Traditional polyetherimides (PEIs) are commonly synthesized from an aromatic diamine and an aromatic dianhydride (e.g., 3,4′-oxidianiline (ODA) and 4,4′-oxidiphtalic anhydride (ODPA)) leading to the ...imide linkage and outstanding chemical, thermal and mechanical properties yet lacking any self-healing functionality. In this work, we have replaced the traditional aromatic diamine by a branched aliphatic fatty dimer diamine (DD1). This led to a whole family of self-healing polymers not containing reversible chemical bonds, capable of healing at (near) room temperature yet maintaining very high elastomeric-like mechanical properties (up to 6 MPa stress and 570% strain at break). In this work, we present the effect of the DD1/ODPA ratio on the general performance and healing behavior of a room temperature healing polyetherimide. A dedicated analysis suggests that healing proceeds in three steps: (i) an initial adhesive step leading to the formation of a relatively weak interface; (ii) a second step at long healing times leading to the formation of an interphase with different properties than the bulk material and (iii) disappearance of the damaged zone leading to full healing. We argue that the fast interfacial adhesive step is due to van der Waals interactions of long dangling alkyl chains followed by an interphase formation due to polymer chain interdiffusion. An increase in DD1/ODPA ratio leads to an increase in the healing kinetics and displacement shift of the first healing step toward lower temperatures. An excess of DD1 leads to the cross-linking of the polymer thereby restricting the necessary mobility for the interphase formation and limiting the self-healing behavior. The results here presented offer a new route for the development of room temperature self-healing thermoplastic elastomers with improved mechanical properties using fatty dimer diamines.
Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. ...Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics.
MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab high tumor mutational burden (TMB). The primary endpoint is the objective response rate (ORR).
As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred.
Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.
•Pertuzumab + trastuzumab produced a response in 60% (9/15) of patients with HER2-amplified/overexpressing salivary cancer.•Stable disease was observed in a patient with HER2-mutated salivary cancer treated with pertuzumab + trastuzumab.•Vismodegib, vemurafenib, and atezolizumab produced responses in salivary tumors with matched genomic alterations.•Safety for each treatment was consistent with previously reported safety profiles.•Results support use of molecular profiling to identify effective chemotherapy-free targeted treatments for salivary cancers.
Dealing With Concept Drifts in Process Mining Bose, R. P. Jagadeesh Chandra; van der Aalst, Wil M. P.; Zliobaite, Indre ...
IEEE transaction on neural networks and learning systems,
2014-Jan., 2014-Jan, 2014-1-00, 20140101, Letnik:
25, Številka:
1
Journal Article
Although most business processes change over time, contemporary process mining techniques tend to analyze these processes as if they are in a steady state. Processes may change suddenly or gradually. ...The drift may be periodic (e.g., because of seasonal influences) or one-of-a-kind (e.g., the effects of new legislation). For the process management, it is crucial to discover and understand such concept drifts in processes. This paper presents a generic framework and specific techniques to detect when a process changes and to localize the parts of the process that have changed. Different features are proposed to characterize relationships among activities. These features are used to discover differences between successive populations. The approach has been implemented as a plug-in of the ProM process mining framework and has been evaluated using both simulated event data exhibiting controlled concept drifts and real-life event data from a Dutch municipality.
