), those positive or negative for HSV1 and positive for HSV2 (HSV1±/HSV2+), and those positive for HSV1 and negative for HSV2 (HSV1+/HSV2−). Sixty participants received vaccine or placebo at 0, 1, and 6 months. The primary end point was the frequency of solicited local and systemic reactions to vaccination. Results Eighty-nine percent of vaccinees experienced mild-to-moderate solicited injection site reactions, compared with 47% of placebo recipients (95% confidence interval [CI], 12.9%–67.6%; P = .006). Sixty-four percent of vaccinees experienced systemic reactions, compared with 53% of placebo recipients (95% CI, −17.9% to 40.2%; P = .44). Seventy-eight percent of HSV1−/HSV2− vaccine recipients had a ≥4-fold increase in neutralizing antibody titer after 3 doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36%, 46%, and 27% of HSV1−/HSV2−, HSV1±/HSV2+, and HSV1+/HSV2− participants, respectively, 1 month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants, respectively. Conclusions HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV-seronegative vaccinees. Clinical Trials Registration NCT01915212.

This paper considers the problem of simultaneous testing of multiple hypotheses in a multi-stage group sequential setting subject to control over the false discovery rate (FDR). A multi-stage group sequential form of the BH procedure is developed, and a proof of its FDR control for p -values satisfying a positive dependence condition both between and within stages is given. This group sequential BH is adapted to the proportion of true nulls in two different ways, resulting in the proposal of two adaptive group sequential BH. While one of these adaptive procedures is theoretically shown to control its FDR when the p -values are positively dependent between but independent within stages, the other one’s FDR control is assessed through simulations. Comparative performance studies of the proposed procedures in terms of FDR control, power, and proportion of sample saved carried out through extensive simulations provide evidence of superior performance of the proposed adaptive procedures.

In this work, ultrathin WO3 nanosheets were prepared by self-assembly approach and their phase and morphology were regulated by changing the heat treatment temperature. Then, g-C3N4 modified WO3 nanosheets sensitive material was fabricated via a facile liquid ultrasonic mixing method. The microstructure, morphology, chemical composition, oxidation state and surface area of WO3 nanosheets and g-C3N4/WO3 nanocomposite were comparatively studied by X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscope (TEM), X-ray Photoelectron Spectroscopy (XPS), and Brunauer-Emmett-Teller (BET). Sensing performances of WO3 nanosheets and g-C3N4/WO3 composite with different g-C3N4 loading amount were investigated with acetone as a target gas. Compared to WO3 nanosheets, the g-C3N4/WO3 gas sensor exhibits good response, excellent selectivity, transient response and trace detection ability to acetone vapor. Effects of g-C3N4 content on gas sensitivity were also investigated. The response (Ra/Rg) of the gas sensor based on 1 wt% g-C3N4/WO3 was 35 toward 100 ppm acetone at 340 °C, which was about 300% higher than the response value of pure WO3 sensor. The sensor also showed a fast response/recovery speed (9 s/3.8 s) and a wide linear detection range (from 0.5 ppm to 500 ppm). These unique sensing properties were attributed to the synergistic effects including the contribution of WO3 ultrathin nanosheets, suitable crystal phase and porous surface, and the sensitization of g-C3N4, which increases the specific surface area and regulates the electrical properties. This work will contribute to the development of new acetone sensors and expand the application of g-C3N4 composite materials.

In this article, we demonstrated an extremely high-sensitivity formaldehyde (HCHO) gas sensor, where the graphene oxide (GO) in situ modified two-dimensional (2D) SnO2 nanosheets with in-plane mesopores were utilized as the sensing materials. The sensor response ( Ra/ Rg) was larger than 2000 toward 100 ppm HCHO at 60 °C. In addition, the selectivity for detecting HCHO was excellent against other interferences including ethanol, acetone, methanol, toluene, ammonia, water, etc. The outstanding sensing performance of 2D mesoporous GO/SnO2 nanosheets was attributed to the synergism of the sensitizer effect of GO, large surface areas of 2D nanostructure, suitable particle size, and abundant in-plane mesopores. The high sensitivity, high selectivity, and low working temperature of the sensor reported here endowed it a great potential in selective detection of HCHO. Meanwhile, the design and synthesis of GO/SnO2 nanocomposites will provide new paradigms in the future development of HCHO-sensitive materials.

