| 1. |
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| 2. |
- Ferreira, Letícia Tiburcio, et al.
(författare)
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Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax.
- 2020
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Ingår i: Antimicrobial Agents and Chemotherapy. - 1098-6596. ; 64:9
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Tidskriftsartikel (refereegranskat)abstract
- Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii Transmission-blocking activity was observed for epirubicin in vitro and in vivo Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.
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| 3. |
- Ribeiro, Luiz Antonio, et al.
(författare)
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Charge Carrier Scattering in Polymers: A New Neutral Coupled Soliton Channel
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The dynamical scattering of two oppositely charged bipolarons in non-degenerate organic semiconducting lattices is numerically investigated in the framework of a one-dimensional tight-biding-Hubbard model that includes lattice relaxation. Our findings show that it is possible for the bipolaron pair to merge into a state composed of a confined soliton-antisoliton pair, which is characterized by the appearance of states within less than 0.1 eV from the Fermi level. This compound is in a narrow analogy to a meson confining a quark-antiquark pair. Interestingly, solitons are quasi-particles theoretically predicted to arise only in polymer lattices with degenerate ground state: in the general case of nondegenerate ground state polymers, isolated solitons are not allowed.
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| 4. |
- Ribeiro, Luiz Antonio, et al.
(författare)
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Dynamic Formation of Bipolaron-Exciton Complexes in Conducting Polymers
- 2018
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Ingår i: Journal of Physical Chemistry A. - : AMER CHEMICAL SOC. - 1089-5639 .- 1520-5215. ; 122:15, s. 3866-3872
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Tidskriftsartikel (refereegranskat)abstract
- The recombination dynamics of two oppositely charged bipolarons within a single polymer chain is numerically studied in the scope of a one-dimensional tight-binding model that considers electron electron and electron-phonon (e-ph) interactions. By scanning among values of e-ph coupling and electric field, novel channels for the bipolaron recombination were yielded based on the interplay between these two parameters. The findings point to the formation of a compound species formed from the coupling between a bipolaron and an exciton. Depending on the electric field and e-ph coupling strengths, the recombination mechanism may yield two distinct products: a trapped (and almost neutral) or a moving (and partially charged) bipolaron-exciton. These results might enlighten the understanding of the electroluminescence processes in organic light-emitting devices.
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| 5. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 6. |
- Aijaz, Asim, et al.
(författare)
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Mechanical Properties of Hydrogen Free Diamond-Like Carbon Thin Films Deposited by High Power Impulse Magnetron Sputtering with Ne
- 2018
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Ingår i: Coatings. - : MDPI AG. - 2079-6412. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Hydrogen-free diamond-like carbon (DLC) thin films are attractive for a wide range of industrial applications. One of the challenges related to the use of hard DLC lies in the high intrinsic compressive stresses that limit the film adhesion. Here, we report on the mechanical and tribological properties of DLC films deposited by High Power Impulse Magnetron Sputtering (HiPIMS) with Ne as the process gas. In contrast to standard magnetron sputtering as well as standard Ar-based HiPIMS process, the Ne-HiPIMS lead to dense DLC films with increased mass density (up to 2.65 g/cm(3)) and a hardness of 23 GPa when deposited on steel with a Cr + CrN adhesion interlayer. Tribological testing by the pin-on-disk method revealed a friction coefficient of 0.22 against steel and a wear rate of 2 x 10(-17) m(3)/Nm. The wear rate is about an order of magnitude lower than that of the films deposited using Ar. The differences in the film properties are attributed to an enhanced C ionization in the Ne-HiPIMS discharge.
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| 7. |
- Alves, Rita, et al.
(författare)
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GATA2 at the mitosis-to-G1 transition is critical for definitive hematopoiesis
- 2021
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 100:Suppl, s. 35-35
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Konferensbidrag (refereegranskat)abstract
- In mitosis, transcription factors (TFs) and RNA polymerase disperse across the cytoplasm leading to transcriptional silencing, but some TFs are retained on condensed chromatin and mark genomic sites, a mechanism termed mitotic bookmarking. In pluripotent and differentiated cells this mechanism is important for pluripotency maintenance, cell reprogramming and lineage inheritance. However, the role of bookmarking in adult stem cells or in an in vivo system is yet to be addressed. Hematopoietic stem cells undergo drastic changes in cell cycle during development while balancing self-renewal and differentiation, suggesting a possible role for bookmarking.Here, we first addressed the mitotic retention capacity of the hemogenic TFs GATA2, GFI1B and FOS. We show that GATA2 remains bound to chromatin at all phases of cell cycle, as opposed to GFI1B and FOS. The C-terminal zinc finger (C-ZF) and the nuclear localization signal domains are required for GATA2 mitotic binding. Point mutations in the C-ZF associated with leukemia also impact GATA2 retention. To address the role of GATA2-mediated mitotic bookmarking, we have fused GATA2 to a mitosis degradation (MD) domain, which promotes protein destruction at the mitosis-to-G1 transition (M-G1). Degradation of GATA2 at M-G1 impacts the reprogramming of human fibroblasts to hemogenic cells. To address the role of GATA2 at M-G1 in vivo, we have generated a mouse model with the MD domain inserted upstream the Gata2 gene. Remarkably, homozygous mice are lethal, phenocopying Gata2 null mice which die at the onset of definitive hematopoiesis, showing a deficit in hematopoietic stem and progenitor cells.These findings implicate GATA2 as a mitotic bookmarking factor and its critical role at M-G1 for definitive hematopoiesis. Overall, our study highlights a dependency on mitotic bookmarkers for in vivo lineage commitment.
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| 8. |
- Ascic, Ervin, et al.
