Toward a pan-SARS-CoV-2 vaccine targeting conserved epitopes on spike and non-spike proteins for potent, broad and durable immune responses.

BACKGROUND: The SARS-CoV-2 non-Spike (S) structural protein targets on nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, are grossly overlooked in COVID vaccine development. The current Spike-only vaccines bear an intrinsic shortfall for promotion of a fuller T cell immunity. Vaccines designed to target conserved epitopes could elicit strong cellular immune responses that would synergize with B cell responses and lead to long-term vaccine success. We pursue a universal (pan-SARS-CoV-2) vaccine against Delta, Omicrons and ever-emergent new mutants. METHODS AND FINDINGS: We explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation (N = 1,478) of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). This UB-612 booster vaccination is safe and well tolerated without SAEs. CONCLUSIONS: By targeting conserved epitopes on viral S2, M and N proteins, UB-612 could provide potent, broad and long-lasting B-cell and T-cell memory immunity and offers the potential as a universal vaccine to fend off Omicrons and new VoCs without resorting to Omicron-specific immunogens. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04773067; ClinicalTrials.gov ID: NCT05293665; ClinicalTrials.gov ID: NCT05541861.

Age-period-cohort analysis of kidney cancer deaths attributable to high body-mass index in China and U.S. adults.

BACKGROUND: Statistical data on burden of kidney cancer and the relavant risk factors are valuable for policy-making. This study aims to estimate kidney cancer deaths and high body-mass index (BMI) attributable to the deaths by gender and age group in China adults, compared with U.S. METHODS: We extracted kidney cancer data (1990-2017) about the age-standardized rates using the comparative risk assessment framework of the 2017 Global Burden of Disease study. We performed an age-period-cohort (APC) analysis to estimate trends of kidney cancer mortality attributable to high BMI. RESULTS: During 1990-2017, age-standardized mortality rate of kidney cancer was increasing in China but decreasing in U.S. The mortality attributable to high BMI in China showed a general increasing trend, while that in U.S. men was increasing and tended to be stable in women since 1995. APC analysis showed a similar pattern of age effect between China and U.S. adults, which substantially increased from 20 to 24 to 90-94 age group. Differently, the period effect rapidly increased in China than U.S. adults during 1990-2017. The cohort effect peaked in the earlier cohort born in 1902-1906 in China, and it declined consistently in U.S. with exception of 1902-1906 and 1907-1911 birth cohort. CONCLUSIONS: The kidney cancer deaths attributable to high BMI, and period effect have been generally increasing in China adults, compared with U.S. adults in which the trend tends to be stable in recent years. The rapid aging may also intensify the increasing trend of kidney cancer death in China. Effective measures should be conducted on body weight control and care for kidney cancer prevention.

Vertical graphene-base hot-electron transistor.

We demonstrate vertical graphene-base hot-electron transistors (GB-HETs) with a variety of structures and material parameters. Our GB-HETs exhibit a current saturation with a high current on-off ratio (>10(5)), which results from both the vertical transport of hot electrons across the ultrathin graphene base and the filtering of hot electrons through a built-in energy barrier. The influences of the materials and their thicknesses used for the tunneling and filtering barriers on the common-base current gain α are studied. The optimization of the SiO2 thickness and using HfO2 as the filtering barrier significantly improves the common-base current gain α by more than 2 orders of magnitude. The results demonstrate that GB-HETs have a great potential for high-frequency, high-speed, and high-density integrated circuits.

A Sustainable and Cost-Effective Nitrogen-Doped Three-Dimensional Porous Carbon for High-Performance Lithium-Sulfur Batteries.

