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1.
Endocrinology ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32005991

RESUMO

Evidence suggests that the hypothalamic-pituitary-gonadal (HPG) axis is active during the critical period for sexual differentiation of the ovine sexually dimorphic nucleus, which occurs between gestational day (GD) 60 and 90. Two possible neuropeptides that could activate the fetal HPG axis are kisspeptin and neurokinin B (NKB). We used GD85 fetal lambs to determine whether i.v. administration of kisspeptin-10 (KP-10) or senktide (NKB agonist) could elicit LH release. Immunohistochemistry and fluorescent in situ hybridization (FISH) were employed to localize these peptides in brains of GD60 and 85 lamb fetuses. In anesthetized fetuses, KP-10 elicited robust release of LH that was accompanied by a delayed rise in serum testosterone in males. Pretreatment with the GnRH receptor antagonist (acyline) abolished the LH response to KP-10 confirming a hypothalamic site of action. In unanesthetized fetuses, senktide, as well as KP-10, elicited LH release. The senktide response of females was greater than that of males indicating a difference in NKB sensitivity between sexes. GnRH also induced a greater LH discharge in females than in males indicating that testosterone negative feedback is mediated through pituitary gonadotrophs. Kisspeptin and NKB-immunoreactive cells in the arcuate nucleus were more abundant in females than in males. Greater than 85% of arcuate kisspeptin cells co-stained for NKB. FISH revealed that the majority of these were kisspeptin/NKB/dynorphin (KNDy) neurons. These results support the hypothesis that kisspeptin-GnRH signaling regulates the reproductive axis of the ovine fetus during the prenatal critical period acting to maintain a stable androgen milieu necessary for brain masculinization.

2.
Sci Rep ; 10(1): 1767, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019991

RESUMO

Increased extracellular volume (ECV) by CMR is a marker of interstitial myocardial fibrosis and is associated with diastolic dysfunction in sickle cell anemia (SCA). Left atrial (LA) dysfunction and stiffness contribute to the development of diastolic heart failure in other settings. We aimed to evaluate LA function and stiffness associations with ECV, tricuspid regurgitation jet velocity (TRV) and exercise abnormalities in SCA. In a prospective study, individuals with SCA underwent CMR, echocardiography and exercise test. ECV was measured using MOLLI sequence. Atrial strain was studied in the 4- and 2-chamber views. LA stiffness was calculated as the ratio of echocardiographic E/e'-to-LA reservoir strain. Twenty-four participants with SCA were included (median age 20 years). ECV was increased in participant with SCA compared to our lab normal values (mean 0.44 ± 0.08 vs 0.26 ± 0.02, P < 0.0001). Six (25%) had LA LGE. ECV positively correlated with LA stiffness (r = 0.45, p = 0.04). There was a negative correlation between LA stiffness and %predicted VO2 (r = -0.50, p = 0.04). LA stiffness was moderately associated with increased TRV (r = 0.55, p < 0.005). LA stiffness is associated with ECV, exercise impairment and increased TRV. This study sheds insights on the interaction between LA function, RV hypertension, and myocardial fibrosis in SCA.

3.
Ecotoxicology ; 2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32037482

RESUMO

Mercury (Hg) is a potent neurotoxin that biomagnifies within both aquatic and terrestrial food webs resulting in adverse physiological and reproductive effects on impacted wildlife populations, including songbird communities. Due to reducing conditions, wetland ecosystems promote the formation of methylmercury. Regional studies have documented elevated blood mercury concentrations in songbird species within these habitat types. The overall goal of this research was to examine spatial and seasonal patterns of Hg exposure for targeted songbird species within Sphagnum bog wetland systems and compare these patterns with adjacent upland forests in the Adirondack Park of New York State. Project sampling was conducted at study plots within four Sphagnum bog and associated upland forest sites from May - August during the 2008, 2009, and 2011 field seasons. The overall results documented: (1) blood Hg concentrations were elevated in songbird species inhabiting Sphagnum bog habitats as compared to nearby upland forest species; (2) target species within each habitat type exhibited consistent species-level patterns in blood Hg concentrations at each study site; and (3) no seasonal change in blood Hg concentrations within Sphagnum bog habitats was documented, but an increasing, followed by a decreasing seasonal pattern in mercury exposure was detected for upland forest species. Habitat type was demonstrated to influence avian Hg exposure levels. Moreover, Sphagnum bog ecosystems may be contributing to elevated Hg concentrations in biota within the surrounding environment. Seasonal patterns for blood Hg concentrations were found to vary between habitat type and are likely related to a combination of variables including habitat-driven Hg concentrations in prey items, seasonal dietary shifts, and annual molting cycles. This project emphasizes the importance of prioritizing future research efforts within identified high Hg habitat types, specifically wetland systems, to better characterize associated avian exposure levels, estimate the spatial extent of wetland systems on the surrounding environment, and identify locations of potential biological hotspots across the Adirondack Park.

