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V̇O2max is recognized as a key measure in exercise physiology and sports medicine. However, only 20–50% of maximal incremental exercise tests (IET) result in a plateau of V̇O2 (V̇O2pl). To our knowledge, no study has yet examined the possible difference in brain activity during an IET, in V̇O2pl and non-plateau athletes with the same V̇O2max and age. This study aimed to shed light on the central governor hypothesis, namely that the inability to reach a V̇O2pl may be dictated by the brain rather than by a peripheral physical limit. This hypothesis can now be explored using electroencephalography (EEG) during IET, measuring concomitant power in specific frequency bands. Forty-two athletes were divided into two groups: those who practiced endurance sports and those who did not, and were asked to perform an IET. EEG signals and gas exchange were recorded. A V̇O2pl was observed in twenty-two subjects (52%). EEG power increased in all subjects during IET, except in the alpha band, which showed variability, but not significantly (64% increase, 34% decrease, p = 0.07). No differences were found between endurance athletes and non-endurance athletes, except for V̇O2max (60.10 ± 6.16 vs. 51.77 ± 6.41, p < 0.001). However, the baseline-corrected ratio of EEG power to V̇O2 was found to decrease in all subjects during IET, in the alpha, beta and theta bands. In conclusion, the presence or absence of a V̇O2pl is not related to the type of EEG response during an IET. Nevertheless, the decline in brain and V̇O2 powers/ratios in all frequency bands suggests that aerobic power may be constrained by brain mobilization.

Individual heterozygosity may influence the expression of fitness‐related traits, via genome‐wide or local genetic effects. Earlier studies have shown negative relationships between heterozygosity and sperm variation, predominantly in captive, highly inbred populations. Little is known about the possible influence of variation in heterozygosity on sperm traits in wild, outbred populations. We studied two populations of the bluethroat, one from the widely distributed northern subspecies Luscinia. s. svecica and the other from the smaller, more patchily distributed subspecies breeding along the French coast of Brittany L. s. namnetum. The two subspecies differed significantly in body size, plumage colour, sperm traits and the degree of genetic diversity. However, there was no evidence that sperm traits (total length and motility) were influenced by the degree of heterozygosity at the individual level. In contrast, we found that male body size was positively related to heterozygosity across both populations, indicating a possible relationship between overall genetic diversity and general vigour or ability to obtain food. We conclude that sperm traits are unrelated to levels of heterozygosity in the studied outbred and weakly genetically depauperate bluethroat populations.

SPA09 is a polyacrylate-based clinical stage vaccine adjuvant that was found to exert a strong adjuvant effect on various vaccine antigens including recombinant cytomegalovirus glycoprotein B (CMV-gB). For the characterization of antigen-adjuvant interactions, which is a regulatory requirement and an important piece of information for the understanding of adjuvant mechanism of action, we developed a set of orthogonal techniques, comprising thermal analyses, biolayer interferometry and agarose gel migration assays. Here we apply these techniques to study the interaction between SPA09 and two recombinant proteins from the Sanofi new vaccine portfolio, CMV-gB and the Staphylococcus aureus chaperone protein, PrsA, that we used as model antigens. We believe that the techniques developed for this work could be useful to study the interactions between adjuvants and vaccine antigens in general and could be broadly applicable for the characterization of adjuvanted vaccine products.

