Evaluation of simulated O-3 production efficiency during the KORUS-AQ campaign: Implications for anthropogenic NOx emissions in Korea

We examine O3 production and its sensitivity to precursor gases and boundary layer mixing in Korea by using a 3-D global chemistry transport model and extensive observations during the KORea-US cooperative Air Quality field study in Korea, which occurred in May–June 2016. During the campaign, observed aromatic species onboard the NASA DC-8 aircraft, especially toluene, showed high mixing ratios of up to 10 ppbv, emphasizing the importance of aromatic chemistry in O3 production. To examine the role of VOCs and NOx in O3 chemistry, we first implement a detailed aromatic chemistry scheme in the model, which reduces the normalized mean bias of simulated O3 mixing ratios from –26% to –13%. Aromatic chemistry also increases the average net O3 production in Korea by 37%. Corrections of daytime PBL heights, which are overestimated in the model compared to lidar observations, increase the net O3 production rate by ~10%. In addition, increasing NOx emissions by 50% in the model shows best performance in reproducing O3 production characteristics, which implies that NOx emissions are underestimated in the current emissions inventory. Sensitivity tests show that a 30% decrease in anthropogenic NOx emissions in Korea increases the O3 production efficiency throughout the country, making rural regions ~2 times more efficient in producing O3 per NOx consumed. Simulated O3 levels overall decrease in the peninsula except for urban and other industrial areas, with the largest increase (~6 ppbv) in the Seoul Metropolitan Area (SMA). However, with simultaneous reductions in both NOx and VOCs emissions by 30%, O3 decreases in most of the country, including the SMA. This implies the importance of concurrent emission reductions for both NOx and VOCs in order to effectively reduce O3 levels in Korea

Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.Comment: paper + supporting information, total 35 pages, 15 figure

Genes involved in platelet aggregation and activation are downregulated during acute anaphylaxis in humans

Objective: Mechanisms underlying the anaphylactic reaction in humans are not fully understood. Here, we aimed at improving our understanding of anaphylaxis by investigating gene expression changes. Methods: Microarray data set GSE69063 was analysed, describing emergency department (ED) patients with severe anaphylaxis (n = 12), moderate anaphylaxis (n = 6), sepsis (n = 20) and trauma (n = 11). Samples were taken at ED presentation (T0) and 1 h later (T1). Healthy controls were age and sex matched to ED patient groups. Gene expression changes were determined using limma, and pathway analysis applied. Differentially expressed genes were validated in an independent cohort of anaphylaxis patients (n = 31) and matched healthy controls (n = 10), using quantitative reverse transcription-polymerase chain reaction. Results: Platelet aggregation was dysregulated in severe anaphylaxis at T0, but not in moderate anaphylaxis, sepsis or trauma. Dysregulation was not observed in patients who received adrenaline before T0. Seven genes (GATA1 (adjusted P-value = 5.57 × 10−4), TLN1 (adjusted P-value = 9.40 × 10−4), GP1BA (adjusted P-value = 2.15 × 10−2), SELP (adjusted P-value = 2.29 × 10−2), MPL (adjusted P-value = 1.20 × 10−2), F13A1 (adjusted P-value = 1.39 × 10−2) and SPARC (adjusted P-value = 4.06 × 10−2)) were significantly downregulated in severe anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. One gene (TLN1 (adjusted P-value = 1.29 × 10−2)) was significantly downregulated in moderate anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. Conclusion: Downregulation of genes involved in platelet aggregation and activation is a unique feature of the early anaphylactic reaction not previously reported and may be associated with reaction severity

The tumor suppressor miR-642a-5p targets Wilms tumor 1 gene and cell-cycle progression in prostate cancer

RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle; downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2; and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2; and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control; and restoration of miR-642-5p in PCa could represent a novel therapeutic approach

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLCβ3- or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLCβ3 and the TRPV1 channel; 2) serotonin, or a selective agonist, α-methyl-serotonin (α-Me-5-HT), requires the presence of PLCβ3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLCβ3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD^+ neurons that represent ≈90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1+ nociceptors led to a significant behavioral deficit for pruritogens, including α-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways

ACE-ASIA - Regional climatic and atmospheric chemical effects of Asian dust and pollution

Although continental-scale plumes of Asian dust and pollution reduce the amount of solar radiation reaching the earth's surface and perturb the chemistry of the atmosphere, our ability to quantify these effects has been limited by a lack of critical observations, particularly of layers above the surface. Comprehensive surface, airborne, shipboard, and satellite measurements of Asian aerosol chemical composition, size, optical properties, and radiative impacts were performed during the Asian Pacific Regional Aerosol Characterization Experiment (ACE-Asia) study. Measurements within a massive Chinese dust storm at numerous widely spaced sampling locations revealed the highly complex structure of the atmosphere, in which layers of dust, urban pollution, and biomass-burning smoke may be transported long distances as distinct entities or mixed together. The data allow a first-time assessment of the regional climatic and atmospheric chemical effects of a continental-scale mixture of dust and pollution. Our results show that radiative flux reductions during such episodes are sufficient to cause regional climate change

FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops

© The Author(s) 2019. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.Research in the Azzalin laboratory was supported by the Swiss National Science Foundation (31003A_160338), the European Molecular Biology Organization (IG3576) and the Fundação para a Ciência e a Tecnologia (IF/01269/2015; PTDC/MED-ONC/28282/2017; PTDC/BIA-MOL/29352/2017). R.P. was supported by a Swiss National Science Foundation Doc.Mobility fellowship (P1EZP3-168771). Research in the Deans laboratory was supported by the Cancer Council of Victoria, Australian National Health and Medical Research Council (APP1139099), Buxton trust and the Victorian Government’s OIS Program. A.J.D is a Victorian Cancer Agency fellow. Publication costs were supported by UID/BIM/50005/2019, project funded by the Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

Alterations in cortical thickness development in preterm-born individuals:Implications for high-order cognitive functions

AbstractVery preterm birth (gestational age <33weeks) is associated with alterations in cortical thickness and with neuropsychological/behavioural impairments. Here we studied cortical thickness in very preterm born individuals and controls in mid-adolescence (mean age 15years) and beginning of adulthood (mean age 20years), as well as longitudinal changes between the two time points. Using univariate approaches, we showed both increases and decreases in cortical thickness in very preterm born individuals compared to controls. Specifically (1) very preterm born adolescents displayed extensive areas of greater cortical thickness, especially in occipitotemporal and prefrontal cortices, differences which decreased substantially by early adulthood; (2) at both time points, very preterm-born participants showed smaller cortical thickness, especially in parahippocampal and insular regions. We then employed a multivariate approach (support vector machine) to study spatially discriminating features between the two groups, which achieved a mean accuracy of 86.5%. The spatially distributed regions in which cortical thickness best discriminated between the groups (top 5%) included temporal, occipitotemporal, parietal and prefrontal cortices. Within these spatially distributed regions (top 1%), longitudinal changes in cortical thickness in left temporal pole, right occipitotemporal gyrus and left superior parietal lobe were significantly associated with scores on language-based tests of executive function. These results describe alterations in cortical thickness development in preterm-born individuals in their second decade of life, with implications for high-order cognitive processing