Children’s tolerance of word-form variation

How much morphological variation can children tolerate when identifying familiar words? This is an important question in the context of the acquisition of richly inflected languages where identical word forms occur far less frequently than in English. To address this question, we compared children’s (N = 96, mean age 4;1, range 2;11–5;1) and adults’ (N = 96, mean age 21 years) tolerance of word-onset modifications (e.g., for stug: wug and wastug) and pseudoaffixes (e.g., kostug and stugko) in a labelextension task. Word-form modifications were repeated within each experiment to establish productive inflectional patterns. In two experiments, children and adults exhibited similar strategies: they were more tolerant of prefixes (wastug) than substitutions of initial consonants (wug), and more tolerant of suffixes (stugko) than prefixes (kostug). The findings point to word-learning strategies as being flexible and adaptive to morphological patterns in languages

A distributed approach for parameter estimation in Systems Biology models

Due to the lack of experimental measurements, biological variability and experimental errors, the value of many parameters of the systems biology Mathematical models is yet unknown or uncertain. A possible computational solution is the parameter estimation, that is the identification of the parameter values that determine the best model fitting respect to experimental data. We have developed an environment to distribute each run of the parameter estimation algorithm on a different computational resource. The key feature of the implementation is a relational database that allows the user to swap the candidate solutions among the working nodes during the computations. The comparison of the distributed implementation with the parallel one showed that the presented approach enables a faster and better parameter estimation of systems biology models

Understanding stochastic perturbation theory: toy models and statistical analysis

The numerical stochastic perturbation method based on Parisi-Wu quantisationis applied to a suite of simple models to test its validity at high orders.Large deviations from normal distribution for the basic estimators aresystematically found in all cases (``Pepe effect''). As a consequence oneshould be very careful in estimating statistical errors. We present someresults obtained on Weingarten's ``pathological'' model where reliable resultscan be obtained by an application of the bootstrap method. We also present someevidence that in the far less trivial application to Lattice Gauge Theory asimilar problem should not arise at moderately high loops (up toO(\alpha^{10}))

Multiple effects of CDK4/6 inhibition in cancer: From cell cycle arrest to immunomodulation

Dysregulation of the cell cycle is a hallmark of cancer that leads to aberrant cellular proliferation. CDK4/6 are cyclin-dependent kinases activated in response to proliferative signaling, which induce RB hyper-phosphorylation and hence activation of E2F transcription factors, thus promoting cell cycle progression through the S phase. Pharmacologic inhibition of CDK4/6 by palbociclib, ribociclib, or abemaciclib has been showing promising activity in multiple cancers with the best results achieved in combination with other agents. Indeed, CDK4/6 inhibitors are currently approved in combination with endocrine therapy for the treatment of estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. Moreover, a number of clinical trials are currently underway to test the efficacy of combining CDK4/6 inhibitors with different drugs not only in breast but also in other types of cancer. Beyond the inhibition of cell proliferation, CDK4/6 inhibitors have recently revealed new effects on cancer cells and on tumor microenvironment. In particular, it has been reported that these agents induce a senescent-like phenotype, impact on cell metabolism and exert both immunomodulatory and immunogenic effects. Here we describe recent data on the anti-tumor effects of CDK4/6 inhibitors as single agents or in combined therapies, focusing in particular on their metabolic and immunomodulatory activities

Efficient Circulation of Railway Rolling Stock

Railway rolling stock (locomotives, carriages, and train units) is oneof the most significant cost sources for operatorsof passenger trains,both public and private. Rolling stock costsare due to materialacquisition, power supply, and material maintenance. The efficientcirculation of rolling stock material is therefore one of theobjectives pursued. In this paper we focus on the circulation of trainunits on a single line. In order to utilize the train units on thisline in an efficient way, they are added to or removed from the trainsin certain stations, according to the passengers' seat demand. Sinceadding and removing train units has to respect specific rules, it isimportant to know the exact order of the train units in the trains.This aspect strongly increases the complexity of the rolling stockcirculation problem. In this paper we present aninteger programmingapproach to solve this problem. We also apply this approach to a reallife case study based on the 2001-2002 timetable of NS Reizigers, themajor Dutch operator of passenger trains.logistics;operations research;public transportation;railways;rolling stock circulation

GridCertLib: a Single Sign-on Solution for Grid Web Applications and Portals

This paper describes the design and implementation of GridCertLib, a Java library leveraging a Shibboleth-based authentication infrastructure and the SLCS online certificate signing service, to provide short-lived X.509 certificates and Grid proxies. The main use case envisioned for GridCertLib, is to provide seamless and secure access to Grid/X.509 certificates and proxies in web applications and portals: when a user logs in to the portal using Shibboleth authentication, GridCertLib can automatically obtain a Grid/X.509 certificate from the SLCS service and generate a VOMS proxy from it. We give an overview of the architecture of GridCertLib and briefly describe its programming model. Its application to some deployment scenarios is outlined, as well as a report on practical experience integrating GridCertLib into portals for Bioinformatics and Computational Chemistry applications, based on the popular P-GRADE and Django softwares.Comment: 18 pages, 1 figure; final manuscript accepted for publication by the "Journal of Grid Computing

“Salus Populi Suprema Lex”: Considerations on the Initial Response of the United Kingdom to the SARS-CoV-2 Pandemic

In several countries worldwide, the initial response to coronavirus disease 2019 (COVID-19) has been heavily criticized by general public, media, and healthcare professionals, as well as being an acrimonious topic in the political debate. The present article elaborates on some aspects of the United Kingdom (UK) primary reaction to SARS-CoV-2 pandemic; specifically, from February to July 2020. The fact that the UK showed the highest mortality rate in Western Europe following the first wave of COVID-19 certainly has many contributing causes; each deserves an accurate analysis. We focused on three specific points that have been insofar not fully discussed in the UK and not very well known outside the British border: clinical governance, access to hospital care or intensive care unit, and implementation of non-pharmaceutical interventions. The considerations herein presented on these fundamental matters will likely contribute to a wider and positive discussion on public health, in the context of an unprecedented crisis

Structure of a nucleosome-bound MuvB transcription factor complex reveals DNA remodelling.

Genes encoding the core cell cycle machinery are transcriptionally regulated by the MuvB family of protein complexes in a cell cycle-specific manner. Complexes of MuvB with the transcription factors B-MYB and FOXM1 activate mitotic genes during cell proliferation. The mechanisms of transcriptional regulation by these complexes are still poorly characterised. Here, we combine biochemical analysis and in vitro reconstitution, with structural analysis by cryo-electron microscopy and cross-linking mass spectrometry, to functionally examine these complexes. We find that the MuvB:B-MYB complex binds and remodels nucleosomes, thereby exposing nucleosomal DNA. This remodelling activity is supported by B-MYB which directly binds the remodelled DNA. Given the remodelling activity on the nucleosome, we propose that the MuvB:B-MYB complex functions as a pioneer transcription factor complex. In this work, we rationalise prior biochemical and cellular studies and provide a molecular framework of interactions on a protein complex that is key for cell cycle regulation