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Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drugs combinations on inflammatory cytokine production, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.

Background: First Nations (FN) women have a higher risk of diabetes than non-FN women in Canada. Prenatal education and breastfeeding may reduce the risk of diabetes in mothers and offspring. The rates of breastfeeding initiation and participation in the prenatal program are low in FN communities. Methods: A prenatal educational website, social media-assisted prenatal chat groups and community support teams were developed in three rural or remote FN communities in Manitoba. The rates of participation of pregnant women in prenatal programs and breastfeeding initiation were compared before and after the start of the remote prenatal education program within 2014-2017. Findings: The participation rate of FN pregnant women in rural or remote communities in the prenatal program and breastfeeding initiation during 1-year after the start of the community-based remote prenatal education program were significantly increased compared to that during 1-year before the start of the program (54% versus 36% for the participation rate, 50% versus 34% for breastfeeding initiation, p

Developing femtosecond resolution methods for directly observing structural dynamics is critical to understanding complex photochemical reaction mechanisms in solution. We have used two recent developments, ultrafast mega-electron-volt electron sources and vacuum compatible sub-micron thick liquid sheet jets, to enable liquid-phase ultrafast electron diffraction (LUED). We have demonstrated the viability of LUED by investigating the photodissociation of tri-iodide initiated with a 400 nm laser pulse. This has enabled the average speed of the bond expansion to be measured during the first 750 fs of dissociation and the geminate recombination to be directly captured on the picosecond time scale.

The conversion of light into usable chemical and mechanical energy is pivotal to several biological and chemical processes, many of which occur in solution. To understand the structure–function relationships mediating these processes, a technique with high spatial and temporal resolutions is required. Here, we report on the design and commissioning of a liquid-phase mega-electron-volt (MeV) ultrafast electron diffraction instrument for the study of structural dynamics in solution. Limitations posed by the shallow penetration depth of electrons and the resulting information loss due to multiple scattering and the technical challenge of delivering liquids to vacuum were overcome through the use of MeV electrons and a gas-accelerated thin liquid sheet jet. To demonstrate the capabilities of this instrument, the structure of water and its network were resolved up to the 3 rd hydration shell with a spatial resolution of 0.6 Å; preliminary time-resolved experiments demonstrated a temporal resolution of 200 fs.

Ultra-low-frequency (ULF) waves are ubiquitous in the magnetosphere. Previous studies mostly focused on ULF waves in the dayside or near-Earth region (with radial distance R<12 RE). In this study, using the data of the Time History of Events and Macroscale Interactions during Substorms (THEMIS) mission during the period from 2008 to 2015, the Pc5–6 ULF waves in the tail region with X∗GSM<0, 8 RE

Size, composition, and mixing state of individual aerosol particles can be analysed in real time using single-particle mass spectrometry (SPMS). In SPMS, laser ablation is the most widely used method for desorption and ionization of particle components, often realizing both in one single step. Excimer lasers are well suited for this task due to their relatively high power density (107–1010 W cm−2) in nanosecond (ns) pulses at ultraviolet (UV) wavelengths and short triggering times. However, varying particle optical properties and matrix effects make a quantitative interpretation of this analytical approach challenging. In atmospheric SPMS applications, this influences both the mass fraction of an individual particle that is ablated, as well as the resulting mass spectral fragmentation pattern of the ablated material. The present study explores the use of shorter (femtosecond, fs) laser pulses for atmospheric SPMS. Its objective is to assess whether the higher laser power density of the fs laser leads to a more complete ionization of the entire particle and higher ion signal and thus improvement in the quantitative abilities of SPMS. We systematically investigate the influence of power density and pulse duration on airborne particle (polystyrene latex, SiO2, NH4NO3, NaCl, and custom-made core-shell particles) ablation and reproducibility of mass spectral signatures. We used a laser ablation aerosol time-of-flight single-particle mass spectrometer (LAAPTOF, AeroMegt GmbH), originally equipped with an excimer laser (wavelength 193 nm, pulse width 8 ns, pulse energy 4 mJ), and coupled it to an fs laser (Spectra Physics Solstice-100F ultrafast laser) with similar pulse energy but longer wavelengths (266 nm with 100 fs and 0.2 mJ, 800 nm with 100 fs and 3.2 mJ). We successfully coupled the free-firing fs laser with the single-particle mass spectrometer employing the fs laser light scattered by the particle to trigger mass spectra acquisition. Generally, mass spectra exhibit an increase in ion intensities (factor 1 to 5) with increasing laser power density (∼ 109 to ∼ 1013 W cm−2) from ns to fs laser. At the same time, fs-laser ablation produces spectra with larger ion fragments and ion clusters as well as clusters with oxygen, which does not render spectra interpretation more simple compared to ns-laser ablation. The idea that the higher power density of the fs laser leads to a more complete particle ablation and ionization could not be substantiated in this study. Quantification of ablated material remains difficult due to incomplete ionization of the particle. Furthermore, the fs-laser application still suffers from limitations in triggering it in a useful time frame. Further studies are needed to test potential advantages of fs- over ns-laser ablation in SPMS.