Background: Hepatitis B virus (HBV) infection is a global health epidemic that causes fatal complications, leading to liver cirrhosis and hepatocellular carcinoma. The link between HBV-related dysbiosis and specific bacterial taxa is still under investigation. Enterocloster is emerging as a new genus (formerly Clostridium), including Enterocloster bolteae, a gut pathogen previously associated with dysbiosis and human diseases such as autism, multiple sclerosis, and inflammatory bowel diseases. Its role in liver diseases, especially HBV infection, is not reported. Methods: The fecal samples of eight patients with chronic HBV infection and ten healthy individuals were analyzed using the high-throughput culturomics approach and compared to 16S rRNA sequencing. Quantification of ethanol, known for its damaging effect on the liver, produced from bacterial strains enriched in chronic HBV was carried out by gas chromatography–mass spectrometry. Results: Using culturomics, 29,120 isolated colonies were analyzed by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI–TOF); 340 species were identified (240 species in chronic HBV samples, 254 species in control samples) belonging to 169 genera and 6 phyla. In the chronic HBV group, 65 species were already known in the literature; 48 were associated with humans but had not been previously found in the gut, and 17 had never been associated with humans previously. Six species were newly isolated in our study. By comparing bacterial species frequency, three bacterial genera were serendipitously found with significantly enriched bacterial diversity in patients with chronic HBV: Enterocloster, Clostridium, and Streptococcus (p = 0.0016, p = 0.041, p = 0.053, respectively). However, metagenomics could not identify this enrichment, possibly concerning its insufficient taxonomical resolution (equivocal assignment of operational taxonomic units). At the species level, the significantly enriched species in the chronic HBV group almost all belonged to class Clostridia, such as Clostridium perfringens, Clostridium sporogenes, Enterocloster aldenensis, Enterocloster bolteae, Enterocloster clostridioformis, and Clostridium innocuum. Two E. bolteae strains, isolated from two patients with chronic HBV infection, showed high ethanol production (27 and 200 mM). Conclusions: Culturomics allowed us to identify Enterocloster species, specifically, E. bolteae, enriched in the gut microbiota of patients with chronic HBV. These species had never been isolated in chronic HBV infection before. Moreover, ethanol production by E. bolteae strains isolated from the chronic HBV group could contribute to liver disease progression. Additionally, culturomics might be critical for better elucidating the relationship between dysbiosis and chronic HBV infection in the future.

Zebrafish possess the innate ability to fully regenerate any neurons lost following a retinal injury. This response is mediated by Müller glia that reprogram and divide asymmetrically to produce neuronal precursor cells that differentiate into the lost neurons. However, little is understood about the early signals that induce this response. Ciliary neurotrophic factor (CNTF) was previously shown to be both neuroprotective and pro-proliferative within the zebrafish retina, however CNTF is not expressed following injury. Here we demonstrate that alternative ligands of the Ciliary neurotrophic factor receptor (CNTFR), such as Cardiotrophin-like cytokine factor 1 (Clcf1) and Cytokine receptor-like factor 1a (Crlf1a), are expressed within Müller glia of the light-damaged retina. We found that CNTFR, Clcf1, and Crlf1a are required for Müller glia proliferation in the light-damaged retina. Furthermore, intravitreal injection of CLCF1/CRLF1 protected against rod photoreceptor cell death in the light-damaged retina and induced proliferation of rod precursor cells in the undamaged retina, but not Müller glia. While rod precursor cell proliferation was previously shown to be Insulin-like growth factor 1 receptor (IGF-1R)-dependent, co-injection of IGF-1 with CLCF1/CRLF1 failed to induce further proliferation of either Müller glia or rod precursor cells. Together, these findings demonstrate that CNTFR ligands have a neuroprotective effect and are required for induction of Müller glia proliferation in the light-damaged zebrafish retina.

