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Abstract Introduction Magnetic resonance direct thrombus imaging (MRDTI) is a promising technique to improve the diagnostic management of patients with a suspected ipsilateral recurrent deep vein thrombosis (DVT) by direct visualization of a thrombus. Another magnetic resonance imaging (MRI) technique, T1-weighted turbo spin-echo spectral attenuated inversion recovery (TSE-SPAIR), has the potential to image a thrombus directly with a high spatial resolution as well. The main aim of this pilot study was to investigate if adding the TSE-SPAIR sequence to an MRDTI sequence performed in patients with suspected recurrent DVT may increase the diagnostic confidence of expert MRDTI readers. Methods Fifteen patients with suspected acute recurrent DVT were included in this study. The TSE-SPAIR sequence was scanned directly after the MRDTI scan but not used to guide clinical decision making, and both scans were adjudicated post hoc two times separately by three independent expert MRDTI readers. Diagnostic confidence was scored on a 4-point Likert scale: (1) poor (definite diagnosis impossible), (2) fair (evaluation of major findings possible), (3) good (definite diagnosis possible), and (4) excellent (exact diagnosis possible). Results The diagnostic confidence of expert readers increased when adding the TSE-SPAIR sequence on top of the MRDTI sequence from “good” (median, 3.0; interquartile range [IQR], 2.66–3.0) to “excellent” (median, 3.67; IQR 3.33–3.67; p = 0.001). Evaluation of the scans in the reversed order 5 months after initial reading showed similar results. Diagnostic accuracy for proximal DVT of both scan techniques was good. Conclusion The extra TSE-SPAIR sequence may help increase diagnostic confidence of radiologists in cases of uncertain diagnosis in patients with suspected ipsilateral recurrent DVT.

Contagious agalactia (CA) is suspected when small ruminants show all or several of the following clinical signs: mastitis, arthritis, keratoconjunctivitis and occasionally abortion. It is confirmed following mycoplasma isolation or detection. The historical and major cause is Mycoplasma agalactiae which was first isolated from sheep in 1923. Over the last thirty years, three other mycoplasmas (Mycoplasma mycoides subsp. capri, Mycoplasma capricolum subsp. capricolum and Mycoplasma putrefaciens) have been added to the etiology of CA because they can occasionally cause clinically similar outcomes though nearly always in goats. However, only M. agalactiae is subject to animal disease regulations nationally and internationally. Consequently, it makes little sense to list mycoplasmas other than M. agalactiae as causes of the OIE-listed CA when they are not officially reported by the veterinary authorities and unlikely to be so in the future. Indeed, encouraging countries just to report M. agalactiae may bring about a better understanding of the importance of CA. In conclusion, we recommend that CA should only be diagnosed and confirmed when M. agalactiae is detected either by isolation or molecular methods, and that the other three mycoplasmas be removed from the OIE Manual of Diagnostic Tests and Vaccines in Terrestrial Animals and associated sources.

Coffee brews have High Molecular Weight (HMW) compounds with described immunostimulatory activity, namely polysaccharides and melanoidins. Melanoidins are formed during roasting and are modified during brews technological processing. In addition, brews have Low Molecular Weight (LMW) compounds, namely free chlorogenic acids and caffeine, with well-known anti-inflammatory properties. However, this study shows that both espresso and instant coffee brews did not present immunostimulatory neither anti-inflammatory in vitro activities. It is possible that the simultaneous existence of compounds with antagonistic effects can mitigate their individual effects. To test this hypothesis, an ultrafiltration separation process was applied, studying the behavior of coffee brews’ HMW on retention of LMW compounds. Several ultrafiltration sequential cycles were required to separate retentates from LMW compounds, suggesting their retention. This effect was higher in instant coffee, attributed to its initial higher carbohydrate content when compared to espresso. Separation of HMW and LMW compounds boosted their immunostimulatory (6.2–7.8 µM nitrites) and anti-inflammatory (LPS induced nitrite production decrease by 36–31%) in vitro activities, respectively. As coffee anti-inflammatory compounds are expected to be first absorbed during digestion, a potential in vivo fractionation of LMW and HMW compounds can promote health relevant effects after coffee intake.

