Characteristics and Source Apportionment of Volatile Organic Compounds in a Coastal Industrial Area: A Case Study in the Yangtze River Delta of China.

In recent years, the coastal area in East China has experienced elevated volatile organic compounds (VOCs) levels during specific periods. VOCs have become one of the major atmospheric pollutants in these areas. In this study, 64 compounds including alkanes, alkenes, halohydrocarbons, aromatics, and oxygenated VOCs (OVOCs) were obtained by the TO-15 method through a 12-month campaign in industrial, urban and suburban areas in the Yangtze River Delta of China. The overall trends of total VOC (TVOC) concentrations at eight sampling sites were as follows: winter > autumn > spring > summer. The proportion of VOC categories was various at industrial sites, while OVOCs and halohydrocarbons had high proportions at urban sites and suburban sites, respectively. Coating, vehicle emission, petrochemical source, industrial source, and gasoline volatilization were identified as the major VOC emission sources by the positive matrix factorization model. Petrochemical and coating sources were the prime VOC sources at industrial sites. Aromatics contributed the most ozone formation potential at industrial sites, while OVOCs provided the main contributions at both urban and suburban sites during four seasons. According to the health risk assessment, a high probability of non-carcinogenic risk existed at three industrial sites. Special attention should be given to certain VOCs, such as acrolein and 1,2-dibromoethane in industrial areas.

High spatiotemporal resolution scintillation imaging of pulsed pencil beam scanning proton beams produced by a gantry-mounted synchrocyclotron.

BACKGROUND: A dosimeter with high spatial and temporal resolution would be of significant interest for pencil beam scanning (PBS) proton beams' characterization, especially when facing small fields and beams with high temporal dynamics. Optical imaging of scintillators has potential in providing sub-millimeter spatial resolution with pulse-by-pulse basis temporal resolution when the imaging system is capable of operating in synchrony with the beam-producing accelerator. PURPOSE: We demonstrate the feasibility of imaging PBS proton beams as they pass through a plastic scintillator detector to simultaneously obtain multiple beam parameters, including proton range, pencil beam's widths at different depths, spot's size, and spot's position on a pulse-by-pulse basis with sub-millimeter resolution. MATERIALS AND METHODS: A PBS synchrocyclotron was used for proton irradiation. A BC-408 plastic scintillator block with 30 × 30 × 5 cm3 size, and another block with 30 × 30 × 0.5 cm3 size, positioned in an optically sealed housing, were used sequentially to measure the proton range, and spot size/location, respectively. A high-speed complementary metal-oxide-semiconductor (CMOS) camera system synchronized with the accelerator's pulses through a gating module was used for imaging. Scintillation images, captured with the camera directly facing the 5-cm-thick scintillator, were corrected for background (BG), and ionization quenching of the scintillator to obtain the proton range. Spots' position and size were obtained from scintillation images of the 0.5-cm-thick scintillator when a 45° mirror was used to reflect the scintillation light toward the camera. RESULTS: Scintillation images with 0.16 mm/pixel resolution corresponding to all proton pulses were captured. Pulse-by-pulse analysis showed that variations of the range, spots' position, and size were within ± 0.2% standard deviation of their average values. The absolute ranges were within ± 1 mm of their expected values. The average spot-positions were mostly within ± 0.8 mm and spots' sigma agreed within 0.2 mm of the expected values. CONCLUSION: Scintillation-imaging PBS beams with high-spatiotemporal resolution is feasible and may help in efficient and cost-effective acceptance testing and commissioning of existing and even emerging technologies such as FLASH, grid, mini-beams, and so forth.

Concurrence of novel mutations causing Gilbert's and Dubin-Johnson syndrome with poor clinical outcomes in a Han Chinese family.