Affordable clean energy is one of the major sustainable development goals that can transform our world. At present, researchers are working to develop cheap electrode materials to develop energy storage devices, the Lithium-sulfur (Li-S) battery is considered a promising energy storage device owing to its excellent theoretical specific capacity and energy density. Herein, utilizing the ramie degumming waste liquid as raw materials, after freeze-drying and high-temperature calcination, a sustainable and cost-effective three-dimensional (3D) porous nitrogen-doped ramie carbon (N-RC) was synthesized. The N-RC calcined at 800 °C (N-RC-800) shows a superior high specific surface area of 1491.85 m2 ⋅ g-1 and a notable high pore volume of 0.90 cm3 ⋅ g-1. When employed as a sulfur host, the S@N-RC-800 cathode illustrates excellent initial discharge capacity (1120.6 mAh ⋅ g-1) and maintains a reversible capacity of 625.4 mAh ⋅ g-1 after 500 cycles at 1 C. Simultaneously, the S@N-RC-800 cathode also shows excellent coulombic efficiency and ideal rate performance. Such exceptional electrochemical performance of S@N-RC-800 can be primarily attributable to N-RC's high specific surface area, high porosity, and abundant polar functional groups. This green and low-cost synthesis strategy offers a new avenue for harnessing the potential of waste biomass in the context of clean energy storage.

Direct imaging of thermally driven domain wall motion in magnetic insulators.

Thermally induced domain wall motion in a magnetic insulator was observed using spatiotemporally resolved polar magneto-optical Kerr effect microscopy. The following results were found: (i) the domain wall moves towards hot regime; (ii) a threshold temperature gradient (5 K/mm), i.e., a minimal temperature gradient required to induce domain wall motion; (iii) a finite domain wall velocity outside of the region with a temperature gradient, slowly decreasing as a function of distance, which is interpreted to result from the penetration of a magnonic current into the constant temperature region; and (iv) a linear dependence of the average domain wall velocity on temperature gradient, beyond a threshold thermal bias. Our observations can be qualitatively explained using a magnonic spin transfer torque mechanism, which suggests the utility of magnonic spin transfer torque for controlling magnetization dynamics.

A novel RBD-protein/peptide vaccine elicits broadly neutralizing antibodies and protects mice and macaques against SARS-CoV-2.

The development of safe and effective vaccines to respond to COVID-19 pandemic/endemic remains a priority. We developed a novel subunit protein-peptide COVID-19 vaccine candidate (UB-612) composed of: (i) receptor binding domain of SARS-CoV-2 spike protein fused to a modified single-chain human IgG1 Fc; (ii) five synthetic peptides incorporating conserved helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from SARS-CoV-2 structural proteins (three from S2 subunit, one from membrane and one from nucleocapsid), and one universal Th peptide; (iii) aluminum phosphate as adjuvant. The immunogenicity and protective immunity induced by UB-612 vaccine were evaluated in four animal models: Sprague-Dawley rats, AAV-hACE2 transduced BALB/c mice, rhesus and cynomolgus macaques. UB-612 vaccine induced high levels of neutralizing antibody and T-cell responses, in all animals. The immune sera from vaccinated animals neutralized the SARS-CoV-2 original wild-type strains and multiple variants of concern, including Delta and Omicron. The vaccination significantly reduced viral loads, lung pathology scores, and disease progression after intranasal and intratracheal challenge with SARS-CoV-2 in mice, rhesus and cynomolgus macaques. UB-612 has been tested in primary regimens in Phase 1 and Phase 2 clinical studies and is currently being evaluated in a global pivotal Phase 3 clinical study as a single dose heterologous booster.

A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants.

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

Effect of spatial charge inhomogeneity on 1/f noise behavior in graphene.

Scattering mechanisms in graphene are critical to understanding the limits of signal-to-noise ratios of unsuspended graphene devices. Here we present the four-probe low-frequency noise (1/f) characteristics in back-gated single layer graphene (SLG) and bilayer graphene (BLG) samples. Contrary to the expected noise increase with the resistance, the noise for SLG decreases near the Dirac point, possibly due to the effects of the spatial charge inhomogeneity. For BLG, a similar noise reduction near the Dirac point is observed, but with a different gate dependence of its noise behavior. Some possible reasons for the different noise behavior between SLG and BLG are discussed.

Single-crystalline Ni2Ge/Ge/Ni2Ge nanowire heterostructure transistors.