Nickel-iron-based layered double hydroxides (NiFe LDHs) have attracted tremendous research and industrial interests for oxygen evolution reaction (OER) electrocatalysis. However, methodologies on simultaneous regulation of performance-influencing factors remain scarce and their real synergistic effects are not clear enough. Herein, a versatile polyoxometallic acids (POMs) etching approach is reported to ingeniously reconstruct NiFe LDH, including 3D morphological nanotailoring, Fe

Vertically aligned InGaN/GaN nanorod arrays with multiple quantum wells (MQWs) was prepared via inductively coupled plasma (ICP) followed by a further anisotropic wet etching method. It was demonstrated that the sizes of nanorods could be easily regulated in the ranges of 330–1090 nm by simply controlling the ICP etch parameters. The morphology characterisation results indicated that these nanorods are of straight and smooth appearance, and the length of nanorods is about 4 μm. Ultraviolet (UV) detectors based on nanorods arrays with different diameters were fabricated, which exhibited fast response/recovery speed and good response. The UV detecting performance was getting better with the decrease of nanorods diameter, which may be caused by the suppression of the dark current. This work provides an efficient route for fabricating the large-scale vertical aligned MQWs nanorods array and developing their fascinating applications.

We report a feasible strategy via hydrothermal crystallization to activate Kagome lattice-structured Cu3V2O7(OH)2·2H2O volborthite mineral as a stable visible-light-driven photocatalyst. It was demonstrated to play a crucial role in stimulating absorption ability and photodegradation performance for the removal of methylene blue present in high concentration. In contrast, direct calcination was almost ineffective, whereas post-calcination was significantly detrimental. Moreover, the photocatalytic water oxidation activity of hydrothermally crystallizated volborthite was comparable to that of BiVO4, and it was clearly higher than those of WO3 and g-C3N4 from aqueous NaIO3 solution. By further in situ decoration with an optimum amount of CoOx cocatalysts (i.e., 2 wt%), the oxygen evolution rate of volborthite was greatly enhanced, and it was 1.6-fold, 1.8-fold and 2.9-fold higher than those of BiVO4, WO3 and g-C3N4, respectively. The importance of hydrothermal crystallization can be elucidated in terms of water-Kagome lattice structure interactions involving built-in intrinsic electric field and formation of single hydrogen bonds.

Magnesium-based metal glasses (MMGs) have broad application potential as bio-implant materials because of their disordered atomic structure, fine degradability, low elasticity modulus, and high strength. However, their low plasticity and poor corrosion resistance limit their application. In the present study, Mg-Zn-Yb-Ag metallic glasses were fabricated by injecting into a copper roller. The addition of trace amounts of ytterbium (Yb) and precious metal silver significantly improved the ductility of MMGs under bending and tensile loading. The results show that the amorphous alloy with 4 at% of Yb exhibits optimum specific strength mainly because of high-density coarsening shear bands. Electrochemical experiments, immersion test, and analysis of corrosion products by XPS and EDS after immersion showed that the amorphous alloy with 4 at% of Yb exhibits the greatest corrosion resistance among the four samples because of rare earth (Yb) oxide film. The addition of the appropriate amount of the rare-earth element Yb to amorphous Mg-based alloys can not only remarkably influence the alloy plasticity but also improve the alloy corrosion resistance, thereby increasing the alloy application prospects.

