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Background Atopic dermatitis is a chronic, inflammatory condition causing a substantial burden to patients and caregivers. SHR0302 is an oral, highly selective, Janus kinase 1 inhibitor under investigation for inflammatory skin diseases. Objective The aim of this study was to investigate the efficacy and safety of SHR0302 in Chinese patients with moderate to severe atopic dermatitis. Design and Setting A randomized, double-blind, placebo-controlled, multicenter, phase II trial was conducted in China between October 2019 and August 2020. Participants Patients ( n  = 105) aged 18–75 years with moderate to severe dermatitis and nonresponsive or intolerant to topical or conventional systemic treatments were included. Interventions Patients were randomly assigned in a ratio of 1:1:1 to receive SHR0302 4 mg once daily, SHR0302 8 mg once daily, or placebo for 12 weeks. Main Outcome Measures The primary efficacy endpoint was the proportion of patients achieving Investigator’s Global Assessment (IGA) response (IGA of 0 [clear] or 1 [almost clear] with improvement of ≥2 grades) at week 12. Secondary efficacy assessments included Eczema Area and Severity Index (EASI) and pruritus Numerical Rating Scale (NRS) scores. Results At week 12, IGA response was achieved in nine patients (25.7%; 90% confidence interval [CI] 13.6–37.9%; p  = 0.022) in the SHR0302 4 mg group, 19 patients (54.3%; 90% CI 40.4–68.1%; p  < 0.001) in the SHR0302 8 mg group, and two patients (5.7%; 90% CI 0.0–12.2%) in the placebo group. EASI75 was achieved in 51.4% ( p  = 0.013), 74.3% ( p  < 0.001), and 22.9% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively, while an NRS ≥3-point improvement occurred in 65.7% ( p  < 0.001), 74.3% ( p  < 0.001), and 22.9% of patients, respectively. Treatment-emergent adverse events were reported in 60.0%, 68.6%, and 51.4% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively. The adverse events were mild in most cases. Three serious adverse events were reported, all being worsening of atopic dermatitis. No serious infection was reported. Conclusions and Relevance Oral SHR0302 was effective and well tolerated in Chinese adult patients with moderate to severe atopic dermatitis. Trial Registration ClinicalTrials.gov identifier: NCT04162899; URL: https://clinicaltrials.gov/ . Date first registered: 14 November 2019.

Atmospheric new-particle formation affects climate and is one of the least understood atmospheric aerosol processes. The complexity and variability of the atmosphere has hindered elucidation of the fundamental mechanism of new-particle formation from gaseous precursors. We show, in experiments performed with the CLOUD (Cosmics Leaving Outdoor Droplets) chamber at CERN, that sulfuric acid and oxidized organic vapors at atmospheric concentrations reproduce particle nucleation rates observed in the lower atmosphere. The experiments reveal a nucleation mechanism involving the formation of clusters containing sulfuric acid and oxidized organic molecules from the very first step. Inclusion of this mechanism in a global aerosol model yields a photochemically and biologically driven seasonal cycle of particle concentrations in the continental boundary layer, in good agreement with observations.

Amines at typical atmospheric concentrations of a only few molecules per trillion air molecules combine with sulphuric acid to form highly stable aerosol particles at rates similar to those observed in the lower atmosphere. Atmospheric chemistry of anthropogenic amines Amines emitted into the atmosphere from anthropogenic sources are thought to enhance nucleation from trace atmospheric vapours, stimulate particle formation and influence the development and properties of clouds. Direct evidence for this under atmospheric conditions has been lacking; however, this study, using the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN, demonstrates that amines at atmospherically relevant concentrations can sufficiently increase nucleation rates to be able to account for the particle formation rates observed in the atmospheric environment. Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei 1 . Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes 2 . Atmospheric aerosols derived from human activities are thought to have compensated for a large fraction of the warming caused by greenhouse gases 2 . However, despite its importance for climate, atmospheric nucleation is poorly understood. Recently, it has been shown that sulphuric acid and ammonia cannot explain particle formation rates observed in the lower atmosphere 3 . It is thought that amines may enhance nucleation 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , but until now there has been no direct evidence for amine ternary nucleation under atmospheric conditions. Here we use the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN and find that dimethylamine above three parts per trillion by volume can enhance particle formation rates more than 1,000-fold compared with ammonia, sufficient to account for the particle formation rates observed in the atmosphere. Molecular analysis of the clusters reveals that the faster nucleation is explained by a base-stabilization mechanism involving acid–amine pairs, which strongly decrease evaporation. The ion-induced contribution is generally small, reflecting the high stability of sulphuric acid–dimethylamine clusters and indicating that galactic cosmic rays exert only a small influence on their formation, except at low overall formation rates. Our experimental measurements are well reproduced by a dynamical model based on quantum chemical calculations of binding energies of molecular clusters, without any fitted parameters. These results show that, in regions of the atmosphere near amine sources, both amines and sulphur dioxide should be considered when assessing the impact of anthropogenic activities on particle formation.