Landscape fires are substantial sources of (greenhouse) gases and aerosols. Fires in savanna landscapes represent more than half of global fire carbon emissions. Quantifying emissions from fires relies on accurate burned area, fuel load and burning efficiency data. Of these, fuel load remains the source of the largest uncertainty. In this study, we used high spatial resolution images from an Unmanned Aircraft System (UAS) mounted multispectral camera, in combination with meteorological data from the ERA-5 land dataset, to model instantaneous pre-fire above-ground biomass. We constrained our model with ground measurements taken in two locations in savanna-dominated regions in Southern Africa, one low-rainfall region (660 mm year−1) in the North-West District (Ngamiland), Botswana, and one high-rainfall region (940 mm year−1) in Niassa Province (northern Mozambique). We found that for fine surface fuel classes (live grass and dead plant litter), the model was able to reproduce measured Above-Ground Biomass (AGB) (R2 of 0.91 and 0.77 for live grass and total fine fuel, respectively) across both low and high rainfall areas. The model was less successful in representing other classes, e.g., woody debris, but in the regions considered, these are less relevant to biomass burning and make smaller contributions to total AGB.

Background. Liver cirrhosis is associated with intestinal epithelial barrier dysfunction, which may be affected by oxidative stress. Studies in cirrhotic rats provided evidence for intestinal oxidative stress, but studies in cirrhotic patients are scarce. We have shown intestinal barrier dysfunction in patients with compensated cirrhosis.Aim. The present study aimed to investigate whether oxidative stress occurs in the intestinal mucosa of compensated cirrhotic patients and may contribute to barrier dysfunction.Material and methods. Oxidative stress was studied in duodenal and sigmoid biopsies from 15 cirrhotic patients and 22 controls by analyzing transcription of genes involved in glutathione and uric acid metabolism using quantitative real-time polymerase chain reaction. Protein levels of glutathione and glutathione disulphide were measured and the glutathione/glutathione disulphide ratio was calculated as marker of oxidative stress. In addition, intestinal myeloperoxidase and fecal calprotectin were determined.Results. Gene transcription of glutathione synthetase and glutathione reductase were significantly different in duodenal and sigmoid biopsies of cirrhotic patients vs. controls, but no alterations were found for other genes nor for glutathione, glutathione disulphide, glutathione/glutathione disulphide ratio and intestinal myeloperoxidase and fecal calprotectin concentrations.Conclusion. This study did not find indications for oxidative stress and low-grade inflammation in the small and large intestine of stable compensated cirrhotic patients. Although these preliminary findings need further validation, we found intestinal oxidative stress not to be a major mechanism contributing to epithelial barrier dysfunction in patients with compensated cirrhosis.

Several clinically used drugs are mitotoxic causing mitochondrial DNA (mtDNA) variations, and thereby influence cancer treatment response. We hypothesized that radiation responsiveness will be enhanced in cellular models with decreased mtDNA content, attributed to altered reactive oxygen species (ROS) production and antioxidant capacity. For this purpose BEAS-2B, A549, and 143B cell lines were depleted from their mtDNA (ρ0). Overall survival after irradiation was increased (p

