Climate change is exposing subarctic ecosystems to higher temperatures, increased nutrient availability, and increasing cloud cover. In this study, we assessed how these factors affect the fluxes of greenhouse gases (GHGs) (i.e., methane (CH4), nitrous oxide (N2O), and carbon dioxide (CO2)), and biogenic volatile organic compounds (BVOCs) in a subarctic mesic heath subjected to 34 years of climate change related manipulations of temperature, nutrient availability, and light. GHGs were sampled from static chambers and gases analyzed with gas chromatograph. BVOCs were measured using the push-pull method and gases analyzed with chromatography-mass spectrometry. The soil temperature and moisture content in the warmed and shaded plots did not differ significantly from that in the controls during GHG and BVOC measurements. Also, the enclosure temperatures during BVOC measurements in the warmed and shaded plots did not differ significantly from temperatures in the controls. Hence, this allowed for assessment of long-term effects of the climate treatment manipulations without interference of temperature and moisture differences at the time of measurements. Warming enhanced CH4 uptake and the emissions of CO2, N2O, and isoprene. Increased nutrient availability increased the emissions of CO2 and N2O but caused no significant changes in the fluxes of CH4 and BVOCs. Shading (simulating increased cloudiness) enhanced CH4 uptake but caused no significant changes in the fluxes of other gases compared to the controls. The results show that climate warming and increased cloudiness will enhance CH4 sink strength of subarctic mesic heath ecosystems, providing negative climate feedback, while climate warming and enhanced nutrient availability will provide positive climate feedback through increased emissions of CO2 and N2O. Climate warming will also indirectly, through vegetation changes, increase the amount of carbon lost as isoprene from subarctic ecosystems.

Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal-regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine-induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p-ERK in the spinal cord in a dry skin mouse model induced by acetone-ether-water (AEW). q-PCR, Western blot, pharmacology and immunofluorescence  were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c-Fos and p-ERK expression in the spinal cord neurons were increased and co-labelled with GRPR-positive neurons in AEW mice. Furthermore, H4R agonist 4-methyhistamine dihydrochloride (4-MH)induced itch. Both 4-MH-induced itch and the spontaneous itch in AEW mice were blocked by p-ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p-ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW-induced dry skin mice.

Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RAS-mediated RAF/MEK/ERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.

The blend of butadiene and acrylonitrile copolymer (NBR) with natural poly-cis-isoprene (NR) shows increased resistance to swelling in solvents in comparison to the individual components. In aerospace, NBR rubber is used as thermal protection for rockets and shall not contain other polymers, even in low contents, otherwise, it can affect the protection performance and rocket safety by causing detachment of the elastomer/propellant interface; therefore, this investigation presents methodologies to determine the NR/NBR contents. This study explores different analytical techniques, such as Raman spectroscopy and Fourier transform infrared (FTIR) spectroscopy, in the mid-infrared (MIR) by reflection and in the near-infrared by reflectance (NIRA) modes, Furthermore, quantification strategies by univariate, bivariate and multivariate (chemometric) models are evaluated and compared. A proposed methodology, based on multivariate Raman microscopy with partial least squares regression (PLS), showed high linearity (R2 > 0.99) and low error (< 0.82 %). The validation of FT-MIR data for the CH3, which presented lower error (1.3%) than vinylidene band (6%), showed that both methodologies (reflection and NIRA reflectance) can be used for the quantification of NR in NR/NBR. These results constitute a contribution to the state of the art in researching industrial and aerospace elastomeric applications.