In this study, we report on the formation of a single-crystalline Ni(2)Ge/Ge/Ni(2)Ge nanowire heterostructure and its field effect characteristics by controlled reaction between a supercritical fluid-liquid-solid (SFLS) synthesized Ge nanowire and Ni metal contacts. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies reveal a wide temperature range to convert the Ge nanowire to single-crystalline Ni(2)Ge by a thermal diffusion process. The maximum current density of the fully germanide Ni(2)Ge nanowires exceeds 3.5 × 10(7) A cm(-2), and the resistivity is about 88 µΩ cm. The in situ reaction examined by TEM shows atomically sharp interfaces for the Ni(2)Ge/Ge/Ni(2)Ge heterostructure. The interface epitaxial relationships are determined to be [Formula: see text] and [Formula: see text]. Back-gate field effect transistors (FETs) were also fabricated using this low resistivity Ni(2)Ge as source/drain contacts. Electrical measurements show a good p-type FET behavior with an on/off ratio over 10(3) and a one order of magnitude improvement in hole mobility from that of SFLS-synthesized Ge nanowire.

[Ala499Val (C > T) and Lys939Gln (A > C) polymorphisms of the XPC gene: their correlation with male infertility].

OBJECTIVE: The Ala499Val (C > T) and Lys939Gln (A > C) of the XPC gene are two potentially functional nonsynonymous polymorphisms, which affect the rate of DNA repair and might change XPC production and activity. This study aimed to explore the distribution of these two polymorphisms in the Chinese Han population and their relationship with male infertility. METHODS: We genotyped the two polymorphisms of the XPC gene by the PCR-restriction fragment length polymorphism (PCR-RFLP) method in 318 infertile patients and 228 fertile male controls, detected the frequency of the alleles, and analyzed both the individual and the joint contribution of the two polymorphisms to male infertility. RESULTS: For the Ala499Val (C > T) polymorphism, the frequencies of the CC, CT, and TT genotypes were significantly different in distribution between the patients and the controls (P = 0.020). Males with the TT genotype had a lower risk of male infertility than those with the CC genotype (adjusted OR = 0.49, 95% CI: 0.23-0.88), and even lower than those with both CC and CT genotypes (adjusted OR = 0.39, 95% CI: 0.22-0.71). The Lys939Gln (A > C) polymorphism was not related with male infertility. The combined genotype analysis showed that the individuals with 1-4 risk alleles had a significantly higher risk of male infertility (adjusted OR = 2.75, 95% CI = 1.50-5.04) than those with 0 risk allele. CONCLUSION: The Ala499Val (C > T) polymorphism of the XPC gene is correlated with male infertility and may be a potential genetic risk factor for male infertility in the Chinese Han population.

The mortality of lung cancer attributable to smoking among adults in China and the United States during 1990-2017.

BACKGROUND: Statistical data on the burden and relevant risk factors of lung cancer are valuable for policy-making. This study aimed to compare the mortality of lung cancer attributable to smoking stratified by sex and age among adults in China and the United States (US). METHODS: We extracted age-standardized mortality rates of lung cancer during 1990-2017 using the comparative risk assessment framework of the 2017 Global Burden of Disease study. We performed an age-period-cohort analysis to estimate time trend of lung cancer mortality attributable to smoking. RESULTS: During 1990-2017, the age-standardized mortality rate of lung cancer was increasing in China but decreasing in the US for both sexes. The mortality attributable to smoking in China showed a generally increasing trend, while a continuous decrease was observed in the US. The age-period-cohort analysis showed a similar trend of age effect among adults between China and the US: the mortality substantially increased from the 30-34 to 80-84 age group and subsequently decreased in the 90-94 age group. However, the period effect rapidly increased in Chinese adults during 1990-2017, while it tended to be stable in the US although it was still slightly increasing in women. The cohort effect generally peaked in the earlier cohort born in 1902-1906 in the two countries. CONCLUSIONS: During 1990-2017, the lung cancer mortality attributable to smoking and the period effect are generally increasing in Chinese adults; the mortality attributable to smoking is decreasing in the US adults, but the period effect tends to be stable. The rapid aging and prevalence of smoking may intensify the increasing mortality of lung cancer in China.

