Academic literature on the topic 'AP4S1'
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Journal articles on the topic "AP4S1"
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Behne, Robert, Julian Teinert, Miriam Wimmer, Angelica D’Amore, Alexandra K. Davies, Joseph M. Scarrott, Kathrin Eberhardt, et al. "Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking." Human Molecular Genetics 29, no. 2 (January 9, 2020): 320–34. http://dx.doi.org/10.1093/hmg/ddz310.
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Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.
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Vill, Katharina, Wolfgang Müller-Felber, Bader Alhaddad, Tim M. Strom, Veronika Teusch, Heike Weigand, Astrid Blaschek, Thomas Meitinger, and Tobias B. Haack. "A homozygous splice variant in AP4S1 mimicking neurodegeneration with brain iron accumulation." Movement Disorders 32, no. 5 (February 2, 2017): 797–99. http://dx.doi.org/10.1002/mds.26922.
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D’Amore, Angelica, Alessandra Tessa, Valentina Naef, Maria Teresa Bassi, Andrea Citterio, Romina Romaniello, Gianluca Fichi, et al. "Loss of ap4s1 in zebrafish leads to neurodevelopmental defects resembling spastic paraplegia 52." Annals of Clinical and Translational Neurology 7, no. 4 (March 25, 2020): 584–89. http://dx.doi.org/10.1002/acn3.51018.
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Carmona, Susana, Clara Marecos, Marta Amorim, Ana C. Ferreira, Carla Conceição, José Brás, Sofia T. Duarte, and Rita Guerreiro. "AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria." Neurology Genetics 4, no. 5 (September 19, 2018): e273. http://dx.doi.org/10.1212/nxg.0000000000000273.
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McCullough, Carmel G., Szabolcs Szelinger, Newell Belnap, Keri Ramsey, Isabelle Schrauwen, Ana M. Claasen, Leah W. Burke, et al. "Utilizing RNA and outlier analysis to identify an intronic splice‐altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia." Human Mutation 41, no. 2 (November 14, 2019): 412–19. http://dx.doi.org/10.1002/humu.23939.
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Hardies, Katia, Patrick May, Tania Djémié, Oana Tarta-Arsene, Tine Deconinck, Dana Craiu, Ingo Helbig, et al. "Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly." Human Molecular Genetics 24, no. 8 (December 30, 2014): 2218–27. http://dx.doi.org/10.1093/hmg/ddu740.
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Klee, Katharina M. C., Andreas R. Janecke, Hasret A. Civan, Štefan Rosipal, Peter Heinz-Erian, Lukas A. Huber, Thomas Müller, and Georg F. Vogel. "AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect." Human Genetics 139, no. 10 (April 18, 2020): 1247–59. http://dx.doi.org/10.1007/s00439-020-02168-w.
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Abstract Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.
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Hannan, Fadil M., Mark Stevenson, Asha L. Bayliss, Victoria J. Stokes, Michelle Stewart, Kreepa G. Kooblall, Caroline M. Gorvin, et al. "Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2." Human Molecular Genetics 30, no. 10 (March 17, 2021): 880–92. http://dx.doi.org/10.1093/hmg/ddab076.
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Abstract Adaptor protein 2 (AP2), a heterotetrameric complex comprising AP2α, AP2β2, AP2μ2 and AP2σ2 subunits, is ubiquitously expressed and involved in endocytosis and trafficking of membrane proteins, such as the calcium-sensing receptor (CaSR), a G-protein coupled receptor that signals via Gα11. Mutations of CaSR, Gα11 and AP2σ2, encoded by AP2S1, cause familial hypocalciuric hypercalcaemia types 1–3 (FHH1–3), respectively. FHH3 patients have heterozygous AP2S1 missense Arg15 mutations (p.Arg15Cys, p.Arg15His or p.Arg15Leu) with hypercalcaemia, which may be marked and symptomatic, and occasional hypophosphataemia and osteomalacia. To further characterize the phenotypic spectrum and calcitropic pathophysiology of FHH3, we used CRISPR/Cas9 genome editing to generate mice harboring the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, and had marked hypercalcaemia, hypermagnesaemia, hypophosphataemia, and increases in alkaline phosphatase activity and fibroblast growth factor-23. Plasma 1,25-dihydroxyvitamin D was normal, and no alterations in bone mineral density or bone turnover were noted. Homozygous (Ap2s1L15/L15) mice invariably died perinatally. Co-immunoprecipitation studies showed that the AP2S1 p.Arg15Leu mutation impaired protein–protein interactions between AP2σ2 and the other AP2 subunits, and also with the CaSR. Cinacalcet, a CaSR positive allosteric modulator, decreased plasma calcium and parathyroid hormone concentrations in Ap2s1+/L15 mice, but had no effect on the diminished AP2σ2-CaSR interaction in vitro. Thus, our studies have established a mouse model that is representative for FHH3 in humans, and demonstrated that the AP2S1 p.Arg15Leu mutation causes a predominantly calcitropic phenotype, which can be ameliorated by treatment with cinacalcet.
