A Thermostable mRNA Vaccine against COVID-19.

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.

An accumulated mutation gained in mosquito cells enhances Zika virus virulence and fitness in mice.

Zika virus (ZIKV) remains a significant public health threat worldwide. A number of adaptive mutations have accumulated within the genome of ZIKV during global transmission, some of which have been linked to specific phenotypes. ZIKV maintains an alternating cycle of replication between mosquitoes and vertebrate hosts, but the role of mosquito-specific adaptive mutations in ZIKV has not been well investigated. In this study, we demonstrated that serial passaging of ZIKV in mosquito Aag2 cells led to the emergence of critical amino acid substitutions, including A94V in the prM protein and V153D and H401Y in the E protein. Further characterization via reverse genetics revealed that the H401Y substitution in the E protein did not augment viral replication in mosquitoes but significantly enhanced neurovirulence and lethality compared with those of the wild-type (WT) virus in mice. More importantly, the H401Y mutant maintained its virulence phenotype in mice after propagation in mosquitoes in mosquito-mouse cycle model. In particular, recombinant ZIKV harboring the H401Y substitution showed enhanced competitive fitness over WT ZIKV in various mammalian cells and mouse brains, but not in mosquito cells. Notably, the H401Y substitution in the ZIKV E protein has been detected in recent isolates derived from both mosquitoes and humans in Asia and the Americas. In summary, our findings not only identify a novel virulence determinant of ZIKV but also highlight the complexity of the relationship between the evolution of vector-borne viruses and their clinical outcome in nature. IMPORTANCE: Zika virus (ZIKV) is an important arbovirus with a global impact. Experimental evolution by serial passaging of ZIKV in susceptible cells has led to the identification of a panel of critical amino acid substitutions with specific functions. Herein, we identified a mosquito cell-derived substitution, H401Y, in the ZIKV E protein via experimental evolution. The H401Y substitution significantly enhanced viral virulence and fitness in mammal cells and mice. Notably, the H401Y substitution has been detected in recent mosquito and human isolates from regions spanning Asia to the Americas. Our work elucidates unrecognized virulence determinant in the ZIKV genome that warrants urgent attention. Moreover, the findings underscore the critical need for extensive molecular surveillance and rigorous clinical observation to establish the potential impact in natural circulation. These endeavors are crucial for unraveling the potential of mutation to act as a catalyst for future epidemics, thereby preempting the public health challenges it may pose.

Theoretical and experimental studies on channel impulse response of short-range non-line-of-sight ultraviolet communications.

A theoretical channel impulse response (CIR) model of short-range non-line-of-sight (NLOS) ultraviolet communications (UVC) in noncoplanar geometry under the single-scatter condition is proposed. Simulation results obtained from the widely accepted Monte-Carlo (MC)-based channel model of NLOS UVC are provided to verify corresponding theoretical results obtained from the proposed theoretical single-scatter CIR model. Additionally, an outdoor experiment with a light-emitting diode (LED) as the light source is first designed to measure the channel step response of NLOS UVC and to further validate the proposed theoretical single-scatter CIR model. By varying the different parameters of the transmitter and the receiver, such as the baseline range, the inclination angle, the azimuth angle, the beam divergence angle, and the field-of-view angle, the results of the proposed theoretical single-scatter CIR model and the MC-based channel model are exhibited and further analyzed in detail. Results indicate that the computational time cost by the proposed theoretical single-scatter CIR model is decreased to less than 0.6% of the MC-based one with comparable accuracy in assessing the temporal characteristics of NLOS UVC channels. Additionally, theoretical results obtained from the proposed theoretical single-scatter CIR model manifest satisfactory agreement with corresponding experimental measurements.

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy.

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1ß processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1ß and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1ß) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.

The Slack Channel Regulates Anxiety-Like Behaviors via Basolateral Amygdala Glutamatergic Projections to Ventral Hippocampus.

