Fast-replicating neurotropic herpesviruses exemplified by herpes simplex virus-1 (HSV-1) naturally infect the central nervous system (CNS). However, most individuals intrinsically suppress the virus ...during a primary infection and preclude it from significantly damaging the CNS. Optineurin (OPTN) is a conserved autophagy receptor with little understanding of its role in neurotropic viral infections. We show that OPTN selectively targets HSV-1 tegument protein, VP16, and the fusion glycoprotein, gB, to degradation by autophagy. OPTN-deficient mice challenged with HSV-1 show significant cognitive decline and susceptibility to lethal CNS infection. OPTN deficiency unveils severe consequences for recruitment of adaptive immunity and suppression of neuronal necroptosis. Ocular HSV-1 infection is lethal without OPTN and is rescued using a necroptosis inhibitor. These results place OPTN at the crux of neuronal survival from potentially lethal CNS viral infections.
Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic ...antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer.
The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5
prostate cancer cell lines and patient-derived xenografts models.
CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor
and
to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the
core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5
prostate cancer cell lines and marked antitumor responses in CEACAM5
CRPC xenograft models including chemotherapy-resistant NEPC.
Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.
Increasing tropospheric ozone levels over the past 150 years have led to a significant climate perturbation; the prediction of future trends in tropospheric ozone will require a full understanding of ...both its precursor emissions and its destruction processes. A large proportion of tropospheric ozone loss occurs in the tropical marine boundary layer and is thought to be driven primarily by high ozone photolysis rates in the presence of high concentrations of water vapour. A further reduction in the tropospheric ozone burden through bromine and iodine emitted from open-ocean marine sources has been postulated by numerical models, but thus far has not been verified by observations. Here we report eight months of spectroscopic measurements at the Cape Verde Observatory indicative of the ubiquitous daytime presence of bromine monoxide and iodine monoxide in the tropical marine boundary layer. A year-round data set of co-located in situ surface trace gas measurements made in conjunction with low-level aircraft observations shows that the mean daily observed ozone loss is ∼50 per cent greater than that simulated by a global chemistry model using a classical photochemistry scheme that excludes halogen chemistry. We perform box model calculations that indicate that the observed halogen concentrations induce the extra ozone loss required for the models to match observations. Our results show that halogen chemistry has a significant and extensive influence on photochemical ozone loss in the tropical Atlantic Ocean boundary layer. The omission of halogen sources and their chemistry in atmospheric models may lead to significant errors in calculations of global ozone budgets, tropospheric oxidizing capacity and methane oxidation rates, both historically and in the future.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Isoprene nitrates are important chemical species in the atmosphere
which contribute to the chemical cycles that form ozone and secondary
organic aerosol (SOA) with implications for climate and air ...quality.
Accurate chemical mechanisms are important for the prediction of the
atmospheric chemistry of species such as isoprene nitrates in chemical
models. In recent years, studies into the chemistry of isoprene nitrates
have resulted in the development of a range of mechanisms available for use
in the simulation of atmospheric isoprene oxidation. This work uses a 0-D
chemical box model to assess the ability of three chemically detailed
mechanisms to predict the observed diurnal profiles of four groups of
isoprene-derived nitrates in the summertime in the Chinese megacity of
Beijing. An analysis of modelled C5H9NO5 isomers, including
isoprene hydroperoxy nitrate (IPN) species, highlights the significant
contribution of non-IPN species to the C5H9NO5 measurement,
including the potentially large contribution of nitrooxy hydroxyepoxide
(INHE). The changing isomer distribution of isoprene hydroxy nitrates (IHNs) derived from OH-initiated and NO3-initiated chemistry is discussed, as
is the importance of up-to-date alkoxy radical chemistry for the accurate
prediction of isoprene carbonyl nitrate (ICN) formation. All mechanisms
under-predicted C4H7NO5 as predominately formed from the
major isoprene oxidation products, methyl vinyl ketone (MVK) and
methacrolein (MACR). This work explores the current capability of existing
chemical mechanisms to accurately represent isoprene nitrate chemistry in
urban areas significantly impacted by anthropogenic and biogenic chemical
interactions. It suggests considerations to be taken when investigating
isoprene nitrates in ambient scenarios, investigates the potential impact of
varying isomer distributions on iodide chemical ionisation mass spectrometry
(I−-CIMS) calibrations, and makes some proposals for the future development of isoprene mechanisms.
