Gauge invariance of the background average effective action

Using the background field method for the functional renormalization group approach in the case of a generic gauge theory, we study the background field symmetry and gauge dependence of the background average effective action, when the regulator action depends on external fields. The final result is that the symmetry of the average effective action can be maintained for a wide class of regulator functions, but in all cases the dependence of the gauge fixing remains on-shell. The Yang-Mills theory is considered as the main particular example.Comment: Fits the version accepted in EPJ

AXL as a modulator of sunitinib response in glioblastoma cell lines

Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that AXL knockdown conferred lower sensitivity to sunitinib by rescuing migratory defects and inhibiting apoptosis in cells expressing high AXL basal levels. Accordingly, overactivation of AXL by its ligand GAS6 rendered AXL positive glioblastoma cells more sensitive to sunitinib. AXL knockdown induced a cellular rewiring of several growth signaling pathways through activation of RTKs, such as EGFR, as well as intracellular pathways such as MAPK and AKT. The combination of sunitinib with a specific AKT inhibitor reverted the resistance of AXL-silenced cells to sunitinib. Together, our results suggest that sunitinib inhibits AXL and AXL activation status modulates therapy response of glioblastoma cells to sunitinib. Moreover, it indicates that combining sunitinib therapy with AKT pathway inhibitors could overcome sunitinib resistance.This work was funded by Fundacao para a Ciencia e Tecnologia (FCT), Portugal (project: PTDC/SAU-TOX/114549/2009). Olga Martinho is a recipient of a Post-Doc fellowship (UMINHO/BPD/32/2013) from QREN. We would like to acknowledge Dr. Shuang-En Chuang from the National Health Research Institute, Taiwan, for providing AXL vectors, and Dr. Raquel Andrade for critical review of the manuscript

Determination of seventeen endocrine disruptor compounds and their spatial and seasonal distribution in Ria Formosa Lagoon (Portugal)

In spite of its outstanding ecological and touristic importance the Ria Formosa Lagoon shows signs of anthropogenic pollution. Nonetheless, until the present survey no studies had ever documented the measurement of natural and pharmaceutical estrogens (17β-estradiol, estrone, and 17α-ethynylestradiol), xenoestrogenic industrial pollutants (4-octylphenol, 4- nonylphenol, and their mono and diethoxylates and bisphenol A), phytoestrogens (formononetin, biochanin A, daidzein, genistein), and sitosterol in this area. The 17 compounds measured herein are known as endocrine disrupters (EDCs) and act over the endocrine system even in few amounts (ng L−1–μg L−1). Thus to conclude about the influx of EDCs in the lagoon, water samples were taken every 2 months, during 1 year (2010), in low tide at nine sites distributed along the coastline. Water samples (1 L) were preconcentrated in the Oasis HLB cartridges and cleaned in silica cartridges before their analysis by GC-MS. Data showed the ubiquitous presence of potentially hazardous amounts of estrogens (particularly of ethynylestradiol, up to 24.3 ng L−1), nonylphenol (up to 547 ng L−1), and sitosterol (up to 12,300 ng L−1), mainly in summer, suggesting that the increase of the local number of inhabitants (tourists), the rise of the water temperature (up to 26 °C), and the blooming of local flora may interfere with the water quality parameters. This makes the lagoon a potential model to study. Taking into account the data, it was concluded that there are conditions for the occurrence of endocrine disruption in aquatic animals, even in areas included in the natural park of the Formosa. Besides, both the high amounts of un-ionized ammonia (up to 0.3 mg L−1) and phosphates (up to 1.6 mg L−1) my pose risks for local fauna and humans.This work was financially supported by FEDER funds through the Competitiveness and Trade Expansion Program—COMPETE and by National Funds provided by Fundação para a Ciência e a Tecnologia (FCT), via the project PTDC/MAR/70436/2006

Chitosan impregnated gutta-percha points: antimicrobial in vitro evaluation and mechanical properties