BACKGROUND AND AIMS:Increased evidence suggests a pro-atherogenic role for conventional dendritic cells (cDC). However, due to the lack of an exclusive marker for cDC, their exact contribution to atherosclerosis remains elusive. Recently, a unique transcription factor was described for cDC, namely Zbtb46, enabling us to selectively target this cell type in mice. METHODS:Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were transplanted with bone marrow from Zbtb46-diphtheria toxin receptor (DTR) transgenic mice following total body irradiation. Zbtb46-DTR→Ldlr-/- chimeras were fed a Western-type diet for 18 weeks while cDC were depleted by administering diphtheria toxin (DT). RESULTS:Although we confirmed efficient direct induction of cDC death in vitro and in vivo upon DT treatment of Zbtb46-DTR mice, advanced atherosclerotic plaque size and composition was not altered. Surprisingly, however, analysis of Zbtb46-DTR→Ldlr-/- chimeras showed that depletion of cDC was not sustained following 18 weeks of DT treatment. In contrast, high levels of anti-DT antibodies were detected. CONCLUSIONS:Because of the observed generation of anti-DT antibodies and consequently the partial depletion of cDC, no clear decision can be taken on the role of cDC in atherosclerosis. Our results underline the unsuitability of Zbtb46-DTR→Ldlr-/- mice for studying the involvement of cDC in maintaining the disease process of atherosclerosis, as well as of other chronic inflammatory diseases.

Carbonic anhydrase IX (CAIX) is a tumor-specific protein that is upregulated during hypoxic conditions where it is involved in maintaining the pH balance. CAIX causes extracellular acidification, thereby limiting the uptake of weak basic chemotherapeutic agents, such as doxorubicin, and decreasing its efficacy. The aim of this study was to determine if doxorubicin efficacy can be increased when combined with the selective sulfamate CAIX inhibitor S4. The effect of S4 on doxorubicin efficacy was tested in vitro using cell viability assays with MDA-MB-231, FaDu, HT29 -CAIX high and HT29 -CAIX low cell lines. In addition, the efficacy of this combination therapy was investigated in tumor xenografts of the same cell lines. The addition of S4 in vitro increased the efficacy of doxorubicin in the MDA-MB-231 during hypoxic exposure (IC50 is 0.25 versus 0.14 µM, p = 0.0003). Similar results were observed for HT29-CAIX high with S4 during normoxia (IC50 is 0.20 versus 0.08 µM, p

Atherosclerosis remains the leading cause of death and disability in our Western society. To investigate whether the dynamics of leukocyte (sub)populations could be predictive for plaque inflammation during atherosclerosis, we analyzed innate and adaptive immune cell distributions in blood, plaques, and lymphoid tissue reservoirs in apolipoprotein E-deficient (ApoE−/−) mice and in blood and plaques from patients undergoing endarterectomy. Firstly, there was predominance of the CD11b+ conventional dendritic cell (cDC) subset in the plaque. Secondly, a strong inverse correlation was observed between CD11b+ cDC or natural killer T (NKT) cells in blood and markers of inflammation in the plaque (including CD3, T-bet, CCR5, and CCR7). This indicates that circulating CD11b+ cDC and NKT cells show great potential to reflect the inflammatory status in the atherosclerotic plaque. Our results suggest that distinct changes in inflammatory cell dynamics may carry biomarker potential reflecting atherosclerotic lesion progression. This not only is crucial for a better understanding of the immunopathogenesis but also bares therapeutic potential, since immune cell-based therapies are emerging as a promising novel strategy in the battle against atherosclerosis and its associated comorbidities. The cDC-NKT cell interaction in atherosclerosis serves as a good candidate for future investigations.

Despite all efforts made to develop predictive biomarkers for antiangiogenic therapies, no unambiguous markers have been identified so far. This is due to among others the lack of standardized tests. This study presents an improved microvessel density quantification method in tumor tissue based on stereological principles and using whole-slide images. Vessels in tissue sections of different cancer types were stained for CD31 by an automated and validated immunohistochemical staining method. The stained slides were digitized with a digital slide scanner. Systematic, uniform, random sampling of the regions of interest on the whole-slide images was performed semi-automatically with the previously published applications AutoTag and AutoSnap. Subsequently, an unbiased counting grid was combined with the images generated with these scripts. Up to six independent observers counted microvessels in up to four cancer types: colorectal carcinoma, glioblastoma multiforme, ovarian carcinoma and renal cell carcinoma. At first, inter-observer variability was found to be unacceptable. However, after a series of consensus training sessions and interim statistical analysis, counting rules were modified and inter-observer concordance improved considerably. Every CD31-positive object was counted, with exclusion of suspected CD31-positive monocytes, macrophages and tumor cells. Furthermore, if interconnected, stained objects were considered a single vessel. Ten regions of interest were sufficient for accurate microvessel density measurements. Intra-observer and inter-observer variability were low (intraclass correlation coefficient > 0.7) if the observers were adequately trained.