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Gavalas, Nikos G., E. Helen Kemp, Kai J. E. Krohn, Edward M. Brown, Philip F. Watson, and Anthony P. Weetman. "The Calcium-Sensing Receptor Is a Target of Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1." Journal of Clinical Endocrinology & Metabolism 92, no. 6 (June 1, 2007): 2107–14. http://dx.doi.org/10.1210/jc.2006-2466.
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Abstract Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) on parathyroid cells. However, the detection of CaSR antibodies in APS1 remains controversial, with some studies disputing the relevance of the receptor as an autoantigen. Objective: The aim of this study was to analyze a defined set of APS1 patient sera for the presence of CaSR antibodies using different assay systems. Results: APS1 patients and individuals with other autoimmune disorders along with healthy subjects were tested for antibody binding to the CaSR. In an immunoprecipitation assay with the CaSR expressed in human embryonic kidney 293 cells, 12 of 14 (85.7%) APS1 and two of 28 (7.1%) Graves’ disease patients were considered positive for CaSR antibodies. The prevalence of receptor antibodies was significantly greater than that in the cohort of healthy individuals only in the APS1 patient group (P < 0.0001). In a flow cytometry assay, seven of 14 (50.0%) APS1 patient sera showed binding to the extracellular domain of the CaSR. The prevalence of receptor antibodies in the APS1 patient group was significantly greater than that in the group of healthy controls (P = 0.023). No CaSR antibodies could be detected in any patients or controls using a radiobinding assay. Conclusion: The CaSR is an autoantigen in APS1, but detection of antibodies against the receptor appears to be influenced by the assay system used.
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Aashiq, Mohamed, Asma Jassim Malallah, Farheen Khan, and Maryam Alsada. "Clinical and Biochemical Features in a Case of Familial Hypocalciuric Hypercalcemia Type 3 with AP2S1 Gene Mutation in Codon Arg15His." Case Reports in Pediatrics 2020 (January 28, 2020): 1–3. http://dx.doi.org/10.1155/2020/7312894.
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Familial hypocalciuric hypercalcemia (FHH) is usually a benign condition divided into three types. FHH-3 occurs in about 20% of the cases and is caused due to missense mutations in AP2S1 (adaptor-related protein complex 2 subunit sigma 1) involving the codon Arg15 (p.R15). We report a case of FHH-3 with a heterozygous mutation in the AP2S1 gene on chr19_47349359 C>T, c.44G>A, p.Arg15His. There are a handful of reports describing the clinical features in patients diagnosed with FHH-3. Herein, we describe the laboratory and clinical features associated with a case of FHH-3 with mutation in the Arg15His codon of the AP2S1 gene.
Dissertations / Theses on the topic "AP4S1"
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Angelica, D'Amore. "Next Generation Molecular Studies of Hereditary Spastic Paraplegias in Men and Zebrafish." Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1105261.
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The term Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that NGS facilitates the diagnostic approach to HSP, but the power of this method as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity— there are over 80 potential disease-associated genes— and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming.
In a single-center, cross-sectional study, spanning 5 years, 242 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP or syndromic conditions. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation
pathogenicity, we gathered a positive diagnostic yield of 30% (73/242), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 (34%) cases remained unsolved. This study is among the largest screening of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern,
first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy. Interestingly, we identified new unreported mutations in the AP4S1 gene (SPG52), the smallest of the four subunits that form the AP-4 complex, a heterotetrameric protein complex which participates in membrane sorting between the trans-Golgi network and the endosomes, and plays a key role in signal-mediated tracking of integral membrane proteins.
