Developing a Conceptual Framework Model of Industry 4.0 for Industrial Management

M. Di Nardo 대한산업공학회 2020 Industrial Engineeering & Management Systems Vol.19 No.3

In this paper, the paradigms of industry 4.0 and its leading technologies enabling their development and dissemination, are introduced. A first outlined overview of this context, in which the Western Industry and its problems to be solved, is presented. This preliminary discussion will schematize a flow model that uses the previously mentioned and described technologies, applicable to production realities confined within a single plant or distribution. Human resource management, as a supervisory role of the entire organization, will receive great importance. News aspects relating to maintenance and safety will be focused in the future.

Pyridostigmine in Pediatric Intestinal Pseudo-obstruction: Case Report of a 2-year Old Girl and Literature Review

( Giovanni Di Nardo ),( Federica Viscogliosi ),( Francesco Esposito ),( Vincenzo Stanghellini ),( Maria Pia Villa ),( Pasquale Parisi ),( Alessia Morlando ),( Girolamo Cal ),( Roberto De Giorgio ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2019 Journal of Neurogastroenterology and Motility (JNM Vol.25 No.4

Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, longacting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility. (J Neurogastroenterol Motil 2019;25:508-514)

Postnatal signalling with homeoprotein transcription factors

Prochiantz, Alain,Fuchs, Julia,Di Nardo, Ariel A. Royal Society 2014 Philosophical transactions. Biological sciences Vol.369 No.1652

<P>Homeoprotein (HP) transcription factors were originally identified for their embryonic cell-autonomous developmental functions. In this review, we discuss their postnatal and adult physiological functions based on the study of Otx2, Engrailed-1 and Engrailed-2 (collectively Engrailed). For Engrailed, we discuss its function in the cell-autonomous regulation of ventral midbrain dopaminergic neuron survival and physiology and in the non-cell-autonomous maintenance of axons. For Otx2, we describe how the protein is expressed in the choroid plexus and transported into cortical parvalbumin cells where it regulates plasticity in the visual cortex. These two examples illustrate how the understanding of HP postnatal and adult functions, including signalling functions, may lead to the identification of disease-associated genetic pathways and to the development of original therapeutic strategies.</P>

Otx2 Binding to Perineuronal Nets Persistently Regulates Plasticity in the Mature Visual Cortex

Beurdeley, M.,Spatazza, J.,Lee, H.H.C.,Sugiyama, S.,Bernard, C.,Di Nardo, A.A.,Hensch, T.K.,Prochiantz, A. Society for Neuroscience 2012 The Journal of neuroscience Vol.32 No.27

A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor

Bernard, Clé,mence,Vincent, Clé,mentine,Testa, Damien,Bertini, Eva,Ribot, Jé,rô,me,Di Nardo, Ariel A.,Volovitch, Michel,Prochiantz, Alain Public Library of Science 2016 PLoS genetics Vol.12 No.5

<▼1><P>During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these “transfer” sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.</P></▼1><▼2><P><B>Author Summary</B></P><P>Classically, cell signaling is based on the secretion of molecules that bind cell surface receptors. Lipophilic agents can do without cell-surface receptors due to their ability to diffuse through the plasma membrane, but this is normally not the case for proteins, which cannot pass the membrane barrier. However, homeoprotein transcription factors represent an exception as they are secreted and internalized by live cells owing to two peptidic domains. An important illustration of this novel signaling mechanism is provided by Otx2, a homeoprotein that travels from the choroid plexus to specific inhibitory neurons in the cerebral cortex, where it regulates physiological plasticity throughout life. Because the two transfer peptides are in the DNA-binding domain of Otx2, it is impossible to mutate them without altering both cell signaling and cell-autonomous functions. We have therefore developed a mouse in which a secreted anti-Otx2 single-chain antibody can be induced to trap extracellular Otx2 while leaving its cell autonomous function untouched. We show that neutralizing extracellular Otx2 modifies the expression of plasticity genes in the visual cortex, thus providing the first genetic demonstration for homeoprotein signaling in a mammal.</P></▼2>

Prevalence of Non-erosive Esophageal Phenotypes in Children: A European Multicenter Study

Elisa Blasi,Ettore Stefanelli,Renato Tambucci,Silvia Salvatore,Paola De Angelis,Paolo Quitadamo,Claudia Pacchiarotti,Giovanni Di Nardo,Fanj Crocco,Valentina Giorgio,Nicoletta Staropoli,Simona Sestito 대한소화기 기능성질환∙운동학회 2023 Journal of Neurogastroenterology and Motility (JNM Vol.29 No.2