Dual-hereditary jaundice (Dubin-Johnson syndrome (DJS) and Gilbert's syndrome (GS)) is a rare clinical entity resulting from defects of the ATP binding cassette subfamily C member 2 (ABCC2) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genes with autosomal recessive inheritance. In this study, we aimed to investigate the mutation profiles and characterize the phenotypes in a Han Chinese family with DJS and GS. Genetic screening for variants in the ABCC2 and UGT1A1, immunohistochemistry for expression of ABCC2, and histopathological examination were carried out. The proband and his brother had unconjugated and conjugated hyperbilirubinemia after birth. The proband's sister had only conjugated hyperbilirubinemia after birth. The proband developed into pleural effusions and ascites, pericardial thickening, intrahepatic and extrahepatic biliary duct dilatation, and enlarged gallbladder at age 50. Hepatocellular carcinoma occurred in the proband's brother at age 46. Seven compound defects of the ABCC2 gene [c.2414delG, p.(Ile1489Gly), p.(Thr1490Pro), and p.(Ile1491Gln)] and the UGT1A1 gene (c.-3279T>G, p.(Gly71Arg), and p.(Pro451Leu)) were identified in family members. Accumulation of pigment in hepatocytes characteristic of that in DJS was present in the proband and his brother. Expression of ABCC2 protein was markedly diminished in the patient's liver. Our results show a different genetic profile of DJS and GS in a Han Chinese family, indicating a more complex pattern of dual-hereditary jaundice among different populations. The present study illuminates the underpinnings of DJS and GS and extends the mutation profiles and phenotypes of these two syndromes in dual-hereditary jaundice.

Immunogenicity, durability, and safety of an mRNA and three platform-based COVID-19 vaccines as a third dose following two doses of CoronaVac in China: A randomised, double-blinded, placebo-controlled, phase 2 trial.

Background: More effective vaccine candidates against variants of concern as a booster dose are needed in people primed with two-dose inactivated COVID-19 vaccines. Methods: This randomised, double-blinded, investigator-initiated phase 2 trial aims to evaluate immunogenicity, durability, and safety of an mRNA vaccine candidate (RQ3013) and three other platform vaccines (an adenovirus-vectored vaccine candidate [ChAdTS-S], a recombinant protein vaccine candidate [ZR202-CoV], and an inactivated vaccine [CoronaVac]) as a booster. 250 eligible volunteers, who had received a prime two-dose CoronaVac (3 to 5 weeks apart) vaccination 100-270 days before, were randomly assigned in a 1:1:1:1:1 ratio to receive a third dose of RQ3013 (30 µg mRNA per 0.15 mL), ChAdTS-S (5×1010 viral particles per 0.5 mL), ZR202-CoV (25 µg prefusion-stabilized Spike ectodomain trimer per 0.5 mL), CoronaVac (3 µg inactivated CN02 strain of SARS-CoV-2 per 0.5 mL) or placebo (0.5 mL of 0.9% sodium chloride solution) via intramuscular injection into the upper arm at a single clinical site in Kunming, China. Participants, investigators, and immunogenicity laboratory were masked to group assignment. The primary immunogenicity outcomes were geometric mean titres (GMTs) of neutralising antibodies against live SARS-CoV-2 (wild-type, delta and omicron) virus at day 0 (before vaccination), day 7, day 14 and day 28 after vaccination, as analysed in a modified intention-to-treat (mITT) population (all participants who completed their booster doses and had at least one post-dose immunogenicity data). Secondary outcomes include T cell responses against the wild-type and omicron SARS-CoV-2 Spike protein. The primary safety outcome was incidence of adverse events within 14 days after the booster vaccination. This trial is registered with ChiCTR.org.cn, ChiCTR2200057758. Findings: Between January 1, 2022, and February 28, 2022, 235 eligible participants were enrolled and vaccinated, and the primary analysis included 234 participants. At baseline, neutralising antibodies against wild-type virus, the delta, or omicron variants were low or undetectable in all groups. After the booster vaccination, GMTs of neutralising antibodies ranged from 75.4 (95% confidence interval [CI] 61.4-92.5) in CoronaVac to 950.1 (95% CI 785.4-1149.3) in RQ3013 against live wild-type SARS-CoV-2, and from 8.1 (95% CI: 6.1-10.7) in CoronaVac to 247.0 (95% CI 194.1-314.3) in RQ3013 against the omicron variant at day 14. Immunogenicities of all heterologous regimens were superior to that of homologous regimen in neutralisation against all tested SARS-CoV-2 strains, with RQ3013 showing the highest geometric mean ratios (GMRs) of 12.6, 14.7, and 31.3 against the wild-type, the delta variant and the omicron variant compared to CoronaVac at day 14 post-vaccination, respectively. Durability analysis at day 90 showed that >90% of participants in RQ3013 and ZR202-CoV were seropositive for the omicron variant while ZR202-CoV with adjuvants containing CpG showed a slightly better durability than RQ3013. T cell responses specific to the omicron variant were similar to that of the wild-type, with RQ3013 showing the highest boosting effect. Any solicited injection site or systemic adverse events reported within 14 days after vaccination were most commonly observed in RQ3013 (47/47, 100%), followed by ZR202-CoV (46/47, 97.9%) and ChAdTS-S (43/48, 89.6%), and then CoronaVac (37/46, 80.4%) and placebo (21/47, 44.7%). More than 90% of the adverse events were grade 1 (mild) or 2 (moderate) with a typical resolution time of 3 days. No grade 4 adverse events or serious adverse events were reported by study vaccines. Interpretation: Although all study vaccines boosted neutralising antibodies with no safety concerns, RQ3013 showed much stronger cross-neutralisation and cellular responses, adding more effective vaccine candidates against the omicron variant. Funding: Yunnan Provincial Science and Technology Department China (202102AA100051 and 202003AC100010), the Double First-class University funding to Yunnan University, National Natural Science Foundation of China (81960116, 82060368 and 82170711), Yunnan Natural Science Foundation (202001AT070085), High-level Health Technical Personnel Project of Yunnan Province (H-2018102) and Spring City Plan: The High-level Talent Promotion and Training Project of Kunming.