Mutations in AP4 subunits have been associated with alterations in neurodevelopment, epilepsy and complicated spastic paraplegia and the relative rarity of patients with mutations in subunits of the AP4 complex makes useful to report additional cases. In this study we described clinical presentations of three additional unrelated patients and their mutations. To improve our understating on to how AP4S1 operates during neurodevelopment, we knocked-down ap4s1 in zebrafish (Danio rerio), using morpholino antisense oligonucleotide technique. Our results showed that morphant embryos displayed an impairment of the neuronal excitability, locomotor defects, development delay, and altered neurogenesis, which are also phenotypic traits of AP4-HSP patients. Whilst we expanded the allelic heterogeneity in AP4-related diseases, we modeled in the simple vertebrate system zebrafish the early steps of abnormal neurodevelopment associated with AP4S1 defects offering a new tool for future therapeutic opportunities. Importantly, AP-complex served as an example for similar strategies in genes associated with HSP.
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Côté, Stéphanie. "Caractérisation fonctionnelle du gène AP1S1 mutant associé au syndrome de MEDNIK." Thèse, 2009. http://hdl.handle.net/1866/4377.
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Dans les cellules eucaryotes, le trafic intracellulaire de nombreuses protéines est assuré par des vésicules de transport tapissées de clathrine. Les complexes adaptateurs de clathrine (AP) sont responsables de l’assemblage de ces vésicules et de la sélection des protéines qui seront transportées. Nous avons étudié cinq familles atteintes du syndrome neurocutané MEDNIK qui est caractérisé par un retard mental, une entéropathie, une surdité, une neuropathie périphérique, de l’icthyose et de la kératodermie. Tous les cas connus de cette maladie à transmission autosomique récessive sont originaires de la région de Kamouraska, dans la province de Québec. Par séquençage direct des gènes candidats, nous avons identifié une mutation impliquant le site accepteur de l’épissage de l’intron 2 du gène codant pour la sous-unité σ1 du complexe AP1 (AP1S1). Cette mutation fondatrice a été retrouvée chez tous les individus atteints du syndrome MEDNIK et altère l’épissage normal du gène, menant à un codon stop prématuré. Afin de valider l’effet pathogène de la mutation, nous avons bloqué la traduction de cette protéine chez le poisson zébré en injectant une séquence d’oligonucléotides antisenses spécifique à AP1S1. À 48 heures après la fertilisation, les larves knock down pour AP1S1 montrent une réduction de la pigmentation, une désorganisation de la structure de l’épiderme et une perturbation du développement moteur. Alors que la surexpression de l’AP1S1 humain dans ce modèle a permis la récupération du phénotype normal, l’expression de l’AP1S1 mutant fut sans effet sur les phénotypes moteurs et cutanés des larves knock down. Les résultats obtenus montrent que la mutation du AP1S1 responsable du syndrome de MEDNIK est associée à une perte de fonction et que la sous-unité σ1 du complexe AP1 joue un rôle crucial dans l’organisation de l’épiderme et le développement de la moelle épinière.Intracellular protein transport between organelles is mainly mediated by clathrin coated vesicles. Clathrin adaptor protein (AP) complexes participate in clathrin coated vesicle formation and in sorting protein cargo. We studied 5 families with MEDNIK syndrome, which is characterized by mental retardation, enteropathy, deafness, neuropathy, ichtyosis and keratoderma. All families affected with this autosomal recessive syndrome originate from an isolated population in the Kamouraska region of Quebec. The candidate genes identified in the positive region were sequenced and a founder mutation was identified in the acceptor splice slice of intron 2 of the AP1S1 gene. This gene encodes for the small subunit σ1 of the complex adaptor 1 (AP1). This splicing mutation leads to a premature stop codon, which is predicted to alter the normal function of this protein. To validate the pathogenic effect of this mutation we blocked the AP1S1 protein translation in zebrafish by injecting an anti-sense oligonucleotide designed against AP1S1. At 48 hours post fertilisation, the knockdown larvae showed reduced pigmentation, perturbation of skin formation, and severe perturbation of motor development and function motor development. Over expression of the human AP1S1 rescued the normal phenotype whereas the expression of the mutant AP1S1 did not. These results show that this mutation is causative for MEDNIK syndrome and demonstrates a critical role of the small subunit σ1 in epidermal organisation and in the development of the spinal cord.
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Chu, Chun-Cheng, and 朱峻成. "Investigation on the survival and adaptive responses of Lactobacillus mali APS1 under various stresses." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/tv9pns.