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors, whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in basolateral amygdala (BLA) glutamatergic neurons and downregulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors, whereas Kcnt1 gene expression in the BLA or BLA-ventral hippocampus (vHPC) glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.SIGNIFICANCE STATEMENT Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. Here, we examined the behaviors of loss- and gain-of-function of Slack channel mice in elevated plus maze and open field tests and found the anxiolytic role of the Slack channel. By altering the Slack channel expression in the specific neuronal circuit, we demonstrated that the Slack channel played its anxiolytic role by decreasing the excitability of BLA-vHPC glutamatergic projections. Our data reveal the role of the Slack channel in the regulation of anxiety, which may provide a potential molecular target for anxiolytic therapies.

Structural characteristics of a low molecular weight velvet antler protein and the anti-tumor activity on S180 tumor-bearing mice.

Velvet antler is a traditional Chinese medicine with various pharmacological values, which is an important raw material for traditional Chinese medicinal wine. Nevertheless, the chemical compositions and bioactivities of velvet antler residue used for making medicinal wine are rarely reported, leading to a waste of resources. In this study, a velvet antler protein (VA-pro) was extracted from velvet antler residue by simulating the gastrointestinal digestion, and its composition, structural characteristics and in vivo anti-tumor activities were determined and investigated. VA-pro possessed high purity with a relatively low molecular weight as 22.589 kDa under HPLC, one- and two-dimensional electrophoresis, and it contained high contents of Pro, Gly, Glu and Ala. Besides, the secondary structure of VA-pro was dominated by ß-turn and ß-sheet, and VA-pro possessed similar protein sequence, isoelectric point and amino acid compositions to hypothetical protein G4228_020061. The in vivo results substantiated that VA-pro could improve the body weights and immune organ indices, increase the expressions of sera cytokines and regulate the distributions of T and B lymphocytes subsets in peripheral blood of S180 tumor-bearing mice. Furthermore, VA-pro could effectively inhibit solid S180 tumors growth by inducing S phase cell cycle arrest mediated through mitochondria. To summarize, our study provided theoretical support that VA-pro had the potential to be used as an immunopotentiator in immunocompromised or cancer-bearing hosts.

Single-collision-induced path loss model of reflection-assisted non-line-of-sight ultraviolet communications.

By considering both scattering and reflection events as collision-induced events (CIEs), an analytical path loss model of reflection-assisted non-line-of-sight (NLOS) ultraviolet communications (UVC) is proposed with single CIE incorporated, which refers to the single-collision-induced (SCI) path loss model. More specifically, the analytical expressions of the received optical energy resulting from single-scatter and single-reflection events in reflection-assisted NLOS UVC are respectively derived. Then, in terms of those two expressions, the expression of the proposed SCI path loss model is obtained. Finally, Monte-Carlo (MC) simulations and experimental results are given to verify the correctness and effectiveness of the proposed SCI path loss model. The results manifest that the proposed SCI path loss model can work well in both coplanar and noncoplanar geometry of the reflection-assisted NLOS UVC.

Modeling of ultraviolet propagation from air to human epidermis with wavelength range of 200-300 nm.

Ultraviolet (UV) technology plays an important role in the fields of sterilization, disinfection, and short-range wireless optical communications. In this Letter, a theoretical model to determine the UV radiation intensity (UVRI) on human skin is put forward based on the Monte Carlo method, where the UV wavelength ranges from 200 to 300 nm. Meanwhile, the UVRI evaluation algorithm is provided to reproduce the simulation results. Furthermore, the penetration depth of UV radiation in the human epidermis is investigated, which can be used to assess whether UV radiation causes damage to human health. Simulation results coincide with the existing experimental results that the 222-nm UV radiation is harmless to humans at the given dose of 1.7 mJ/cm2. This work provides theoretical guidelines for the power control of a UV system when humans are in the vicinity.

Design of self-assembly dipeptide hydrogels and machine learning via their chemical features.