The arenavirus nucleoprotein (NP) plays an important role in the virus' ability to block interferon (IFN) production, and its exonuclease function appears to contribute to this activity. However, efforts to analyze this contribution are complicated by the functional overlap between the exonuclease active site and a neighboring region involved in IKKε-binding and subsequent inhibition of IRF3 activation, which also plays an important role in IFN production. To circumvent this issue, we mutated a residue located away from the active site that is involved in binding of the dsRNA substrate being targeted for exonuclease digestion, i.e. H426A. We found that expression of Tacaribe virus (TCRV) NP containing this RNA-binding H426A mutation was still able to efficiently block IFN-β promoter activity in response to Sendai virus infection, despite being strongly impaired in its exonuclease activity. This was in contrast to a conventional exonuclease active site mutant (E388A), which was impaired with respect to both exonuclease activity and IFN antagonism. Importantly, growth of a recombinant virus encoding the RNA-binding mutation (rTCRV-H426A) was similar to wild-type in IFN-deficient cells, unlike the active site mutant (rTCRV-E388A), which was already markedly impaired in these cells. Further, in IFN-competent cells, the TCRV-H426A RNA-binding mutant showed more robust growth and delayed IFN-β mRNA upregulation compared to the TCRV-E388A active site mutant. Taken together, this novel mutational approach, which allows us to now dissect the different contributions of the NP exonuclease activity and IKKε-binding/IRF3 inhibition to IFN antagonism, clearly suggests that conventional exonuclease mutants targeting the active site overestimate the contribution of the exonuclease function, and that rather other IFN antagonistic functions of NP play the dominant role in IFN-antagonism.

The arenavirus nucleoprotein (NP) plays an important role in the virus’ ability to block interferon (IFN) production, and its exonuclease function appears to contribute to this activity. However, efforts to analyze this contribution are complicated by the functional overlap between the exonuclease active site and a neighboring region involved in IKKε-binding and subsequent inhibition of IRF3 activation, which also plays an important role in IFN production. To circumvent this issue, we mutated a residue located away from the active site that is involved in binding of the dsRNA substrate being targeted for exonuclease digestion, i.e. H426A. We found that expression of Tacaribe virus (TCRV) NP containing this RNA-binding H426A mutation was still able to efficiently block IFN-β promoter activity in response to Sendai virus infection, despite being strongly impaired in its exonuclease activity. This was in contrast to a conventional exonuclease active site mutant (E388A), which was impaired with respect to both exonuclease activity and IFN antagonism. Importantly, growth of a recombinant virus encoding the RNA-binding mutation (rTCRV-H426A) was similar to wild-type in IFN-deficient cells, unlike the active site mutant (rTCRV-E388A), which was already markedly impaired in these cells. Further, in IFN-competent cells, the TCRV-H426A RNA-binding mutant showed more robust growth and delayed IFN-β mRNA upregulation compared to the TCRV-E388A active site mutant. Taken together, this novel mutational approach, which allows us to now dissect the different contributions of the NP exonuclease activity and IKKε-binding/IRF3 inhibition to IFN antagonism, clearly suggests that conventional exonuclease mutants targeting the active site overestimate the contribution of the exonuclease function, and that rather other IFN antagonistic functions of NP play the dominant role in IFN-antagonism. Author summary The ability to suppress interferon production plays an important role in the successful establishment of viral infection, and for arenaviruses, the exonuclease domain of the nucleoprotein is suggested to play an important role in this process. However, analyzing its contribution is challenging because mutations that disrupt the exonuclease active site also block antagonism of IRF3 activation, which is also important for interferon production. Here we report a mutation that instead targets binding of the exonuclease’s dsRNA substrate. As expected, this mutation strongly impaired exonuclease activity; however, unlike classical mutations targeting the exonuclease active site, it was still able to efficiently block interferon production. This suggests that data based on active site mutants overestimate the contribution of the NP exonuclease function to interferon antagonism. This advance in our understanding regarding the specific contributions of different NP functions to interferon antagonism has important implications for understanding arenavirus pathogenesis and the development of future treatment strategies.

The Reproducibility Project: Cancer Biology (RPCB) was established to provide evidence about reproducibility in basic and preclinical cancer research, and to identify the factors that influence reproducibility more generally. In this commentary we address some of the scientific, ethical and policy implications of the project. We liken the basic and preclinical cancer research enterprise to a vast 'diagnostic machine' that is used to determine which clinical hypotheses should be advanced for further development, including clinical trials. The results of the RPCB suggest that this diagnostic machine currently recommends advancing many findings that are not reproducible. While concerning, we believe that more work needs to be done to evaluate the performance of the diagnostic machine. Specifically, we believe three questions remain unanswered: how often does the diagnostic machine correctly recommend against advancing real effects to clinical testing?; what are the relative costs to society of false positive and false negatives?; and how well do scientists and others interpret the outputs of the machine?