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碩士國立臺灣大學
動物科學技術學研究所
106
Lactobacillus mali APS1, a potential probiotic strain isolated from sugar kefir grains, has been proven its functionalities about immune-regulation, anti-colitis, and anti-obesity. Live probiotics with certain amount of number are essential for healthy beneficial. However, probiotics encounter critical environmental stress such as cold, heat, acid and bile salts, which dramatically decrease the survival and functionality of probiotics. Therefore, bacteria evolve a system defensing to help them adapting to lethal or sublethal condition. Thus, the objective of this study was to investigate the adaptive responses and viability of L. mali APS1 to various environmental stresses, such as cold, heat, acid, and bile salts. The stress susceptibility results showed that the sublethal and lethal condition of acid, bile salt, heat and cold for L. mali APS1 were 10°C and -20°C, 42°C and 52°C, pH 3.5 and pH 2.0, and 0.1% and 2%, respectively. The subsequent lethal challenge survival results showed that sublethal adaptation of L. mali APS1 to cold, heat and bile salts could induce homologous tolerance. Adaptation to cold and bile provided cross-protection against heat challenge (52°C). Adaptation to cold and heat improved the resistance to bile salt stress (2%). Adaptation to acid and bile increased survival of L. mali APS1 under cold lethal challenge. Besides, after freeze drying, survival of cold and acid adapted cells was significantly higher than heat and bile adapted cells (p < 0.05). Exopolysaccharides production of all stress-adapted and non-adapted cells have no significant difference (p > 0.05). Adapted cells with higher survival were observed minor cell damage after subsequent lethal challenge by scaning electron microscopy (SEM). For proteomics analysis, no significant difference was observed in Mini SDS-PAGE results, but signal change was detected from matrix-assisted laser desorption/ionization time-of-flight mass spectrometer(MALDI-TOF MS) between adapted and non-adapted cells and further grouped by principle component analysis (PCA). In conclusion, this study revealed that sublethal adaptation could be a possible strategy to improve survival of L. mali APS1 in lethal stress condition. Besides, according to morphological and proteomics analysis results, it was found that some adaptive response could be induced to maintain survival and integrity of adapted L. mali APS1.
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Ho, Yi-Fang, and 何懿芳. "Effects of microencapsulation on heat-tolerance and anti-colitis properties of Lactobacillus kefiranofaciens M1 and Lactobacillus mali APS1." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/k4x764.
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碩士國立臺灣大學
動物科學技術學研究所
101
Microbial viability is an important factor to exert health benefits, especially in host’s lower digestive tract. However, most of microorganisms cannot stand the adverse conditions like industrial heating processes and the digestive juice. Hence the purpose of the study was to develop heat-tolerant probiotic microcapsules to improve the survival of probiotics under heat treatment and the passage through the simulated gastrointestinal fluid (SGIF). The functionality of encapsulated probiotics was also evaluated. Gellan gum, sodium alginate and skim milk powder were incorporated as coating materials to encapsulate Lactobacillus kefiranofaciens M1 (M1) and Lb. mali APS1 (APS1) separately. The optimal proportion of gellan gum, sodium alginate and skim milk powder in microcapsules was determined by preliminary thermal-tolerant test. The bacterial counts in freeze-dried microcapsules stored at 4 oC were determined at different storage periods and heat treatments, followed by treatment of the SGIF. The initial bacteria counts of M1 and APS1 were 8.3 and 10.3 log CFU/g. The bacteria counts of M1 and APS1 after 8 weeks storage were 6.6 and 9.7 log CFU/g. After heat treatment, the bacteria numbers dropped to 5.8 and 9.2 log CFU/g. The viability of encapsulated M1 and APS1 were above 5.0 log CFU/g and 7.0 log CFU/g in SGIF test. On the contrary, the two free strains cannot detect viable bacteria counts after 8 weeks among these tests. Since both M1and APS1 demonstrated an anti-colitis effect in our previous study, we further investigated the anti-colitis effect of encapsulated these two strains in vivo and in vitro. Both heated encapsulated M1 and APS1 could significantly ameliorate the symptoms of DSS-induced colitis, including bleeding score, weight losing and colon length shortening, when compared with non-encapsulated groups in vivo. It is worth to notice that the distribution of lactobacilli and coliform in cecum was no difference among all experimental groups. We further studied the possible mechanism involved in the anti-colitis effect in vitro. The results indicated that both encapsulated strains could significantly increase the transepithelial electrical resistance (TEER) in Caco2 monolayer when compared with the blank group. However, the elevation of TEER value and CCL20 production was not found in the heated encapsulated strains. These findings revealed that encapsulated strains with heat-stable coating materials could elevate the viability during storage, heat resistance and simulated gastrointestinal conditions. Furthermore, the heat encapsulated strains demonstrated an anti-colitis effect in vivo. The heat-tolerant microcapsule might provide a high potential to apply the probiotics in warm drinks in the near future.