Chitosan-impregnated gutta-percha points (ChitGPP) were tested for their ability to inhibit the growth of microorganisms usually involved in root canal infections. Their mechanical properties were also studied and compared with the commonly used commercial points in endodontics. ChitGPP were more efficient in reducing the microbial load than those without chitosan. ChitGPP also possess better tensile and elastic properties than commercial ones. After six months of storage, ChitGPP’s were still able to reduce the bacterial load by 1 log, suggesting that impregnation of gutta-percha points with chitosan could be a good alternative to obtain gutta-percha points with improved antimicrobial properties.info:eu-repo/semantics/publishedVersio

Menthol-based deep eutectic systems as antimicrobial and anti-inflammatory agents for wound healing

Funding Information: This work received funding from Foundation for Science and Technology (FCT) , through project PTDC/BBB- 490 EBB/1676/2014 – Des.Zyme and ERC-2016-CoG 725034 (ERC Consolidator Grant Des.solve). E.S. and J.S. would also like to acknowledge the financial support by the Portuguese Foundation for Science and Technology (FCT) through the doctoral grant with reference number SFRH/BD/143902/2019 and postdoctoral contract CEECIND/01026/2018 , respectively. Publisher Copyright: © 2022Effective antimicrobial treatment has been identified as a serious and unmet medical need. Herein, we present a strategy based on deep eutectic systems (DES) to overcome current limitations, answering the need not only to effectively kill bacterial agents but also to avoid their adhesion and proliferation, which is associated with biofilm formation and have a crucial impact on bacterial virulence. To achieve such a goal, natural deep eutectic systems (NADES) based on menthol (Me) and saturated free fatty acids (FFA) were produced, fully physicochemical characterized, and its bioactive properties were described. The antimicrobial potential of menthol-based NADES with FFA, namely, myristic acid (MA), lauric acid (LA), and stearic acid (SA) were investigated towards a broad panel of microorganisms. The obtained data indicates that NADES possess effective antimicrobial properties towards the Gram-positive bacterial and fungal strains tested. Among the tested formulations, Me:LA at a molar ratio of 4:1 molar was used to carry out a biofilm detachment/removal assay due to is superior microbiological properties. This formulation was able to effectively lead to biofilm removal/dispersion of not only methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans, but also Escherichia coli, without the need of any additional physical force or antibiotic. Furthermore, since microbial invasion and biofilm formation is highly undesired in wound healing, namely in chronic wound healing, the wound healing properties of these eutectic formulations was also investigated. The results suggest that these NADES can cope with microbial invasion and biofilm detachment while not compromising normal keratinocyte proliferation and migration verified in wound healing and epidermis repair, while also contributing to the reduction of cell stress and inflammation via the control of ROS production. In conclusion, these results provide the indication that NADES based on Me and FFA holds great interest as antimicrobial agents for preventive and therapeutic applications in various clinical settings, including wound healing.publishersversionpublishe

Androgen responsive intronic non-coding RNAs

BACKGROUND: Transcription of large numbers of non-coding RNAs originating from intronic regions of human genes has been recently reported, but mechanisms governing their biosynthesis and biological functions are largely unknown. In this work, we evaluated the existence of a common mechanism of transcription regulation shared by protein-coding mRNAs and intronic RNAs by measuring the effect of androgen on the transcriptional profile of a prostate cancer cell line. RESULTS: Using a custom-built cDNA microarray enriched in intronic transcribed sequences, we found 39 intronic non-coding RNAs for which levels were significantly regulated by androgen exposure. Orientation-specific reverse transcription-PCR indicated that 10 of the 13 were transcribed in the antisense direction. These transcripts are long (0.5–5 kb), unspliced and apparently do not code for proteins. Interestingly, we found that the relative levels of androgen-regulated intronic transcripts could be correlated with the levels of the corresponding protein-coding gene (asGAS6 and asDNAJC3) or with the alternative usage of exons (asKDELR2 and asITGA6) in the corresponding protein-coding transcripts. Binding of the androgen receptor to a putative regulatory region upstream from asMYO5A, an androgen-regulated antisense intronic transcript, was confirmed by chromatin immunoprecipitation. CONCLUSION: Altogether, these results indicate that at least a fraction of naturally transcribed intronic non-coding RNAs may be regulated by common physiological signals such as hormones, and further corroborate the notion that the intronic complement of the transcriptome play functional roles in the human gene-expression program