SNARE Proteins Mediate α-Synuclein Secretion via Multiple Vesicular Pathways.

The cell-to-cell transmission of pathological α-synuclein (α-syn) has been proposed to be a critical event in the development of synucleinopathies. Recent studies have begun to reveal the underlying molecular mechanism of α-syn propagation. As one of the central steps, α-syn secretion is reported to be Ca2+-dependent and mediated by unconventional exocytosis. However, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) requirement and vesicle identity of α-syn secretion remain elusive. Here we found that α-syn secretion is SNARE-dependent by systematically knocking down Q-SNAREs and R-SNAREs in exocytosis pathways. α-Syn secretion was mainly mediated by syntaxin 4 (STX4) and synaptosomal-associated protein 23 (SNAP23), but did not require STX1 and SNAP25, in differentiated SH-SY5Y cells. On the other hand, vesicle-associated membrane protein 3 (VAMP3), VAMP7, and VAMP8 were all involved in α-syn secretion, most likely in overlapping pathways. Application of super-resolution microscopy revealed localization of both endogenous and overexpressed α-syn in endosomes, lysosomes, and autophagosomes in rat primary cortical neurons. α-Syn co-localized with microtubule-associated protein 1 light chain 3 (LC3) most extensively, suggesting its tight association with the autophagy pathway. Consistently, α-syn secretion was regulated by the autophagy-lysosome pathway. Collectively, our data suggest that α-syn secretion is SNARE-dependent and is mediated by multiple vesicular pathways including exocytosis of recycling endosomes, multivesicular bodies, autophagosomes, and lysosomes.

Pathogenic Mutations Differentially Regulate Cell-to-Cell Transmission of α-Synuclein.

Recent studies suggest that the cell-to-cell spread of pathological α-synuclein (α-syn) plays important roles in the development of Parkinson's disease (PD). PD patients who carry α-syn gene mutations often have an earlier onset and more severe clinical symptoms and pathology than sporadic PD cases who carry the wild-type (WT) α-syn gene. However, the molecular mechanism by which α-syn gene mutations promote PD remains unclear. Here, we hypothesized that pathogenic mutations facilitate the intercellular transfer and cytotoxicity of α-syn, favoring an early disease onset and faster progression. We investigated the effects of eight known pathogenic mutations in human α-syn (A18T, A29S, A30P, E46K, H50Q, G51D, A53E, and A53T) on its pathological transmission in terms of secretion, aggregation, intracellular level, cytotoxicity, seeding, and induction of neuroinflammation in SH-SY5Y neuroblastoma cells, cultured rat neurons, and microglia, and the rat substantia nigra pars compacta. We found that 2 of the 8 mutations (H50Q and A53T) significantly increased α-syn secretion while 6 mutations (A18T, A29S, A30P, G51D, A53E, and E46K) tended to enhance it. In vitroα-syn aggregation experiments showed that H50Q promoted while G51D delayed aggregation most strongly. Interestingly, 3 mutations (E46K, H50Q, and G51D) greatly increased the intracellular α-syn level when cultured cells were treated with preformed α-syn fibrils (PFFs) compared with the WT, while the other 5 had no effect. We also demonstrated that H50Q, G51D, and A53T PFFs, but not E46K PFFs, efficiently seeded in vivo and acutely induced neuroinflammation in rat substantia nigra pars compacta. Our data indicate that pathogenic mutations augment the prion-like spread of α-syn at different steps and blockade of this pathogenic propagation may serve as a promising therapeutic intervention for PD.