1,721,231 research outputs found
The pro-autophagic protein AMBRA1 coordinates cell cycle progression by regulating CCND (cyclin D) stability
No full textThe scaffold protein AMBRA1 regulates the early steps of autophagosome
formation and cell growth, and its deficiency is associated with
neurodevelopmental defects and cancer. In a recent study, we show that
AMBRA1 is a key factor in the upstream branch of the MYCN-MYC and
CDK4-CDK6-dependent regulation of G1/S phase transition. Indeed, in the
developing neuroepithelium, in neural stem cells, and in cancer cells,
we demonstrate that AMBRA1 regulates the expression of D-type cyclins by
controlling both their proteasomal degradation and their
MYCN-MYC-mediated transcription. Also, we show that this regulation axis
maintains genome integrity during DNA replication, and we identify a
possible line of treatment for tumors downregulating AMBRA1 and/or
overexpressing CCND1 (cyclin D1), by demonstrating that AMBRA1-depleted
cells carry an AMBRA1-loss-specific lethal sensitivity to CHEK1
inhibition. Interestingly, we show that this aspect is specific for
AMBRA1 loss, because ATG7 knockdown does not display the same response
to CHEK1 inhibitors. Hence, our findings underscore that the
AMBRA1-CCND1 pathway represents a novel crucial mechanism of cell cycle
regulation, deeply interconnected with genomic stability in development
and cancer
Cyclers' kinases in cell division: from molecules to cancer therapy
No full textFaithful eucaryotic cell division requires spatio-temporal orchestration
of multiple sequential events. To ensure the dynamic nature of these
molecular and morphological transitions, a swift modulation of key
regulatory pathways is necessary. The molecular process that most
certainly fits this description is phosphorylation, the
post-translational modification provided by kinases, that is crucial to
allowing the progression of the cell cycle and that culminates with the
separation of two identical daughter cells. In detail, from the early
stages of the interphase to the cytokinesis, each critical step of this
process is tightly regulated by multiple families of kinases including
the Cyclin-dependent kinases (CDKs), kinases of the Aurora, Polo, Wee1
families, and many others. While cell-cycle-related CDKs control the
timing of the different phases, preventing replication machinery errors,
the latter modulate the centrosome cycle and the spindle function,
avoiding karyotypic abnormalities typical of chromosome instability.
Such chromosomal abnormalities may result from replication stress (RS)
and chromosome mis-segregation and are considered a hallmark of poor
prognosis, therapeutic resistance, and metastasis in cancer patients.
Here, we discuss recent advances in the understanding of how different
families of kinases concur to govern cell cycle, preventing RS and
mitotic infidelity. Additionally, considering the growing number of
clinical trials targeting these molecules, we review to what extent and
in which tumor context cell-cycle-related kinases inhibitors are worth
exploiting as an effective therapeutic strategy
Doryphagy: when selective autophagy safeguards centrosome integrity
Full text linkAlthough centrosome abnormalities are frequent in cancer, the mechanisms responsible for their accumulation are poorly understood. Here we comment on our recent publication identifying a new type of selective autophagy, named doryphagy, which preserves centrosome organization through targeting Centriolar Satellites (CS). Thus, doryphagy prevents inaccurate mitosis and genomic instability
A gene toolbox for monitoring autophagy transcription
Full text linkAutophagy is a highly dynamic and multi-step process, regulated by many
functional protein units. Here, we have built up a comprehensive and
up-to-date annotated gene list for the autophagy pathway, by combining
previously published gene lists and the most recent publications in the
field. We identified 604 genes and created main categories: MTOR and
upstream pathways, autophagy core, autophagy transcription factors,
mitophagy, docking and fusion, lysosome and lysosome-related genes. We
then classified such genes in sub-groups, based on their functions or on
their sub-cellular localization. Moreover, we have curated two shorter
sub-lists to predict the extent of autophagy activation and/or lysosomal
biogenesis; we next validated the ``induction list{''} by Real-time PCR
in cell lines during fasting or MTOR inhibition, identifying ATG14,
ATG7, NBR1, ULK1, ULK2, and WDR45, as minimal transcriptional targets.
We also demonstrated that our list of autophagy genes can be
particularly useful during an effective RNA-sequencing analysis. Thus,
we propose our lists as a useful toolbox for performing an informative
and functionally-prognostic gene scan of autophagy steps
AMuSE-WSD: an all-in-one multilingual system for easy word sense disambiguation
Full text linkOver the past few years, Word Sense Disambiguation (WSD) has received renewed interest: recently proposed systems have shown the remarkable effectiveness of deep learning techniques in this task, especially when aided by modern pretrained language models. Unfortunately, such systems are still not available as ready-to-use end-to-end packages, making it difficult for researchers to take advantage of their performance. The only alternative for a user interested in applying WSD to downstream tasks is to rely on currently available end-to-end WSD systems, which, however, still rely on graph-based heuristics or non-neural machine learning algorithms. In this paper, we fill this gap and propose AMuSE-WSD, the first end-to-end system to offer high-quality sense information in 40 languages through a state-of-the-art neural model for WSD. We hope that AMuSE-WSD will provide a stepping stone for the integration of meaning into real-world applications and encourage further studies in lexical semantics. AMuSE-WSD is available online at http://nlp.uniroma1.it/amuse-ws
Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency
Full text linkBackgroundAdenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype-phenotype correlations. ResultsData were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years +/- 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years +/- 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense.Conclusions The study adds more details on the spectrum of ADSLD patients' phenotypes and molecular data
InVeRo-XL: Making Cross-Lingual Semantic Role Labeling Accessible with Intelligible Verbs and Roles
Full text linkNotwithstanding the growing interest in cross-lingual techniques for Natural Language Processing, there has been a surprisingly small number of efforts aimed at the development of easy-to-use tools for cross-lingual Semantic Role Labeling. In this paper, we fill this gap and present InVeRo-XL, an off-the-shelf state-of-the-art system capable of annotating text with predicate sense and semantic role labels from 7 predicate-argument structure inventories in more than 40 languages. We hope that our system – with its easy-to-use RESTful API and Web interface – will become a valuable tool for the research community, encouraging the integration of sentence-level semantics into cross-lingual downstream tasks. InVeRo-XL is available online at http://nlp.uniroma1.it/invero
One-dimensional consolidation of unsaturated pyroclastic soils: Theoretical analysis and experimental results
No full textThis paper synthesizes the results of a study aimed at analyzing the one-dimensional consolidation of unsaturated pyroclastic soils from both theoretical and experimental points of view. In order to pursue this goal, the differential equations governing the problem are firstly derived and their set is solved via the use
of the Finite Difference Method. Input data consist of hydraulic and mechanical parameters whereas output data – changing in space and with time – are the settlement, the pore water pressure and the air pressure of the modelled medium. The values of constitutive parameters appearing in the theoretical model are calibrated on the basis of experimental results achieved from laboratory tests carried out, via a suction controlled oedometer, on specimens of unsaturated pyroclastic soils. Considering that consolidation settlements of unsaturated soils are lower than those experienced by the same soils in saturated conditions (changes in boundary conditions being equal), the followed approach – which combines theoretical and experimental results – can be profitably adopted in geotechnical problems in which the quantitative prediction of consolidation settlement values is a requirement of particular concern
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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