Cell-to-cell transfer of Leishmania amazonensis amastigotes is mediated by immunomodulatory LAMP-rich parasitophorous extrusions

The last step of Leishmania intracellular life cycle is the egress of amastigotes from the host cell and their uptake by adjacent cells. Using multidimensional live imaging of long-term-infected macrophage cultures we observed that Leishmania amazonensis amastigotes were transferred from cell to cell when the donor host macrophage delivers warning signs of imminent apoptosis. They were extruded from the macrophage within zeiotic structures (membrane blebs, an apoptotic feature) rich in phagolysosomal membrane components. the extrusions containing amastigotes were selectively internalized by vicinal macrophages and the rescued amastigotes remain viable in recipient macrophages. Host cell apoptosis induced by micro-irradiation of infected macrophage nuclei promoted amastigotes extrusion, which were rescued by non-irradiated vicinal macrophages. Using amastigotes isolated from LAMP1/LAMP2 knockout fibroblasts, we observed that the presence of these lysosomal components on amastigotes increases interleukin 10 production. Enclosed within host cell membranes, amastigotes can be transferred from cell to cell without full exposure to the extracellular milieu, what represents an important strategy developed by the parasite to evade host immune system.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Escola Paulista Medi, Dept Microbiol Imunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Trop Med, Lab Soroepidemiol & Imunobiol, São Paulo, BrazilFdn Oswaldo Cruz FIOCRUZ, INCT DT, Salvador, BrazilUniversidade Federal de São Paulo, Fac Med, Dept Prevent Med, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Medi, Dept Microbiol Imunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Trop Med, Lab Soroepidemiol & Imunobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Fac Med, Dept Prevent Med, São Paulo, BrazilFAPESP: 10/19335-4Web of Scienc

Transcriptional profiling of Neurospora crassa Δmak-2 reveals that mitogen-activated protein kinase MAK-2 participates in the phosphate signaling pathway

AbstractThe filamentous fungus Neurospora crassa is an excellent model system for examining molecular responses to ambient signals in eukaryotic microorganisms. Inorganic phosphate (Pi) is an essential growth-limiting nutrient in nature and is crucial for the synthesis of nucleic acids and the flow of genetic information. The genetic and molecular mechanisms controlling the response to Pi starvation in N. crassa include at least four genes (nuc-2, preg, pogv, and nuc-1), which are involved in a hierarchical regulatory activation network. In a previous work, we identified a number of genes modulated by NUC-2 protein, including the mak-2 gene, which codes for a mitogen-activated protein kinase (MAPK), suggesting its participation in the phosphate signaling pathway. Thus, to identify other genes involved in metabolic responses to exogenous phosphate sensing and the functioning of the MAPK MAK-2, we performed microarray experiments using a mak-2 knockout strain (Δmak-2) grown under phosphate-shortage conditions by comparing its transcription profile to that of a control strain grown in low- and high-phosphate cultures. These experiments revealed 912 unique differentially expressed genes involved in a number of physiological processes related to phosphate transport, metabolism, and regulation as well as posttranslational modification of proteins, and MAPK signaling pathways. Quantitative Real-time PCR gene expression analysis of 18 selected genes, using independent RNA samples, validated our microarray results. A high Pearson correlation between microarray and quantitative Real-time PCR data was observed. The analysis of these differentially expressed genes in the Δmak-2 strain provide evidence that the mak-2 gene participates in the hierarchical phosphate-signaling pathway in N. crassa in addition to its involvement in other metabolic routes such as the isoprenylation pathway, thus revealing novel aspects of the N. crassa phosphorus-sensing network