The chemical composition of the troposphere in the tropics and Southern Hemisphere (SH) is significantly influenced by gaseous emissions released from African biomass burning (BB). Here we investigate how various emission estimates given in bottom-up BB inventories (GFEDv2, GFEDv3, AMMABB) affect simulations of global tropospheric composition using the TM4 chemistry transport model. The application of various model parameterizations for introducing such emissions is also investigated. There are perturbations in near-surface ozone (O3) and carbon monoxide (CO) of ~60–90% in the tropics and ~5–10% in the SH between different inventories. Increasing the update frequency of the temporal distribution to eight days generally results in decreases of between ~5 and 10% in near-surface mixing ratios throughout the tropics, which is larger than the influence of increasing the injection heights at which BB emissions are introduced. There are also associated differences in the long range transport of pollutants throughout the SH, where the composition of the free troposphere in the SH is sensitive to the chosen BB inventory. Analysis of the chemical budget terms reveals that the influence of increasing the tropospheric CO burden due to BB on oxidative capacity of the troposphere is mitigated by the associated increase in NOx emissions (and thus O3) with the variations in the CO/N ratio between inventories being low. For all inventories there is a decrease in the tropospheric chemical lifetime of methane of between 0.4 and 0.8% regardless of the CO emitted from African BB. This has implications for assessing the effect of inter-annual variability in BB on the annual growth rate of methane.

The polyphenol quercetin (Q) that has a high antioxidant capacity is a lead compound in the design of antioxidants. We investigated the possibility of modifying quercetin while retaining its antioxidant capacity as much as possible. To this end, the antioxidant capacities of Q, rutin, monohydroxyethyl rutinoside (monoHER) and a series of synthesized methylated Q derivatives were determined. The results confirm that the electron donating effect of the hydroxyl groups is essential. It was also found that the relatively planar structure of Q needs to be conserved. This planar conformation enables the distribution of the electron donating effect through the large conjugated π-system over the entire molecule. This is essential for the cooperation between the electron donating groups. Based on the activity of the compounds tested, it was concluded that structural modification at the 5 or 7 position is the most optimal to retain most of the antioxidant capacity of Q. This was confirmed by synthesizing and testing Q5OMe (Q6) and Q7OMe (Q7) that indeed displayed antioxidant capacities closest to Q.

Order tracking is a method of analysis used by engineers in the diagnosis of rotating machinery. In many applications, order analysis of non-stationary signals is required. The direct extraction of the amplitude information from the short-time Fourier transform may lead to inaccurate vibration-level estimation in the case of fast changes in the signal frequency content. This article discusses spectral smearing, which is the main reason of the problem, and its sensitivity to the characteristics of the signal (frequency and amplitude variations) and to the input parameters of discrete Fourier transform analysis (window size and type). Through the years, many different approaches to perform order analysis have been developed; this article introduces a novel method for order tracking based on the short-time Fourier transform, which applies a compensation of the smearing effect based on an invariant information contained in autopower spectrum. The limitations and capabilities of the proposed method with respect to other existing techniques are discussed: considering the accuracy of the results, low requirements of computational resources, and ease of implementation, this method proves a valid alternative to currently used techniques.