Food processes use different microorganisms, from bacteria to fungi. Yeast strains have been extensively studied, especially Saccharomyces cerevisiae. However, to date, very little is known about the potential beneficial effects of molds on gut health as part of gut microbiota. We undertook a comprehensive characterization of five mold strains, Penicillium camemberti, P. nalgiovense, P. roqueforti, Fusarium domesticum, and Geotrichum candidum used in food processes, on their ability to trigger or protect intestinal inflammation using in vitro human cell models and in vivo susceptibility to sodium dextran sulfate-induced colitis. Comparison of spore adhesion to epithelial cells showed a very wide disparity in results, with F. domesticum and P. roqueforti being the two extremes, with almost no adhesion and 20% adhesion, respectively. Interaction with human immune cells showed mild pro-inflammatory properties of all Penicillium strains and no effect of the others. However, the potential anti-inflammatory abilities detected for G. candidum in vitro were not confirmed in vivo after oral gavage to mice before and during induced colitis. According to the different series of experiments carried out in this study, the impact of the spores of these molds used in food production is limited, with no specific beneficial or harmful effect on the gut.

Abstract Objective To examine the quality of the evidence relied upon by the World Health Organisation (WHO) in promoting hand hygiene with campaigns such as “Save Lives: Clean Your Hands”. Results The quality of evidence in the studies quoted by the WHO evidence document is highly variable and the methods used limited. In some of the quoted studies, hand hygiene was the primary outcome, rather than the clinically significant outcome of hospital acquired infection (HAI). When HAI was the primary outcome, it was often poorly defined and reported with scant detail. There was wide variation in the hand hygiene compliance achieved in the intervention studies. The majority of studies where the intervention was a campaign to promote hand hygiene used historical control data with variable attempts to account for the fact that HAI rates may have been declining prior to the hand hygiene intervention. The results from trials with a contemporaneous control were conflicting.

There is increasing interest in automating train operations of mainline services, e.g., to increase network capacity. Automatic train operation (ATO) is already achieved by several pilot projects, but is still not implemented on a large scale. Functional, interoperability and performance tests are necessary before ATO can be introduced generally. Virtual preliminary analysis will contribute to the validation process to ensure a safe and successful implementation. This paper aims to present an approach that applies to the performance testing of ATO systems. Therefore, methods and test standards for technologies enabling automatic operation in other transport sectors are reviewed. The main findings have been adapted, transformed and combined to be used as a general strategy for virtual performance testing in the railway sector. Specifically, universal performance indicators commonly used in the railway sector, namely punctuality, accuracy, energy consumption, safety and comfort, are presented. They are refined by adding sub-indicators specific to the performance evaluation of ATO algorithms. A layer model for scenario description is adapted from the automotive sector, as well as the definition of different scenario types. Lastly, factors that can influence the performance of an ATO algorithm are identified. For demonstration purposes, a simple case study is conducted. Thereby we exemplarily show-cased the approach for ATO performance testing using a microscopic train simulator in combination with an ATO algorithm.