4.
J Affect Disord ; 266: 207-214, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32056878

RESUMO

BACKGROUND: Social disconnection is a common and pernicious feature of anxiety and depressive disorders, yet is insufficiently addressed by our best available treatments. To better understand why people with anxiety and depression feel socially disconnected, we tested a positive and negative valence systems framework informed by research on how normative social connections develop and flourish. METHOD: Individuals seeking treatment for anxiety or depression (N = 150) completed measures of perceived social connectedness, positive and negative valence temperament, social goals, affect, symptoms, and life satisfaction. RESULTS: Feeling less socially connected was associated with diminished life satisfaction, beyond clinical symptom severity. Regression analyses revealed that both diminished positive valence and heightened negative valence temperament, and their corresponding motivational and affective outputs, were significantly and uniquely (with no significant interaction between them) associated with lower perceived connectedness. LIMITATIONS: Data was cross-sectional and based on self-report-limiting conclusions about causality and social disconnection processes at different units of analysis. CONCLUSIONS: Understanding social disconnection through the lens of a positive and negative valence systems framework may inform transdiagnostic models and treatment approaches.

5.
Sci Total Environ ; 716: 137113, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32059317

RESUMO

The present-day acid-base chemistry of surface waters can be directly linked to contemporary observations of acid deposition; however, pre-industrial conditions are key to predicting the potential future recovery of stream ecosystems under decreasing loads of atmospheric sulfur (S) and nitrogen (N) deposition. The integrated biogeochemical model PnET-BGC was applied to 25 forest watersheds that represent a range of acid sensitivity in the Adirondack region of New York, USA to simulate the response of streams to past and future changes in atmospheric S and N deposition, and calculate the target loads of acidity for protecting and restoring stream water quality and ecosystem health. Using measured data, the model was calibrated and applied to simulate soil and stream chemistry at all study sites. Model hindcasts indicate that historically stream water chemistry in the Adirondacks was variable, but inherently sensitive to acid deposition. The median model-simulated acid neutralizing capacity (ANC) of the streams was projected to be 55 µeq L-1 before the advent of anthropogenic acid deposition (~1850), decreasing to minimum values of 10 µeq L-1 around the year 2000. The median simulated ANC increased to 13 µeq L-1 by 2015 in response to decreases in acid deposition that have occurred over recent decades. Model projections suggest that simultaneous decreases in sulfate, nitrate and ammonium deposition are more effective in restoring stream ANC than individual decreases in sulfur or nitrogen deposition. However, the increases in stream ANC per unit equivalent decrease in S deposition is greater compared to decreases in N deposition. Using empirical algorithms, fish community density and biomass are projected to increase under several deposition-control scenarios that coincide with increases in stream ANC. Model projections suggest that even under the most aggressive deposition-reduction scenarios, stream chemistry and fisheries will not fully recover from historical acidification by 2200.

6.
Ther Innov Regul Sci ; 54(2): 462-467, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32072587

RESUMO

The EU is a member of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and therefore adopts the ICH Guidelines, including the ICH M3 Guideline on Nonclinical Safety Studies. Following the 2016 incident in France with BIA 10-2474, and in light of the substantial evolvement of how early clinical development has been undertaken during the last 10 years, for example, conducting integrated (FIH) studies that include multiple parts (eg, single ascending doses, multiple ascending doses, food effect), EMA decided to update the existing 2007 FIH guideline. The key revisions to the 2007 guideline, now titled "Guideline on Strategies to Identify and Mitigate Risks for First-in-Human and Early Clinical Trials With Investigational Medicinal Products," include additional information. The revision reinforces the importance and impact of pharmacologic data, which supports the intended efficacy of the compound, risk assessment, and protocol design. The updates, effective February 2018, are intended to provide additional guidance and clarity for Sponsors developing FIH and early phase clinical research programs, and ultimately support subject safety. At the 2018 DIA Europe Annual Meeting in Basel, Switzerland, European regulators, industry representatives and academics convened a DIAlogue Session on April 17 to discuss how the revised 2017 guideline is being applied, and to establish recommendations for its application. Using two case studies as examples, the session participants discussed the nonclinical and clinical considerations for applying the newly revised recommendations, and interacted with a panel including regulators and industry representatives. The proceedings from this session reflect practical considerations for the implementation of the revised guideline.