Recent research [Wang et al., Nature 581, 184–189 (2020)] indicates nitric acid (NA) can participate in sulfuric acid (SA)–ammonia (NH₂) nucleation in the clean and cold upper free troposphere, whereas NA exhibits no obvious effects at the boundary layer with relatively high temperatures. Herein, considering that an SA–dimethylamine (DMA) nucleation mechanism was detected inmegacities [Yao et al., Science 361, 278–281 (2018)], the roles of NA in SA-DMA nucleation are investigated. Different from SA-NH₂ nucleation, we found that NA can enhance SA-DMA–based particle formation rates in the polluted atmospheric boundary layer, such as Beijing in winter, with the enhancement up to 80-fold. Moreover, we found that NA can promote the number concentrations of nucleation clusters (up to 27-fold) and contribute 76% of cluster formation pathways at 280 K. The enhancements on particle formation by NA are critical for particulate pollution in the polluted boundary layer with relatively high NA and DMA concentrations.

Atmospheric aerosols formed by nucleation of vapors affect radiative forcing and therefore climate. However, the underlying mechanisms of nucleation remain unclear, particularly the involvement of organic compounds. Here, we present high-resolution mass spectra of ion clusters observed during new particle formation experiments performed at the Cosmics Leaving Outdoor Droplets chamber at the European Organization for Nuclear Research. The experiments involved sulfuric acid vapor and different stabilizing species, including ammonia and dimethylamine, as well as oxidation products of pinanediol, a surrogate for organic vapors formed from monoterpenes. A striking resemblance is revealed between the mass spectra from the chamber experiments with oxidized organics and ambient data obtained during new particle formation events at the Hyytiälä boreal forest research station. We observe that large oxidized organic compounds, arising from the oxidation of monoterpenes, cluster directly with single sulfuric acid molecules and then form growing clusters of one to three sulfuric acid molecules plus one to four oxidized organics. Most of these organic compounds retain 10 carbon atoms, and some of them are remarkably highly oxidized (oxygen-to-carbon ratios up to 1.2). The average degree of oxygenation of the organic compounds decreases while the clusters are growing. Our measurements therefore connect oxidized organics directly, and in detail, with the very first steps of new particle formation and their growth between 1 and 2 nm in a controlled environment. Thus, they confirm that oxidized organics are involved in both the formation and growth of particles under ambient conditions.

Potato peel waste (PPW) is an underutilized substrate which is produced in huge amounts by food processing industries. Using PPW a feedstock for production of useful compounds can overcome the problem of waste management as well as cost-effective. In present study, potential of PPW was investigated using chemical and thermochemical treatment processes. Three independent variables i.e., PPW concentration, dilute sulphuric acid concentration and liberation time were selected to optimize the production of fermentable sugars (TS and RS) and phenolic compounds (TP). These three process variables were selected in the range of 5–15 g w/v substrate, 0.8–1.2 v/v acid conc. and 4–6 h. Whole treatment process was optimized by using box-behnken design (BBD) of response surface methodology (RSM). Highest yield of total and reducing sugars and total phenolic compounds obtained after chemical treatment was 188.00, 144.42 and 43.68 mg/gds, respectively. The maximum yield of fermentable sugars attained by acid plus steam treatment were 720.00 and 660.62 mg/gds of TS and RS, respectively w.r.t 5% substrate conc. in 0.8% acid with residence time of 6 h. Results recorded that acid assisted autoclaved treatment could be an effective process for PPW deconstruction. Characterization of substrate before and after treatment was checked by SEM and FTIR. Spectras and micrographs confirmed the topographical variations in treated substrate. The present study was aimed to utilize biowaste and to determine cost-effective conditions for degradation of PWW into value added compounds.