Recently, an apolipoprotein E–deficient (ApoE −/− ) mouse model with a mutation (C1039G+/−) in the fibrillin-1 ( Fbn1 ) gene (ApoE −/− Fbn1 C1039G+/− mouse model) was developed showing vulnerable atherosclerotic plaques, prone to rupture, in contrast to the ApoE −/− mouse model, where mainly stable plaques are present. One indicator of plaque vulnerability is the level of macrophage infiltration. Therefore, this study aimed to measure and quantify in vivo the macrophage infiltration related to plaque development and progression. For this purpose, 5-weekly consecutive gold nanoparticle–enhanced micro–computed tomography (microCT) scans were acquired. Histology confirmed that the presence of contrast agent coincided with the presence of macrophages. Based on the microCT scans, regions of the artery wall with contrast agent present were calculated and visualized in three dimensions. From this information, the contrast-enhanced area and contrast-enhanced centerline length were calculated for the branches of the carotid bifurcation (common, external, and internal carotid arteries). Statistical analysis showed a more rapid development and a larger extent of plaques in the ApoE −/− Fbn1 C1039G+/− compared to the ApoE −/− mice. Regional differences between the branches were also observable and quantifiable. We developed and applied a methodology based on gold particle–enhanced microCT to visualize the presence of macrophages in atherosclerotic plaques in vivo.

L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein.

La infección de piel y tejidos blandos por Acinetobacter no relacionada con trauma es una presentación inusual. La mayoría de los casos descritos presentan enfermedades concomitantes y son causados por Acinetobacter baumanii. Se describe un caso de celulitis no traumática por A. junii-johnsonii con bacteriemia, de inicio en la comunidad y asociado con el tratamiento médico. De acuerdo con nuestro conocimiento, éste sería el primer caso reportado de infección de tejidos blandos y piel por A. juniijohnsonii.La vesícula hemorrágica podría ser una característica clínica de celulitis por Acinetobacter. doi: http://dx.doi.org/10.7705/biomedica.v32i2.652

Increasing evidence suggests a beneficial effect of lutein and zeaxanthin on the progression of age-related macular degeneration. The aim of this study was to investigate the effect of lutein or zeaxanthin enriched eggs or a lutein enriched egg-yolk based buttermilk beverage on serum lutein and zeaxanthin concentrations and macular pigment levels. Naturally enriched eggs were made by increasing the levels of the xanthophylls lutein and zeaxanthin in the feed given to laying hens. One hundred healthy volunteers were recruited and randomized into 5 groups for 90 days. Group one added one normal egg to their daily diet and group two received a lutein enriched egg-yolk based beverage. Group three added one lutein enriched egg and group four one zeaxanthin enriched egg to their diet. Group five was the control group and individuals in this group did not modify their daily diet. Serum lutein and zeaxanthin concentrations and macular pigment densities were obtained at baseline, day 45 and day 90. Macular pigment density was measured by heterochromatic flicker photometry. Serum lutein concentration in the lutein enriched egg and egg yolk-based beverage groups increased significantly (p

In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation.Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-α-stimulated endothelial cells. Nuclear factor kappa B (NF-κB) reporter gene assays confirmed that MOF decrease the activity of NF-κB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found.Our study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans.

The consumption of tomato products has been associated with a decreased risk for chronic inflammatory diseases. In this study, the anti-inflammatory potential of tomato ketchup was evaluated by studying the effect of tomato ketchup extracts and bioactives from tomato ketchup on human monocytes and vascular endothelial cells (HUVEC). HUVEC were pre-treated for 1 h with either individual bioactives (7.5 µM lycopene, 1.4 µM α-tocopherol or 55 µM ascorbic acid) or a combination of these three compounds, or with the hydrophilic or lipophilic tomato ketchup extracts or with the two extracts combined. After the pretreatment, the cells were washed and challenged with TNF-α (10 ng/ml) for 6 h. The medium was used for the determination of the release of cytokines and the chemotaxis of monocytes. Inflammatory protein expression and production were assayed with real-time RT-PCR and ELISA. It was found that tomato ketchup extracts significantly reduced gene expression and release of the pro-inflammatory cytokines TNF-α and IL-8 in HUVEC after the inflammatory challenge, whereas the release of the anti-inflammatory cytokine IL-10 was increased. Chemotaxis was effectively impeded as demonstrated by a reduced monocyte migration. This effect correlated with the reduction of IL-8 production in the presence of the test compounds and extracts. The results consistently emphasize the contribution of lycopene to the anti-inflammatory effect of tomato ketchup. Other compounds in tomato ketchup such as α-tocopherol and ascorbic acid appeared to strengthen the anti-inflammatory effect of lycopene. The tomato ketchup extracts subtly interfered with several inflammatory phases that inhibit chemotaxis. Such a pleotropic mode of action exemplifies its potential mitigation of diseases characterized by prolonged low grade inflammation.