7.
Ecotoxicology ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974921

RESUMO

Nearly half of freshwater wetlands have been lost due to human disturbance. In response, wetlands are being restored to retain their ecosystem services. A potentially adverse consequence of wetland function is the production of methylmercury (MeHg). We measured concentrations of mercury (Hg) species and ancillary parameters in groundwaters and surface waters from four natural and 16 restored wetlands in northern New York State, USA to investigate differences in concentrations of Hg species among wetlands. We found no obvious differences in concentrations of total mercury (THg) and methylmercury in pond waters between natural and restored wetlands. High values of %methylmercury were evident in both ground (38.8 ± 27.6%) and surface waters (43.4 ± 25.6%) suggesting these wetland complexes are highly efficient in converting ionic Hg to methylmercury, regardless if restored or natural. High methylation efficiency may be due to observed drying and rewetting cycles. Hg in pond waters is likely derived from direct atmospheric deposition or by mobilization from near-wetland shallow sediments, in addition to groundwater inflows. Water flow of groundwaters from the associated watershed into pond waters resulted in increases in concentrations of THg and methylmercury. Dissolved organic matter likely plays an important role in the supply of Hg to pond waters. Relationships between methylmercury and %methylmercury with sulfate and nitrate in groundwaters may suggest some chemical limitation on Hg methylation at higher concentrations of these anions. Because of the similarity in Hg dynamics for natural and restored wetlands, the most effective strategy to mitigate methylmercury production would be to decrease atmospheric Hg deposition.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31989803

RESUMO

BACKGROUND: Low muscle radiodensity is associated with mortality in a variety of cancer types. Biochemical and morphological correlates are unknown. We aimed to evaluate triglyceride (TG) content and location as a function of computed tomography (CT)-derived measures of skeletal muscle radiodensity in cancer patients. METHODS: Rectus abdominis (RA) biopsies were collected during cancer surgery from 75 patients diagnosed with cancer. Thin-layer chromatography and gas chromatography were used for quantification of TG content of the muscle. Axial CT images of lumbar vertebra were used to measure muscle radiodensity. Oil Red O staining was used to determine the location of neutral lipids in frozen muscle sections. RESULTS: There was wide variation in RA radiodensity in repeated measures (CV% ranged from 3 to 55% based on 10 serial images) as well as within one slice (CV% ranged from 6 to 61% based on 10 subregions). RA radiodensity and total lumbar muscle radiodensity were inversely associated with TG content of RA (r = -0.396, P < 0.001, and r = -0.355, P = 0.002, respectively). Of the total percentage area of muscle staining positive for neutral lipid, 54 ± 17% was present as extramyocellular lipids (range 23.5-77.8%) and 46 ± 17% (range 22.2-76.5%) present as intramyocellular lipid droplets. CONCLUSIONS: Repeated measures revealed wide variation in radiodensity of RA muscle, both vertically and horizontally. Low muscle radiodensity reflects high level of TG in patients with cancer. Non-uniform distribution of intramyocellular and extramyocellular lipids was evident using light microscopy. These results warrant investigation of mechanisms resulting in lipid deposition in muscles of cancer patients.

9.
Exp Biol Med (Maywood) ; 245(2): 146-154, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31985279
10.
Glycobiology ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897489

RESUMO

High dose irradiation poses extreme risk of mortality from acute damage to the hematopoietic compartment and gastrointestinal tract. While bone marrow transplantation can re-establish the hematopoietic compartment, a more imminent risk of death is posed by gastrointestinal acute radiation syndrome, for which there are no FDA approved medical countermeasures. Although the mechanisms dictating the severity of GI-ARS remain incompletely understood, sialylation by ST6GAL1 has been shown to protect against radiation induced apoptosis in vitro. Here, we used a C57BL/6 St 6 gal1-KO mouse model to investigate the contribution of ST6GAL1 to susceptibility to total body irradiation in vivo. 12 grays TBI followed by BMT is not lethal to wild-type mice, but St 6 gal1-KO counterparts succumbed within 7 days. Both St 6 gal1-KO and wild-type animals exhibited damage to the GI epithelium, diarrhea and weight loss, but these symptoms became progressively more severe in the St 6 gal1-KO animals while wild-type counterparts showed signs of recovery by 120 hours after TBI. Increased apoptosis in the GI tracts of St 6 gal1-KO mice and the absence of regenerative crypts were also observed. Together, these observations highlight an important role for ST6GAL1 in protection and recovery from GI-ARS in vivo.