Hollow SnO 2 nanofibers were prepared by electrospinning followed by calcination treatment. The carbon materials including graphene, carbon nanotubes and graphene oxide (GO) were utilized as sensitization materials to enhance the formaldehyde (HCHO) sensing properties. The results showed that the HCHO sensing properties of hollow SnO 2 nanofibers were greatly improved by mixing with a small amount of GO. X-ray diffraction (XRD), Field emission scanning electron microscopy (FE-SEM), Transmission Electron Microscope (TEM), X-ray photoelectron spectroscopy (XPS), and Brunauer-Emmett-Teller (BET) were used to characterize their microstructures, morphologies, compositions and surface areas. The effect of GO loading amount in the nanocomposites on the sensing performances was also investigated. 1 wt% GO was the optimized loading amount and the response value reached 32 under the exposure of 100 ppm HCHO at the optimum temperature of 120 °C, which was 4 times higher than that of hollow SnO 2 nanofibers. The detection limit of HCHO was as low as 500 ppb. The unique sensing properties were attributed to the synergistic effects of hollow SnO 2 nanofibers and GO nanosheets network, including large specific surface area, rich functional groups and the electric regulation effects of GO.

Austenite stainless steels with gradient nanostructure exhibit exceptional combination of high yield strength and high ductility. In order to describe their structure-property relation, a theoretical model is proposed in this work, in which the depth-dependent bimodal grain size distribution and nanotwin-nanograin composite structure are taken into account. The micromechanical model and the Voigt rule of mixture are adopted in deriving the constitutive relations. Furthermore, the evolution and influence of the nano/micro cracks/voids are considered for predicting the failure strain. The numerical results based on the theoretical model agree well with experimental results in terms of the yield strength, ductility, and the strain hardening rate, demonstrating that the proposed model can well describe the mechanical properties of gradient-nanostructured austenite stainless steels. We further study the variations of the yield strength and ductility of gradient-nanograined and gradient-nanotwinned 304 stainless steels with different distribution of grain size and twin spacing along the depth, which shows that the present model can be applied to optimize the combination of strength and ductility of the gradient-nanostructured metals by tuning depth-dependent distributions of microstructures.

A hierarchical nanoporous gold (HNPG) membrane with a bimodal pore size distribution was fabricated by a simple one-step dehydration reaction of H3BO3, which is different from the complex methods of multi-cyclic electrochemical co-alloying/dealloying. The HNPG exhibits a wide pore distribution from 10 to 120 nm. The special architecture of HNPG significantly enhances the Raman signal to crystal violet and electrocatalytic activity toward the oxidation of methanol. The formation mechanism of the bimodal structure is discussed.

Element doping is recognized as a powerful way to modify surface defect structure and further enhance the fluorescence performance of graphene quantum dots (GQDs). N-doped, S-doped and S, N co-doped GQDs were synthesized to explore the influence of element doping on fluorescence sensing of dopamine (DA) biomolecules. Two interesting works are found, one is that the N-doped GQDs with urea as N source are more effective than the S-doped and S,N co-doped GQDs, characterized by the higher quantum yield (QY) up to 78% and sensitive fluorescence quenching performance to DA. The other is that the N-doped GQDs with ethylenediamine as N source have the highest QY up to 95%, however, exhibits no quenching performance to DA. This abnormal observation is discussed based on the microstructure analysis. Under the optimal reaction condition, the N-doped GQDs exhibit a dual linear relationship of quenching intensity with DA concentration in the range of 10–3000 nM and 3000–7000 nM with detection limits of 3.3 and 611 nM, respectively. The quenching mechanism of N-doped GQDs toward DA is explored from the view of N chemical states, biomolecule structure of DA homologues and redox reaction of DA.