The Relationship of Children's Intelligence Quotient and Blood Lead and Zinc Levels: a Meta-analysis and System Review.

The purpose of this study was to analyze the existing studies and to investigate the relationship between children's full-scale intelligence quotient (FIQ), verbal IQ (VIQ), and performance IQ (PIQ) and their blood lead (Pb) and zinc (Zn) levels. All documents in Chinese and English were collected from the PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases from inception date to December 30, 2016. RevMan software (version 5.2) was used for the meta-analysis and Stata software (version 12.0) for the meta-regression and sensitivity analyses. A total of 32 eligible literatures was included in the study. Seven prevalence studies showed that the blood Pb level was negatively correlated with children's IQ. The results of the meta-analysis from 22 case-control studies indicate a significant difference between FIQ and PIQ with blood Pb levels, detailed as the FIQ score with a weighted mean difference (WMD) = -6.60 (95% CI: -9.01, -4.20), P < 0.001; PIQ WMD = -8.85 (95% CI: -12.651, -5.05), P < 0.001; but VIQ WMD = -3.32 (95% CI: -6.98, 0.33), P > 0.05. Three studies on the blood Zn concentrations were with a FIQ WMD = 7.88 (95% CI: -0.07, 15.83), VIQ WMD = 7.73 (95% CI: -7.40, 22.86), and PIQ WMD = 6.69 (95% CI: -7.13, 20.51), all P > 0.05. The results indicate that Pb is harmful to children's intelligence development, especially in PIQ. Zn is beneficial to intelligence, although more studies are needed.

Different exposure levels of fine particulate matter and preterm birth: a meta-analysis based on cohort studies.

The previous studies estimated the association between PM2.5 (particulate matter with aerodynamic diameter less than or equal to 2.5 µm) exposure during pregnancy and preterm birth, only considered and highlighted the hazard effects of high levels of air pollutant exposure, and underestimated that low levels of pollutant exposure might also affect pregnancy outcome. We conducted a meta-analysis of 11 cohort studies, a total of more than 1,500,000 subjects. The results of these studies were pooled by exposure levels and study periods. PM2.5 exposure during pregnancy was positively associated with preterm birth (OR = 1.15, 95% CI = 1.07-1.23), and during the first trimester of pregnancy, low levels of PM2.5 exposure were also positively associated with preterm birth (OR = 1.17, 95% CI = 1.04-1.30). It is important to protect pregnant women from PM2.5 exposures, especially during their first trimester of pregnancy even when the ambient PM2.5 concentration is relatively low. More relevant health policy should be carried out to prevent hazard effect of air pollutants.

Genotoxicity of inorganic lead salts and disturbance of microtubule function.

Lead compounds are known genotoxicants, principally affecting the integrity of chromosomes. Lead chloride and lead acetate induced concentration-dependent increases in micronucleus frequency in V79 cells, starting at 1.1 microM lead chloride and 0.05 microM lead acetate. The difference between the lead salts, which was expected based on their relative abilities to form complex acetato-cations, was confirmed in an independent experiment. CREST analyses of the micronuclei verified that lead chloride and acetate were predominantly aneugenic (CREST-positive response), which was consistent with the morphology of the micronuclei (larger micronuclei, compared with micronuclei induced by a clastogenic mechanism). The effects of high concentrations of lead salts on the microtubule network of V79 cells were also examined using immunofluorescence staining. The dose effects of these responses were consistent with the cytotoxicity of lead(II), as visualized in the neutral-red uptake assay. In a cell-free system, 20-60 microM lead salts inhibited tubulin assembly dose-dependently. The no-observed-effect concentration of lead(II) in this assay was 10 microM. This inhibitory effect was interpreted as a shift of the assembly/disassembly steady-state toward disassembly, e.g., by reducing the concentration of assembly-competent tubulin dimers. The effects of lead salts on microtubule-associated motor-protein functions were studied using a kinesin-gliding assay that mimics intracellular transport processes in vitro by quantifying the movement of paclitaxel-stabilized microtubules across a kinesin-coated glass surface. There was a dose-dependent effect of lead nitrate on microtubule motility. Lead nitrate affected the gliding velocities of microtubules starting at concentrations above 10 microM and reached half-maximal inhibition of motility at about 50 microM. The processes reported here point to relevant interactions of lead with tubulin and kinesin at low dose levels.

