69,454 research outputs found
Aspectes moleculars de dues malalties de transport lisosòmic: la cistinosi i la malaltia de Niemann-Pick tipus C
No full text[cat] La cistinosi i la malaltia de Niemann-Pick tipus C (NPC) són dues patologies hereditàries monogèniques poc freqüents, per aquest motiu estan classificades dins del grup de malalties anomenades rares. La cistinosi està causada per mutacions al gen CTNS, que codifica per una proteïna transmembrana del lisosoma que rep el nom de cistinosina. En canvi, la malaltia de NPC és deguda a mutacions al gen NPC1 o al gen NPC2, que codifiquen per una proteïna integral de la membrana lisosòmica i una proteïna soluble del lisosoma, respectivament, i aquestes reben el mateix nom que el gen, NPC1 i NPC2. El funcionament incorrecte d’aquestes proteïnes de transport dóna lloc a una acumulació de productes, diferent a ambdós casos, a l’interior del lisosoma, sent classificades com a malalties d’acumulació lisosòmica. Aquesta tesi doctoral s’ha centrat en l’anàlisi molecular de pacients afectes d’alguna d’aquestes dues malalties.
S’ha realitzat el primer estudi mutacional de cistinosi a la població espanyola, que ha permès la identificació de 15 mutacions diferents, 7 de les quals no havien estat descrites: tres mutacions de canvi de sentit (p.M1T, p.S270F i p.G309V), tres delecions (c.1-19_61del, c.295_310del i c.320_323delATCA) i una mutació de splicing (c.682-1G>T). La deleció de 57 kb és la mutació més freqüent a Espanya (38% dels al•lels) i conjuntament amb altres 5 mutacions representen el 73% dels al•lels estudiats. S’ha establert que els pacients amb fenotip clínic infantil tenen a ambdós al•lels mutacions que trunquen o que afecten aminoàcids conservats de les regions transmembrana de la proteïna. En canvi, la mutació p.S139F s’ha associat a la forma juvenil de la malaltia.
L’estudi mutacional realitzat a la malaltia de Niemann-Pick tipus C ha permès establir el genotip d’un gran nombre de pacients, identificant 74 mutacions diferents, 17 de les quals no havien estat descrites: set mutacions de canvi de sentit (p.P474A, p.G535V, p.F995L, p.F1079S, p.L1106P, p.G1209E i p.S1249G), dues mutacions sense sentit (p.Q775X i p.E1089X), dues insercions (p.L1117PfsX4 i p.I1061NfsX4), una deleció en pauta (p.N916del), quatre mutacions de splicing (c.58-3280C>G, c.882-28A>T, c.2604+5G>A i c.3591+5G>A) i la primera gran deleció que afecta al gen NPC1 i gens flanquejants. També s’han pogut establir correlacions genotip-fenotip per a un conjunt de mutacions.
També s’ha demostrat la implicació de diferents mecanismes cel•lulars en la malaltia de Niemann-Pick tipus C, segons els tipus de mutacions causants: el “splicing”, el procés de “nonsense-mediated mRNA decay” i la degradació proteica portada a terme pel proteasoma. S’han identificat mutacions intròniques profundes i s’ha caracteritzat el seu efecte en el mRNA, conjuntament amb el de les mutacions de “splicing” que afecten als llocs canònics. El mecanisme de NMD és el responsable de la degradació del mRNA en tots els al•lels analitzats que codifiquen per un PTC al gen NPC1. La majoria de mutacions de canvi de sentit analitzades condueixen a una reducció significativa o a l’absència de la proteïna NPC1, degut a què la proteïna NPC1 mutada és degradada per la via de la ubiquitina-proteasoma. La proteïna NPC1 mutada recuperada, després del tractament amb els inhibidors del proteasoma (ALLN i MG132), és capaç de disminuir els nivells de colesterol a totes les línies cel•lulars NPC estudiades. Aquesta observació podria obrir la porta a l’ús d’aquests fàrmacs com a futur tractament per a la malaltia de NPC causada per determinades mutacions de canvi de sentit.[eng] “Molecular aspects of both lysosomal transport diseases: cystinosis and Niemann-Pick disease type”. The cystinosis and Niemann-Pick disease type C (NPC) are two rare monogenic hereditary diseases. The cystinosis is caused by mutations in the gene CTNS, which encodes a transmembrane protein of the lysosome that is called cystinosin. NPC disease is caused by mutations in the NPC1 or NPC2 gene, encoding an integral lysosomal membrane protein and a soluble protein of the lysosome, respectively, and these are the same name as the gene, NPC1 and NPC2. The impaired transport leads to an accumulation of products, different in both cases, inside the lysosome, being classified as lysosomal storage disorders. This thesis has focused on the molecular analysis of patients with any of these diseases.