(författare)
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Eliciting Anti-Tumor Immunity by Reprogramming Cancer Cells to Type 1 Conventional Dendritic Cells
- 2022
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionAn important hallmark of cancer is escaping the immune system. Despite advances in immunotherapy, only a subset of patients experiences clinical benefits. It was shown that adoptive T cell or checkpoint inhibition therapy rely on the presence of conventional dendritic cells type 1 (cDC1). cDC1 excel in recruiting and priming protective CD8+ T cells through cross-presentation. However, in tumors cDC1 are often impaired in function. Recently, we demonstrated that overexpression of PU.1, IRF8 and BATF3 (PIB) imposes a cDC1 fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors would reprogram cancer cells into tumor-antigen presenting cells (tumor-APCs) and set in motion antigen-specific immunity.Material and Methods30 mouse tumor lines were selected to evaluate reprogramming into tumor-APCs. Reprogramming was induced by overexpression of PIB via lentiviral transduction. The phenotype was profiled by flow cytometry for cDC1 markers CD45, MHC-II, CLEC9A, XCR1 and APC markers MHC-I, CD80/86. Population mRNA-seq was applied to assess transcriptional changes. To assess cDC1 functions, cytokine secretion, cross-presentation and T cell cytotoxicity assays were performed. In vivo, ovalbumin expressing tumors were established and treated by adoptive transfer of tumor-APCs. Tumor growth and animal survival were monitored.Results and DiscussionsUpon transduction with PIB, 26 solid tumor and 4 leukemia lines initiated expression of CD45, MHC-II, at efficiencies ranging from 0.5-57.7%. Reprogramming was accompanied by CLEC9A, XCR1 and MHC-I, CD80/86 upregulation. Transcriptomic analysis of low immunogenic lines B16 and LLC, reveals that PIB overwrites the cancer transcriptome and imposes antigen presentation and cDC1 gene signatures. Importantly, tumor-APCs present endogenous antigens on MHC-I and become prone to T cell mediated killing. Functionally, reprogrammed tumor-APCs secrete inflammatory cytokines such as IL12p70 and strikingly, acquire the ability to crosspresent antigens and prime naïve CD8+ T cells. In vivo, adoptive transfer of cross-presenting tumor-APCs delays tumor growth and extends survival of animals.ConclusionThis approach combines cDC1 antigen presentation abilities with endogenous generation of tumor antigens. The induction of a cDC1 identity in tumor cells sets in motion T cell responses and makes them target for T cell mediated killing. Our study represents a pioneering contribution merging cell reprogramming with immunotherapy.
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| 9. |
- Ascic, Ervin, et al.
(författare)
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Harnessing Dendritic Cell Reprogramming to Elucidate Mechanisms of Tumor Immunity
- 2022
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The presence of conventional dendritic cells type 1 (cDC1) in the tumor correlates with positive treatment outcome. The ability to cross-present neoantigens and prime protective CD8+ T-cell responses, makes cDC1s central for tumor immunity. However, in tumors cDC1 are rare and often functionally impaired. Our group reported that overexpression of the transcription factors PU.1, IRF8 and BATF3 (PIB) converts mouse and human fibroblasts into cross-presenting cDC1-like cells. We employed the minimal gene regulatory network of highly immunogenic cDC1 and restored the immunogenicity of low immunogenic lung cancer and melanoma cell lines by reprogramming into professional tumor antigen presenting cells (tumor-APCs). Here, we report that upon transduction with PIB, 23 solid syngeneic cancer lines initiate reprogramming into cDC1-like cells expressing CD45 and MHC-II at efficiencies ranging from 0.5-57.7%. Functionally, PIB overexpression endows tumor cells with the capacity to cross-present exogenous antigen and prime naïve CD8+ T-cells. Adoptive transfer of ovalbumin cross-presenting B16 tumor-APCs into established ovalbumin expressing B16 tumors (B16-OVA) elicits tumor growth control and extends animal survival. Treated animals show a systemic antigen-specific T cell response against ovalbumin and endogenous tumor-associated antigen MuLV p15E. Intratumoral injection of reprogrammed B2905 and LLC into tumors shows differential response, correlating with their cross-presentation capacity. This approach combines cDC1 antigen cross-presentation abilities with the generation of tumor antigens. The induction of a cDC1 identity in tumor cells sets in motion T cell responses in vitro and in vivo. In the future of this project, dendritic cell reprogramming will be object in a 2-cell CRISPR/Cas9 screen using induced cDC1-like tumor cells and reporter T-cells to explore mechanistically cross-presentation regulators. The generation of cross-presenting tumor-APCs will be also used to map and characterize presented and cross-presented neoantigens. Finally, dendritic cell reprogramming of tumor cells will be explored in vivo by replenishing cDC1 within the tumor microenvironment through in vivo reprogramming. Ultimately, this project will provide insight into mechanisms of cross-presentation and pave the way for the development of novel cDC1-centric therapies.
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| 10. |
- Birnsteinova, Sarlota, et al.
(författare)
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Online dynamic flat-field correction for MHz microscopy data at European XFEL
- 2023
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Ingår i: Journal of Synchrotron Radiation. - 1600-5775. ; 30:6, s. 1030-1037
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Tidskriftsartikel (refereegranskat)abstract
- The high pulse intensity and repetition rate of the European X-ray Free-Electron Laser (EuXFEL) provide superior temporal resolution compared with other X-ray sources. In combination with MHz X-ray microscopy techniques, it offers a unique opportunity to achieve superior contrast and spatial resolution in applications demanding high temporal resolution. In both live visualization and offline data analysis for microscopy experiments, baseline normalization is essential for further processing steps such as phase retrieval and modal decomposition. In addition, access to normalized projections during data acquisition can play an important role in decision-making and improve the quality of the data. However, the stochastic nature of X-ray free-electron laser sources hinders the use of standard flat-field normalization methods during MHz X-ray microscopy experiments. Here, an online (i.e. near real-time) dynamic flat-field correction method based on principal component analysis of dynamically evolving flat-field images is presented. The method is used for the normalization of individual X-ray projections and has been implemented as a near real-time analysis tool at the Single Particles, Clusters, and Biomolecules and Serial Femtosecond Crystallography (SPB/SFX) instrument of EuXFEL.
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| 11. |
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| 12. |
- Dominguez, Mev, et al.
(författare)
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Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals
- 2011
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 10:4, s. 641-647
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Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.