The laser ablation aerosol particle time-of-flight mass spectrometer (LAAPTOF, AeroMegt GmbH) is able to identify the chemical composition and mixing state of individual aerosol particles, and thus is a tool for elucidating their impacts on human health, visibility, ecosystem, and climate. The overall detection efficiency (ODE) of the instrument we use was determined to range from ∼ (0.01 ± 0.01) to ∼ (4.23 ± 2.36) % for polystyrene latex (PSL) in the size range of 200 to 2000 nm, ∼ (0.44 ± 0.19) to ∼ (6.57 ± 2.38) % for ammonium nitrate (NH4NO3), and ∼ (0.14 ± 0.02) to ∼ (1.46 ± 0.08) % for sodium chloride (NaCl) particles in the size range of 300 to 1000 nm. Reference mass spectra of 32 different particle types relevant for atmospheric aerosol (e.g. pure compounds NH4NO3, K2SO4, NaCl, oxalic acid, pinic acid, and pinonic acid; internal mixtures of e.g. salts, secondary organic aerosol, and metallic core–organic shell particles; more complex particles such as soot and dust particles) were determined. Our results show that internally mixed aerosol particles can result in spectra with new clusters of ions, rather than simply a combination of the spectra from the single components. An exemplary 1-day ambient data set was analysed by both classical fuzzy clustering and a reference-spectra-based classification method. Resulting identified particle types were generally well correlated. We show how a combination of both methods can greatly improve the interpretation of single-particle data in field measurements.