Background/AimsSince available data on pediatric non-erosive esophageal phenotypes (NEEPs) are scant, we investigated their prevalence and the phenotype-dependent treatment response in these children. MethodsOver a 5-year period, children with negative upper endoscopy, who underwent esophageal pH-impedance (off-therapy) for persisting symptoms not responsive to proton pump inhibitor (PPI)-treatment, were recruited. Based on the results of acid reflux index (RI) and symptom association probability (SAP), patients were categorized into: (1) abnormal RI (non-erosive reflux disease [NERD]), (2) normal RI and abnormal SAP (reflux hypersensitivity [RH]), (3) normal RI and normal SAP (functional heartburn [FH]), and (4) normal RI and not-reliable SAP (normal-RI-not otherwise-specified [normal-RI-NOS]). For each subgroup, treatment response was evaluated. ResultsOut of 2333 children who underwent esophageal pH-impedance, 68 cases, including 18 NERD, 14 RH, 26 FH, and 10 normal-RI-NOS were identified as fulfilling the inclusion criteria and were analyzed. Considering symptoms before endoscopy, chest pain was more reported in NERD than in other cases (6/18 vs 5/50, P = 0.031). At long-term follow-up of 23 patients (8 NERD, 8 FH, 2 RH, and 5 normal-RI-NOS): 17 were on PPIs and 2 combined alginate, 1 (FH) was on benzodiazepine + anticholinergic, 1 (normal-RI-NOS) on citalopram, and 3 had no therapy. A complete symptom-resolution was observed in 5/8 NERD, in 2/8 FH, and in 2/5 normal-RI-NOS. ConclusionsFH may be the most common pediatric NEEP. At long-term follow-up, there was a trend toward a more frequent complete symptom resolution with PPI-therapy in NERD patients while other groups did not benefit from extended acid-suppressive-treatment.

Graded Otx2 activities demonstrate dose-sensitive eye and retina phenotypes

Bernard, Clé,mence,Kim, Hyoung-Tai,Torero Ibad, Raoul,Lee, Eun Jung,Simonutti, Manuel,Picaud, Serge,Acampora, Dario,Simeone, Antonio,Di Nardo, Ariel A.,Prochiantz, Alain,Moya, Kenneth L.,Kim, Ji Oxford University Press 2014 Human Molecular Genetics Vol.23 No.7

<P>In the human, mutations of <I>OTX2</I> (<I>Orthodenticle homeobox 2</I> transcription factor) translate into eye malformations of variable expressivity (even between the two eyes of the same individual) and incomplete penetrance, suggesting the existence of subtle thresholds in OTX2 activity. We have addressed this issue by analyzing retinal structure and function in six mutant mice with graded Otx2 activity: <I>Otx2<SUP>+/+</SUP></I>, <I>Otx2<SUP>+/AA</SUP></I>, <I>Otx2<SUP>+/GFP</SUP></I>, <I>Otx2<SUP>AA/AA</SUP></I>, <I>Otx2<SUP>AA/GFP</SUP></I> and <I>Otx2<SUP>GFP/GFP</SUP></I>. Null mice (<I>Otx2<SUP>GFP/GFP</SUP></I>) fail to develop the head and are embryonic lethal, and compound heterozygous <I>Otx2<SUP>AA/GFP</SUP></I> mice show a truncated head and die at birth. All other genotypes develop until adulthood. We analyzed eye structure and visual physiology in the genotypes that develop until adulthood and report that phenotype severity parallels Otx2 activity. <I>Otx2<SUP>+/AA</SUP></I> are only mildly affected whereas <I>Otx2<SUP>+/GFP</SUP></I> are more affected than <I>Otx2<SUP>+/AA</SUP></I> but less than <I>Otx2<SUP>AA/AA</SUP></I> mice. <I>Otx2<SUP>AA/AA</SUP></I> mice later manifest the most severe defects, with variable expressivity. Electrophysiological and histological analyses of the mouse retina revealed progressive death of bipolar cells and cone photoreceptors that is both Otx2 activity- and age-dependent with the same ranking of phenotypic severity. This study demonstrates the importance of gene dosage in the development of age-dependent pathologies and underscores the fact that small gene dosage differences can cause significant pathological states.</P>

Collagen Synthesis Is Suppressed in Dermal Fibroblasts by the Human Antimicrobial Peptide LL-37

Park, Hyun Jeong,Cho, Dae Ho,Kim, Hee Jung,Lee, Jun Young,Cho, Baik Kee,Bang, Sa Ik,Song, Sang Yong,Yamasaki, Kenshi,Di Nardo, Anna,Gallo, Richard L The Society for Investigative Dermatology, Inc 2009 The Journal of investigative dermatology Vol.129 No.4

LL-37 is a human cathelicidin antimicrobial peptide that is released in the skin after injury and acts to defend against infection and modulate the local cellular immune response. We observed in human dermal keloids that fibrosis was inversely related to the expression of cathelicidin and sought to determine how LL-37 influenced expression of types I and III collagen genes in dermal fibroblasts. At nano-molar concentrations, LL-37 inhibited baseline and transforming growth factor-β-induced collagen expression. At these concentrations, LL-37 also induced phosphorylation of extracellular signal-regulated kinase (ERK) within 30 minutes. Activation of ERK, and the activation of a G-protein-dependent pathway, was essential for inhibition of collagen expression as pertussis toxin or an inhibitor of ERK blocked the inhibitory effects of LL-37. c-Jun N-terminal kinase and p38 mitogen-activated protein kinase inhibitors did not alter the effects of cathelicidin. Silencing of the Ets-1 reversed inhibitory effects of LL-37. Taken together, these findings show that LL-37 can directly act on dermal fibroblasts and may have antifibrotic action during the wound repair process.Journal of Investigative Dermatology (2009) 129, 843–850; doi:10.1038/jid.2008.320; published online 16 October 2008