Near-continuous measurements of hydroxyl radical (OH) reactivity in the urban background atmosphere of central London during the summer of 2012 are presented. OH reactivity behaviour is seen to be ...broadly dependent on air mass origin, with the highest reactivity and the most pronounced diurnal profile observed when air had passed over central London to the east, prior to measurement. Averaged over the entire observation period of 26 days, OH reactivity peaked at ∼ 27 s−1 in the morning, with a minimum of ∼ 15 s−1 during the afternoon. A maximum OH reactivity of 116 s−1 was recorded on one day during morning rush hour. A detailed box model using the Master Chemical Mechanism was used to calculate OH reactivity, and was constrained with an extended measurement data set of volatile organic compounds (VOCs) derived from a gas chromatography flame ionisation detector (GC-FID) and a two-dimensional GC instrument which included heavier molecular weight (up to C12) aliphatic VOCs, oxygenated VOCs and the biogenic VOCs α-pinene and limonene. Comparison was made between observed OH reactivity and modelled OH reactivity using (i) a standard suite of VOC measurements (C2–C8 hydrocarbons and a small selection of oxygenated VOCs) and (ii) a more comprehensive inventory including species up to C12. Modelled reactivities were lower than those measured (by 33 %) when only the reactivity of the standard VOC suite was considered. The difference between measured and modelled reactivity was improved, to within 15 %, if the reactivity of the higher VOCs (⩾ C9) was also considered, with the reactivity of the biogenic compounds of α-pinene and limonene and their oxidation products almost entirely responsible for this improvement. Further improvements in the model's ability to reproduce OH reactivity (to within 6 %) could be achieved if the reactivity and degradation mechanism of unassigned two-dimensional GC peaks were estimated. Neglecting the contribution of the higher VOCs (⩾ C9) (particularly α-pinene and limonene) and model-generated intermediates increases the modelled OH concentrations by 41 %, and the magnitude of in situ ozone production calculated from the production of RO2 was significantly lower (60 %). This work highlights that any future ozone abatement strategies should consider the role that biogenic emissions play alongside anthropogenic emissions in influencing London's air quality.
Soil has the potential to be valuable forensic evidence linking a person or item to a crime scene; however, there is no established soil individualization technique. In this study, the utility of ...soil bacterial profiling via next‐generation sequencing of the 16S rRNA gene was examined for associating soils with their place of origin. Soil samples were collected from ten diverse and nine similar habitats over time, and within three habitats at various horizontal and vertical distances. Bacterial profiles were analyzed using four methods: abundance charts and nonmetric multidimensional scaling provided simplification and visualization of the massive datasets, potentially aiding in expert testimony, while analysis of similarities and k‐nearest neighbor offered objective statistical comparisons. The vast majority of soil bacterial profiles (95.4%) were classified to their location of origin, highlighting the potential of bacterial profiling via next‐generation sequencing for the forensic analysis of soil samples.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Isoprene and monoterpene emissions to the atmosphere are generally
dominated by biogenic sources. The oxidation of these compounds can lead to
the production of secondary organic aerosol; however the ...impact of this
chemistry in polluted urban settings has been poorly studied. Isoprene and
monoterpenes can form secondary organic aerosol (SOA) heterogeneously via anthropogenic–biogenic
interactions, resulting in the formation of organosulfate (OS) and
nitrooxy-organosulfate (NOS) species. Delhi, India, is one of the most polluted
cities in the world, but little is known about the emissions of biogenic
volatile organic compounds (VOCs) or the sources of SOA. As part of the DELHI-FLUX project, gas-phase
mixing ratios of isoprene and speciated monoterpenes were measured during
pre- and post-monsoon measurement campaigns in central Delhi. Nocturnal
