EFFECT OF AN INNOVATIVE ISOLATION SYSTEM ON THE SEISMIC RESPONSE OF CULTURAL HERITAGE BUILDING CONTENTS

An experimental study was conducted at the University of Pavia and at the EUCENTRE Foundation (Pavia, Italy) to assess the effectiveness of an innovative seismic isolation device at protecting cultural heritage building contents. The recently patented isolator, named “Kinematic Steel Joint (KSJ)”, is based on a multiple articulated quadrilateral mechanism and is entirely made of steel components obtained by simply cutting, folding, and pinning metal sheets, eventually employing stainless steel to limit corrosion issues. The trajectory imposed by the KSJ isolator to the supported mass combines horizontal with increasing vertical displacements, resulting in a pendulum-type motion with self-centering behavior. The friction developing within the pinned joints can be exploited to grant energy dissipation capacity to the device. The KSJ isolator can be manufactured with different sizes, payloads, and displacement ranges. In fact, seismic isolation can be applied at a global building level as an integrated system or as a retrofit solution in new or existing construction, respectively, or at a local scale as a passive protection technique for non-structural components. Despite their undeniable effectiveness in reducing the seismic accelerations transmitted to the isolated structure and to its content, currently available isolation devices may add significantly to the construction cost of buildings, and may require particular maintenance to preserve a stable performance over time. The proposed KSJ solution will allow for a reduction in manufacturing and maintenance burdens compared to established technologies. This paper discusses the main results of a shake-table test conducted at the EUCENTRE Foundation laboratories on an assembly with four prototypes of the KSJ device. The experimental setup included a 19-t rigid mass supported by the isolators, simulating the building superstructure, and four marble blocks installed above the rigid mass, representing non-structural rocking components such as parapets, pinnacles, statues, or other architectural ornaments. Moreover, a museum showcase with a small-scale replica of Michelangelo’s David was mounted above the rigid block, while two clay vases completed the setup, to encompass additional cultural heritage features. Accelerometers and potentiometers were deployed at several locations to monitor the kinematic response of the individual isolators, as well as their effect on the dynamic response of the rigid mass and of the different non-structural elements. The experiment was conducted first with the KSJ devices allowed to displace freely, then after fastening the rigid mass to the shake-table through post-tensioning rods, following the same incremental dynamic test sequence. This allowed comparing the response of the non-structural components with and without seismic isolation, to better understand the effect of the proposed isolation devices on the overall test assembly and on each sub-component

What if? Mouse proteomics after gene inactivation

The complex interactions among proteins and of proteins with small molecular weight protein ligands are overturned every time one of the components of the network is missing. For study purposes, animal models lacking one protein are obtained by experimental manipulation of the genome: in the knocking out approach, a gene is altered through the insertion of an artificial DNA sequence, which halts the transcription-translation sequence of events. In this review we have compiled the research papers that analyze the effects of knocking out individual genes on the proteomes of various tissues/organs throughout the body. We have gathered and organized all the available evidence and then compared the proteomic data in order to stress the context-specificity of the outcome every time two or more organs were investigated in the same KO mice. Finally, in a symmetrical approach to the above, we surveyed whether there is any obvious overlap among the effects of different KO on the same organ, marking affection of general pathways or lacking specificity of the gene targeting. Specific attention was put on the possible involvement of cellular stress markers

Heparin and Heparan Sulfate: Analyzing Structure and Microheterogeneity [chapter]

available in PMC 2013 August 28The structural microheterogeneity of heparin and heparan sulfate is one of the major reasons for the multifunctionality exhibited by this class of molecules. In a physiological context, these molecules primarily exert their effects extracellularly by mediating key processes of cellular cross-talk and signaling leading to the modulation of a number of different biological activities including development, cell proliferation, and inflammation. This structural diversity is biosynthetically imprinted in a nontemplate-driven manner and may also be dynamically remodeled as cellular function changes. Understanding the structural information encoded in these molecules forms the basis for attempting to understand the complex biology they mediate. This chapter provides an overview of the origin of the structural microheterogeneity observed in heparin and heparan sulfate, and the orthogonal analytical methodologies that are required to help decipher this information

GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome

OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia

SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane \u3b1-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure-function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport

In silico prioritization of endocrine active substances (EAS) and their in vitro validation

In silico molecular docking can be a cheap and fast strategy to estimate the binding free energies, and consequently the dissociation constants, for a set of compounds with respect to their putative targets. Interesting targets for EAS are the ligand binding domains (LBD) of the human nuclear receptors for the sex hormones, i.e. the estrogen, androgen, progesterone, and (gluco)corticoid receptor. The Horizon 2020 project EuroMix (http://euromixproject.eu) aims to establish and disseminate new, efficient and validated strategies for the risk assessment of mixtures, while limiting the use of test animals. The present presentation deals with a part of EuroMix that is intended to set up a testing approach for mixtures of endocrine disrupting chemicals, focusing on estrogenic and anti-androgenic effects. For that purpose, a combined Adverse Outcome Pathway (AOP) was constructed, including Molecular Initiating Events, Key Events, and Adverse Outcome (reproductive dysfunction). Using this combined AOP as framework, cognate in silico and in vitro tools as well as the in vivo confirmation studies were selected, i.e. in silico: h-ER and h-AR docking; in vitro: cell-based ER and AR transcriptional activation bioassays and the H295R steroidogenesis assay; and in vivo: the Fish Sexual Development Test (FSDT, OECD Test No. 234) and a rat study, examining in (male) offspring a number of parameters, such as anogenital distance, cryptorchidism, and nipple retention. Reference chemicals were selected and in silico and in vitro testing was started, showing that when testing single compounds, there is a very good correlation between the in silico determined binding energies and the in vitro measured hormonal activities

Comparison of teratogenic potency of azoles using in silico and in vitro methods

Craniofacial morphogenesis is affected in rodents by a number of clinical or agrochemical azole fungicides. The hypothesized mode of action of azoles includes abnormal neural crest cell specification and migration from hindbrain to the embryonic branchial region due to retinoic acid (RA) excess. Moreover, the additive effects after the multiple exposure to triazole fungicides account for a common mode of action. In analogy to their antifungal mode of action and hepatic side effects (inhibition of CYP isozymes), the proposed molecular initiating event for azole teratogenicity is the inhibition of embryonic CYP26 isozymes which are key proteins in RA catabolism. Experiments performed on postimplantation rat whole embryo cultures show that all tested azoles are teratogenic at micromolar concentrations, but characterized by different potencies (flusilazole=imazalil=ketoconazole>triadimefon=triadimenol>cyproconazole>tebuconazole>fluconazole). Molecular docking of eight azoles has been performed on CYP26a1, CYP26b1 and CYP26c1 isozymes, which play different roles in their teratogenic outcomes. Different affinities, consistent with the different azole teratogenic profiles and potencies, have been computed, confirming this hypothesis