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| 13. |
- Dominguez, Mev, et al.
(författare)
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Evaluation of MLH1 I219V Polymorphism in Unrelated South American Individuals Suspected of Having Lynch Syndrome.
- 2012
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Ingår i: Anticancer research. - 1791-7530. ; 32:10, s. 4347-4351
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Tidskriftsartikel (refereegranskat)abstract
- Some single-nucleotide polymorphisms are associated with higher risk of colorectal cancer development and are suggested to explain part of the genetic contribution to Lynch syndrome. Aim: To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features.
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| 14. |
- Fecchio, Alan, et al.
(författare)
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Global drivers of avian haemosporidian infections vary across zoogeographical regions
- 2021
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 30:12, s. 2393-2406
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Macroecological analyses provide valuable insights into factors that influence how parasites are distributed across space and among hosts. Amid large uncertainties that arise when generalizing from local and regional findings, hierarchical approaches applied to global datasets are required to determine whether drivers of parasite infection patterns vary across scales. We assessed global patterns of haemosporidian infections across a broad diversity of avian host clades and zoogeographical realms to depict hotspots of prevalence and to identify possible underlying drivers. Location: Global. Time period: 1994–2019. Major taxa studied: Avian haemosporidian parasites (genera Plasmodium, Haemoproteus, Leucocytozoon and Parahaemoproteus). Methods: We amalgamated infection data from 53,669 individual birds representing 2,445 species world-wide. Spatio-phylogenetic hierarchical Bayesian models were built to disentangle potential landscape, climatic and biotic drivers of infection probability while accounting for spatial context and avian host phylogenetic relationships. Results: Idiosyncratic responses of the three most common haemosporidian genera to climate, habitat, host relatedness and host ecological traits indicated marked variation in host infection rates from local to global scales. Notably, host ecological drivers, such as migration distance for Plasmodium and Parahaemoproteus, exhibited predominantly varying or even opposite effects on infection rates across regions, whereas climatic effects on infection rates were more consistent across realms. Moreover, infections in some low-prevalence realms were disproportionately concentrated in a few local hotspots, suggesting that regional-scale variation in habitat and microclimate might influence transmission, in addition to global drivers. Main conclusions: Our hierarchical global analysis supports regional-scale findings showing the synergistic effects of landscape, climate and host ecological traits on parasite transmission for a cosmopolitan and diverse group of avian parasites. Our results underscore the need to account for such interactions, in addition to possible variation in drivers across regions, to produce the robust inference required to predict changes in infection risk under future scenarios.
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| 15. |
- Ferreira, Alexandra Gabriela, et al.
(författare)
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Restoring the immunogenicity of cancer cells with dendritic cell reprogramming
- 2021
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 100:Suppl, s. 72-72
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Konferensbidrag (refereegranskat)abstract
- An important hallmark of cancer is the ability to evade the immune system. Genetic mutations may result in the accumulation of tumor antigens, however, downregulation of antigen presentation in tumor cells results in decreased immunogenicity and immune surveillance evasion. Recently, we demonstrated that enforced expression of PU.1, IRF8 and BATF3 (PIB) imposes a conventional dendritic cell type 1 (cDC1) fate in fibroblasts by direct cell reprogramming. As such, we hypothesise that a similar combination of transcription factors can reprogram cancer cells into antigen presenting cells.Here, we show that expression of PIB factors is sufficient to induce hematopoietic and cDC1 markers in the mouse melanoma and lung cancer cell lines B16 and 3LL. We further show that reprogramming restores the expression of antigen presentation molecules (MHC-II, MHC-I and B2M) at cancer cell surface. This is accompanied by the activation of the co-stimulatory molecules CD80 and CD86. This reprogrammed tumor antigen presenting cell (tumor-APC) phenotype is specified gradually within the course of 9 days. PIB overwrites the cancer transcriptional program imposing global antigen presentation and cDC1 gene signatures. Functionally, tumor-APCs secrete inflammatory cytokines such as IL-12, IL-6, CXCL10 and type 1 interferons. After reprogramming they also acquire the capacity to uptake and process proteins as well as dead cells. Importantly, tumor-APCs directly prime antigen-specific naïve CD8+ T-cells after antigen loading. Finally, tumor-APCs are capable to show endogenous antigens to T cells and become prone to T cell mediated cell killing.Our approach combines cDC1’s antigen processing and presenting abilities with the endogenous generation of tumor antigens, and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.
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| 16. |
- Ferreira, Alexandra Gabriela, et al.
(författare)
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Restoring tumor immunogenicity with dendritic cell reprogramming
- 2022
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Ingår i: Cancer immunology research. - 2326-6074. ; 10:12 suppl
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Konferensbidrag (refereegranskat)abstract
- Immunotherapy is revolutionizing cancer treatment, but success is limited to a fraction of patients. Tumor immunosurveillance and immunotherapy relies on presentation of tumor-associated antigens by conventional dendritic cells type 1 (cDC1). However, tumors develop mechanisms to avoid immune recognition such as downregulation of antigen presentation and exclusion of cDC1. We have previously demonstrated that enforced expression of the transcription factors PU.1, IRF8 and BATF3 (PIB) imposes the lineage conversion of fibroblasts to cDC1 by direct cell reprogramming. Here, we hypothesize that PIB reprograms cancer cells directly into functional tumor-antigen presenting cells (tumor-APCs) with enhanced immunogenicity. First, we show that enforced expression of PIB in a wide range of murine and human cancer cells from different origins is sufficient to induce surface expression of hematopoietic and DC-lineage specific markers (CD45 and Clec9a). Moreover, reprogramming restored the expression of antigen presentation complexes (MHC-I and MHC-II) and activated the expression of the co-stimulatory molecules CD40, CD80 and CD86, required for productive T cell activation. Transcriptomic analysis using mRNA-sequencing showed that PIB imposes a global cDC1 gene signature and an antigen presentation program in tumor cells as early as day 3 of reprogramming, overriding the original cancer cell program. Furthermore, Assay for Transposase-Accessible Chromatin (ATAC) sequencing analysis revealed that PIB-mediated cDC1 reprogramming elicited rapid epigenetic remodeling followed by gradual rewiring of transcriptional program and stabilization of cDC1 identity. Functionally, tumor-APCs present endogenous antigens on MHC-I, prime naïve CD8+ T and become prone to CD8+ T cell mediated killing. Tumor-APCs secrete pro-inflammatory cytokines (IL-12) and chemoattractants (CXCL10), uptake and process exogenous antigens, phagocyte dead cells, and cross-present exogenous antigens to activate naïve T-cells. In addition, reprogrammed tumor cells harboring TP53, KRAS and PTEN mutations downregulated proliferation and showed impaired tumorigenicity in vitro and in vivo. Importantly, we show that intra-tumoral injection of reprogrammed tumor-APCs elicited tumour growth control in vivo alongside increasing infiltration of CD8+ T and NK cells in B16-OVA tumors. Finally, we showed that our approach can be employed to convert primary cancer cells derived from melanoma, lung, breast, pancreatic, urothelial, and head and neck carcinomas as well as cancer associated fibroblasts. In summary, we provide evidence for the direct reprogramming of tumor cells into immunogenic cDC1-like cells, with restored antigen presentation capacity and the ability to reinstate anti-tumor immunity. Our approach elicits the immune system against cancer and counteract major tumor evasion mechanisms including tumor heterogeneity and impaired antigen presentation, laying the foundation for developing immunotherapeutic strategies based on the cellular reprogramming of human cancer cells.
