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Rabies, caused by the rabies virus (RABV), remains a significant public health issue in the Philippines despite efforts to control it. To eliminate rabies by 2030, effective surveillance strategies are crucial. In this study, we examined RABV evolution and phylodynamics in the Davao Region using genome sequences from Davao City and nearby provinces. We adapted the RABV ARTIC Protocol for Oxford Nanopore High-Throughput Sequencing to optimize workflow efficiency under limited resources. Comparing new virus samples collected from June 2019 to June 2021 (n = 38) with baseline samples from June 2018 to May 2019 (n = 49), new sub-clades were observed in the phylogenetic tree, suggesting divergence from older variants that were previously undetected. Most of the new viruses belonged to the Asian SEA4_A1.1.1 lineage, but new (SEA4_B1 and SEA4_B1.1) and emerging (SEA4_B1.1_E1) lineages that have never been reported in the Philippines were also identified. The baseline study reported phylogeographic clustering of RABV isolates from the same areas. However, this pattern was disrupted in the current biosurveillance, with variants detected in areas outside the original cluster. Furthermore, our findings revealed significant transmission routes between Davao City and neighboring provinces, contrasting with the predominantly intra-city transmission observed in the baseline study. These results underscore the need for ongoing and timely genomic surveillance to monitor genetic diversity changes and the emergence of novel strains, as well as to track alterations in transmission pathways. Implementing cost-effective next-generation sequencing workflows will facilitate the integration of genomic surveillance into rabies control programs, particularly in resource-limited settings. Collaborations between different sectors can empower local laboratories and experts in genomic technologies and analysis.

Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro , E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro . Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin.

This paper presents a time-sequential probabilistic simulation model for the detailed design of maintenance strategies for turbine critical items. The term item shall refer to any part, component, device, subsystem, or functional unit of a wind turbine that can be individually described and considered. The model enables wind farm operators and turbine manufactures to find the most cost-effective maintenance strategy for each turbine critical item. Cost optimizations are realized through a better adaptation of the maintenance strategy to the item-specific failure modes, degradation processes, failure detection capabilities and the given operational configuration of the wind farm. Based on a time-sequential Monte Carlo simulation technique, the maintenance activities at turbine level are simulated over the windfarm’s operational lifetime, considering correlations between the stochastic variables. The results of the Monte Carlo simulation are evaluated using statistical means, thereby, determining the optimal maintenance strategy and associated parameters. The developed model is implemented as a Python application and equally applicable for onshore and offshore windfarms.

Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo . Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.

Because our in silico analysis with a human transcription factor database demonstrated the presence of several binding sites for NF-κB, a central regulator of cellular immune and inflammatory responses, in the adeno-associated virus (AAV) genome, we investigated whether AAV uses NF-κB during its life cycle. We used small molecule modulators of NF-κB in HeLa cells transduced with recombinant AAV vectors. VP16, an NF-κB activator, augmented AAV vector-mediated transgene expression up to 25-fold. Of the two NF-κB inhibitors, Bay11, which blocks both the canonical and the alternative NF-κB pathways, totally ablated transgene expression, whereas pyrrolidone dithiocarbamate, which interferes with the classical NF-κB pathway, had no effect. Western blot analyses confirmed the abundance of the nuclear p52 protein component of the alternative NF-κB pathway in the presence of VP16, which was ablated by Bay11, suggesting that AAV transduction activates the alternative NF-κB pathway. In vivo, hepatic AAV gene transfer activated the canonical NF-κB pathway within 2 h, resulting in expression of proinflammatory cytokines and chemokines (likely reflecting the sensing of viral particles by antigen-presenting cells), whereas the alternative pathway was activated by 9 h. Bay11 effectively blocked activation of both pathways without interfering with long-term transgene expression while eliminating proinflammatory cytokine expression. These studies suggest that transient immunosuppression with NF-κB inhibitors before transduction with AAV vectors should lead to a dampened immune response, which has significant implications in the optimal use of AAV vectors in human gene therapy.

