3,540 research outputs found
A Transgenic Mouse Model of Merkel Cell Virus Small Tumor Antigen
No full textMerkel cell carcinoma (MCC), a primary cutaneous neoplasm, originates in the mechanoreceptor Merkel cells in the basal layer of the epidermis. Risk factors include UV exposure, advanced age and immunosuppression, suggesting an infectious etiology. MCC
incidence in the US is rising, with approximately 1500 cases per year. The non-enveloped, double-stranded DNA Merkel cell polyomavirus (MCV) is responsible for approximately 80% of MCC cases. The virus was discovered by subjecting MCC tissue samples to digital transcriptome subtraction, in which mRNA is isolated, the human transcripts subtracted in silico and the remaining transcripts compared to viral sequences.
MCV expresses differentially spliced Large (LT), Small (sT) and 57 kT tumor antigens from the T antigen early locus, similar to other polyomaviruses such as SV40. Both LT and sT are critical for transformation. LT is a helicase responsible for replication of the viral genome, however in integrated viral genomes it is either truncated or mutated to eliminate its replicative functions. sT contributes to transformation via hyperphosphorylation and inhibition of the cap-dependent translation inhibitor 4E-BP1. The function of 57 kT remains unknown. Knockdown of LT induces necroptosis of MCVpositive MCC cells, whereas sT expression in rodent Rat-1 cells is transformative.
Being that sT is the transformative agent in rodent cells, it would be of interest to develop a mouse model expressing sT in a tissue-specific manner to determine whether tumor formation occurs. Indeed, several mouse models of SV40 T antigen have been developed over the past decades, each resulting in tissue-specific tumor formation. We developed a MCV sT transgenic mouse model, in which a lox-stop-lox sT is expressed via an ER-inducible Cre gene under the control of the ubiquitin promoter. Upon tamoxifen induced MCV sT expression, ER-Cre-positive mice demonstrate severe weight loss, ruffled fur and a hunched posture, necessitating euthanasia. Western blotting reveals sT expression in several tissues, whereas TUNEL staining shows significant cell death. While
we were unable to observe transformation, we believe this drastic phenotype demonstrates the validity of our MCV sT transgenic mouse model and warrants further investigation into the mechanism of death
FGFRL1 is a neglected putative actor of the FGF signalling pathway present in all major metazoan phyla
No full textAssociation pour la Recherche contre le Cancer, Centre National de la Recherche Scientifique, the European Molecular Biology Organization, and the Cascade network of excellence in the 6th Framework Programme for financial support. The laboratory of HE is supported by the Cascade EU Network of Excellence and Agence Nationale de la Recherche. The laboratory of JGF is supported by BMC2008-03776 (Ministerio de Educación y Ciencia). IS' postdoctoral position was supported by a CNRS fellowship. SB's postdoctoral position was supported by an ARC fellowship.Background: Fibroblast Growth Factors (FGF) and their receptors are well known for having major implications in cell signalling controlling embryonic development. Recently, a gene coding for a protein closely related to FGFRs (Fibroblast Growth Factor Receptors) called FGFR5 or FGFR-like 1 (FGFRL1), has been described in vertebrates. An orthologous gene was also found in the cephalochordate amphioxus, but no orthologous genes were found by the authors in other non-vertebrate species, even if a FGFRL1 gene was identified in the sea urchin genome, as well as a closely related gene, named nou-darake, in the planarian Dugesia japonica. These intriguing data of a deuterostome-specific gene that might be implicated in FGF signalling prompted us to search for putative FGFRL1 orthologues in the completely sequenced genomes of metazoans. Results: We found FGFRL1 genes in the cnidarian Nematostella vectensis as well as in many bilaterian species. Our analysis also shows that FGFRL1 orthologous genes are linked in the genome with other members of the FGF signalling pathway from cnidarians to bilaterians (distance < 10 Mb). To better understand the implication of FGFRL1 genes in chordate embryonic development, we have analyzed expression patterns of the amphioxus and the mouse genes by whole mount in situ hybridization. We show that some homologous expression territories can be defined, and we propose that FGFRL1 and FGF8/17/18 were already co-expressed in the pharyngeal endoderm in the ancestor of chordates. Conclusion: Our work sheds light on the existence of a putative FGF signalling pathway actor present in the ancestor of probably all metazoans, the function of which has received little attention until now.Peer reviewe
Lineage-specific evolution of the vertebrate Otopetrin gene family revealed by comparative genomic analyses