Background MenACYW-TT is a new quadrivalent meningococcal conjugate vaccine approved by the US FDA for use in individuals 2 years and older. We present the structured benefit-risk assessment conducted by Sanofi Pasteur in support of the initial biological license application for MenACYW-TT. Methods The safety and immunogenicity of MenACYW-TT in subjects ≥ 2 years was evaluated in 5 pivotal randomized, active-controlled clinical trials. Collectively, 4,919 subjects received either a single primary dose (n=4517) or a booster dose (n=402) of MenACYW-TT. A semi-quantitative framework was used to establish favorable and unfavorable effects of MenACYW-TT relative to comparators: MenACWY-CRM in children 2-9 years and adolescents 10-17 years, MenACWY-D in adolescents 10-17 years and adults 18-55 years, and MPSV4 in older adults ≥ 56 years. Benefit outcome measures included vaccine seroresponse and seroprotection (titers ≥ 1:8) at D30 evaluated by serum bactericidal assay using human complement, for each serogroup. Risk outcome measures included rates of solicited injection site and systemic reactions (including grade 3 reactions) within 7 days after vaccination, and rates of serious adverse events within 6 months after vaccination. The differences in rates for MenACWY-TT vs comparator vaccines were calculated along with 95% confidence intervals. Results For all benefit criteria, and in all age groups, rate differences favored MenACYW-TT in meningococcal vaccine-naïve individuals. Immune response differences were more pronounced for serogroup C. Differences showed favorable (seroresponse criteria) or comparable (seroprotection criteria) effects for MenACYW-TT in adolescents and adults previously primed with MenACWY-D or MenACWY-CRM. For the risk criteria, rate differences generally showed comparable effects between MenACYW-TT and MenACWY-D or MenACWY-CRM in children, adolescents and adults, while the rate differences for both solicited injection site and systemic reactions favored MPSV4 in older adults. The latter was possibly due to the use of a protein carrier in MenACYW-TT. Conclusion The benefit risk-profile of MenACYW-TT in individuals ≥ 2 years is considered favorable relative to comparator licensed vaccines. Disclosures David Neveu, MPharm, Sanofi Pasteur (Employee) Marie-Laure Kürzinger, MSc, Sanofi (Employee) Aiying Chen, PhD, Sanofi Pasteur (Employee) Mandeep S. Dhingra, MD, Sanofi Pasteur (Employee)

Cancer is becoming a collection of “niche diseases” defined by the molecular subtypes. Such understanding forms the basis of the basket trial, which pools together multiple cohorts of patients with the same molecular subtype across different tumor indications and thus facilitates the development of targeted therapies. Efficient pruning is critical in basket designs as it ensures the internal consistency of the selected indications and improves the probability of success on the selected pool of indications. In this article, we consider pruning both inactive and extremely active indications and propose a group sequential enrichment design with testing procedures to both control the family-wise error rate (FWER) in the weak sense and maintain the power for basket trials with such pruning strategy. We compare the proposed design with a relevant design which prunes only unresponsive subgroups. The total misclassification rates and misclassification rates among truly unresponsive indications are smaller...

A novel kind of highly efficient photocatalyst composed of ultrathin P doped ZnO (ZnO:P) nanosheets decorated with graphene nanodots (GNDs) was fabricated. Taking the unique advantages of the ultrathin ZnO nanosheet structure, and the excellent properties of the GNDs, a 1.6 wt% ZnO:P/GNDs nanosheet composite exhibited an optimum visible-light photocatalytic oxidation activity of 0.442 min−1 for RhB degradation and an excellent photostability over five cycles. This can be attributed to the synergistic effect between the ZnO:P nanosheets and GNDs, leading to a significantly enhanced charge efficiency and visible light absorption.