Chemical composition, size distributions, and degree of oligomerization of secondary organic aerosol (SOA) from α-pinene (C10H16) ozonolysis were investigated for low-temperature conditions (223 K). Two types of experiments were performed using two simulation chambers at the Karlsruhe Institute of Technology: the Aerosol Preparation and Characterization (APC) chamber, and the Aerosol Interaction and Dynamics in the Atmosphere (AIDA) chamber. Experiment type 1 simulated SOA formation at upper tropospheric conditions: SOA was generated in the AIDA chamber directly at 223 K at 61 % relative humidity (RH; experiment termed cold humid, CH) and for comparison at 6 % RH (experiment termed cold dry, CD) conditions. Experiment type 2 simulated SOA uplifting: SOA was formed in the APC chamber at room temperature (296 K) and warm dry, WD) or 21 % RH (experiment termed warm humid, WH) conditions, and then partially transferred to the AIDA chamber kept at 223 K, and 61 % RH (WDtoCH) or 30 % RH (WHtoCH), respectively. Precursor concentrations varied between 0.7 and 2.2 ppm α-pinene, and between 2.3 and 1.8 ppm ozone for type 1 and type 2 experiments, respectively. Among other instrumentation, a chemical ionization mass spectrometer (CIMS) coupled to a filter inlet for gases and aerosols (FIGAERO), deploying I− as reagent ion, was used for SOA chemical composition analysis. For type 1 experiments with lower α-pinene concentrations and cold SOA formation temperature (223 K), smaller particles of 100–300 nm vacuum aerodynamic diameter (dva) and higher mass fractions (> 40 %) of adducts (molecules with more than 10 carbon atoms) of α-pinene oxidation products were observed. For type 2 experiments with higher α-pinene concentrations and warm SOA formation temperature (296 K), larger particles ( ∼ 500 nm dva) with smaller mass fractions of adducts ( We also observed differences (up to 20 °C) in maximum desorption temperature (Tmax) of individual compounds desorbing from the particles deposited on the FIGAERO Teflon filter for different experiments, indicating that Tmax is not purely a function of a compound's vapor pressure or volatility, but is also influenced by diffusion limitations within the particles (particle viscosity), interactions between particles deposited on the filter (particle matrix), and/or particle mass on the filter. Highest Tmax were observed for SOA under dry conditions and with higher adduct mass fraction; lowest Tmax were observed for SOA under humid conditions and with lower adduct mass fraction. The observations indicate that particle viscosity may be influenced by intra- and inter-molecular hydrogen bonding between oligomers, and particle water uptake, even under such low-temperature conditions. Our results suggest that particle physicochemical properties such as viscosity and oligomer content mutually influence each other, and that variation in Tmax of particle desorptions may have implications for particle viscosity and particle matrix effects. The differences in particle physicochemical properties observed between our different experiments demonstrate the importance of taking experimental conditions into consideration when interpreting data from laboratory studies or using them as input in climate models.

In this work, the spatial extent of new particle formation (NPF) events and the relative probability of observing particles originating from different spatial origins around three rural sites in eastern China were investigated using the NanoMap method, using particle number size distribution (PNSD) data and air mass back trajectories. The length of the datasets used were 7, 1.5, and 3 years at rural sites Shangdianzi (SDZ) in the North China Plain (NCP), Mt. Tai (TS) in central eastern China, and Lin'an (LAN) in the Yangtze River Delta region in eastern China, respectively. Regional NPF events were observed to occur with the horizontal extent larger than 500 km at SDZ and TS, favoured by the fast transport of northwesterly air masses. At LAN, however, the spatial footprint of NPF events was mostly observed around the site within 100–200 km. Difference in the horizontal spatial distribution of new particle source areas at different sites was connected to typical meteorological conditions at the sites. Consecutive large-scale regional NPF events were observed at SDZ and TS simultaneously and were associated with a high surface pressure system dominating over this area. Simultaneous NPF events at SDZ and LAN were seldom observed. At SDZ the polluted air masses arriving over the NCP were associated with higher particle growth rate (GR) and new particle formation rate (J) than air masses from Inner Mongolia (IM). At TS the same phenomenon was observed for J, but GR was somewhat lower in air masses arriving over the NCP compared to those arriving from IM. The capability of NanoMap to capture the NPF occurrence probability depends on the length of the dataset of PNSD measurement but also on topography around the measurement site and typical air mass advection speed during NPF events. Thus the long-term measurements of PNSD in the planetary boundary layer are necessary in the further study of spatial extent and the probability of NPF events. The spatial extent, relative probability of occurrence, and typical evolution of PNSD during NPF events presented in this study provide valuable information to further understand the climate and air quality effects of new particle formation.

Although magnetostriction is universal in magnetic materials, understanding its microscopic origin remains challenging. Here the authors use X-ray and ultrafast electron diffraction to separate the material’s sub-picosecond spin and lattice responses and reveal the magnetoelastic stress generated by demagnetization.