The human TERT (hTERT) gene encodes the telomerase catalytic subunit which plays a role in telomerase regulation. Telomerase is activated in more than 90% of all human malignancies and understanding ...how telomerase is regulated is necessary for implementation of successful anti-cancer therapies. microRNAs (miRNAs) are important regulators of gene expression in eukaryotic cells but evidence of their role in telomerase regulation has not been documented. To determine whether hTERT activity is regulated by multiple miRNAs, eight miRNAs which have putative binding sites in the hTERT 3'UTR together with miR-138-5p were evaluated in luciferase assays with a reporter containing the hTERT 3'UTR. Six miRNAs (let-7g*, miR-133a, miR-138-5p, miR-342-5p, miR-491-5p, and miR-541-3p) specifically inhibited the expression of the reporter luciferase-driven constructs and let-7g*, miR-133a, miR-138-5p, and miR-491-5p also downregulated endogenous telomerase activity in cells. Moreover, all six miRNAs significantly inhibited cell proliferation. miRNAs (miR-133a, miR-138-5p, 342-5p, 491-5p, 541-3p) also have predicted binding sites within the 3'UTR of three genes involved in Wnt signaling (TCF7, MSI1, and PAX5). These miRNAs inhibited the expression of the luciferase reporter constructs containing 3'UTRs of these genes and downregulated protein expression of the TCF7 transcription factor, which mediates the canonical Wnt pathway. Together, these results suggest the existence of a miRNA regulatory network involving the hTERT and Wnt pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This manuscript presents the first extensive phylogenetics analysis of a key family of immune regulators, the interferon regulatory factor (IRF) family. The IRF family encodes transcription factors ...that play important roles in immune defense, stress responses, reproduction, development, and carcinogenesis. Several times during their evolution, the IRF genes have undergone expansion and diversification. These genes were also completely lost on two separate occasions in large groups of metazoans. The origin of the IRF family coincides with the appearance of multicellularity in animals. IRF genes are present in all principal metazoan groups, including sea sponges, placozoans, comb jellies, cnidarians, and bilaterians. Although the number of IRF family members does not exceed two in sponges and placozoans, this number reached five in cnidarians. At least four additional independent expansions lead up to 11 members in different groups of bilaterians. In contrast, the IRF genes either disappeared or mutated beyond recognition in roundworms and insects, the two groups that include most of the metazoan species. The IRF family separated very early into two branches ultimately leading to vertebrate IRF1 and IRF4 supergroups (SGs). Genes encoding the IRF-SGs are present in all bilaterians and cnidarians. The evolution of vertebrate IRF family members further proceeded with at least two additional steps. First, close to the appearance of the first vertebrate, the IRF family probably expanded to four family members, predecessors of the four vertebrate IRF groups (IRF1, 3, 4, 5 groups). In the second step, 10 vertebrate family members evolved from these four genes, likely as a result of the 2-fold duplication of the entire genome. Interestingly, the IRF family coevolved with the Rel/NF-κB family with which it shares some important evolutionary characteristics, including roles in defense responses, metazoan specificity, extensive diversification in vertebrates, and elimination of all family members in nematodes.
Amongst environmental chemical contaminants, methylmercury (MeHg) remains a major concern because of its detrimental effects on developing organisms, which appear to be particularly susceptible to ...its toxicity. Here, we investigated the effects of low MeHg levels on the development of the nervous system using both in vitro and in vivo experimental models. In neural stem cells (NSCs), MeHg decreased proliferation and neuronal differentiation and induced cellular senescence associated with impairment in mitochondrial function and a concomitant decrease in global DNA methylation. Interestingly, the effects were heritable and could be observed in daughter NSCs never directly exposed to MeHg. By chronically exposing pregnant/lactating mice to MeHg, we found persistent behavioural changes in the male offspring, which exhibited depression‐like behaviour that could be reversed by chronic treatment with the antidepressant fluoxetine. The behavioural alterations were associated with a decreased number of proliferating cells and lower expression of brain‐derived neurotrophic factor (Bdnf) mRNA in the hippocampal dentate gyrus. MeHg exposure also induced long‐lasting DNA hypermethylation, increased histone H3‐K27 tri‐methylation and decreased H3 acetylation at the Bdnf promoter IV, indicating that epigenetic mechanisms play a critical role in mediating the long‐lasting effects of perinatal exposure to MeHg. Fluoxetine treatment restored the Bdnf mRNA expression levels, as well as the number of proliferating cells in the granule cell layer of the dentate gyrus, which further supports the hypothesis that links depression to impaired neurogenesis. Altogether, our findings have shown that low concentrations of MeHg induce long‐lasting effects in NSCs that can potentially predispose individuals to depression, which we have reported earlier to occur in experimental animals exposed to MeHg during prenatal and early postnatal development.