No full textGrupo de trabajo: NISC Comparative Sequencing Program. -- 18 páginas, 6 figuras, 2 tablas.[Background]: Mutations in the Otopetrin 1 gene (Otop1) in mice and fish produce an unusual bilateral vestibular pathology that involves the absence of otoconia without hearing impairment. The encoded protein, Otop1, is the only functionally characterized member of the Otopetrin Domain Protein (ODP) family; the extended sequence and structural preservation of ODP proteins in metazoans suggest a conserved functional role. Here, we use the tools of sequence- and cytogenetic-based comparative genomics to study the Otop1 and the Otop2-Otop3 genes and to establish their genomic context in 25 vertebrates. We extend our evolutionary study to include the gene mutated in Usher syndrome (USH) subtype 1G (Ush1g), both because of the head-to-tail clustering of Ush1g with Otop2 and because Otop1 and Ush1g mutations result in inner ear phenotypes.[Results]: We established that OTOP1 is the boundary gene of an inversion polymorphism on human chromosome 4p16 that originated in the common human-chimpanzee lineage more than 6 million years ago. Other lineagespecific evolutionary events included a three-fold expansion of the Otop genes in Xenopus tropicalis and of Ush1g in teleostei fish. The tight physical linkage between Otop2 and Ush1g is conserved in all vertebrates. To further understand the functional organization of the Ushg1-Otop2 locus, we deduced a putative map of binding sites for CCCTC-binding factor (CTCF), a mammalian insulator transcription factor, from genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) data in mouse and human embryonic stem (ES) cells combined with detection of CTCF-binding motifs.[Conclusions]: The results presented here clarify the evolutionary history of the vertebrate Otop and Ush1g families, and establish a framework for studying the possible interaction(s) of Ush1g and Otop in developmental pathways.This work was supported by the NHGRI Intramural Research Program, NIDCD grant DC02236 (DMO); and NHGRI grants HG002385 and HG0058815 (EEE). EEE is an investigator of the Howard Hughes Medical Institute.Peer Reviewe
Entanglement and quantity in quantum space - About quantum measurement (II)
No full textAs a continuation and extension of "quantity in phase space" "quantity in quantum space" is introduced. With that, the disappearing of quantum interference discussed in a previous paper [S. Durr, et al., Nature 395 (1998) 33] is explained in the same spirit as our recent papers [Ren De-Ming, Commun. Theor. Phys. (Beijing, China) 41 (2004) 685, 833].Physics, MultidisciplinarySCI(E)中国科学引文数据库(CSCD)1ARTICLE133-364
Sneutrino DM in the NMSSM with inverse seesaw mechanism
No full textIn supersymmetric theories like the Next-to-Minimal Supersymmetric Standard Model (NMSSM), the lightest neutralino with bino or singlino as its dominant component is customarily taken as dark matter (DM) candidate. Since light Higgsinos favored by naturalness can strength the couplings of the DM and thus enhance the DM-nucleon scattering rate, the tension between naturalness and DM direct detection results becomes more and more acute with the improved experimental sensitivity. In this work, we extend the NMSSM by inverse seesaw mechanism to generate neutrino mass, and show that in certain parameter space the lightest sneutrino may act as a viable DM candidate, i.e. it can annihilate by multi-channels to get correct relic density and meanwhile satisfy all experimental constraints. The most striking feature of the extension is that the DM-nucleon scattering rate can be naturally below its current experimental bounds regardless of the higgsino mass, and hence it alleviates the tension between naturalness and DM experiments. Other interesting features include that the Higgs phenomenology becomes much richer than that of the original NMSSM due to the relaxed constraints from DM physics and also due to the presence of extra neutrinos, and that the signatures of sparticles at colliders are quite different from those with neutralino as DM candidate.National Natural Science Foundation of China (NNSFC) [11575053]SCI(E)ARTICLE1
Classical mechanics and quantum mechanics
No full textThe Newton equation of motion is derived from quantum mechanics.Physics, MultidisciplinarySCI(E)中国科学引文数据库(CSCD)2ARTICLE5685-6884
Policy-driven Data Sharing over Attribute-Based Encryption supporting Dual Membership
No full textAttribute-Based Encryption (ABE) plays an important role in current secure data sharing through fine-grained customizable policies. However, the existing ABE schemes only support simple predicates, = and ≠, but cannot express a more general membership predicates, ∈ and ∉, in policies. The low expressivity of ABE will enlarge the ciphertext storage and reduce the communication efficiency. To overcome this problem, we propose an ABE supporting Dual Membership (DM-ABE). The core problem for implementing this scheme is how to use cryptographic methods to decide the membership between the verified element and the given set. In order to solve this problem, we design a cryptographic algorithm, called Secure Decision of Membership (SDM), based on aggregation functions. In this algorithm, any set can be aggregated into one cryptographic element, and the verified element and the given set can be converted into another cryptographic element in decision process. The membership between them can be decided by the above two cryptographic elements. Furthermore, we construct the DM-ABE by using SDM. Because of the good expressivity of our DM-ABE, we further propose a novel cryptographic data sharing framework by integrating DM-ABE and attribute-based access control to provide fine-grained access control and security protection for private data. In the security proof of DM-ABE, we prove that the DM-ABE satisfies the semantic security against chosen-plaintext attacks under the DBDHE assumption in the standard model through a unified way, considering both two encryption methods for ∈ and ∉ at the same time. Finally, we analyze our scheme in terms of time and space complexity, and compare it with some existing schemes. The results show that our DM-ABE has a better expressive ability on the boolean logic of general membership predicates, ∈ and ∉.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Cyber Securit
Constraining the Inner Galactic DM Density Profile with H.E.S.S.