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| 17. |
- Ferreira, Fabio, et al.
(författare)
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Hard and dense diamond like carbon coatings deposited by deep oscillations magnetron sputtering
- 2018
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Ingår i: Surface & Coatings Technology. - : ELSEVIER SCIENCE SA. - 0257-8972 .- 1879-3347. ; 336, s. 92-98
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Tidskriftsartikel (refereegranskat)abstract
- Recent developments in the automotive industry to improve engine efficiency and minimize pollutant emissions are driving the need for higher operating temperatures and loading densities in internal combustion engines. Future engines for internal combustion engines will require coatings with increased temperature stability (up to 500 degrees C) and wear resistance as compared to present day solutions. Hard tetrahedral DLC coatings (ta-C coatings) very low coefficient of friction and performed very well under mixed and boundary lubrication, and, thus, they are very attractive for automotive industry. In this work, DLC coatings were deposited by deep oscillations magnetron sputtering (DOMS), a variant of high power magnetron sputtering (HiPIMS). The main objective is to increase the sp(3) content in the films, as compared to d.c. magnetron sputtering (DCMS), and thus extend their operating range to higher temperatures. Increasing the bias voltage results in denser and smoother films with increasing hardness, as measured by nano-indentation, and increasing mass density, as measured by x-ray reflectivity. Accordingly, the UV Raman spectroscopy analysis of the films shows that the sp(3)/sp(2) ratio in the films increases with increasing substrate biasing. However, the sp(3) bonds convert back to sp(2) upon annealing. Never the less, a significantly higher amount of sp(3) bonds is formed in the DLC films deposited by DOMS, as compared to the DCMS ones, showing that DOMS is a promising path for the development of hard DLC films.
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| 18. |
- Ferreira, Julia, et al.
(författare)
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Evolution of Gender Disparities Among Brazilian Surgical, Anesthesia, and Obstetric Providers.
- 2022
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Ingår i: Journal of Surgical Research. - : Elsevier. - 0022-4804 .- 1095-8673. ; 275, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Since 2010, most graduating physicians in Brazil have been female, nevertheless gender disparities among surgical specialties still exist. This study aims to explore whether the increase in female physicians has translated to increased female representation among surgical specialties in Brazil.METHODS: Data on gender, years of practice, and specialty was extracted from Demografia Médica do Brasil, from 2015 to 2020. The percentage of women across 18 surgical, anesthesia, and obstetric (SAO) specialties and the relative increases in female representation during the study period were calculated.RESULTS: Of the 18 SAO specialties studied, 16 (88%) were predominantly male (>50%). Only obstetrics/gynecology and breast surgery showed a female predominance, with 58% and 52%, respectively. Urology, neurosurgery, and orthopedic surgery and traumatology were the three specialties with the largest presence of men - and the lowest absolute growth in the female workforce from 2015 to 2020.CONCLUSIONS: In Brazil, where significant gender disparities persist, women are still underrepresented in surgical specialties. Female presence is predominant in surgical specialties dedicated to the care of female patients, while it remains poor in those with male patient dominance. Over the last 5 y, the proportion of women working in SAO specialties has grown, but not as much as in nonsurgical specialties. Future studies should focus on investigating the causes of gender disparities in Brazil to understand and tackle the barriers to pursuing surgical specialties.
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| 19. |
- Ferreira, Letícia T, et al.
(författare)
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Chemical Genomic Profiling Unveils the in Vitro and in Vivo Antiplasmodial Mechanism of Açaí (Euterpe oleracea Mart.) Polyphenols.
- 2019
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:13, s. 15628-15635
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Tidskriftsartikel (refereegranskat)abstract
- Malaria remains a major detrimental parasitic disease in the developing world, with more than 200 million cases annually. Widespread drug-resistant parasite strains push for the development of novel antimalarial drugs. Plant-derived natural products are key sources of antimalarial molecules. Euterpe oleracea Martius ("açaí") originates from Brazil and has anti-inflammatory and antineoplasic properties. Here, we evaluated the antimalarial efficacy of three phenolic fractions of açaí; total phenolics (1), nonanthocyanin phenolics (2), and total anthocyanins (3). In vitro, fraction 2 moderately inhibited parasite growth in chloroquine-sensitive (HB3) and multiresistant (Dd2) Plasmodium falciparum strains, while none of the fractions was toxic to noncancer cells. Despite the limited activity in vitro, the oral treatment with 20 mg/kg of fraction 1 reduced parasitemia by 89.4% in Plasmodium chabaudi-infected mice and prolonged survival. Contrasting in vitro and in vivo activities of 1 suggest key antiplasmodial roles for polyphenol metabolites rather than the fraction itself. Finally, we performed haploinsufficiency chemical genomic profiling (HIP) utilizing heterozygous Saccharomyces cerevisiae deletion mutants to identify molecular mechanisms of açaí fractions. HIP results indicate proteostasis as the main cellular pathway affected by fraction 2. These results open avenues to develop açaí polyphenols as potential new antimalarial candidates.