11.
Int J Qual Stud Health Well-being ; 15(1): 1713657, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31924131

RESUMO

Background: Widows are socioeconomically disadvantaged, especially in low resource regions. Childless widows are a group whose plight may be worse given sociocultural circumstances. In the current study, we examined the lived experiences of childless widows living in remote Nigeria, highlighting this group as being in critical need for social interventions.Method: Childless widows (n = 11) in rural settings in South East Nigeria were interviewed. Narrative analysis was used in navigating the lived experiences of the widows.Results: Extreme distress, ostracism, stigma, and traumatic experiences were common in the narratives of the widows. However, childlessness was at the core of their distress. Treated as outcasts, the widows resigned to God, though some were scarcely allowed to play supportive roles among relatives. As social welfare packages are almost non-existent in this region, religious groups often played supportive roles.Conclusion: Legislation protecting widows are good but may not be sufficient if it does not translate to improved wellbeing/welfare for widows. Childless widows, especially those in rural areas, are especially vulnerable as they face peculiar deprivation and psychological distress arising from cultural/social realities. Recognising the limited resources in low income countries, mobilisation of local structures and resources to educate and monitor local communities are important.

12.
Ecotoxicology ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925620

RESUMO

Mercury is a neurotoxic pollutant and contamination in remote ecosystems due to atmospheric mercury deposition coupled with watershed characteristics that influence mercury bioavailability. Biological interactions that affect mercury bioaccumulation are especially relevant as fish assemblages change in response to species introductions and lake management practices. We studied the influence of shifting food web dynamics on mercury in fisheries of Little Moose Lake in the southwestern Adirondack Mountains of New York, USA. Annual removal of non-native Smallmouth Bass (Micropterus dolomieu) has been used as a management strategy since 2000 to restore the native fish assemblage and food web in favor of Lake Trout (Salvelinus namaycush). Changes in total mercury, stable carbon (13C/12C) and nitrogen (15N/14N) isotopes, and growth were evaluated for Lake Trout and Smallmouth Bass. Growth rates increased for both predators and trophic position increased for Lake Trout post-removal. Mercury concentrations in Lake Trout increased over the 16-year study period influenced by a diet shift from invertebrates to higher trophic level prey fish, regardless of increased growth. Smallmouth Bass mercury concentrations decreased with compensatory growth from a reduced population size. These contrasting trends indicate that changes in mercury deposition were not the primary driver for mercury bioaccumulation responses in Little Moose Lake. Stable isotope values changed for both predators and for several lower trophic level organisms, likely reflecting changes in nutrient cycling and/or inputs. Our findings emphasize the potential role of fisheries management on whole-lake and predatory fish responses to mercury contamination in temperate lakes.

13.
Ecotoxicology ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925621

RESUMO

Mercury (Hg) concentrations and speciation were measured in nine tributaries to Lake Ontario as part of two independent field-sampling programs. Among the study tributaries, mean total Hg (THg) concentrations ranged from 0.9 to 2.6 ng/L; mean dissolved Hg (THgD) ranged from 0.5 to 1.5 ng/L; mean particulate Hg (THgP) ranged from 0.3 to 2.0 ng/L; and mean methylmercury (MeHg) ranged from 0.06 to 0.14 ng/L. Watershed land cover, total suspended solids (TSS), and dissolved organic carbon (DOC) were evaluated as potential controls of tributary Hg. Significant relationships between THgD and DOC were limited, whereas significant relationships between THgP and TSS were common across watersheds. Total suspended solids was strongly correlated with the percentage of agricultural land in watersheds. Particle enrichment of Hg (mass Hg/mass TSS) was highly variable, but distinctly higher in US tributaries likely due to higher TSS in Canadian tributaries associated with higher urban and agricultural land cover. MeHg was largely associated with the aqueous phase, and MeHg as a fraction of THg was positively correlated to percent open water coverage in the watershed. Wetland cover was positively correlated to THg and MeHg concentrations, while urban land cover was only related to higher THgP.

