An active power filter and static var compensator with active power generation capability has been implemented using a 27-level inverter. Each phase of this inverter is composed of three ldquoHrdquo ...bridges, all of them connected to the same dc link and their outputs connected through output transformers scaled in the power of three. The filter can compensate load currents with a high harmonic content and a low power factor, resulting in sinusoidal currents from the source. To take advantage of this compensator, the dc link, instead of a capacitor, uses a battery pack, which is charged from a photovoltaic array connected to the batteries through a maximum power point tracker. This combined topology make it possible to produce active power and even to feed the loads during prolonged voltage outages. Simulation results for this application are shown, and some experiments with a 3-kVA device are displayed.
Corynebacterium diphtheriae, the agent of diphtheria, is a genetically diverse bacterial species. Although antimicrobial resistance has emerged against several drugs including first-line penicillin, ...the genomic determinants and population dynamics of resistance are largely unknown for this neglected human pathogen.
Here, we analyzed the associations of antimicrobial susceptibility phenotypes, diphtheria toxin production, and genomic features in C. diphtheriae. We used 247 strains collected over several decades in multiple world regions, including the 163 clinical isolates collected prospectively from 2008 to 2017 in France mainland and overseas territories.
Phylogenetic analysis revealed multiple deep-branching sublineages, grouped into a Mitis lineage strongly associated with diphtheria toxin production and a largely toxin gene-negative Gravis lineage with few toxin-producing isolates including the 1990s ex-Soviet Union outbreak strain. The distribution of susceptibility phenotypes allowed proposing ecological cutoffs for most of the 19 agents tested, thereby defining acquired antimicrobial resistance. Penicillin resistance was found in 17.2% of prospective isolates. Seventeen (10.4%) prospective isolates were multidrug-resistant (≥ 3 antimicrobial categories), including four isolates resistant to penicillin and macrolides. Homologous recombination was frequent (r/m = 5), and horizontal gene transfer contributed to the emergence of antimicrobial resistance in multiple sublineages. Genome-wide association mapping uncovered genetic factors of resistance, including an accessory penicillin-binding protein (PBP2m) located in diverse genomic contexts. Gene pbp2m is widespread in other Corynebacterium species, and its expression in C. glutamicum demonstrated its effect against several beta-lactams. A novel 73-kb C. diphtheriae multiresistance plasmid was discovered.
This work uncovers the dynamics of antimicrobial resistance in C. diphtheriae in the context of phylogenetic structure, biovar, and diphtheria toxin production and provides a blueprint to analyze re-emerging diphtheria.
Human eye-tracking studies have shown that gaze fixations are biased toward the center of natural scene stimuli ("center bias"). This bias contaminates the evaluation of computational models of ...attention and oculomotor behavior. Here we recorded eye movements from 17 participants watching 40 MTV-style video clips (with abrupt scene changes every 2-4 s), to quantify the relative contributions of five causes of center bias: photographer bias, motor bias, viewing strategy, orbital reserve, and screen center. Photographer bias was evaluated by five naive human raters and correlated with eye movements. The frequently changing scenes in MTV-style videos allowed us to assess how motor bias and viewing strategy affected center bias across time. In an additional experiment with 5 participants, videos were displayed at different locations within a large screen to investigate the influences of orbital reserve and screen center. Our results demonstrate quantitatively for the first time that center bias is correlated strongly with photographer bias and is influenced by viewing strategy at scene onset, while orbital reserve, screen center, and motor bias contribute minimally. We discuss methods to account for these influences to better assess computational models of visual attention and gaze using natural scene stimuli.
For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, ...whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.
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•Chronic IFN signaling induces epigenetic rewiring of tumor cells and immune escape•MHC-I and PD-L1 expression enables the evasion of NK cells and suppression of T cells•LN colonization induces broad alterations in the local immune repertoire•LN metastases induce antigen-specific Tregs that promote distant metastasis
Facilitated by a tumor-intrinsic interferon response program, lymph node colonization promotes metastasis to distant organs by inducing broad alterations in tumor immunity and generating tumor-specific immune tolerance.