Noise induced hearing loss (NIHL) is accompanied by a reduction of cochlear hair cells and spiral ganglion neurons. Different approaches have been applied to prevent noise induced apoptosis / necrosis. Physical intervention is one technique currently under investigation. Specific wavelengths within the near-infrared light (NIR)-spectrum are known to influence cytochrome-c-oxidase activity, which leads in turn to a decrease in apoptotic mechanisms. It has been shown recently that NIR can significantly decrease the cochlear hair cell loss if applied daily for 12 days after a noise exposure. However, it is still unclear if a single NIR-treatment, just before a noise exposure, could induce similar protective effects. Therefore, the present study was conducted to investigate the effect of a single NIR-pre-treatment aimed at preventing or limiting NIHL. The cochleae of adult NMRI-mice were pre-treated with NIR-light (808 nm, 120 mW) for 5, 10, 20, 30 or 40 minutes via the external ear canal. All animals were noised exposed immediately after the pre-treatment by broad band noise (5–20 kHz) for 30 minutes at 115 dB SPL. Frequency specific ABR-recordings to determine auditory threshold shift were carried out before the pre-treatment and two weeks after the noise exposure. The amplitude increase for wave IV and cochlear hair cell loss were determined. A further group of similar mice was noise exposed only and served as a control for the NIR pre-exposed groups. Two weeks after noise exposure, the ABR threshold shifts of NIR-treated animals were significantly lower (p

The aim of the present study was the in vitro and in vivo analysis of a bi-layered 3D-printed scaffold combining a PLA layer and a biphasic PLA/bioglass G5 layer for regeneration of osteochondral defects in vivo Focus of the in vitro analysis was on the (molecular) weight loss and the morphological and mechanical variations after immersion in SBF. The in vivo study focused on analysis of the tissue reactions and differences in the implant bed vascularization using an established subcutaneous implantation model in CD-1 mice and established histological and histomorphometrical methods. Both scaffold parts kept their structural integrity, while changes in morphology were observed, especially for the PLA/G5 scaffold. Mechanical properties decreased with progressive degradation, while the PLA/G5 scaffolds presented higher compressive modulus than PLA scaffolds. The tissue reaction to PLA included low numbers of BMGCs and minimal vascularization of its implant beds, while the addition of G5 lead to higher numbers of BMGCs and a higher implant bed vascularization. Analysis revealed that the use of a bi-layered scaffold shows the ability to observe distinct in vivo response despite the physical proximity of PLA and PLA/G5 layers. Altogether, the results showed that the addition of G5 enables to reduce scaffold weight loss and to increase mechanical strength. Furthermore, the addition of G5 lead to a higher vascularization of the implant bed required as basis for bone tissue regeneration mediated by higher numbers of BMGCs, while within the PLA parts a significantly lower vascularization was found optimally for chondral regeneration. Thus, this data show that the analyzed bi-layered scaffold may serve as an ideal basis for the regeneration of osteochondral tissue defects. Additionally, the results show that it might be able to reduce the number of experimental animals required as it may be possible to analyze the tissue response to more than one implant in one experimental animal.

Rice production in Ghana has become unsustainable due to the extremely nutrient-poor soils. It is caused by inadequate soil fertility management, including the inefficient application of fertilizers. A practical solution could be the biofertilizers, Azospirillum sp. B510. We performed field trials in Ghana and Japan to compare the effects of B510 colonization on selected Ghanaian rice varieties grown. The B510 inoculation significantly enhanced the rice cultivars’ growth and yield. The phenotypic characteristics observed in rice varieties Exbaika, Ex-Boako, AgraRice, and Amankwatia were mainly short length and high tillering capacity. These features are attributed to the host plant (cv. Nipponbare), from which the strain B510 was isolated. Furthermore, Azospirillum species has been identified as the dominant colonizing bacterium of rice rhizosphere across a diverse range of agroecologies in all major rice-growing regions in Ghana. Our results suggest that the utilization of B510 as a bio-fertilizer presents a promising way to improve rice growth, enhance soil fertility, and sustain rice productivity in Ghana.