14.
Plant Sci ; 291: 110329, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31928686

RESUMO

Little is known regarding insect defense pathways in Setaria viridis (setaria), a model system for panicoid grasses, including Zea mays (maize). It is thus of interest to compare insect herbivory responses of setaria and maize. Here we use metabolic, phylogenetic, and gene expression analyses to measure a subset of jasmonic acid (JA)-related defense responses to leaf-chewing caterpillars. Phylogenetic comparisons of known defense-related maize genes were used to identify putative orthologs in setaria, and candidates were tested by quantitative PCR to determine transcriptional responses to insect challenge. Our findings show that while much of the core JA-related metabolic and genetic responses appear conserved between setaria and maize, production of downstream secondary metabolites such as benzoxazinoids and herbivore-induced plant volatiles are dissimilar. This diversity of chemical defenses and gene families involved in secondary metabolism among grasses presents new opportunities for cross species engineering. The high degree of genetic similarity and ease of orthologous gene identification between setaria and maize make setaria an excellent species for translational genetic studies, but the species specificity of downstream insect defense chemistry makes some pathways unamenable to cross-species comparisons.

15.
Bone ; 133: 115248, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31972314

RESUMO

Recent developments in in situ microscopy have enabled unparalleled resolution of the architecture of the bone marrow (BM) niche for murine hematopoietic stem and progenitor cells (HSPCs). However, the extent to which these observations can be extrapolated to human BM remains unknown. In humans, adipose tissue occupies a significant portion of the BM medullary cavity, making quantitative immunofluorescent analysis difficult due to lipid-mediated light scattering. In this study, we employed optical clearing, confocal microscopy and nearest neighbor analysis to determine the spatial distribution of CD34+ HSPCs in the BM in a translationally relevant rhesus macaque model. Immunofluorescent analysis revealed that femoral BM adipocytes are associated with the branches of vascular sinusoids, with half of HSPCs localizing in close proximity of the nearest BM adipocyte. Immunofluorescent microscopy and flow cytometric analysis demonstrate that BM adipose tissue exists as a multicellular niche consisted of adipocytes, endothelial cells, granulocytes, and macrophages. Analysis of BM adipose tissue conditioned media using liquid chromatography-tandem mass spectrometry revealed the presence of multiple bioactive proteins involved in regulation of hematopoiesis, inflammation, and bone development, with many predicted to reside inside microvesicles. Pretreatment of purified HSPCs with BM adipose tissue conditioned media, comprising soluble and exosomal/microvesicle-derived factors, led to enhanced proliferation and an increase in granulocyte-monocyte differentiation potential ex vivo. Our work extends extensive studies in murine models, indicating that BM adipose tissue is a central paracrine regulator of hematopoiesis in nonhuman primates and possibly in humans.

16.
J Biol Rhythms ; 35(2): 180-194, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31975640

RESUMO

Life in the Arctic presents organisms with multiple challenges, including extreme photic conditions, cold temperatures, and annual loss and daily movement of sea ice. Polar bears (Ursus maritimus) evolved under these unique conditions, where they rely on ice to hunt their main prey, seals. However, very little is known about the dynamics of their daily and seasonal activity patterns. For many organisms, activity is synchronized (entrained) to the earth's day/night cycle, in part via an endogenous (circadian) timekeeping mechanism. The present study used collar-mounted accelerometer and global positioning system data from 122 female polar bears in the Chukchi and Southern Beaufort Seas collected over an 8-year period to characterize activity patterns over the calendar year and to determine if circadian rhythms are expressed under the constant conditions found in the Arctic. We reveal that the majority of polar bears (80%) exhibited rhythmic activity for the duration of their recordings. Collectively within the rhythmic bear cohort, circadian rhythms were detected during periods of constant daylight (June-August; 24.40 ± 1.39 h, mean ± SD) and constant darkness (23.89 ± 1.72 h). Exclusive of denning periods (November-April), the time of peak activity remained relatively stable (acrophases: ~1200-1400 h) for most of the year, suggesting either entrainment or masking. However, activity patterns shifted during the spring feeding and seal pupping season, as evidenced by an acrophase inversion to ~2400 h in April, followed by highly variable timing of activity across bears in May. Intriguingly, despite the dynamic environmental photoperiodic conditions, unpredictable daily timing of prey availability, and high between-animal variability, the average duration of activity (alpha) remained stable (11.2 ± 2.9 h) for most of the year. Together, these results reveal a high degree of behavioral plasticity in polar bears while also retaining circadian rhythmicity. Whether this degree of plasticity will benefit polar bears faced with a loss of sea ice remains to be determined.