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| 20. |
- Ferreira Monteiro, Fabio, et al.
(författare)
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Encapsulated beta-carotene in ZnO nanotubes: Theoretical insight into the stabilization dynamics
- 2015
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Ingår i: Chemical Physics Letters. - : ELSEVIER SCIENCE BV. - 0009-2614 .- 1873-4448. ; 636, s. 62-66
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Tidskriftsartikel (refereegranskat)abstract
- The stabilization dynamics of a molecular dye (beta-carotene) encapsulated in single-wall zinc oxide nanotubes (ZnONTs) is theoretically investigated in the scope of molecular dynamics and density functional theory simulations. Our findings show that the beta-carotene encapsulation in ZnONTs is an energetically favorable process. Once encapsulated, this molecular dye remains close to the ZnONT wall, in accordance with recent experimental reports. Interestingly, the interaction between the beta-carotene and ZnONT can form a charge delocalization state, where an amount of charge concentrated on beta-carotene is transferred to ZnONT. (C) 2015 Elsevier B.V. All rights reserved.
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| 21. |
- Fiúza Rosa, Fábio, et al.
(författare)
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Direct Reprogramming of Mouse and Human Fibroblasts into Conventional Dendritic Cells Type 1
- 2022
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Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 150, s. 22-22
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Konferensbidrag (refereegranskat)abstract
- Cell fate reprogramming of adult cells towards pluripotency or unrelated somatic cell-types has been explored in the context of regenerative medicine. Dendritic cells (DCs) are professional antigen presenting cells (APCs) specialized in the recognition, processing and presentation of antigens to T-cells, inducing adaptive immunity. In particular, the mouse conventional DCs type 1 (cDC1) subset or DC1 human equivalent excel on the ability to perform antigen cross-presentation, a critical step for inducing cytotoxic responses. We hypothesized that the unique properties of cDC1s could be induced in unrelated cell-types, allowing the direct control of immune responses with cell reprogramming.Here, the requirements to induce cDC1s were investigated using combinatorial overexpression of Transcription Factors (TFs) in Clec9a-tdTomato mouse fibroblasts. In the hematopoietic system, Clec9a specifically marks the DC lineage, including all conventional dendritic cells type 1 (cDC1). We have identified PU.1, IRF8 and BATF3 (PIB) as sufficient and necessary to induce Clec9a reporter activation, establish DC morphology and activate a cDC1 transcriptional program in mouse fibroblasts. The over- expression of PIB ignites the expression of DC markers including CD103, XCR1, MHC-I, MHC-II and co-stimulatory molecules. Functionally, Induced DCs (iDCs) secrete inflammatory cytokines and engulf, process, present and cross-present antigens to CD4+ and CD8+ T cells, respectively. Additionally, we have demonstrated that combined expression of PIB factors induces DC1 reprogramming in human fibroblasts. Human iDC1s acquire DC morphology, express DC1 markers, including Clec9a, CD141 and the co-stimulatory molecules CD40, CD80 and CD86, and acquire a DC1 transcriptional signature at the single cell level. Interestingly, DC1 reprogramming efficiency can be enhanced 70-fold by supplementing culture media with inflammatory cytokines, suggesting a regulatory role of inflammation during DC1 reprogramming.Hence, we provide evidence that antigen presentation and cross-presentation can be dynamically programmed by a small combination of TFs. These findings provide insights into cDC1 specification and a platform for developing cancer immunotherapies based on cell reprogramming.
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| 22. |
- Gomes-Ferreira, Pedro Henrique Silva, et al.
(författare)
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PTH 1-34-functionalized bioactive glass improves peri-implant bone repair in orchiectomized rats: Microscale and ultrastructural evaluation
- 2022
-
Ingår i: Biomaterials Advances. - : Elsevier BV. - 2772-9508. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this work was to investigate the use of Biogran® functionalized with parathyroid hormone (PTH) 1–34 by sonochemistry for the local delivery of this anabolic agent to the implant site. The effects of Biogran® and topical administration of PTH 1–34 on peri-implant bone regeneration were evaluated from the microscale to ultrastructural levels in healthy (SHAM) and orchiectomized (ORQ). While some animals only received a titanium implant in their tibial metaphyses (CLOT group), in others the peri-implant defect was first filled with Biogran® either without or with PTH 1–34 functionalization (BG and BGPTH groups, respectively) prior to implant installation. Osseointegration was characterized from a biomechanical perspective by measuring the removal torque with the counter-torque technique. Micro-CT was used to evaluate the percentage of bone volume, trabecular thickness, number and separation, and bone-implant contact (BIC). Dynamics of new bone formation were assessed by measuring fluorochrome area, daily mineral apposition rate, and neoformed bone area using confocal laser microscopy. RT-PCR was performed to evaluate ALP and osteocalcin expression. The interface between newly formed bone and Biogran® was examined using scanning electron microscopy (SEM) and scanning transmission electron microscopy (STEM) at the micro-and nanoscale, respectively, while elemental analyses were completed in SEM with energy-dispersive X-ray spectroscopy (EDS). STEM imaging demonstrated the intimate attachment of bone to Biogran® (nanoscale level). Overall, the results suggest that the effectiveness of the topical administration of PTH 1–34 at the implant site seems enhanced in osteoporotic bone, promoting peri-implant bone regeneration to comparable levels in healthy conditions.
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| 23. |
- Graco-Roza, Caio, et al.