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease. Diabetes is a major cause of kidney disease. Here Kikuchi et al. show that phenol sulfate, a gut microbiota-derived metabolite, is increased in diabetic kidney disease and contributes to the pathology by promoting kidney injury, suggesting phenyl sulfate could be used a marker and therapeutic target for the treatment of diabetic kidney disease.

New particle formation in the atmosphere is an important parameter in governing the radiative forcing of atmospheric aerosols. However, detailed nucleation mechanisms remain ambiguous, as laboratory data have so far not been successful in explaining atmospheric nucleation. We investigated the formation of new particles in a smog chamber simulating the photochemical formation of H₂SO₄ and organic condensable species. Nucleation occurs at H₂SO₄ concentrations similar to those found in the ambient atmosphere during nucleation events. The measured particle formation rates are proportional to the product of the concentrations of H₂SO₄ and an organic molecule. This suggests that only one H₂SO₄ molecule and one organic molecule are involved in the rate-limiting step of the observed nucleation process. Parameterizing this process in a global aerosol model results in substantially better agreement with ambient observations compared to control runs.

The atmospheric effects of soot aerosols include interference with radiative transfer, visibility impairment, and alteration of cloud formation and are highly sensitive to the manner by which soot is internally mixed with other aerosol constituents. We present experimental studies to show that soot particles acquire a large mass fraction of sulfuric acid during atmospheric aging, considerably altering their properties. Soot particles exposed to subsaturated sulfuric acid vapor exhibit a marked change in morphology, characterized by a decreased mobility-based diameter but an increased fractal dimension and effective density. These particles experience large hygroscopic size and mass growth at subsaturated conditions (<90% relative humidity) and act efficiently as cloud-condensation nuclei. Coating with sulfuric acid and subsequent hygroscopic growth enhance the optical properties of soot aerosols, increasing scattering by [almost equal to]10-fold and absorption by nearly 2-fold at 80% relative humidity relative to fresh particles. In addition, condensation of sulfuric acid is shown to occur at a similar rate on ambient aerosols of various types of a given mobility size, regardless of their chemical compositions and microphysical structures. Representing an important mechanism of atmospheric aging, internal mixing of soot with sulfuric acid has profound implications on visibility, human health, and direct and indirect climate forcing.

For atmospheric sulfuric acid (SA) concentrations the presence of dimethylamine (DMA) at mixing ratios of several parts per trillion by volume can explain observed boundary layer new particle formation rates. However, the concentration and molecular composition of the neutral (uncharged) clusters have not been reported so far due to the lack of suitable instrumentation. Here we report on experiments from the Cosmics Leaving Outdoor Droplets chamber at the European Organization for Nuclear Research revealing the formation of neutral particles containing up to 14 SA and 16 DMA molecules, corresponding to a mobility diameter of about 2 nm, under atmospherically relevant conditions. These measurements bridge the gap between the molecular and particle perspectives of nucleation, revealing the fundamental processes involved in particle formation and growth. The neutral clusters are found to form at or close to the kinetic limit where particle formation is limited only by the collision rate of SA molecules. Even though the neutral particles are stable against evaporation from the SA dimer onward, the formation rates of particles at 1.7-nm size, which contain about 10 SA molecules, are up to 4 orders of magnitude smaller compared with those of the dimer due to coagulation and wall loss of particles before they reach 1.7 nm in diameter. This demonstrates that neither the atmospheric particle formation rate nor its dependence on SA can simply be interpreted in terms of cluster evaporation or the molecular composition of a critical nucleus. Significance A significant fraction of atmospheric aerosols is formed from the condensation of low-volatility vapors. These newly formed particles can grow, become seeds for cloud particles, and influence climate. New particle formation in the planetary boundary layer generally proceeds via the neutral channel. However, unambiguous identification of neutral nucleating clusters has so far not been possible under atmospherically relevant conditions. We explored the system of sulfuric acid, water, and dimethylamine in a well-controlled laboratory experiment and measured the time-resolved concentrations of neutral clusters. Clusters containing up to 14 sulfuric acid and 16 dimethylamine molecules were observed. Our results demonstrate that a cluster containing as few as two sulfuric acid and one or two dimethylamine molecules is already stable against evaporation.