Molecular analysis in the Spanish cystinosis patients has allowed the identification of 15 different mutations, 7 of which had not been described. The 57-kb deletion is the most common mutation in Spain (38% of alleles) and together with other 5 mutations accounted for 73% of the studied alleles. The p.S139F mutation has been associated with the juvenile form of the disease.
Molecular analysis in NPC disease has established the mutation profile in a large number of patients. 74 different mutations have been identified, 17 of which had not been described previously, including the first large deletion affecting the whole NPC1 gene and flanking genes. Genotype-phenotype correlations have been established for several mutations.
Different cellular mechanisms are involving in NPC disease: splicing, nonsense-mediated mRNA decay and proteasomal degradation. Deep intronic mutations have been identified and the effect on the mRNA has been characterized. NMD process is responsible for the mRNA decay for all analyzed NPC1 PTC-encoding mutations. Several missense mutations lead to a significant reduction or absence of NPC1 protein, because the NPC1 mutant protein is degraded by the ubiquitin-proteasome pathway. Treatment with proteasome inhibitors partially reverses the NPC1 decrease and reduces cholesterol levels in all studied NPC cell lines. This observation might represent a therapeutical approach for future treatments of NPC disease caused by specific missense mutations
Performance Approximation and Design of Pick-and-Pass Order Picking Systems
No full textIn this paper, we discuss an approximation method based on G/G/m queuing network modeling using Whitt’s (1983) queuing network analyzer to analyze pick-and-pass order picking systems. The objective of this approximation method is to provide an instrument for obtaining rapid performance estimates (such as order lead time and station utilization) of the order picking system. The pick-and-pass system is decomposed into conveyor pieces and pick stations. Conveyor pieces have a constant processing time, whereas the service times at a pick station depend on the number of order lines in the order to be picked at the station, the storage policy at the station, and the working methods. Our approximation method appears to be sufficiently accurate for practical purposes. It can be used to rapidly evaluate the effects of the storage methods in pick stations, the number of order pickers at stations, the size of pick stations, the arrival process of customer orders, and the impact of batching and splitting orders on system performance.simulation;warehousing;order picking;queuing network;pick-and-pass
Order batching in multi-server pick-and-sort warehouses.
No full textIn many warehouses, customer orders are batched to profit from a reduction in the order picking effort. This reduction has to be offset against an increase in sorting effort. This paper studies the impact of the order batching policy on average customer order throughput time, in warehouses where the picking and sorting functions are executed separately by either a single operator or multiple parallel operators. We present a throughput time estimation model based on Whitt's queuing network approach, assuming that the number of order lines per customer order follows a discrete probability distribution and that the warehouse uses a random storage strategy. We show that the model is adequate in approximating the optimal pick batch size, minimizing average customer order throughput time. Next, we use the model to explore the different factors influencing optimal batch size, the optimal allocation of workers to picking and sorting, and the impact of different order picking strategies such as sort-while-pick (SWP) versus pick-and-sort (PAS)Order batching; Order picking and sorting; Queueing; Warehousing;
Adulte Form des M. Niemann-Pick Typ C
No full textWe report the case of a 43-year-old male patient, who presented with a slowly progressive gait disorder since the age of 27. In the neurological examination he showed a supranuclear vertical gaze palsy, cognitive impairment, limb and gait ataxia and dystonia. The MRI scan showed marked temporal und cerebellar atrophy, an ultrasound of the abdomen revealed splenomegaly. Bone marrow cytology revealed seablue histiocytes and foamy storage macrophages. Fibroblast cultures were assayed with the Filipin method and revealed positive lysosomal cholesterol accumulation. Genetic testing demonstrated two heterozygous mutations of defect alleles in the NPC1 gene (compound heterozygousity). Niemann-Pick disease type C is a rare autosomal recessive lipid storage disorder with variable clinical presentation, mostly beginning in early childhood or adolescence. Late manifestations have only rarely been reported. With oral Miglustat, an inhibitor of ceramide-specific glycosyltransferase, a first therapeutic strategy with possible benefits is currently under investigation