Cardiac troponin is the biochemical gold standard to diagnose acute myocardial infarction. Interestingly however, elevated cardiac troponin concentrations are also frequently observed during and after endurance-type exercise. Oxidative stress associated with prolonged exercise has been proposed to contribute to cardiac troponin release. Therefore, the aim of this study was to assess the effect of 4 week astaxanthin supplementation (a potent cartenoid antioxidant) on antioxidant capacity and exercise-induced cardiac troponin release in cyclists.Thirty-two well-trained male cyclists (age 25±5, weight 73±7 kg, maximum O2 uptake 60±5 mL·kg(-1)·min(-1), Wmax 5.4±0.5 W·kg(-1); mean ± SD) were repeatedly subjected to a laboratory based standardized exercise protocol before and after 4 weeks of astaxanthin (20 mg/day), or placebo supplementation in a double-blind randomized manner. Blood samples were obtained at baseline, at 60 min of cycling and immediately post-exercise (≈ 120 min).The pre-supplementation cycling trial induced a significant rise of median cardiac troponin T concentrations from 3.2 (IQR 3.0-4.2) to 4.7 ng/L (IQR 3.7-6.7), immediately post-exercise (p

Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded.In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets.In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P

Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized.

Fires, among other forms of natural and anthropogenic disturbance, play a central role in regulating the location, composition and biomass of forests. Understanding the role of fire in global forest loss is crucial in constraining land-use change emissions and the global carbon cycle. We analysed the relationship between forest loss and fire at 500 m resolution based on satellite-derived data for the 2003-2018 period. Satellite fire data included burned area and active fire detections, to best account for large and small fires, respectively. We found that, on average, 38 ± 9% (± range) of global forest loss was associated with fire, and this fraction remained relatively stable throughout the study period. However, the fraction of fire-related forest loss varied substantially on a regional basis, and showed statistically significant trends in key tropical forest areas. Decreases in the fraction of fire-related forest loss were found where deforestation peaked early in our study period, including the Amazon and Indonesia while increases were found for tropical forests in Africa. The inclusion of active fire detections accounted for 41%, on average, of the total fire-related forest loss, with larger contributions in small clearings in interior tropical forests and human-dominated landscapes. Comparison to higher-resolution fire data with resolutions of 375 and 20 m indicated that commission errors due to coarse resolution fire data largely balanced out omission errors due to missed small fire detections for regional to continental-scale estimates of fire-related forest loss. Besides an improved understanding of forest dynamics, these findings may help to refine and separate fire-related and non-fire-related land-use change emissions in forested ecosystems.