Abstract Background Characterizing membrane dynamics is a key issue to understand cell exchanges with the extra-cellular medium. Total internal reflection fluorescence microscopy (TIRFM) is well suited to focus on the late steps of exocytosis at the plasma membrane. However, it is still a challenging task to quantify (lateral) diffusion and estimate local dynamics of proteins. Results A new model was introduced to represent the behavior of cargo transmembrane proteins during the vesicle fusion to the plasma membrane at the end of the exocytosis process. Two biophysical parameters, the diffusion coefficient and the release rate parameter, are automatically estimated from TIRFM image sequences, to account for both the lateral diffusion of molecules at the membrane and the continuous release of the proteins from the vesicle to the plasma membrane. Quantitative evaluation on 300 realistic computer-generated image sequences demonstrated the efficiency and accuracy of the method. The application of our method on 16 real TIRFM image sequences additionally revealed differences in the dynamic behavior of Transferrin Receptor (TfR) and Langerin proteins. Conclusion An automated method has been designed to simultaneously estimate the diffusion coefficient and the release rate for each individual vesicle fusion event at the plasma membrane in TIRFM image sequences. It can be exploited for further deciphering cell membrane dynamics.

In this article, the results of studying the polarization characteristics of magnesium covered with corrosion film in aqueous solutions of MgSO4 and Na2SO4 are presented. The absence of a corrosion-free magnesium surface was shown; in this connection, it was proposed to interpret the larger values of Tafel’s coefficients obtained in the experiment from the point of view of limiting the electrochemical process by charge transfer in the film phase. Charge transfer in corrosion films obeys the regularities of particle movement in high electric fields, and it is not only cationic. According to the impedance measurements, the resistance of the oxide and hydroxide layer of the magnesium-based corrosion film in the studied solutions was calculated. The largest contribution to the restriction of charge transfer in the initial stages of corrosion is made by a dense primary film defining the polarization resistance. Correlation of transfer parameters in high electric fields with thickness and resistance of corrosion film was demonstrated.

DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.

Recently isolated spore-forming pigmented marine bacteria Bacillus indicus HU36 are sources of oxygenated carotenoids with original structures (about fifteen distinct yellow and orange pigments with acylated d-glucosyl groups). In this study, we evaluated the stability (sensitivity to iron-induced autoxidation) and antioxidant activity (inhibition of iron-induced lipid peroxidation) of combinations of bacterial HU36 carotenoids with the bacterial vitamin menaquinone MQ-7 and with phenolic antioxidants (vitamin E, chlorogenic acid, rutin). Unexpectedly, MQ-7 strongly improves the ability of HU36 carotenoids to inhibit FeII-induced lipid peroxidation, although MQ-7 was not consumed in the medium. We propose that their interaction modifies the carotenoid antioxidant mechanism(s), possibly by allowing carotenoids to scavenge the initiating radicals. For comparison, β-carotene and lycopene in combination were shown to exhibit a slightly higher stability toward iron-induced autoxidation, as well as an additive antioxidant activity as compared to the carotenoids, individually. HU36 carotenoids and phenolic antioxidants displayed synergistic activities in the inhibition of linoleic acid peroxidation induced by heme iron, but not by free iron. Synergism could arise from antioxidants interacting via electron transfer through the porphyrin nucleus of heme iron. Overall, combining antioxidants acting via complementary mechanisms could be the key for optimizing the activity of this bacterial carotenoid cocktail.

Postnatal mammary gland development and differentiation occur during puberty and pregnancy. To explore the role of DNA methylation in these processes, we determined the genome-wide DNA methylation and gene expression profiles of CD24+CD61+CD29hi, CD24+CD61+CD29lo, and CD24+CD61−CD29lo cell populations that were previously associated with distinct biological properties at different ages and reproductive stages. We found that pregnancy had the most significant effects on CD24+CD61+CD29hi and CD24+CD61+CD29lo cells, inducing distinct epigenetic states that were maintained through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell-type- and reproductive-stage-specific changes. We identified p27 and TGFβ signaling as key regulators of CD24+CD61+CD29lo cell proliferation, based on their expression patterns and results from mammary gland explant cultures. Our results suggest that relatively minor changes in DNA methylation occur during luminal differentiation compared with the effects of pregnancy on CD24+CD61+CD29hi and CD24+CD61+CD29lo cells.