Currently new competitive environment and fundamental changes in the traditional industries are taking place. The digital transformation of companies can be an effective tool to gain a competitive advantage, but its success requires consistent actions, from the strategic vision to implementation. New architectural solutions are needed to ensure a strategic alignment of business and IT architecture for further successful development. The purpose of this research paper is to develop a conceptual approach and method of Enterprise Architecture modeling for global container shipping lines, allowing the companies an effective development in the context of global changes in business forms and methods, reducing negative impacts and taking advantage arising from these changes.

Maritime Autonomous Surface Ships (MASS) do require shifting from human information processing to automation functions. While supporting the sensory processing of human navigation by automated information acquisition from different sensors is an already established (and even in many cases mandatory) technology with a set of framing standards and information exchanges, defining a common data set for a perceived environment model is currently neglected which hinders modularization of MASS technology development. Beginning with an introduction into the navigational process as well as information processing, this paper subsequently proposes an initial minimum data set for different aspects of ship navigation.

While rapamycin and the \"rapalogs\" Everolimus and Temsirolimus have been approved for clinical use in the treatment of a number of forms of cancer, they have not met overarching success. Some tumors are largely refractory to rapamycin treatment, with some even undergoing an increase in growth rates. However the mechanisms by which this occurs are largely unknown. The results presented here reveal novel cell-signaling mechanisms that may lead to this resistance. The absence of TGFβ signaling results in resistance to rapamycin. Additionally, we observed that treatment of some cancer cell lines with rapamycin and its analogs not only potentiates mitogenic signaling and proliferation induced by HGF, but also stimulates the pro-survival kinase Akt. Together, the data show that the effectiveness of rapamycin treatment can be influenced by a number of factors and bring to light potential biomarkers for the prediction of responsiveness to treatment, and suggest combination therapies to optimize rapalog anticancer efficacy.

Vessel groundings pose a major risk for maritime safety, constituting 20 percent of all incidents in the last decade. Frequent dredging and bottom mapping are resource intensive solutions currently employed, but these services cannot be maintained with the necessary frequency in all critical areas. While ships are carrying echo sounders to acquire precise and current under keel clearance data, it does not allow the vessel to react to possible deviations from the map data. Within the RoboVaaS project, a service is designed, implemented and tested in simulation. This service consists of one or more small MASS travelling ahead of a merchant vessel, collecting bathymetric data with enough lead time for the merchant vessel to react to possible threats, e.g. by course correction. This service is tested in compliance with the IMO HCD guideline in a quick approach and safe environment using a ship handling simulator. The simulator is augmented by a display system based on an ECDIS map and displaying the bathymetric data in three different scenarios. These scenarios are tested with nautical officers to collect feedback for service design and implementation with trained personnel and show the effectiveness of the chosen human machine interface.

The transposon-like elements TBE1, Tec1, and Tec2 of hypotrichous ciliated protozoa appear to encode a protein that belongs to the IS630-Tc1 family of transposases. The Anabaena IS895 transposase also is placed in this family. We note that most family members transpose into the dinucleotide target, TA, and that members with eukaryotic hosts have a tendency for somatic excision that is carried to an extreme by the ciliate elements. Alignments including the additional members, and also mariner elements, show that transposases of this family share strongly conserved residues in a large C-terminal portion, including a fully conserved dipeptide, Asp-Glu (DE), and a block consisting of a fully conserved Asp and highly conserved Glu, separated by 34 or 35 residues (D35E). This D35E motif likely is homologous to the previously characterized D35E motif of the family of retroviral-retrotransposon integrases and IS3-like transposases. Because it is known that the IS3-retroposon D35E region is a critical portion of a domain capable of various in vitro transposition-related reactions, the results suggest that the two families share homologous catalytic transposase domains and that members of both families may share a common transposition mechanism.