No full text© 2024 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).In this short review, corresponding to a talk given at the conference “Cosmology 2023 in Miramare”, we combine an analysis of five regions observed by H.E.S.S. in the Galactic Center, intending to constrain the Dark Matter (DM) density profile in a WIMP annihilation scenario. For the analysis, we include the state-of-the-art Galactic diffuse emission Gamma-optimized model computed with DRAGON and a wide range of DM density profiles from cored to cuspy profiles, including different kinds of DM spikes. Our results are able to constrain generalized NFW profiles with an inner slope ≳1.3 . When considering DM spikes, the adiabatic spike is completely ruled out. However, smoother spikes given by the interactions with the bulge stars are compatible if ≲0.8 , with an internal slope of sp-stars=1.5.This work has been supported by the grants PID2021-125331NB-I00, PID2022-139841NB-I00, and CEX2020-001007-S, funded by MCIN/AEI/10.13039/501100011033, by “ERDF A way of making Europe”, and the MULTIDARK Project RED2022-134411-T. The author’s contribution to this work has been supported by the FPI Severo Ochoa PRE2021-099137 grant.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2020-001007-S).Peer reviewe
Diabetes mellitus (DM) related lower extremity amputations (LEA) rate and risk factors.
No full textAuthor: Ieva Vasiliūtė Title: Diabetes mellitus (DM) related lower extremity amputations (LEA) rate and risk factors. Aim: To investigate LEA rate and risk factors in patients with DM. Objectives: To evaluate DM related LEA rate. To determine DM related LEAs levels and patients demographic factors relation. To determine DM related LEAs levels and type of DM relation. To determine DM related LEAs levels and DM duration, body mass index (BMI), glycated hemoglobin (HbA1c) meanings relation. To evaluate expected mathematically based risk factors. Methods: Retrospective medical records study of 153 patients with DM, who underwent LEAs at the Hospital of Lithuanian University of Health Sciences Kaunas clinics was performed during the 2012 01 01 – 2014 12 31 period. Statistical analysis was performed using the standard SPSS 20.0 program. Results: 33,33% of legs amputations occured among people with DM and 66,67% of them were male (p<0,001). Major LEAs were performed mostly in patients with type 2 DM (86,96%) than those with type 1 DM (p<0,001). Male patients LEAs were performed in patients suffering for shorter duration of DM than in women (19,18 m. (±95% PI 16,71-21,65) vs. 23,36 m. (±95% PI 20,07-26,65), p=0,053). Patients with type 2 DM underwent LEAs had DM for shorter durations (16,19 m. (±95% PI 14,32-18,06)) than those with type 1 DM patients (31,43 m. (±95% PI 28,40-34,45)) ( p<0,001). Major LEAs remove patients had BMI (32,86±5,55 kg/m2) than minor LEAs remove patients (29,13±5,91 kg/m2) (p=0,027). No significant relation was found with amputation level and HbA1c average (p=0,246). DM related eye damage increases the risk of minor LEAs 3,10 times (p=0,001). Obesity/overweight the risk of major LEAs increases 5,65 times (p=0,036) and 2,56 times with obliterate atherosclerosis (p=0,006). Patients with type 2 DM have a 3,2 times (p=0,002) higher risk of undergoing major LEA. Conclusions: A third of patients who had undergone LEAs had DM. Amputations were carried out more frequently in men. DKA arose more often in patients with type 2 DM. LEAs were performed a shorter duration male DM patients. Type 2 DM patients suffered LEAs nearly 2 times shorter duration. Major LEAs experienced patients had a higher BMI. The average of HbA1c is not significantly related with amputation levels. DM related eye damage increases the minor LEAs risk by 3,10 times. Obesity/being overweight increases the risk of major LEAs 5,65 times, obliterate atherosclerosis - 2,56 times. Patients with type 2 DM have a 3,2 times higher risk of major LEA
Approaches for Dialog Management in Conversational Agents
No full textDialog agents, like digital assistants and automated chat interfaces (e.g., chatbots), are becoming more and more popular as users adapt to conversing with their devices as they do with humans. In this paper, we present approaches and available tools for dialog management (DM), a component of dialog agents that handles dialog context and decides the next action for the agent to take. In this paper, we establish an overview of the field of DM, compare approaches and state-of-the-art tools in industry and research work on a set of dimensions, and identify directions for further research work.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Web Information SystemsHuman-Centred Artificial Intelligenc
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