Several different concentrations of α-tocopherol were applied to Carex leucochlora after plants had been treated with high salinity (0.8 % NaCl) in a greenhouse for one month. The results revealed that 0.8 mM α-tocopherol treatment showed the greatest alleviation of growth inhibition and cell membrane damage induced by salt stress. In comparison with NaCl alone, the 0.8 mM α-tocopherol application significantly decreased the content of hydrogen peroxide and the rate of superoxide radical generation, and increased the content of chlorophyll b, carotenoids, free proline, and soluble protein, but had no effect on the content of chlorophyll a and soluble sugar. These results suggest that α-tocopherol could effectively protect C. leucochlora plants from salt stress damage presumably by quenching the excessive reactive oxygen species to protect the photosynthetic pigments and by enhancing the osmotic adjustment.

Catchment flood response consists of multiple components of flow originating from different surface and subsurface layers. This study proposes an extension of Viglione et al. (2010a) analytical framework to represent the dependence of catchment flood response to the different runoff generation processes. The analytical framework is compared to simulations from a distributed hydrologic model. A large number of rainfall–runoff events from three catchments of Tar River basin in North Carolina are used to illustrate the analytical framework. Specifically, the framework is used to estimate three flood event characteristics (cumulative runoff volume, centroid, and spreadness of hydrograph) through three corresponding framework parameters: the rainfall excess and the mean and variance of catchment response time. Results show that, under the smooth topographic setups of the study area, the spatial and/or temporal correlation between rainfall and runoff generation are insignificant to flood response; delay in flood response due to runoff generation and routing are of equal importance; the shape of the flood is mainly controlled by the variability in runoff generation stage but with non-negligible contribution from the runoff routing stage. Sensitivity tests show that the framework's main error source is the systematic underestimation of the flood event's centroid and spreadness, while the random error is relatively low.

In response to the recent rise in numbers of diabetes patients, many treatments have been developed; but currently, oral antihyperglycemic agents and insulin are still the main clinical treatments. Since current drugs have limitations and harmful side effects, research in alternative treatments has been sought. This article reviews recent research updates of Saskatoon berries (SB), covering its background information, its main active ingredients, its structure, and its function. Flavonoid compounds in Saskatoon berries, in particular flavanol, anthocyanin, and proanthocyanin, possess anti-inflammatory, antitumor, and antidiabetes impacts. The current review synthesizes the latest research on the health benefits of Saskatoon berry in a variety of domains. With further research, SB has the potential to help treat and prevent diabetes in the future.

ABSTRACT The melanocortin 1 receptor (MC1R) gene plays a key role in controlling the deposition of melanin. In mammals, the MC1Rgene is regarded as a major candidate gene in the control of melanin formation. In domestic animals, the MC1R gene mainly controls the expression of coat, skin, and plumage color in mammals and birds. In order to breed chickens with dark-green shank faster, we screened the molecular markers for shank color in a HS chicken population by exploring the relationship between polymorphism of the MC1R gene and three different shank colors (light green, dark green and yellow). Two primer pairs for code region of the MC1R gene were designed in the basic of chicken genomic sequence. DNA sequencing was performed to detect the polymorphisms and PCR was used to amplify DNA fragment. Sequences analysis indicated that 7 SNPs were predominant the three HS chicken populations with different shank color, including g.18,287,945C>T, g.18,288,088T>C, g.18,288,150G>A, g.18,288,303A>G, g.18,288,512G>A, g.18,288,513T>C, and g.18,288,520A>C. Association analysis revealed that the dark-green shank population showed moderate polymorphism, whereas the light-green shank population showed low polymorphism among overall 7 SNPs and that SNP6 (g.18,288,513T>C) may be significantly associated with three different shank colors in HS chickens. The haplotype CTGGACA had the largest haplotype frequencies, accounting for 56.22%, and the haplotype combination H1H1 is mainly distributed in the dark-green shank population, and may be used as molecular maker for marker-assisted selection of shank color in HS chickens.