Bardet-Biedl syndrome (BBS) is a heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, hypogenitalism, ...and an increased incidence of diabetes and hypertension. No information is available regarding the specific function of BBS2. We show that mice lacking Bbs2 gene expression have major components of the human phenotype, including obesity and retinopathy. In addition, these mice have phenotypes associated with cilia dysfunction, including retinopathy, renal cysts, male infertility, and a deficit in olfaction. With the exception of male infertility, these phenotypes are not caused by a complete absence of cilia. We demonstrate that BBS2 retinopathy involves normal retina development followed by apoptotic death of photoreceptors, the primary ciliated cells of the retina. Photoreceptor cell death is preceded by mislocalization of rhodopsin, indicating a defect in transport. We also demonstrate that Bbs2-/-mice and a second BBS mouse model, Bbs4-/-, have a defect in social function. The evaluation of Bbs2-/-mice indicates additional phenotypes that should be evaluated in human patients, including deficits in social interaction and infertility.
The paper presents the first modelling experiment of the European-scale olive pollen dispersion, analyses the quality of the predictions, and outlines the research needs. A 6-model strong ensemble of ...Copernicus Atmospheric Monitoring Service (CAMS) was run throughout the olive season of 2014, computing the olive pollen distribution. The simulations have been compared with observations in eight countries, which are members of the European Aeroallergen Network (EAN). Analysis was performed for individual models, the ensemble mean and median, and for a dynamically optimised combination of the ensemble members obtained via fusion of the model predictions with observations. The models, generally reproducing the olive season of 2014, showed noticeable deviations from both observations and each other. In particular, the season was reported to start too early by 8 days, but for some models the error mounted to almost 2 weeks. For the end of the season, the disagreement between the models and the observations varied from a nearly perfect match up to 2 weeks too late. A series of sensitivity studies carried out to understand the origin of the disagreements revealed the crucial role of ambient temperature and consistency of its representation by the meteorological models and heat-sum-based phenological model. In particular, a simple correction to the heat-sum threshold eliminated the shift of the start of the season but its validity in other years remains to be checked. The short-term features of the concentration time series were reproduced better, suggesting that the precipitation events and cold/warm spells, as well as the large-scale transport, were represented rather well. Ensemble averaging led to more robust results. The best skill scores were obtained with data fusion, which used the previous days' observations to identify the optimal weighting coefficients of the individual model forecasts. Such combinations were tested for the forecasting period up to 4 days and shown to remain nearly optimal throughout the whole period.
Consanguineous unions increase the rate at which identical genomic segments are paired within individuals to produce runs of homozygosity (ROH). The extent to which such unions affect ...identity-by-descent (IBD) genomic sharing
rather than
individuals in a population, however, is not immediately evident from within-individual ROH levels. Using the fact that the time to the most recent common ancestor Formula: see text for a pair of genomes at a specific locus is inversely related to the extent of IBD sharing between the genomes in the neighborhood of the locus, we study IBD sharing for a pair of genomes sampled either within the same individual or in different individuals. We develop a coalescent model for a set of mating pairs in a diploid population, treating the fraction of consanguineous unions as a parameter. Considering mating models that include unions between sibs, first cousins, and
th cousins, we determine the effect of the consanguinity rate on the mean Formula: see text for pairs of lineages sampled either within the same individual or in different individuals. The results indicate that consanguinity not only increases ROH sharing between the two genomes within an individual, it also increases IBD sharing between individuals in the population, the magnitude of the effect increasing with the kinship coefficient of the type of consanguineous union. Considering computations of ROH and between-individual IBD in Jewish populations whose consanguinity rates have been estimated from demographic data, we find that, in accord with the theoretical results, increases in consanguinity and ROH levels inflate levels of IBD sharing between individuals in a population. The results contribute more generally to the interpretation of runs of homozygosity, IBD sharing between individuals, and the relationship between ROH and IBD.
Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2hiCD5⁺CD81⁺ pDC subset, distinguished by prominent dendrites and a mature ...phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34⁺ progenitors. These CD2hiCD5⁺CD81⁺ cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5⁺CD81⁺ pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5⁻CD81⁻ pDCs, human CD5⁺CD81⁺ pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.
Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic ...organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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