Past research in the field of cryptography has not given much consideration to arithmetic coding as a feasible encryption technique, with studies proving compression-specific arithmetic coding to be ...largely unsuitable for encryption. Nevertheless, adaptive modeling, which offers a huge model, variable in structure, and as completely as possible a function of the entire text that has been transmitted since the time the model was initialized, is a suitable candidate for a possible encryption-compression combine. The focus of the work presented in this paper has been to incorporate recent results of chaos theory, proven to be cryptographically secure, into arithmetic coding, to devise a convenient method to make the structure of the model unpredictable and variable in nature, and yet to retain, as far as is possible, statistical harmony, so that compression is possible. A chaos-based adaptive arithmetic coding-encryption technique has been designed, developed and tested and its implementation has been discussed. For typical text files, the proposed encoder gives compression between 67.5% and 70.5%, the zeroth-order compression suffering by about 6% due to encryption, and is not susceptible to previously carried out attacks on arithmetic coding algorithms.
Aim: Species distribution modelling typically relies completely or partially on climatic variables as predictors, overlooking the fact that these are themselves predictions with associated ...uncertainties. This is particularly critical when such predictors are interpolated between sparse station data, such as in the tropics. The goal of this study is to provide a new set of satellite-based climatic predictor data and to evaluate its potential to improve modelled species-climate associations and transferability to novel geographical regions. Location: Rain forests areas of Central Africa, the Western Ghats öf India and South America. Methods: We compared models calibrated on the widely used WorldClim stationinterpolated climatic data with models where either temperature or precipitation data from WorldClim were replaced by data from CRU, MODIS, TRMM and CHIRPS. Each predictor set was used to model 451 plant species distributions. To test for chance associations, we devised a null model with which to compare the accuracy metric obtained for every species. Results: Fewer than half of the studied rain forest species distributions matched the climatic pattern better than did random distributions. The inclusion of MODIS temperature and CHIRPS precipitation estimates derived from remote sensing each allowed for a better than random fit for respectively 40% and 22% more species than models calibrated on WorldClim. Furthermore, their inclusion was positively related to a better transferability of models to novel regions. Main conclusions: We provide a newly assembled dataset of ecologically meaningful variables derived from MODIS and CHIRPS for download, and provide a basis for choosing among the plethora of available climate datasets. We emphasize the need to consider the method used in the production of climate data when working on a region with sparse meteorological station data. In this context, remote sensing data should be the preferred choice, particularly when model transferability to novel climates or inferences on causality are invoked.
XL-Calibur is a hard X-ray (15-80 keV) polarimetry mission operating from a stabilised balloon-borne platform in the stratosphere. It builds on heritage from the X-Calibur mission, which observed the ...accreting neutron star GX 301 - 2 from Antarctica, between December 29th 2018 and January 1st 2019. The XL-Calibur design incorporates an X-ray mirror, which focusses X-rays onto a polarimeter comprising a beryllium rod surrounded by Cadmium Zinc Telluride (CZT) detectors. The polarimeter is housed in an anticoincidence shield to mitigate background from particles present in the stratosphere. The mirror and polarimeter-shield assembly are mounted at opposite ends of a 12 m long lightweight truss, which is pointed with arcsecond precision by WASP – the Wallops Arc Second Pointer. The XL-Calibur mission will achieve a substantially improved sensitivity over X-Calibur by using a larger effective area X-ray mirror, reducing background through thinner CZT detectors, and improved anticoincidence shielding. When observing a 1 Crab source for tdaydays, the Minimum Detectable Polarisation (at 99% confidence level) is ∼2%·tday−1/2. The energy resolution at 40 keV is ∼5.9 keV. The aim of this paper is to describe the design and performance of the XL-Caliburmission, as well as the foreseen science programme.
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