Salicylic acid (SA) is an essential hormone in plant immunity, but its receptor has remained elusive for decades. The transcriptional coregulator NPR1 is central to the activation of SA-dependent defense genes, and we previously found that Cys521 and Cys529 of Arabidopsis NPR1's transactivation domain are critical for coactivator function. Here, we demonstrate that NPR1 directly binds SA, but not inactive structural analogs, with an affinity similar to that of other hormone-receptor interactions and consistent with in vivo Arabidopsis SA concentrations. Binding of SA occurs through Cys521/529 via the transition metal copper. Mechanistically, our results suggest that binding of SA causes a conformational change in NPR1 that is accompanied by the release of the C-terminal transactivation domain from the N-terminal autoinhibitory BTB/POZ domain. While NPR1 is already known as a link between the SA signaling molecule and defense-gene activation, we now show that NPR1 is the receptor for SA.

Vismodegib, an inhibitor of the Hedgehog signaling pathway, is an approved drug for monotherapy in locally advanced or metastatic basal cell carcinoma (BCC). Data on combined modality treatment by vismodegib and radiation therapy, however, are rare. In the present study, we examined the radiation sensitizing effects of vismodegib by analyzing viability, cell cycle distribution, cell death, DNA damage repair and clonogenic survival in three-dimensional cultures of a BCC and a head and neck squamous cell carcinoma (HNSCC) cell line. We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells. Furthermore, vismodegib significantly reduced proliferation in both cell lines, while additional irradiation only slightly further impacted on viability. Analyses of cell cycle distribution and cell death induction indicated a G1 arrest in BCC and a G2 arrest in HNSCC cells and an increased fraction of cells in SubG1 phase following combined treatment. Moreover, a significant rise in the number of phosphorylated histone-2AX/p53-binding protein 1 (γH2AX/53BP1) foci in vismodegib- and radiation-treated cells was associated with a significant radiosensitization of both cell lines. In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.

Vitamin E (VE) is the generic term for four tocopherols and four tocotrienols that exhibit the biological activity of α-tocopherol. VE status, which is usually estimated by measuring fasting blood VE concentration, is affected by numerous factors, such as dietary VE intake, VE absorption efficiency, and VE catabolism. Several of these factors are in turn modulated by genetic variations in genes encoding proteins involved in these factors. To identify these genetic variations, two strategies have been used: genome-wide association studies and candidate gene association studies. Each of these strategies has its advantages and its drawbacks, nevertheless they have allowed us to identify a list of single nucleotide polymorphisms associated with fasting blood VE concentration and α-tocopherol bioavailability. However, much work remains to be done to identify, and to replicate in different populations, all the single nucleotide polymorphisms involved, to assess the possible involvement of other kind of genetic variations, e.g., copy number variants and epigenetic modifications, in order to establish a reliable list of genetic variations that will allow us to predict the VE status of an individual by knowing their genotype in these genetic variations. Yet, the potential usefulness of this area of research is exciting with regard to personalized nutrition and for future clinical trials dedicated to assessing the biological effects of the various isoforms of VE.

The International Long-Term Ecological Research (ILTER) network comprises > 600 scientific groups conducting site-based research within 40 countries. Its mission includes improving the understanding of global ecosystems and informs solutions to current and future environmental problems at the global scales. The ILTER network covers a wide range of social-ecological conditions and is aligned with the Programme on Ecosystem Change and Society (PECS) goals and approach. Our aim is to examine and develop the conceptual basis for proposed collaboration between ILTER and PECS. We describe how a coordinated effort of several contrasting LTER site-based research groups contributes to the understanding of how policies and technologies drive either toward or away from the sustainable delivery of ecosystem services. This effort is based on three tenets: transdisciplinary research; cross-scale interactions and subsequent dynamics; and an ecological stewardship orientation. The overarching goal is to design management practices taking into account trade-offs between using and conserving ecosystems toward more sustainable solutions. To that end, we propose a conceptual approach linking ecosystem integrity, ecosystem services, and stakeholder well-being, and as a way to analyze trade-offs among ecosystem services inherent in diverse management options. We also outline our methodological approach that includes: (i) monitoring and synthesis activities following spatial and temporal trends and changes on each site and by documenting cross-scale interactions; (ii) developing analytical tools for integration; (iii) promoting trans-site comparison; and (iv) developing conceptual tools to design adequate policies and management interventions to deal with trade-offs. Finally, we highlight the heterogeneity in the social-ecological setting encountered in a subset of 15 ILTER sites. These study cases are diverse enough to provide a broad cross-section of contrasting ecosystems with different policy and management drivers of ecosystem conversion; distinct trends of biodiversity change; different stakeholders' preferences for ecosystem services; and diverse components of well-being issues.