Isoprenoid metabolism and its derivatives took part in photosynthesis, growth regulation, signal transduction, and plant defense to biotic and abiotic stresses. However, how aluminum (Al) stress affects the isoprenoid metabolism and whether isoprenoid metabolism plays a vital role in the Citrus plants in coping with Al stress remain unclear. In this study, we reported that Al-treatment-induced alternation in the volatilization rate of monoterpenes (α-pinene, β-pinene, limonene, α-terpinene, γ-terpinene and 3-carene) and isoprene were different between Citrus sinensis (Al-tolerant) and C. grandis (Al-sensitive) leaves. The Al-induced decrease of CO2 assimilation, maximum quantum yield of primary PSII photochemistry (Fv/Fm), the lower contents of glucose and starch, and the lowered activities of enzymes involved in the mevalonic acid (MVA) pathway and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway might account for the different volatilization rate of isoprenoids. Furthermore, the altered transcript levels of genes related to isoprenoid precursors and/or derivatives metabolism, such as geranyl diphosphate (GPP) synthase (GPPS) in GPP biosynthesis, geranylgeranyl diphosphate synthase (GGPPS), chlorophyll synthase (CHS) and GGPP reductase (GGPPR) in chlorophyll biosynthesis, limonene synthase (LS) and α-pinene synthase (APS) in limonene and α-pinene synthesis, respectively, might be responsible for the different contents of corresponding products in C. grandis and C. sinensis. Our data suggested that isoprenoid metabolism was involved in Al tolerance response in Citrus, and the alternation of some branches of isoprenoid metabolism could confer different Al-tolerance to Citrus species.

While volatile organic compounds (VOCs) impair various organs, their influence on hearing loss (HL) has not been extensively researched. We aimed to identify the association between VOCs and HL or high-frequency hearing loss (HFHL). We extracted data on age, sex, pure tone audiometry, hypertension, occupational noise exposure, and creatinine-corrected urine VOC metabolite concentrations from the eighth Korea National Health and Nutrition Survey. Among the VOC metabolites, N-acetyl-S-(benzyl)-L-cysteine (BMA, P = 0.004), N-acetyl-S-(phenyl)-L-cysteine (SPMA, P = 0.027), and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA, P < 0.001) showed associations with HL. Additionally, HFHL exhibited significant associations with BMA (P = 0.005), 3- and 4-methylhippuric acid (3, 4 MHA, P = 0.049), mandelic acid (MA, P = 0.015), SPMA (P < 0.001), N-acetyl-S-(3-hydroxypropyl)-L-cysteine (3-HPMA, P < 0.001), and DHBMA (P < 0.001). After controlling other factors, DHBMA were associated with HL (P = 0.021) and HFHL (P = 0.014) and exhibited a linear association with the mean hearing level (β = 0.054, P = 0.024) and high-frequency hearing level (β = 0.045, P = 0.037). Since 1,3-butadiene may act as an ototoxic material, early screening for workers exposed to 1,3-butadiene and reducing exposure to 1,3-butadiene in everyday life may be helpful to prevent further HL.

The leaves of many trees emit volatile organic compounds (abbreviated as BVOCs), which protect them from various damages, such as herbivory, pathogens, and heat stress. For example, isoprene is highly volatile and is known to enhance the resistance to heat stress. In this study, we analyze the optimal seasonal schedule for producing isoprene in leaves to mitigate damage. We assume that photosynthetic rate, heat stress, and the stress-suppressing effect of isoprene may vary throughout the season. We seek the seasonal schedule of isoprene production that maximizes the total net photosynthesis using Pontryagin\'s maximum principle. The isoprene production rate is determined by the changing balance between the cost and benefit of enhanced leaf protection over time. If heat stress peaks in midsummer, isoprene production can reach its highest levels during the summer. However, if a large portion of leaves is lost due to heat stress in a short period, the optimal schedule involves peaking isoprene production after the peak of heat stress. Both high photosynthetic rate and high isoprene volatility in midsummer make the peak of isoprene production in spring. These results can be clearly understood by distinguishing immediate impacts and the impacts of future expectations.