(författare)
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Distance decay 2.0 – A global synthesis of taxonomic and functional turnover in ecological communities
- 2022
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:7, s. 1399-1421
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Understanding the variation in community composition and species abundances (i.e., beta-diversity) is at the heart of community ecology. A common approach to examine beta-diversity is to evaluate directional variation in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distance. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 148 datasets comprising different types of organisms and environments.Location: Global.Time period: 1990 to present.Major taxa studied: From diatoms to mammals.Method: We measured the strength of the decay using ranked Mantel tests (Mantel r) and the rate of distance decay as the slope of an exponential fit using generalized linear models. We used null models to test whether functional similarity decays faster or slower than expected given the taxonomic decay along the spatial and environmental distance. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm and organismal features.Results: Taxonomic distance decay was stronger than functional distance decay along both spatial and environmental distance. Functional distance decay was random given the taxonomic distance decay. The rate of taxonomic and functional spatial distance decay was fastest in the datasets from mid-latitudes. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distance but a higher rate of decay along environmental distance. Marine ecosystems had the slowest rate of decay along environmental distances.Main conclusions: In general, taxonomic distance decay is a useful tool for biogeographical research because it reflects dispersal-related factors in addition to species responses to climatic and environmental variables. Moreover, functional distance decay might be a cost-effective option for investigating community changes in heterogeneous environments.
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| 24. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 25. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 26. |
- Khan, Sharjeel Ahmed, et al.
(författare)
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A comparative study in the tribological behaviour of different DLC coatings sliding against titanium alloys
- 2024
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Ingår i: Wear. - : Elsevier. - 0043-1648 .- 1873-2577. ; 554-555
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Tidskriftsartikel (refereegranskat)abstract
- In this study, the tribological behaviour of different Diamond-like-Carbon (DLC) coatings sliding against titanium alloy (Ti6Al4V) was analysed in a pin-on-disc tribometer at different applied loads to study effectiveness of tool coatings in titanium alloys machining. Three different DLC coatings were deposited on cemented carbide substrate using HiPIMS (DLC-Ar, DLC-Ne) and arc (DLC-Bn) deposition techniques. A detailed analysis of the wear track and titanium countersurfaces were performed following the tribotest to develop understanding about the wear mechanism and associated variation in the friction response. The results indicated that DLC-Ar presents low friction and reduced wear of coating and respective titanium countersurface at lowest load, seemingly due to its inherent tendency to spontaneously form graphitic transfer-layer at the interface. With an increase in the applied load, the tendency to retain tribofilm decreases as shearing ensue quickly exposing the underneath substrate material. The wear performance of DLC-Ne coatings is better than DLC-Ar under highest load and friction behaviour relatively close to DLC-Ar coatings. In comparison, under increased applied loads, DLC-Bn coatings offered better wear resistance and low friction compared with DLC-Ne and DLC-Ar coatings, which would offer improved performance in machining of titanium alloys.
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| 27. |
- Khan, Sharjeel Ahmed, et al.
(författare)
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Surface Roughness Influence on Tribological Behavior of HiPIMS DLC Coatings
- 2023
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Ingår i: Tribology Transactions. - : Taylor & Francis. - 1040-2004 .- 1547-397X. ; 66:3, s. 565-575
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Tidskriftsartikel (refereegranskat)abstract
- The application of diamond-like carbon (DLC) coatings in dry machining of difficult-to-machine materials has been gaining popularity due to high inertness, low coefficient of friction (COF), and high hardness of these coatings. Although the effect of surface roughness on the tribological properties of DLC coatings is of paramount importance, usually it is overlooked and coatings performance analysis was accomplished generally on highly polished substrates. The generation of polished surfaces is a time-consuming, labor-intensive process and, in most cases, not feasible for the industry due to its high cost. This article focuses on determining the effect of substrate (cemented carbide, WC-Co) surface roughness on the load-bearing capacity and tribological properties of DLC coatings deposited by High Power Impulse Magnetron Sputtering (HiPIMS) in Ne–Ar gas plasma. The DLC films were deposited onto WC-Co substrates with three different surface roughness profiles and their tribological performance were evaluated using a reciprocating tribotest. The high surface roughness resulted in increased wear rate due to high levels of asperities and increased potential for premature delamination of the coatings, while also causing severe damage to the counterbody due to inhibition of transfer film formation.
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| 28. |
- Kubart, Tomas, 1977-, et al.
(författare)
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High power impulse magnetron sputtering of diamond-like carbon coatings
- 2020
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Ingår i: Journal of Vacuum Science & Technology. A. Vacuum, Surfaces, and Films. - : American Vacuum Society. - 0734-2101 .- 1520-8559. ; 38:4
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Tidskriftsartikel (refereegranskat)abstract
- High power impulse magnetron sputtering (HiPIMS) of diamond-like carbon coatings is reviewed. Three variations of HiPIMS were used to deposit diamond-like carbon coatings: use of neon as compared to argon for sputtering, very high discharge peak current density in an Ar atmosphere, and the use of bursts of short sputtering pulses. All three variations were able to provide sufficient ion-to-neutral ratios to effectively control the coating quality using substrate bias. The resulting coatings are typically smooth, amorphous, hard (up to 25 GPa), and dense but have low stress (below 2.5 GPa). The coatings exhibit an increased stability at higher temperature (up to 500 °C) compared to the coatings prepared using standard magnetron sputtering. The resulting coatings also exhibited low wear rates in ambient ball-on-disc tests (2.1 × 10−8 mm3 N−1 m−1). These improvements are explained in terms of the rate of sputtered carbon atom ionization in the plasma and material transport to the substrate. However, the chemical bonding in the films is not yet well understood as relatively low sp3 bond content has been observed.
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| 29. |
- Oliveira, Joao, et al.