Fires, among other forms of natural and anthropogenic disturbance, play a central role in regulating the location, composition and biomass of forests. Understanding the role of fire in global forest loss is crucial in constraining land-use change emissions and the global carbon cycle. We analysed the relationship between forest loss and fire at 500 m resolution based on satellite-derived data for the 2003-2018 period. Satellite fire data included burned area and active fire detections, to best account for large and small fires, respectively. We found that, on average, 38 ± 9% (± range) of global forest loss was associated with fire, and this fraction remained relatively stable throughout the study period. However, the fraction of fire-related forest loss varied substantially on a regional basis, and showed statistically significant trends in key tropical forest areas. Decreases in the fraction of fire-related forest loss were found where deforestation peaked early in our study period, including the Amazon and Indonesia while increases were found for tropical forests in Africa. The inclusion of active fire detections accounted for 41%, on average, of the total fire-related forest loss, with larger contributions in small clearings in interior tropical forests and human-dominated landscapes. Comparison to higher-resolution fire data with resolutions of 375 and 20 m indicated that commission errors due to coarse resolution fire data largely balanced out omission errors due to missed small fire detections for regional to continental-scale estimates of fire-related forest loss. Besides an improved understanding of forest dynamics, these findings may help to refine and separate fire-related and non-fire-related land-use change emissions in forested ecosystems.

Nitrous oxide (N2O), like carbon dioxide, is a long-lived greenhouse gas that accumulates in the atmosphere. Over the past 150 years, increasing atmospheric N2O concentrations have contributed to stratospheric ozone depletion1 and climate change2, with the current rate of increase estimated at 2 per cent per decade. Existing national inventories do not provide a full picture of N2O emissions, owing to their omission of natural sources and limitations in methodology for attributing anthropogenic sources. Here we present a global N2O inventory that incorporates both natural and anthropogenic sources and accounts for the interaction between nitrogen additions and the biochemical processes that control N2O emissions. We use bottom-up (inventory, statistical extrapolation of flux measurements, process-based land and ocean modelling) and top-down (atmospheric inversion) approaches to provide a comprehensive quantification of global N2O sources and sinks resulting from 21 natural and human sectors between 1980 and 2016. Global N2O emissions were 17.0 (minimum-maximum estimates: 12.2-23.5) teragrams of nitrogen per year (bottom-up) and 16.9 (15.9-17.7) teragrams of nitrogen per year (top-down) between 2007 and 2016. Global human-induced emissions, which are dominated by nitrogen additions to croplands, increased by 30% over the past four decades to 7.3 (4.2-11.4) teragrams of nitrogen per year. This increase was mainly responsible for the growth in the atmospheric burden. Our findings point to growing N2O emissions in emerging economies-particularly Brazil, China and India. Analysis of process-based model estimates reveals an emerging N2O-climate feedback resulting from interactions between nitrogen additions and climate change. The recent growth in N2O emissions exceeds some of the highest projected emission scenarios3,4, underscoring the urgency to mitigate N2O emissions.

Fire emissions of gases and aerosols alter atmospheric composition and have substantial impacts on climate, ecosystem function, and human health. Warming climate and human expansion in fire-prone landscapes exacerbate fire impacts and call for more effective management tools. Here we developed a global fire forecasting system that predicts monthly emissions using past fire data and climate variables for lead times of 1 to 6 months. Using monthly fire emissions from the Global Fire Emissions Database (GFED) as the prediction target, we fit a statistical time series model, the Autoregressive Integrated Moving Average model with eXogenous variables (ARIMAX), in over 1,300 different fire regions. Optimized parameters were then used to forecast future emissions. The forecast system took into account information about region-specific seasonality, long-term trends, recent fire observations, and climate drivers representing both large-scale climate variability and local fire weather. We cross-validated the forecast skill of the system with different combinations of predictors and forecast lead times. The reference model, which combined endogenous and exogenous predictors with a 1 month forecast lead time, explained 52% of the variability in the global fire emissions anomaly, considerably exceeding the performance of a reference model that assumed persistent emissions during the forecast period. The system also successfully resolved detailed spatial patterns of fire emissions anomalies in regions with significant fire activity. This study bridges the gap between the efforts of near-real-time fire forecasts and seasonal fire outlooks and represents a step toward establishing an operational global fire, smoke, and carbon cycle forecasting system.