Hydrogels that are self-assembled by peptides have attracted great interest for biomedical applications. However, the link between chemical structures of peptides and their corresponding hydrogel properties is still unclear. Here, we showed a combinational approach to generate a structurally diverse hydrogel library with more than 2,000 peptides and evaluated their corresponding properties. We used a quantitative structure-property relationship to calculate their chemical features reflecting the topological and physicochemical properties, and applied machine learning to predict the self-assembly behavior. We observed that the stiffness of hydrogels is correlated with the diameter and cross-linking degree of the nanofiber. Importantly, we demonstrated that the hydrogels support cell proliferation in culture, suggesting the biocompatibility of the hydrogel. The combinatorial hydrogel library and the machine learning approach we developed linked the chemical structures with their self-assembly behavior and can accelerate the design of novel peptide structures for biomedical use.

Single-scatter path loss model of LED-based non-line-of-sight ultraviolet communications.

Light-emitting diodes (LEDs) are popularly used as light sources in non-line-of-sight (NLOS) ultraviolet communications (UVC). However, currently reported single-scatter path loss (PL) models of NLOS UVC links assume that the radiant intensity of the light source is uniformly distributed within the beam divergence angle, which cannot well characterize the light emission pattern of LEDs. In this Letter, we propose a single-scatter PL model for LED-based NLOS UVC systems, and the corresponding analytical expression is derived by modeling the LED emission pattern as a Lambertian distribution. Monte Carlo simulations and experimental results are provided to verify the effectiveness of the proposed PL model. Results show that the proposed model can accurately predict PL results in actual situations. The root-mean-square error of the proposed PL model is only about 1 dB in typical scenarios with experimental results as benchmarks. Also, the proposed model is much easier to implement than the currently reported PL model with the light source model of a uniformly distributed emission pattern.

Single-scatter path loss model of LED-based non-line-of-sight ultraviolet communications: publisher's note.

This publisher's note contains corrections to Opt. Lett.46, 4013 (2021)OPLEDP0146-959210.1364/OL.435418.

Application of Electrocardiogram Localization during Peripherally Inserted Central Catheter Line Insertion into the Persistent Left Superior Vena Cava of Neonates.

BACKGROUND: Most neonates with persistent left superior vena cava (PLSVC) have no clinical symptoms or hemodynamic changes, and this anomaly is only found during cardiac catheterization, pacemaker implantation, or central venous catheterization. Electrocardiogram (ECG) localization is helpful for the application of the peripherally inserted central catheter (PICC) technique in neonates with PLSVC. OBJECTIVE: To explore the characteristic waveforms of the P wave when a PICC under ECG localization is applied in neonates with PLSVC. STUDY DESIGN: The observation and management strategies for the P wave changes during catheter insertion (CI) of two neonates with PLSVC admitted to our institution between January and July 2020, who underwent PICC line insertion, were summarized. RESULTS: The characteristic P wave changes in two children with a PICC line inserted via the PLSVC were observed. When a wide inverted P wave appeared on ECG, the catheter was immediately withdrawn by 0.5 cm, a bidirectional P wave gradually appeared and then disappeared. After that, the catheter was further withdrawn by 0.5 cm. After catheterization, the optimal position of the PICC was confirmed by X-ray photography and bedside B-ultrasound. The PICC line was removed as scheduled after indwelling for 18 and 29 days, respectively, in the two cases, and no PICC-related complications occurred during indwelling. CONCLUSION: The characteristic P wave changes on ECG during CI provide important clinical reference values for the application of the PICC technique under ECG localization in neonates with PLSVC. KEY POINTS: · Electrocardiogram localization.. · Peripherally inserted central catheter.. · Persistent left superior vena cava..

The relationship between ecosystem service supply and demand in plain areas undergoing urbanization: A case study of China's Baiyangdian Basin.