Debate over repealing the ivory trade ban dominates conferences of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Resolving this controversy requires accurate estimates of elephant population trends and rates of illegal killing. Most African savannah elephant populations are well known; however, the status of forest elephants, perhaps a distinct species, in the vast Congo Basin is unclear. We assessed population status and incidence of poaching from line-transect and reconnaissance surveys conducted on foot in sites throughout the Congo Basin. Results indicate that the abundance and range of forest elephants are threatened from poaching that is most intense close to roads. The probability of elephant presence increased with distance to roads, whereas that of human signs declined. At all distances from roads, the probability of elephant occurrence was always higher inside, compared to outside, protected areas, whereas that of humans was always lower. Inside protected areas, forest elephant density was correlated with the size of remote forest core, but not with size of protected area. Forest elephants must be prioritised in elephant management planning at the continental scale.

Ranching is important to Florida's economy and environment. Of Florida's 34.5-plus million acres of land, 10.2 million acres were utilized for farmland in 2003, with the majority partially or totally used for cattle production. Cattle production contributed more than $348 million to the state's economy in 2003. Ranching helps protect water resources, provides natural greenways for wildlife and recreation, and preserves many components of the natural landscape. Both the environmental and economical health of ranching are therefore critical to the state's citizens. This document is WEC 187, one of a series of the Wildlife Ecology and Conservation Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida. First published as Extension document SS-SA-8, February 2000; revised September 2004. https://edis.ifas.ufl.edu/uw202

Ranching is important to Florida's economy and environment. Of Florida's 34.5-plus million acres of land, 10.2 million acres were utilized for farmland in 2003, with the majority partially or totally used for cattle production. Cattle production contributed more than $348 million to the state's economy in 2003. Ranching helps protect water resources, provides natural greenways for wildlife and recreation, and preserves many components of the natural landscape. Both the environmental and economical health of ranching are therefore critical to the state's citizens. This document is WEC 187, one of a series of the Wildlife Ecology and Conservation Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida. First published as Extension document SS-SA-8, February 2000; revised September 2004. https://edis.ifas.ufl.edu/uw202

Ranching is important to Florida's economy and environment. Of Florida's 34.5-plus million acres of land, 10.2 million acres were utilized for farmland in 2003, with the majority partially or totally used for cattle production. Cattle production contributed more than $348 million to the state's economy in 2003. Ranching helps protect water resources, provides natural greenways for wildlife and recreation, and preserves many components of the natural landscape. Both the environmental and economical health of ranching are therefore critical to the state's citizens. This document is WEC 187, one of a series of the Wildlife Ecology and Conservation Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida. First published as Extension document SS-SA-8, February 2000; revised September 2004. https://edis.ifas.ufl.edu/uw202

This document is AN141, one of a series of the Animal Sciences Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida. Original publication date May 2003. https://edis.ifas.ufl.edu/an141

This document is AN141, one of a series of the Animal Sciences Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida. Original publication date May 2003. https://edis.ifas.ufl.edu/an141

This document is AN141, one of a series of the Animal Sciences Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida. Original publication date May 2003. https://edis.ifas.ufl.edu/an141