(författare)
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Correlation between Substrate Ion Fluxes and the Properties of Diamond-Like Carbon Films Deposited by Deep Oscillation Magnetron Sputtering in Ar and Ar plus Ne Plasmas
- 2020
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Ingår i: Coatings. - : MDPI. - 2079-6412. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the use of Ne as a processing gas has been shown to increase the ionization degree of carbon in High Power Impulse Magnetron Sputtering (HiPIMS) plasmas. In this work, time-resolved measurements of the substrate's current density were carried out in order to study the time evolution of the ionic species arriving at the growing film. The addition of Ne to the plasma resulted in a steep increase of the sp(3)/sp(2) ratio in the films once the Ne contents in the processing atmosphere exceeded 26%. Increasing the Ne content is shown to increase both the total number of C ions generated in the plasmas and the ratio of C/gaseous ions. The time-resolved substrate ion current density was used to evaluate the possibility of substrate biasing synchronizing with the discharge pulses in the HiPIMS process. It is shown that in pure Ar plasmas, substrate biasing should be confined to the time interval between 25 and 40 mu s after the pulse starts, in order to maximize the C+/Ar+ ratio bombarding the substrate and minimize the formation of film stresses. However, Ne addition to the processing gas shortens the traveling time of the carbon species towards the substrate, reducing the separation between the gaseous and carbon ion arrival times.
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| 30. |
- Pereira, Carlos-Filipe
(creator_code:cre_t)
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Compositions for reprogramming into dendritic cells type 2 competent for antigen presentation, methods and uses thereof
- 2021
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Patent (övrigt vetenskapligt/konstnärligt)abstract
- The present disclosure relates to compositions for reprogramming cells into conventional dendritic cells (cDC), particularly into cDC type 2 (hereinafter referred to as “cDC2” or “CD11b-positive dendritic cells”), methods and uses thereof. The present disclosure relates to the development of methods for making conventional dendritic cells with antigen presenting capacity from differentiated, multipotent or pluripotent stem cells by introducing and expressing isolated/synthetic transcription factors. More particularly, the disclosure provides methods for obtaining conventional dendritic cells (cDC), particularly cDC type 2 or CD11b-positive dendritic cells, by direct cell reprogramming with the surprisingly use of combinations of specific transcription factors.
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| 31. |
- Perez-Nadales, Elena, et al.
(författare)
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Predictors of mortality in solid organ transplant recipients with bloodstream infections due to carbapenemase-producing Enterobacterales : The impact of cytomegalovirus disease and lymphopenia
- 2020
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Ingår i: American Journal of Transplantation. - : WILEY. - 1600-6135 .- 1600-6143. ; 20:6, s. 1629-1641
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of carbapenemase-producing Enterobacterales bloodstream infections in solid organ transplant recipients is challenging. The objective of this study was to develop a specific score to predict mortality in solid organ transplant recipients with carbapenemase-producing Enterobacterales bloodstream infections. A multinational, retrospective (2004-2016) cohort study (INCREMENT-SOT, ClinicalTrials.gov NCT02852902) was performed. The main outcome variable was 30-day all-cause mortality. The INCREMENT-SOT-CPE score was developed using logistic regression. The global cohort included 216 patients. The final logistic regression model included the following variables: INCREMENT-CPE mortality score >= 8 (8 points), no source control (3 points), inappropriate empirical therapy (2 points), cytomegalovirus disease (7 points), lymphopenia (4 points), and the interaction between INCREMENT-CPE score >= 8 and CMV disease (minus 7 points). This score showed an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI] 0.76-0.88) and classified patients into 3 strata: 0-7 (low mortality), 8-11 (high mortality), and 12-17 (very-high mortality). We performed a stratified analysis of the effect of monotherapy vs combination therapy among 165 patients who received appropriate therapy. Monotherapy was associated with higher mortality only in the very-high (adjusted hazard ratio [HR] 2.82, 95% CI 1.13-7.06, P = .03) and high (HR 9.93, 95% CI 2.08-47.40, P = .004) mortality risk strata. A score-based algorithm is provided for therapy guidance.
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| 32. |
- Rosa, Fábio F., et al.
(författare)
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Direct reprogramming of fibroblasts into antigen-presenting dendritic cells
- 2018
-
Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 3:30
-
Tidskriftsartikel (refereegranskat)abstract
- Ectopic expression of transcription factors has been used to reprogram differentiated somatic cells toward pluripotency or to directly reprogram them to other somatic cell lineages. This concept has been explored in the context of regenerative medicine. Here, we set out to generate dendritic cells (DCs) capable of presenting antigens from mouse and human fibroblasts. By screening combinations of 18 transcription factors that are expressed in DCs, we have identified PU.1, IRF8, and BATF3 transcription factors as being sufficient to reprogram both mouse and human fibroblasts to induced DCs (iDCs). iDCs acquire a conventional DC type 1-like transcriptional program, with features of interferon-induced maturation. iDCs secrete inflammatory cytokines and have the ability to engulf, process, and present antigens to T cells. Furthermore, we demonstrate that murine iDCs generated here were able to cross-present antigens to CD8+ T cells. Our reprogramming system should facilitate better understanding of DC specification programs and serve as a platform for the development of patient-specific DCs for immunotherapy.
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| 33. |
- Rosa, Fábio F, et al.
(författare)
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Single-cell transcriptional profiling informs efficient reprogramming of human somatic cells to cross-presenting dendritic cells
- 2022
-
Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 7:69, s. 1-18
-
Tidskriftsartikel (refereegranskat)abstract
- Type 1 conventional dendritic cells (cDC1s) are rare immune cells critical for the induction of antigen-specific cytotoxic CD8+ T cells, although the genetic program driving human cDC1 specification remains largely unexplored. We previously identified PU.1, IRF8, and BATF3 transcription factors as sufficient to induce cDC1 fate in mouse fibroblasts, but reprogramming of human somatic cells was limited by low efficiency. Here, we investigated single-cell transcriptional dynamics during human cDC1 reprogramming. Human induced cDC1s (hiDC1s) generated from embryonic fibroblasts gradually acquired a global cDC1 transcriptional profile and expressed antigen presentation signatures, whereas other DC subsets were not induced at the single-cell level during the reprogramming process. We extracted gene modules associated with successful reprogramming and identified inflammatory signaling and the cDC1-inducing transcription factor network as key drivers of the process. Combining IFN-γ, IFN-β, and TNF-α with constitutive expression of cDC1-inducing transcription factors led to improvement of reprogramming efficiency by 190-fold. hiDC1s engulfed dead cells, secreted inflammatory cytokines, and performed antigen cross-presentation, key cDC1 functions. This approach allowed efficient hiDC1 generation from adult fibroblasts and mesenchymal stromal cells. Mechanistically, PU.1 showed dominant and independent chromatin targeting at early phases of reprogramming, recruiting IRF8 and BATF3 to shared binding sites. The cooperative binding at open enhancers and promoters led to silencing of fibroblast genes and activation of a cDC1 program. These findings provide mechanistic insights into human cDC1 specification and reprogramming and represent a platform for generating patient-tailored cDC1s, a long-sought DC subset for vaccination strategies in cancer immunotherapy.