Urbanization is an inevitable trend associated with social development that occurs preferentially in plain areas. Ecosystem services (ES) refer to the various benefits that human beings obtain from ecosystems. Competing priorities of economic development and ecological protection lead to conflicts in land use under conditions of urbanization, the root cause of which is an imbalance in the ES supply and demand. Whereas existing studies have mainly focused on the decline of ES supply capacities, an exploration of the extent to which the supply and demand of ES are matched and of their changing trends would be instructive and have practical implications. In this study, we examined changes in the temporal and spatial characteristics of the relationship between ES supply and demand in the Baiyangdian Basin in the North China Plain. We found that ES supply and demand were spatially distinctive. ES supply areas were concentrated in the western mountainous region, whereas ES demand areas were predominantly located in the eastern plain area. The main sources of ES surplus in the study area were woodland and grassland in mountainous areas, comprising 12% of the study region. Strict protection on these lands during the period 1980-2015 ensured a consistently high level of ES supply. In recent years, urbanization has been a major driver of increasing ES demand and decreasing ES surplus and is projected to accentuate the trend of declining ES surplus in the future. However, current policies remain focused on the protection of forests and grassland that predominate in mountainous areas, where urban expansion poses a lower threat compared with plain areas. We therefore recommend a policy emphasis on sustainable urban planning to mitigate ES degradation.

Application of a modified electrocardiogram-guided technique for umbilical venous catheterisation in neonates: A retrospective trial.

AIM: To investigate the effectiveness and safety of modified electrocardiogram (ECG)-guided technique in umbilical venous catheterisation in neonates. METHODS: Sixty-six critically ill neonates underwent umbilical venous catheterisation with (ECG group) or without (control group) ECG guidance from January 2017 to March 2019. We retrospectively analysed and compared the rate of correct tip placement on first try, unplanned extubation rate and incidence of catheter-related complications between the two groups. RESULTS: There were 33 patients in each group. The ECG group showed significantly higher rate of correct tip placement on first try (P < 0.001), lower unplanned extubation rate (P < 0.001), but identical incidence of catheter-related complications (P = 0.492) comparing with the control group. CONCLUSION: The ECG-guided technique is an effective and safe method for umbilical venous catheterisation. The connecting method we modified made this technique more practical and can be promoted to areas without access to specific ECG adaptors.

Lip position analysis of young women with different skeletal patterns during posed smiling using 3-dimensional stereophotogrammetry.

INTRODUCTION: The aim of this study was to explore the internal relationship between posed smile characteristics, lip position, and skeletal patterns in young women. METHODS: Fifty women between the ages of 20 and 30 years were enrolled and divided into 3 groups-vertical, average, and horizontal patterns- using the following parameters: FMA, GoGn-SN, and Jarabak ratio. Each subject was scanned in natural head position and with a posed smile. The interlabial gap, intercommissural width, and smile index were calculated. The frontal region was selected as the reference plane for superimpositions. The changes of the lip landmarks in the vertical, sagittal, and coronal directions were investigated. RESULTS: The smile indexes were listed in the following sequence: vertical < average < horizontal. Significant differences were found in the interlabial gap among the 3 groups. Compared with the average and horizontal groups, the upper lip landmarks of the vertical group showed differences and changed more only in the vertical direction. However, the lower lip landmark showed no differences in any direction. CONCLUSIONS: Different skeletal patterns have characteristic smile features. The vertical skeletal pattern affects upper lip movements because there is more space for upper-lip elevation. However, the vertical skeletal pattern has no effect on lower lip movement.

Pentacoordinated Al3+ -Stabilized Active Pd Structures on Al2 O3 -Coated Palladium Catalysts for Methane Combustion.

Supported Pd catalysts are active in catalyzing the highly exothermic methane combustion reaction but tend to be deactivated owing to local hyperthermal environments. Herein we report an effective approach to stabilize Pd/SiO2 catalysts with porous Al2 O3 overlayers coated by atomic layer deposition (ALD). 27 Al magic angle spinning NMR analysis showed that Al2 O3 overlayers on Pd particles coated by the ALD method are rich in pentacoordinated Al3+ sites capable of strongly interacting with adjacent surface PdOx phases on supported Pd particles. Consequently, Al2 O3 -decorated Pd/SiO2 catalysts exhibit active and stable PdOx and Pd-PdOx structures to efficiently catalyze methane combustion between 200 and 850 °C. These results reveal the unique structural characteristics of Al2 O3 overlayers on metal surfaces coated by the ALD method and provide a practical strategy to explore stable and efficient supported Pd catalysts for methane combustion.

An in situ DRIFTS mechanistic study of CeO2-catalyzed acetylene semihydrogenation reaction.

