In order to understand the aging and processing of organic aerosols (OA), an intensive field campaign (Campaign of Air Pollution at Typical Coastal Areas IN Eastern China, CAPTAIN) was conducted ...March–April at a receptor site (a Changdao island) in central eastern China. Multiple fast aerosol and gas measurement instruments were used during the campaign, including a high resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) that was applied to measure mass concentrations and non-refractory chemical components of submicron particles (PM1nr). The average mass concentration of PM1(PM1nr+black carbon) was 47 ± 36 μg m−3 during the campaign and showed distinct variation, depending on back trajectories and their overlap with source regions. Organic aerosol (OA) is the largest component of PM1 (30%), followed by nitrate (28%), sulfate (19%), ammonium (15%), black carbon (6%), and chloride (3%). Four OA components were resolved by positive matrix factorization (PMF) of the high-resolution spectra, including low-volatility oxygenated organic aerosol (LV-OOA), semi-volatile oxygenated OA (SV-OOA), hydrocarbon-like OA (HOA) and a coal combustion OA (CCOA). The mass spectrum of CCOA had high abundance of fragments from polycyclic aromatic hydrocarbons (PAHs) (m/z 128, 152, 178, etc.). The average atomic ratio of oxygen to carbon in OA (O / C) at Changdao was 0.59, which is comparable to other field studies reported at locations downwind of large pollution sources, indicating the oxidized nature of most OA during the campaign. The evolution of OA elemental composition in the van Krevelen diagram (H / C vs. O / C) showed a slope of −0.63; however, the OA influenced by coal combustion exhibits a completely different evolution that appears dominated by physical mixing. The aging of organic aerosols vs. photochemical age was investigated. It was shown that OA / ΔCO, as well as LV-OOA / ΔCO and SV-OOA / ΔCO, positively correlated with photochemical age. LV-OOA accounted for 73% of the OA secondary formation (SOA) in the oldest plumes (photochemical age of 25 h). The kOH at Changdao, by assuming SOA formation and aging as a first-order process proportional to OH, was calculated to be 5.2 × 10−12 cm3 molec.−1 s−1, which is similar to those determined in recent studies of polluted air in other continents.
Summary
Background
Little is known about the role of the microbiome in primary sclerosing cholangitis.
Aim
To explore the mucosa‐associated microbiota in primary sclerosing cholangitis (PSC) patients ...across different locations in the gut, and to compare it with inflammatory bowel disease (IBD)‐only patients and healthy controls.
Methods
Biopsies from the terminal ileum, right colon, and left colon were collected from patients and healthy controls undergoing colonoscopy. Microbiota profiling using bacterial 16S rRNA sequencing was performed on all biopsies.
Results
Forty‐four patients were recruited: 20 with PSC (19 with PSC‐IBD and one with PSC‐only), 15 with IBD‐only and nine healthy controls. The overall microbiome profile was similar throughout different locations in the gut. No differences in the global microbiome profile were found. However, we observed significant PSC‐associated enrichment in Barnesiellaceae at the family level, and in Blautia and an unidentified Barnesiellaceae at the genus level. At the operational taxa unit level, most shifts in PSC were observed in Clostridiales and Bacteroidales orders, with approximately 86% of shifts occurring within the former order.
Conclusions
The overall microbiota profile was similar across multiple locations in the gut from the same individual regardless of disease status. In this study, the mucosa associated‐microbiota of patients with primary sclerosing cholangitis was characterised by enrichment of Blautia and Barnesiellaceae and by major shifts in operational taxa units within Clostridiales order.
Genetic polymorphisms of CYP2C9 significantly influence the pharmacokinetics and pharmacodynamics of some drugs, which might result in adverse drug effects and therapeutic failure. Several studies ...have been performed on CYP2C9 genetic polymorphisms in Han Chinese populations. However, these studies only focused on two commonly investigated alleles, *2 and *3, in relatively small sample sizes. To scale up the gene-scanning region and determine relatively precise data on the genetic distribution pattern in Chinese populations, unrelated healthy Han Chinese volunteers from Zhejiang Province (n=1127) and Hebei (n=1000) Province were recruited as subjects for the direct sequencing of all exons of CYP2C9. As a result, 14 previously reported alleles were detected in this work, and 8 of these alleles (*14, *16, *19, *23, *27, *29, *33 and *34) were described for the first time in Chinese populations. In addition, 37 novel mutations were also detected, of which 22 variants were non-synonymous, and 21 new alleles, *36-*56, were designated by the Human CYP Allele Nomenclature Committee. In vitro functional analysis of these 22 novel CYP2C9 variants revealed that 17 mutations had a significant influence on the protein's catalytic activity. Our study provides the most accurate data on CYP2C9 polymorphisms in Han Chinese populations and detects the largest number of novel allelic variants existing to date. These new alleles will greatly enrich the current knowledge of naturally occurring CYP2C9 variants in Chinese populations.
Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI; OMIM #130900) is a genetic disorder exhibiting severe hardness defects and reduced fracture toughness of dental enamel. While the ...condition is nonsyndromic, it can be associated with other craniofacial anomalies, such as malocclusions and delayed or failed tooth eruption. Truncation mutations in FAM83H (OMIM *611927) are hitherto the sole cause of ADHCAI. With human genetic studies, Fam83h knockout and mutation–knock-in mouse models indicated that FAM83H does not serve a critical physiologic function during enamel formation and suggested a neomorphic mutation mechanism causing ADHCAI. The function of FAM83H remains obscure. FAM83H has been shown to interact with various isoforms of casein kinase 1 (CK1) and keratins and to mediate organization of keratin cytoskeletons and desmosomes. By considering FAM83H a scaffold protein to anchor CK1s, further molecular characterization of the protein could gain insight into its functions. In this study, we characterized 9 kindreds with ADHCAI and identified 3 novel FAM83H truncation mutations: p.His437*, p.Gln459*, and p.Glu610*. Some affected individuals exhibited hypoplastic phenotypes, in addition to the characteristic hypocalcification enamel defects, which have never been well documented. Failed eruption of canines or second molars in affected persons was observed in 4 of the families. The p.Glu610* mutation was located in a gap area (amino acids 470 to 625) within the zone of previously reported pathogenic variants (amino acids 287 to 694). In vitro pull-down studies with overexpressed FAM83H proteins in HEK293 cells demonstrated an interaction between FAM83H and SEC16A, a protein component of the COP II complex at endoplasmic reticulum exit sites. The interaction was mediated by the middle part (amino acids 287 to 657) of mouse FAM83H protein. Results of this study significantly extended the phenotypic and genotypic spectrums of FAM83H-associated ADHCAI and suggested a role for FAM83H in endoplasmic reticulum–to–Golgi vesicle trafficking and protein secretion (dbGaP phs001491.v1.p1).
The pelagic brown macroalgae Sargassum spp. have grown for centuries in oligotrophic waters of the North Atlantic Ocean supported by natural nutrient sources, such as excretions from associated ...fishes and invertebrates, upwelling, and N
fixation. Using a unique historical baseline, we show that since the 1980s the tissue %N of Sargassum spp. has increased by 35%, while %P has decreased by 44%, resulting in a 111% increase in the N:P ratio (13:1 to 28:1) and increased P limitation. The highest %N and δ
N values occurred in coastal waters influenced by N-rich terrestrial runoff, while lower C:N and C:P ratios occurred in winter and spring during peak river discharges. These findings suggest that increased N availability is supporting blooms of Sargassum and turning a critical nursery habitat into harmful algal blooms with catastrophic impacts on coastal ecosystems, economies, and human health.
High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
Equilibrium condensation of solar gas is often invoked to explain the abundance of refractory elements in planets and meteorites. This is partly motivated, by the observation that the depletions in ...both the least and most refractory rare earth elements (REEs) in meteoritic group II calcium-aluminum-rich inclusions (CAIs) can be reproduced by thermodynamic models of solar nebula condensation. We measured the isotopic compositions of Ce, Nd, Sm, Eu, Gd, Dy, Er, and Yb in eight CAIs to test this scenario. Contrary to expectation for equilibrium condensation, we find light isotope enrichment for the most refractory REEs and more subdued isotopic variations for the least refractory REEs. This suggests that group II CAIs formed by a two-stage process involving fast evaporation of preexisting materials, followed by near-equilibrium recondensation. The calculated time scales are consistent with heating in events akin to FU Orionis- or EX Lupi-type outbursts of eruptive pre-main-sequence stars.
Over the last few years, a number of authors have suggested that, under certain circumstances, molecular oxygen (O2) or ozone (O3) generated by abiotic processes may accumulate to detectable ...concentrations in a habitable terrestrial planet's atmosphere, producing so-called "false positives" for life. But the models have occasionally disagreed with each other, with some predicting false positives, and some not, for the same apparent set of circumstances. We show here that photochemical false positives derive either from inconsistencies in the treatment of atmospheric and global redox balance or from the treatment (or lack thereof) of lightning. For habitable terrestrial planets with even trace amounts of atmospheric N2, NO produced by lightning catalyzes the recombination of CO and O derived from CO2 photolysis and should be sufficient to eliminate all reported false positives. Molecular oxygen thus remains a useful biosignature gas for Earth-like extrasolar planets, provided that the planet resides within the conventional liquid water habitable zone and has not experienced distinctly non-Earth-like, irrecoverable water loss.
Accurate segmentation of the jaw (i.e., mandible and maxilla) and the teeth in cone beam computed tomography (CBCT) scans is essential for orthodontic diagnosis and treatment planning. Although ...various (semi)automated methods have been proposed to segment the jaw or the teeth, there is still a lack of fully automated segmentation methods that can simultaneously segment both anatomic structures in CBCT scans (i.e., multiclass segmentation). In this study, we aimed to train and validate a mixed-scale dense (MS-D) convolutional neural network for multiclass segmentation of the jaw, the teeth, and the background in CBCT scans. Thirty CBCT scans were obtained from patients who had undergone orthodontic treatment. Gold standard segmentation labels were manually created by 4 dentists. As a benchmark, we also evaluated MS-D networks that segmented the jaw or the teeth (i.e., binary segmentation). All segmented CBCT scans were converted to virtual 3-dimensional (3D) models. The segmentation performance of all trained MS-D networks was assessed by the Dice similarity coefficient and surface deviation. The CBCT scans segmented by the MS-D network demonstrated a large overlap with the gold standard segmentations (Dice similarity coefficient: 0.934 ± 0.019, jaw; 0.945 ± 0.021, teeth). The MS-D network–based 3D models of the jaw and the teeth showed minor surface deviations when compared with the corresponding gold standard 3D models (0.390 ± 0.093 mm, jaw; 0.204 ± 0.061 mm, teeth). The MS-D network took approximately 25 s to segment 1 CBCT scan, whereas manual segmentation took about 5 h. This study showed that multiclass segmentation of jaw and teeth was accurate and its performance was comparable to binary segmentation. The MS-D network trained for multiclass segmentation would therefore make patient-specific orthodontic treatment more feasible by strongly reducing the time required to segment multiple anatomic structures in CBCT scans.
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