The construction and control of high‐order coupled vortices are a significant challenge for promoting the application of magnetic vortices. Thus far, only double‐coupled vortices have been produced and modulated in some ferromagnetic nanostructures. Here, an effective approach is provided to obtain a high‐order coupled vortex structure by using a chiral nanostructure. Double‐vortex, triple‐vortex, and n‐vortex chains can be successfully constructed using structured Fe4N nanostrips and bias nanomagnets. The designed chiral nanostructure cannot only control the transport and hybridization of vortices but also modulate the domain walls of the vortex chain for spin wave (SW) propagation. At the exciting frequency of 1.2 GHz, the SW propagates along the domain walls formed in the vortex chain. Upon increasing the frequency to 5.0 GHz, the SW gradually spreads from the domain walls into domains. This technique will present a new perspective for the design and application of magnetic vortex‐based devices., An effective approach to obtain a 1D vortex chain by using a chiral nanostructure is provided. Double‐vortex, triple‐vortex, and n‐vortex chain are constructed using structured Fe4N nanostrips and bias nanomagnets. The spin wave propagates along the domain walls formed in the vortex chain at the frequency of 1.2 GHz, and spreads from the domain walls into domains at 5.0 GHz.

A novel isotype heterojunction ultraviolet photodetector was fabricated by growing n-ZnO nanorod arrays on n-GaN thin films and then spin-coated with graphene quantum dots (GQDs). Exposed to UV illumination with a wavelength of 365 nm, the time-dependent photoresponse of the hybrid detectors manifests high sensitivity and consistent transients with a rise time of 100 ms and a decay time of 120 ms. Meanwhile, an ultra-high specific detectivity (up to ~ 1012 Jones) and high photoresponsivity (up to 34 mA W−1) are obtained at 10 V bias. Compared to the bare heterojunction detectors, the excellent performance of the GQDs decorated n-ZnO/n-GaN heterostructure is attributed to the efficient immobilization of GQDs on the ZnO nanorod arrays. GQDs were exploited as a light absorber and act like an electron donor to effectively improve the effective carrier concentration in interfacial junction. Moreover, appropriate energy band alignment in GQDs decorated ZnO/GaN hybrids can also be a potential factor in facilitating the UV-induced photocurrent and response speed.

We report a feasible strategy via hydrothermal crystallization to activate Kagome lattice-structured Cu3V2O7(OH)2·2H2O volborthite mineral as a stable visible-light-driven photocatalyst. It was demonstrated to play a crucial role in stimulating absorption ability and photodegradation performance for the removal of methylene blue present in high concentration. In contrast, direct calcination was almost ineffective, whereas post-calcination was significantly detrimental. Moreover, the photocatalytic water oxidation activity of hydrothermally crystallizated volborthite was comparable to that of BiVO4, and it was clearly higher than those of WO3 and g-C3N4 from aqueous NaIO3 solution. By further in situ decoration with an optimum amount of CoOx cocatalysts (i.e., 2 wt%), the oxygen evolution rate of volborthite was greatly enhanced, and it was 1.6-fold, 1.8-fold and 2.9-fold higher than those of BiVO4, WO3 and g-C3N4, respectively. The importance of hydrothermal crystallization can be elucidated in terms of water-Kagome lattice structure interactions involving built-in intrinsic electric field and formation of single hydrogen bonds.

Glucagon-like peptide 1 receptor (GLP-1R) agonists administered before or immediately after induction of experimental stroke have been shown to provide acute neuroprotection. Here, we determined whether delayed treatment with a GLP-1R agonist could improve metabolic and functional recovery after stroke. Rats were subjected to middle cerebral artery occlusion (MCAO) and given the well-established GLP-1R agonist liraglutide (50, 100, or 200μg/kg) or normal saline (NS) daily for 4 weeks, starting 1 day after MCAO. Cerebral glucose metabolism and neurological deficits were evaluated using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging and modified neurological severity score (mNSS) test. Levels of neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), von Willebrand factor (vWF), and GLP-1R were assessed by immunohistochemical staining and Western blot analysis. PET imaging showed that animals treated with liraglutide had significantly higher 18F-FDG accumulation in the cerebral infarction compared with animals treated with NS. Liraglutide significantly reduced the mNSS score. It also greatly increased the expression of NeuN, GFAP, vWF, and GLP-1R in the cerebral ischemic area at postoperative week 4. These results demonstrated metabolic and functional recovery after delayed treatment with liraglutide in a rat model of cerebral ischemia.