[Clinical application and experimental studies of the pulsed inhaled nitric oxide flow controlling instrument].

A flow controlling system for pulsed inhaled nitric oxide has been developed and tested, and here its features and initial animal experiments and clinical applications are described. The physical characteristic test indicates that the practical released dose of NO gas is very close to the theoretical flow of NO gas at variant pressures. Animal experiments demonstrate that inhaled NO gas concentration is lower than the concentration of theoretical inhalation, but the variance is not remarkable (p>0.05). When sixteen cases with CHD and PH were chosen to inhale NO gas (15 ppm, 15 min) PAP and PVR of all cases were reduced after inhalation of NO gas from 617 +/-51.3 dyn x s x cm(-5), 54.4+/-13.1 mmHg to 417+/-36.9 dym x s x cm(-5), 33.8+/-12.3 mmHg (PVR, p<0.01; PAP, p<0.01) respectively. When gas inhalation was stopped, these values returned to their base lines after a short period of time. All these show that the pulsed inhaled NO flow controlling instrument in accordance with the requirements of the designing, can be widely used in clinical diagnoses and treatments and will be a new tool offered for the treatments of the patients with PH.

Quantum dot behavior in bilayer graphene nanoribbons.

Bilayer graphene has recently earned great attention for its unique electronic properties and commendable use in electronic applications. Here, we report the observation of quantum dot (QD) behaviors in bilayer graphene nanoribbons (BL-GNRs). The periodic Coulomb oscillations indicate the formation of a single quantum dot within the BL-GNR because of the broad distribution function of the carrier concentration fluctuation at the charge neutrality point. The size of the QD changes as we modulate the relative position between the Fermi level and surface potential. Furthermore, the potential barriers forming the QD remain stable at elevated temperatures and external bias. In combination with the observation of transport gaps, our results suggest that the disordered surface potential creates QDs along the ribbon and governs the electronic transport properties in BL-GNRs.

Very large magnetoresistance in graphene nanoribbons.

Graphene has unique electronic properties, and graphene nanoribbons are of particular interest because they exhibit a conduction bandgap that arises due to size confinement and edge effects. Theoretical studies have suggested that graphene nanoribbons could have interesting magneto-electronic properties, with a very large predicted magnetoresistance. Here, we report the experimental observation of a significant enhancement in the conductance of a graphene nanoribbon field-effect transistor by a perpendicular magnetic field. A negative magnetoresistance of nearly 100% was observed at low temperatures, with over 50% magnetoresistance remaining at room temperature. This magnetoresistance can be tuned by varying the gate or source-drain bias. We also find that the charge transport in the nanoribbons is not significantly modified by an in-plane magnetic field. The large observed values of magnetoresistance may be attributed to the reduction of quantum confinement through the formation of cyclotron orbits and the delocalization effect under the perpendicular magnetic field.

Synthesis of nanometre-thick MoO3 sheets.

The formation of MoO(3) sheets of nanoscale thickness is described. They are made from several fundamental sheets of orthorhombic alpha-MoO(3), which can be processed in large quantities via a low cost synthesis route that combines thermal evaporation and mechanical exfoliation. These fundamental sheets consist of double-layers of linked distorted MoO(6) octahedra. Atomic force microscopy (AFM) measurements show that the minimum resolvable thickness of these sheets is 1.4 nm which is equivalent to the thickness of two double-layers within one unit cell of the alpha-MoO(3) crystal.

Chemically induced folding of single and bilayer graphene.

Here we report chemically induced folding of thin graphene flakes. The folding occurs spontaneously when an intercalating species interrupts the adhesion between graphene and a supporting substrate. The morphology of induced folds suggests that the conjugated pi network is capable of extremely sharp curvature. Adjacent folds are often parallel, suggesting preferential deformation along certain crystallographic planes.