The development of ultrafast gas electron diffraction with nonrelativistic electrons has enabled the determination of molecular structures with atomic spatial resolution. It has, however, been challenging to break the picosecond temporal resolution barrier and achieve the goal that has long been envisioned—making space- and-time resolved molecular movies of chemical reaction in the gas-phase. Recently, an ultrafast electron diffraction (UED) apparatus using mega-electron-volt (MeV) electrons was developed at the SLAC National Accelerator Laboratory for imaging ultrafast structural dynamics of molecules in the gas phase. The SLAC gas-phase MeV UED has achieved 65 fs root mean square temporal resolution, 0.63 Å spatial resolution, and 0.22 Å−1 reciprocal-space resolution. Such high spatial-temporal resolution has enabled the capturing of real-time molecular movies of fundamental photochemical mechanisms, such as chemical bond breaking, ring opening, and a nuclear wave packet crossing a conical intersection. In this paper, the design that enables the high spatial-temporal resolution of the SLAC gas phase MeV UED is presented. The compact design of the differential pump section of the SLAC gas phase MeV UED realized five orders-of-magnitude vacuum isolation between the electron source and gas sample chamber. The spatial resolution, temporal resolution, and long-term stability of the apparatus are systematically characterized.

Drug-induced liver injury (DILI) is a major concern for the pharmaceutical industry and constitutes one of the most important reasons for the termination of promising drug development projects. Reliable prediction of DILI liability in preclinical stages is difficult, as current experimental model systems do not accurately reflect the molecular phenotype and functionality of the human liver. As a result, multiple drugs that passed preclinical safety evaluations failed due to liver toxicity in clinical trials or postmarketing stages in recent years. To improve the selection of molecules that are taken forward into the clinics, the development of more predictive in vitro systems that enable high-throughput screening of hepatotoxic liabilities and allow for investigative studies into DILI mechanisms has gained growing interest. Specifically, it became increasingly clear that the choice of cell types and culture method both constitute important parameters that affect the predictive power of test systems. In this review, we present current 3D culture paradigms for hepatotoxicity tests and critically evaluate their utility and performance for DILI prediction. In addition, we highlight possibilities of these emerging platforms for mechanistic evaluations of selected drug candidates and present current research directions towards the further improvement of preclinical liver safety tests. We conclude that organotypic and microphysiological liver systems have provided an important step towards more reliable DILI prediction. Furthermore, we expect that the increasing availability of comprehensive benchmarking studies will facilitate model dissemination that might eventually result in their regulatory acceptance.

Administration of freeze-dried powder of Saskatoon berry (SB), a popular fruit enriched with antioxidants, reduced glucose level, inflammatory markers and gut microbiota disorder in high fat-high sucrose (HFHS) diet-induced insulin resistant mice. The present study examined the dose-response relationship in metabolic, inflammatory and gut microbiotic variables to SB power (SBp) supplementation in HFHS diet-fed mice. Male C57 BL/6J mice were fed with HFHS diet supplemented with 0, 1%, 2.5% or 5% SBp for 11 weeks. HFHS diet significantly increased the levels of fast plasma glucose (FPG), cholesterol, triglycerides, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), tumor necrosis factor-α, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1, but decreased fecal Bacteroidetes phylum bacteria and Muribaculaceae family bacteria compared to low fat diet. SBp dose-dependently reduced metabolic and inflammatory variables and gut dysbiosis in mice compared with mice receiving HFHS diet alone. Significant attenuation of HFHS diet-induced biochemical disorders were detected in mice receiving ≥1% SBp. The abundances of Muribaculaceae family bacteria negatively correlated with body weights, FPG, lipids, insulin, HOMA-IR and inflammatory markers in the mice. The results suggest that SBp supplementation dose-dependently attenuated HFHS diet-induced metabolic and inflammatory disorders, which was associated with the amelioration of gut dysbiosis in the mice.