About 18% of all human cancers carry a mutation in the KRAS gene making it among the most sought-after anticancer targets. However, mutant KRas protein has proved remarkably undruggable. The recent approval of the first generation of RAS inhibitors therefore marks a seminal milestone in the history of cancer research. It also raises the predictable challenges of limited drug efficacies and acquired resistance. Hence, new approaches that improve our understanding of the tumorigenic mechanisms of oncogenic RAS within more physiological settings continue to be essential. Here, we have used the near-diploid hTERT RPE-1 cells to generate isogenic cell lines in which one of the endogenous KRAS alleles carries an oncogenic KRAS mutation at glycine 12. Cells with a KRASG12V/+, KRASG12C/+, or KRASG12D/+ genotype, together with WT KRASG12G(WT)/+ cells, reveal that oncogenic KRAS.G12X mutations increase cell proliferation rate and cell motility and reduced focal adhesions in KRASG12V/+ cells. Epidermal growth factor -induced phosphorylation of ERK and AKT was comparable between KRASG12V/+, KRASG12C/+, KRASG12D/+, and KRASG12G(WT)/+ cells. Interestingly, KRASG12X/+ cells showed varying responses to distinct inhibitors with the KRASG12V/+ and KRASG12D/+ cells more sensitive to hydroxyurea and MEK inhibitors, U0126 and trametinib, but more resistant to PI3K inhibitor, PIK-90, than the KRASG12G(WT)/+ cells. A combination of low doses of hydroxyurea and U0126 showed an additive inhibition on growth rate that was greater in KRASG12V/+ than WT cells. Collectively, these cell lines will be a valuable resource for studying oncogenic RAS signaling and developing effective anti-KRAS reagents with minimum cytotoxicity on WT cells.

Eucommia ulmoides rubber (EUR) is a high-quality natural rubber resource, which can be extracted from different organs of the Eucommia ulmoides tree. In this study, EUR was isolated from the leaves, barks, and pericarps, and the structural characteristics and physicochemical properties of EUR were systematically determined. The accumulation and distribution of EUR in different tissues were assessed through in situ observations combined with cellular and subcellular scales. The preliminary analyses indicated that the variations in the physicochemical properties of EUR across different tissues were associated with its accumulation microstructure. Further analyses by SEM and TEM showed that the initial cell differentiation and fusion resulted in the formation of tubular structures without any nucleus. A limited number of rubber particles were generated within the cytoplasm, concurrent with aggregation and fusion. Eventually, rubber particles filled the entire cytoplasm, and organelles disappeared to form highly aggregated filamentous structures. In addition, the number and area of EUR-containing cells were closely related to the organization sizes of barks and leaves. This study provided valuable insights into Eucommia ulmoides histology and the rubber industry.

Toll-like receptor 2 (TLR2) and galectin-3 (Gal-3) are involved in the pathological process of asthma, but the underlying mechanism is not fully understood. We hypothesized that TLR2 pathway may regulate expression of Gal-3 in allergic airway inflammation. Wild-type (WT) and TLR2-/- mice were sensitized on day 0 and challenged with ovalbumin (OVA) on days 14-21 to establish a model of allergic airway inflammation, and were treated with a specific ERK inhibitor U0126. Histological changes in the lungs were analyzed by hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining; cytokines and anti-OVA immunoglobulin E (IgE) were tested by ELISA; and related protein expression in lung tissues was measured by western blot. We found that the expression levels of TLR2 and Gal-3 markedly increased concomitantly with airway inflammation after OVA induction, while TLR2 deficiency significantly alleviated airway inflammation and reduced Gal-3 expression. Moreover, the expression levels of phosphorylated mitogen-activated protein kinases (p-MAPKs) were significantly elevated in OVA-challenged WT mice, while TLR2 deficiency only significantly decreased phosphorylated extracellular signal-regulated kinase (p-ERK) levels. Furthermore, we found that U0126 treatment significantly alleviated allergic airway inflammation and decreased Gal-3 levels in OVA-challenged WT mice, but had no further effect in OVA-challenged TLR2-/- mice. These above results suggested that TLR2 is an upstream signal molecule of ERK. We further demonstrated that TLR2 regulates Gal-3 expression through the ERK pathway in LTA-stimulated macrophages in vitro. Our findings showed that the TLR2-ERK signaling pathway regulates Gal-3 expression in a murine model of allergic airway inflammation.