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| 34. |
- Rothfuss, Jonas, et al.
(författare)
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Deep Episodic Memory : Encoding, Recalling, and Predicting Episodic Experiences for Robot Action Execution
- 2018
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Ingår i: IEEE Robotics and Automation Letters. - Piscataway, NJ : IEEE. - 2377-3766. ; 3:4, s. 4007-4014
-
Tidskriftsartikel (refereegranskat)abstract
- We present a novel deep neural network architecture for representing robot experiences in an episodic-like memory that facilitates encoding, recalling, and predicting action experiences. Our proposed unsupervised deep episodic memory model as follows: First, encodes observed actions in a latent vector space and, based on this latent encoding, second, infers most similar episodes previously experienced, third, reconstructs original episodes, and finally, predicts future frames in an end-to-end fashion. Results show that conceptually similar actions are mapped into the same region of the latent vector space. Based on these results, we introduce an action matching and retrieval mechanism, benchmark its performance on two large-scale action datasets, 20BN-something-something and ActivityNet and evaluate its generalization capability in a real-world scenario on a humanoid robot.
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| 35. |
- Tavella, Tatyana Almeida, et al.
(författare)
-
Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity.
- 2021
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Ingår i: ACS Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 7:4, s. 759-776
-
Tidskriftsartikel (refereegranskat)abstract
- Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, PfHsp90 and PfHsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation-a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design.
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| 36. |
- Truche, Paul, et al.
(författare)
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Association between government policy and delays in emergent and elective surgical care during the COVID-19 pandemic in Brazil : a modeling study
- 2021
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Ingår i: The Lancet Regional Health - Americas. - : Elsevier. - 2667-193X.
-
Tidskriftsartikel (refereegranskat)abstract
- Background:The impact of public health policy to reduce the spread of COVID-19 on access to surgical care is poorly defined. We aim to quantify the surgical backlog during the COVID-19 pandemic in the Brazilian public health system and determine the relationship between state-level policy response and the degree of state-level delays in public surgical care.Methods:Monthly estimates of surgical procedures performed per state from January 2016 to December 2020 were obtained from Brazil's Unified Health System Informatics Department. Forecasting models using historical surgical volume data before March 2020 (first reported COVID-19 case) were constructed to predict expected monthly operations from March through December 2020. Total, emergency, and elective surgical monthly backlogs were calculated by comparing reported volume to forecasted volume. Linear mixed effects models were used to model the relationship between public surgical delivery and two measures of health policy response: the COVID-19 Stringency Index (SI) and the Containment & Health Index (CHI) by state.Findings:Between March and December 2020, the total surgical backlog included 1,119,433 (95% Confidence Interval 762,663–1,523,995) total operations, 161,321 (95%CI 37,468–395,478) emergent operations, and 928,758 (95%CI 675,202–1,208,769) elective operations. Increased SI and CHI scores were associated with reductions in emergent surgical delays but increases in elective surgical backlogs. The maximum government stringency (score = 100) reduced emergency delays to nearly zero but tripled the elective surgical backlog.Interpretation:Strong health policy efforts to contain COVID-19 ensure minimal reductions in delivery of emergent surgery, but dramatically increase elective backlogs. Additional coordinated government efforts will be necessary to specifically address the increased elective backlogs that accompany stringent responses.
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| 37. |
- Zerbinato de Andrade Silva, Duilio Mazzoni, et al.
(författare)
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Long-term persistence of supernumerary B chromosomes in multiple species of Astyanax fish
- 2021
-
Ingår i: BMC Biology. - : BioMed Central (BMC). - 1741-7007. ; 19
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Eukaryote genomes frequently harbor supernumerary B chromosomes in addition to the "standard" A chromosome set. B chromosomes are thought to arise as byproducts of genome rearrangements and have mostly been considered intraspecific oddities. However, their evolutionary transcendence beyond species level has remained untested.Results: Here we reveal that the large metacentric B chromosomes reported in several fish species of the genus Astyanax arose in a common ancestor at least 4 million years ago. We generated transcriptomes of A. scabripinnis and A. paranae 0B and 1B individuals and used these assemblies as a reference for mapping all gDNA and RNA libraries to quantify coverage differences between B-lacking and B-carrying genomes. We show that the B chromosomes of A. scabripinnis and A. paranae share 19 protein-coding genes, of which 14 and 11 were also present in the B chromosomes of A. bockmanni and A. fasciatus, respectively. Our search for B-specific single-nucleotide polymorphisms (SNPs) identified the presence of B-derived transcripts in B-carrying ovaries, 80% of which belonged to nobox, a gene involved in oogenesis regulation. Importantly, the B chromosome nobox paralog is expressed >30x more than the A chromosome paralog. This indicates that the normal regulation of this gene is altered in B-carrying females, which could potentially facilitate B inheritance at higher rates than Mendelian law prediction.Conclusions: Taken together, our results demonstrate the long-term survival of B chromosomes despite their lack of regular pairing and segregation during meiosis and that they can endure episodes of population divergence leading to species formation.
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| 38. |
- Zimmermannova, Olga, et al.
(författare)
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Restoring tumor immunogenicity with dendritic cell reprogramming
- 2023
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Ingår i: Science Immunology. - 2470-9468. ; 8:85
-
Tidskriftsartikel (refereegranskat)abstract
- Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8 + T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8 + T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
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