The present study assessed the effects of freeze-dried cyanidin-3-glucoside (C3G), an anthocyanin enriched in dark-red berries, compared to Saskatoon berry powder (SBp) on metabolism, inflammatory markers and gut microbiota in high fat-high sucrose (HFHS) diet-induced insulin-resistant mice. Male C57 BL/6J mice received control, HFHS, HFHS + SBp (8.0 g/kg/day) or HFHS + C3G (7.2 mg/kg/day, equivalent C3G in SBp) diet for 11 weeks. The HFHS diet significantly increased plasma levels of glucose, cholesterol, triglycerides, insulin resistance and inflammatory markers. The HFHS + SBp diet increased the Bacteroidetes/Firmicutes (B/F) ratio and relative abundance of Muriculaceae family bacteria in mouse feces detected using 16S rRNA gene sequencing. The HFHS + SBp or HFHS + C3G diet attenuated glucose, lipids, insulin resistance and inflammatory markers, and increased the B/F ratio and Muriculaceae relative abundance compared to the HFHS diet alone. The relative abundances of Muriculaceae negatively correlated with body weight, glucose, lipids, insulin resistance and inflammatory mediators. Functional predication analysis suggested that the HFHS diet upregulated gut bacteria genes involved in inflammation, and downregulated bacteria involved in metabolism. C3G and SBp partially neutralized HFHS diet-induced alterations of gut bacteria. The results suggest that C3G is a potential prebiotic, mitigating HFHS diet-induced disorders in metabolism, inflammation and gut dysbiosis, and that C3G contributes to the metabolic beneficial effects of SBp.

Whilst excited electronic states may exhibit unique non-equilibrium behavior, order is inhibited by fluctuations. Here, the authors use femtosecond photoemission spectroscopy to demonstrate transient stabilization of charge density wave order in rare earth tritellurides after near-infrared excitation.

ABSTRACTThis study aimed at examining the effect of overfeeding on the activity of the mTOR pathway in the liver and muscle tissues of Gang geese. Eighty healthy male Gang geese were reared under the same feeding conditions, and were divided at 14 weeks of age into a control group and an overfed group. All birds were slaughtered after three weeks of over feeding. Gene expression and protein content of several genes involved in the mTOR pathway were evaluated. The results showed that the gene expression of mTOR, raptor, and rictor, and the protein contents of mTOR and PI3K were higher in liver, breast muscle, and leg muscle of the overfed group than that of control group. However, the S6K expression level was clearly lower in the liver of the overfed group than that of control group, and there was no evident difference in both breast muscle and leg muscle between the control group and the overfed group. These results suggest that overfeeding induces the activity of raptor, rictor, and mTOR, and that mTOR signaling pathway was closely linked with PI3K pathway in the evaluated geese.

In this paper we introduce an approach for automatic recognition and reconstruction of building facade structure from oblique aerial images. Contrast to street-view image oblique aerial image has larger field of view but lower resolution, weaker texture and more noise. To overcome these shortcomings, our approach firstly analyses the horizontal distribution density to extract individual facade area from image. Then a hierarchical repetition detection method is employed to partition the facade and recognize structural elements. Finally, the geometry structure of each facade element is reconstructed jointly by all repetitive image tiles. Results show the potentials of the proposed approach.

In this paper, an efficient and conservative collocation method is proposed and used to develop a global shallow-water model. Being a nodal type high-order scheme, the present method solves the pointwise values of dependent variables as the unknowns within each control volume. The solution points are arranged as Gauss–Legendre points to achieve high-order accuracy. The time evolution equations to update the unknowns are derived under the flux reconstruction (FR) framework (Huynh, 2007). Constraint conditions used to build the spatial reconstruction for the flux function include the pointwise values of flux function at the solution points, which are computed directly from the dependent variables, as well as the numerical fluxes at the boundaries of the computational element, which are obtained as Riemann solutions between the adjacent elements. Given the reconstructed flux function, the time tendencies of the unknowns can be obtained directly from the governing equations of differential form. The resulting schemes have super convergence and rigorous numerical conservativeness. A three-point scheme of fifth-order accuracy is presented and analyzed in this paper. The proposed scheme is adopted to develop the global shallow-water model on the cubed-sphere grid, where the local high-order reconstruction is very beneficial for the data communications between adjacent patches. We have used the standard benchmark tests to verify the numerical model, which reveals its great potential as a candidate formulation for developing high-performance general circulation models.