17.
Cancer Discov ; 10(1): 72-85, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31594766

RESUMO

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

18.
Plant Cell Environ ; 43(1): 223-234, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31411732

RESUMO

To grow and thrive plants must be able to adapt to both adverse environmental conditions and attack by a variety of pests. Elucidating the sophisticated mechanisms plants have developed to achieve this has been the focus of many studies. What is less well understood is how plants respond when faced with multiple stressors simultaneously. In this study, we assess the response of Zea mays (maize) to the combinatorial stress of flooding and infestation with the insect pest Spodoptera frugiperda (fall armyworm). This combined stress leads to elevated production of the defence hormone salicylic acid, which does not occur in the individual stresses, and the resultant salicylic acid-dependent increase in S. frugiperda resistance. Remodelling of phenylpropanoid pathways also occurs in response to this combinatorial stress leading to increased production of the anti-insect C-glycosyl flavones (maysins) and the herbivore-induced volatile phenolics, benzyl acetate, and phenethyl acetate. Furthermore, changes in cellular redox status also occur, as indicated by reductions in peroxidase and polyphenol oxidase activity. These data suggest that metabolite changes important for flooding tolerance and anti-insect defence may act both additively and synergistically to provide extra protection to the plant.

19.
J Thromb Haemost ; 18(1): 180-190, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31549765

RESUMO

BACKGROUND: Sepsis triggers dysfunction of coagulation and fibrinolytic systems leading to disseminated intravascular coagulation (DIC) that contributes to organ failure and death. Fondaparinux (FPX) is a synthetic pentasaccharide that binds to antithrombin (AT) and selectively inhibits factor (F) Xa and other upstream coagulation proteases but not thrombin (T). OBJECTIVES: We used a baboon model of lethal Escherichia coli sepsis to investigate the effects of FPX treatment on DIC, organ function, and outcome. METHODS: Two experimental groups were studied: (a) E. coli challenge (n = 4); and (b) E coli plus FPX (n = 4). Bacteremia was modeled by intravenous infusion of pathogen (1-2 × 1010  CFU/kg). Fondaparinux (0.08 mg/kg) was administered subcutaneously, 3 h prior to and 8 h after bacteria infusion. RESULTS: Bacteremia rapidly increased plasma levels of inhibitory complexes of AT with coagulation proteases. Activation markers of both intrinsic (FXIa-AT), and extrinsic (FVIIa-AT) pathways were significantly reduced in FPX-treated animals. Factor Xa-AT and TAT complexes were maximal at 4 to 8 h post challenge and reduced >50% in FPX-treated animals. Fibrinogen consumption, fibrin generation and degradation, neutrophil and complement activation, and cytokine production were strongly induced by sepsis. All parameters were significantly reduced, while platelet count was unchanged by the treatment. Fondaparinux infusion attenuated organ dysfunction, prolonged survival, and saved two of four challenged animals (log-rank Mantel-Cox test, P = .0067). CONCLUSION: Our data indicate that FPX-mediated inhibition of coagulation prevents sepsis coagulopathy; protects against excessive complement activation, inflammation, and organ dysfunction; and provides survival benefit in E. coli sepsis.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31669707

RESUMO

The purpose of this study was to investigate changes in expression of known cellular regulators of metabolism during hyperphagia (Sept) and hibernation (Jan) in skeletal muscle and adipose tissue of brown bears and determine whether signaling molecules and transcription factors known to respond to changes in cellular energy state are involved in the regulation of these metabolic adaptations. During hibernation, serum levels of cortisol, glycerol, and triglycerides were elevated, and protein expression and activation of AMPK in skeletal muscle and adipose tissue were reduced. mRNA expression of the co-activator PGC-1α was reduced in all tissues in hibernation whereas mRNA expression of the transcription factor PPAR-α was reduced in the vastus lateralis muscle and adipose tissue only. During hibernation, gene expression of ATGL and CD36 was not altered; however, HSL gene expression was reduced in adipose tissue. During hibernation gene expression of the lipogenic enzyme DGAT in all tissues and the expression of the FA oxidative enzyme LCAD in the vastus lateralis muscle were reduced. Gene and protein expression of the glucose transporter GLUT4 was decreased in adipose tissue in hibernation. Our data suggest that high cortisol levels are a key adaptation during hibernation and link cortisol to a reduced activation of the AMPK/PGC-1α/PPAR-α axis in the regulation of metabolism in skeletal muscle and adipose tissue. Moreover, our results indicate that during this phase of hibernation at a time when metabolic rate is significantly reduced metabolic adaptations in peripheral tissues seek to limit the detrimental effects of unduly large energy dissipation.

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