CeO2-Catalyzed C2H2 semihydrogenation reaction is a newly emerging catalytic reaction, but the reaction mechanism is not established. We herein report a comprehensive mechanistic study by in situ diffuse reflectance infrared Fourier transformed spectroscopy. Various types of surface species were observed to form upon C2H2 and C2H4 adsorption on CeO2 at different temperatures, including molecularly-adsorbed π-bonded and di-σ-bonded species, dissociatively-adsorbed species of C2H and C2H3, carbonates and formate species, and oligomers species, respectively. During the C2H2 semihydrogenation reaction, the CeO2 surface is partially reduced and strongly hydroxylated. Both O and Ce sites on CeO2 are capable of catalyzing C2H2 semihydrogenation reaction to C2H4, and the O site is more active than the Ce site. The reaction mechanism was elucidated with observed molecularly-adsorbed C2H2 species, a C2H3 intermediate and adsorbed C2H4 species on CeO2. The π-bonded C2H2 species at the O site was identified as the dominant active surface species for CeO2-catalyzed C2H2 semihydrogenation reaction. These results greatly advance the fundamental understanding of CeO2-catalyzed C2H2 semihydrogenation reaction.

Surface chemistry of group IB metals and related oxides.

Understanding the surface chemistry of solid catalysts is of great importance for the rational design of structures of advanced catalysts; however, long-term challenges remain due to the complex and non-uniform catalyst structures and the lack of suitable characterization techniques. Surface chemistry studies of single-crystal-based model catalysts with well-defined surface structures under ultra-high vacuum conditions have been developed as one approach, but the so-called materials gap and pressure gap are sometimes encountered when the acquired understanding is extended to the industrial reaction conditions. Recently emerging uniform catalytic nanocrystals with well-defined surface structures consist of a novel type of model catalysts, whose surface chemistry can be studied under the same conditions as the industrial reaction conditions; meanwhile, the surface chemistry of powder catalysts can be studied to some extent due to the development of advanced characterization techniques. Group IB metals (Cu, Ag, Au) and related oxides constitute a class of catalysts with unique catalytic properties and wide catalytic applications. We herein review the recent progress in the surface chemistry of Group IB metals and related oxides from single-crystal-based model catalysts to nanocrystal-based model catalysts and powder catalysts in an attempt to summarize the commonalities and to discuss the differences among the surface chemistry acquired from the catalysts with different levels of complexity. The surface chemistry of Group IB metals and related oxides is compared and correlated to their catalytic performance. A concept of model catalysts from single crystals to nanocrystals is prospected for the investigation of the surface chemistry of solid catalysts to approach industrial reaction conditions as closely as possible.

Highly accurate prediction of protein self-interactions by incorporating the average block and PSSM information into the general PseAAC.

It is a challenging task for fundamental research whether proteins can interact with their partners. Protein self-interaction (SIP) is a special case of PPIs, which plays a key role in the regulation of cellular functions. Due to the limitations of experimental self-interaction identification, it is very important to develop an effective biological tool for predicting SIPs based on protein sequences. In the study, we developed a novel computational method called RVM-AB that combines the Relevance Vector Machine (RVM) model and Average Blocks (AB) for detecting SIPs from protein sequences. Firstly, Average Blocks (AB) feature extraction method is employed to represent protein sequences on a Position Specific Scoring Matrix (PSSM). Secondly, Principal Component Analysis (PCA) method is used to reduce the dimension of AB vector for reducing the influence of noise. Then, by employing the Relevance Vector Machine (RVM) algorithm, the performance of RVM-AB is assessed and compared with the state-of-the-art support vector machine (SVM) classifier and other exiting methods on yeast and human datasets respectively. Using the fivefold test experiment, RVM-AB model achieved very high accuracies of 93.01% and 97.72% on yeast and human datasets respectively, which are significantly better than the method based on SVM classifier and other previous methods. The experimental results proved that the RVM-AB prediction model is efficient and robust. It can be an automatic decision support tool for detecting SIPs. For facilitating extensive studies for future proteomics research, the RVMAB server is freely available for academic use at http://219.219.62.123:8888/SIP_AB.