mixing ratios of the VOCs were substantially higher during the post-monsoon
(isoprene: (0.65±0.43) ppbv; limonene: (0.59±0.11) ppbv;
α-pinene: (0.13±0.12) ppbv) than the pre-monsoon (isoprene:
(0.13±0.18) ppbv; limonene: 0.011±0.025 (ppbv); α-pinene: 0.033±0.009) period. At night, isoprene and monoterpene
concentrations correlated strongly with CO during the post-monsoon
period. Filter samples of particulate matter less than 2.5 µm in
diameter (PM2.5) were collected and the OS and NOS content analysed
using ultra-high-performance liquid chromatography tandem mass spectrometry
(UHPLC-MS2). Inorganic sulfate was shown to facilitate the formation of
isoprene OS species across both campaigns. Sulfate contained within OS and
NOS species was shown to contribute significantly to the sulfate signal
measured via AMS. Strong nocturnal enhancements of NOS species were observed
across both campaigns. The total concentration of OS and NOS species contributed
an average of (2.0±0.9) % and (1.8±1.4) % to the total
oxidized organic aerosol and up to a maximum of 4.2 % and 6.6 %
across the pre- and post-monsoon periods, respectively. Overall, this study
provides the first molecular-level measurements of SOA derived from isoprene
and monoterpene in Delhi and demonstrates that both biogenic and
anthropogenic sources of these compounds can be important in urban areas.
Volatile organic compounds (VOCs) play an important role in urban air pollution, both as primary pollutants and through their contribution to the formation of secondary pollutants, such as ...tropospheric ozone and secondary organic aerosols. In this study, more than 30 VOC species were continuously monitored in the two most populous cities in Vietnam, namely Ho Chi Minh City (HCMC, September-October 2018 and March 2019) and Hanoi (March 2019). In parallel with ambient VOC sampling, grab sampling was used to target the most prevalent regional-specific emission sources and estimate their emission factors (EFs).
Emission ratios (ERs) obtained from ambient sampling were compared between Vietnamese cities and other cities across the globe. No significant differences were observed between HCMC and Hanoi, suggesting the presence of similar sources. Moreover, a good global agreement was obtained in the spatial comparison within a factor of 2, with greater ER for aromatics and pentanes obtained in the Vietnamese cities.
The detailed analysis of sources included the evaluation of EF from passenger cars, buses, trucks, motorcycles, 3-wheeled motorcycles, waste burning, and coal-burning emissions. Our comparisons between ambient and near-source concentration profiles show that road transport sources are the main contributors to VOC concentrations in Vietnamese cities.
VOC emissions were calculated from measured EF and consumption data available in Hanoi and compared with those estimated by a global emission inventory (EDGAR v4.3.2). The total VOC emissions from the road transport sector estimated by the inventory do not agree with those calculated from our observations which showed higher total emissions by a factor of 3. Furthermore, the inventory misrepresented the VOCs speciation, mainly for isoprene, monoterpenes, aromatics, and oxygenated compounds. Accounting for these differences in regional air quality models would lead to improved predictions of their impacts and help to prioritise pollution reduction strategies in the region.
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•VOC emission ratios do not show substantial seasonal differences in Ho Chi Minh City.•VOCs from road transport emissions are similar to ambient concentration profiles in Hanoi.•Large differences in speciation are observed between observations and inventory estimations.•Observed total VOC road transport emissions are 3 times higher than those estimated by the inventory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Biomass burning emits significant quantities of intermediate-volatility and semi-volatile organic compounds (I/SVOCs) in a complex mixture, probably containing many thousands of chemical species. ...These components are significantly more toxic and have poorly understood chemistry compared to volatile organic compounds routinely quantified in ambient air; however, analysis of I/SVOCs presents a difficult analytical challenge.
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