Morbus Niemann-Pick Typ C
No full textM. Niemann-Pick Typ C (NPC) ist eine seltene, neuroviszerale lysosomale Speicherkrankheit. Auf der Basis einer Defizienz des NPC1- oder NPC2-Proteins kommt es zu einer Störung der Digestion von Plasmamembranlipiden mit konsekutiver lysosomaler Speicherung. Viszerale Befunde können der neurologischen Manifestation um Jahre vorausgehen. Der Verlaufstyp wird durch den Zeitpunkt und die Progression der Neurodegeneration bestimmt. Zur Behandlung der neurologischen Symptomatik steht eine Substratreduktionstherapie mit Miglustat zur Verfügung, die in einer klinischen Studie bei 72% der Patienten zu einer Stabilisierung bzw. Verlangsamung der Progredienz des Krankheitsbildes führte und heute in Europa die einzige zugelassene Therapieoption für diese Patienten ist. Der Krankheitsverlauf und der Nutzen einer Therapie mit Miglustat sollten regelmäßig standardisiert dokumentiert werden. Weitere Forschungsbemühungen zum molekularen Verständnis und zur Klinik des NPC sind notwendig, um betroffenen Patienten so früh wie möglich einer zielorientierten und wirksamen Behandlung zum Eindämmen der normalerweise progredienten Erkrankung zuzuführen. = Niemann-Pick disease type C (NPC) is a rare, neurovisceral lysosomal storage disease. A deficiency in the NPC1 or NPC2 protein results in impaired digestion and subsequent accumulation of plasma membrane lipids in the lysosomes. Visceral signs and symptoms may occur years before the onset of neurological manifestations. The clinical phenotype of NPC is, however, determined by the onset and progression of neurodegeneration. Neurological manifestations of NPC can be treated using substrate reduction therapy with miglustat. A clinical study showed that 72% of NPC patients treated with miglustat experienced stabilization or slowed progression of the disease. At present, miglustat is the only approved treatment option in Europe for NPC patients with neurological symptoms. Monitoring of disease progression and response to treatment with miglustat should be conducted with regular follow-up and standardized documentation. Additional research on the molecular basis and clinical course of NPC will be required in order to provide affected patients with an early targeted and efficacious treatment to curtail this normally progressive disease
How to pick a fight : Visualisation and sharing in catastrophic times
No full textIn a post September 11 era “the fight”, as a cultural construct, could hardly be more pertinent. We are seemingly forever poised on the edge of controversial U.S. led attacks on wayward Middle Eastern states and unexamined oppositions between the concepts of ‘good’ and ‘evil’ are evoked as valid justifications for battle. Our leaders muster us into wars of vigilance and national cohesion against unseen, unknown and uncomprehended terrorists hiding where communists once lurked under our beds.\ud
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The articles in this issue examine fights in terms of media strategies and cultural divides in a range of contexts
Nieman-Pick Disease Type C: An Epileptologic View
No full textHow to Cite This Article: Mohammadi M. Nieman-Pick Disease Type C: An Epileptologic View. Iran J Child Neurol. 2015 Autumn;9:4(Suppl.1): 11. pls see pdf.
Prenatal Diagnosis and Genetic Counseling for Niemann-Pick C Disease
No full textHow to Cite this Article: Javadzadeh M. Prenatal Diagnosis and Genetic Counseling for Niemann-Pick C Disease. Iran J Child Neurol. 2015 Autumn;9:4(Suppl.1): 22. Pls see pdf.
Fundamental social motives measured across forty-two cultures in two waves
No full textPick C. M., Ko A, Kenrick DT, Wiezel A, Wormley AS, Awad E, Al-Shawaf L, Barry O, Bereby-Meyer Y, Boonyasiriwat W, Brandstatter E, Ceylan-Batur S, Choy BKC, Crispim AC, Cruz JE, David D, David OA, Defelipe RP, Elmas P, Espinosa A, Fernandez AM, Fetvadjiev VH, Fetvadjieva S, Fischer R, Galdi S, Galindo-Caballero OJ, Golovina EV, Golovina GM, Gomez-Jacinto L, Graf S, Grossmann I, Gul P, Halama P, Hamamura T, Han SH, Hansson LS, Hitokoto H, Hrebickova M, Ilic D, Johnson JL, Kara-Yakoubian M, Karl JA, Kim JP, Kohut M, Lasselin J, Lee H, Li NP, Mafra AL, Malanchuk O, Moran S, Murata A, Na J, Ndiaye SAL, Jiaqing O, Onyishi IE, Pasay-an E, Rizwan M, Roth E, Salgado S, Samoylenko ES, Savchenko TN, Sette C, Sevincer AT, Skoog E, Stanciu A, Suh EM, Sznycer D, Talhelm T, Ugwu FO, Uskul AK, Uz I, Valentova JV, Varella MAC, Wei LQ, Zambrano D, Varnum MEW</p
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