By numerically solving the relativistic equations of motion of a single electron in laser fields modeled by those of a Gaussian beam, we demonstrate electron capture by, reflection from, and transmission through the beam. In modeling the fields, terms of order up to ϵ^{5}, where ϵ is the diffraction angle, are retained. All cases of capture are accompanied by energy gain that may reach a few GeV, from fields of present-day intensities. Reflection and transmission, on the other hand, result sometimes in no gain or even in a loss of energy. It is shown that a laboratory static magnetic field may be used to eject a captured electron, a process that sometimes results in even more energy gain. For example, a 2.5 T uniform magnetic field suffices to eject a 3.633 MeV electron injected at 6° to the axis of a linearly polarized beam of a 10 PW power output and aimed at a point near the focus. Such an electron gains 1128 MeV from the laser field alone. However, it emerges with a 1230 MeV net energy gain under the additional action of the small magnetic field.

Simple Summary: Proteasome inhibitors, such as bortezomib and carfilzomib, are vital for treating relapsed or refractory multiple myeloma, but their potential link to cancer therapy-related cardiovascular dysfunction (CTRCD) raises concerns. Bortezomib, a reversible first-generation inhibitor, and carfilzomib, a second-generation irreversible inhibitor, have been associated with hypertension, heart failure, and arrhythmias. This study explored their impact on cardiac function, focusing on left ventricular ejection fraction (LVEF), and vascular function through arterial stiffness and vascular reactivity assessments. Twelve-week-old male mice were treated with either carfilzomib or bortezomib, with some receiving L-NAME to induce hypertension. Echocardiography was used to evaluate cardiac and vascular parameters at different time points, followed by ex vivo arterial stiffness and reactivity measurements. Results showed no significant changes in arterial stiffness at baseline pressures, but a steeper pressure-stiffness curve was noted in carfilzomib-treated normotensive and hypertensive mice. Carfilzomib also showed a trend toward reduced LVEF in hypertensive mice, with bortezomib showing similar trends. Vascular reactivity remained largely unchanged, but proteasome inhibition appeared to enhance endothelial-independent relaxation. Overall, short-term treatment with both drugs was deemed relatively safe under the tested conditions. Proteasome inhibitors such as bortezomib and carfilzomib induce apoptosis and are a cornerstone in the treatment of relapsed or refractory multiple myeloma. However, concerns have emerged concerning their link to cancer therapy-related cardiovascular dysfunction (CTRCD). Bortezomib, a reversible first-generation inhibitor, and carfilzomib, a second-generation irreversible inhibitor, are associated with hypertension, heart failure, and cardiac arrhythmias. The current study investigated the effects of bortezomib and carfilzomib on cardiac (left ventricular ejection fraction, LVEF) and vascular (arterial stiffness, vascular reactivity) function. Cardiac function assessment aimed to build upon existing evidence of proteasome inhibitors CTRCD, while arterial stiffness served as an early indicator of potential vascular remodeling. Groups of 12-week-old C57BL/6J male mice (n = 8 per group) were randomly assigned to receive vehicle, carfilzomib (8 mg/kg I.P.), or bortezomib (0.5 mg/kg I.P.). Additionally, proteasome inhibition was assessed in mice treated with L-NAME (0.5 mg/kg) to induce hypertension. Cardiac and vascular parameters were evaluated via echocardiography on days 0 and 3. On day 6, mice were sacrificed for ex vivo analysis of arterial stiffness and vascular reactivity. Overall, no changes in arterial stiffness were detected either in vivo or ex vivo at basal pressures. However, a steeper pressure–stiffness curve was observed for carfilzomib in normotensive (p < 0.01) and hypertensive (p < 0.0001) mice ex vivo. Additionally, in hypertensive mice, carfilzomib decreased LVEF (p = 0.06), with bortezomib exhibiting similar trends. Vascular reactivity remained largely unchanged, but proteasome inhibition tended to enhance endothelial-independent relaxations in both control and hypertensive mice. In conclusion, short-term treatment with carfilzomib and bortezomib is considered relatively safe for the protocols assessed in the study. [ABSTRACT FROM AUTHOR]