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Chen, Yung-Tsung, and 陳詠宗. "The mechanistic study of Lactobacillus mali APS1 on manipulation of gut microbiome in high-fat diet-induced obesity and non-alcoholic fatty liver disease animal model." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/9k85bh.
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博士國立臺灣大學
生物科技研究所
106
To date, obesity is a widespread disease in developing and developed countries. Some syndromes are accompanied with obesity, such as low grade inflammation and non-alcoholic fatty liver disease (NAFLD). Currently, there are no approved clinical treatment for non-alcoholic fatty liver disease and the difficulty of long-term management has produced a high rate of failure for obesity patients. Therefore, improving the efficacy of obesity and NAFLD treatment is a significant goal. A number of studies indicate that gut microbiota dominates and plays an important role in obesity and non-alcoholic fatty liver disease. Using probiotics to manipulate the gut microbiota has been as the potential approach for improving obesity. However, it remains unclear whether the probiotic can ameliorate the non-alcoholic fatty liver through manipulating the gut microbiota, in addition, the study on the effect of combination of probiotics and diet control in the regulation of obesity-related gut microbiota and metabolites is quite rare. In our previous studies, Lactobacillus mali APS1 (APS1), which is isolated from sugary kefir, has been demonstrated to confer several health benefits in vivo, including amelioration of high-fat diet (HFD)-induced obesity in mice. Therefore, this study aimed to investigate the effect of APS1 on high-fat diet-induced NAFLD and the efficacy of a combination of APS1 and dieting on improvement of obesity in vivo. The results showed that APS1 manipulated the gut microbiota, resulting in reducing the abundance of specific NAFLD-associated bacteria, and significantly reduced hepatic lipid accumulation and increased hepatic antioxidant activity by regulating SIRT-1/Nrf-2 signaling pathway in HFD-fed rats. The combination of APS1 and dieting accelerated body weight loss and reduced fat accumulation though manipulating obesity-associated gut microbiota in preexisting obese mice. Additionally, APS1 intervention modulated the lipid metabolism-associated metabolites, appetitive hormones and increased fecal butyric acid concentration. In conclusion, this study highlighted that APS1 strain isolated from sugary kefir regulating the host gut microbiota and inducing the expressions of short-chain fatty acids and intestinal hormones resulted in reduction of body fat accumulation and hepatic steatosis in vivo. This study provided scientific evidences to show that Lactobacillus mali APS1 can be the potential probiotic to improve metabolic disorder syndrome in the application of functional food.
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Crock, Patricia Anne. "Autoimmune hypophysitis: identifying the molecular mechanisms." Thesis, 2018. http://hdl.handle.net/1959.13/1395983.
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Research Doctorate - Doctor of Medicine (DMed)My research aim has been to develop a specific and sensitive diagnostic assay for pituitary autoantibodies, to identify the relevant target autoantigens and to understand the molecular mechanisms. This specific body of work spans 25 years and includes 21 publications of which six are reviews. I developed and validated the first immunoblotting assay for the detection of pituitary autoantibodies using autopsy pituitary tissue. One of the first target autoantigens identified, a 49 kDa pituitary cytosolic protein, was purified and found to be enolase. Serum from a patient with peripartum lymphocytic hypophysitis reacted to both alpha‐enolase and gamma‐enolase (neuron specific enolase) in the pituitary and placenta, thus explaining, for the first time, the link between pregnancy and hypophysitis. I identified the first pituitary membrane autoantigens in paediatric patients and we described the first convincing case of hypophysitis in a child with APECED (Autoimmune PolyEndocrinopathy Candidiasis and Ectodermal Dystrophy). Together with many national and international collaborators, we applied the immunoblotting assay across the clinical spectrum from acute to chronic autoimmune pituitary disease and other autoimmune conditions. Several novel clinical associations were found in the largest series of 32 Australian patients with hypophysitis and a number of other pituitary autoantigens were identified by molecular weight. I showed that pituitary autoantibodies are found in patients with other endocrine autoimmune diseases and in up to 20% of pituitary tumour cases. Thus, secondary tumoural hypophysitis cannot be differentiated immunologically, as yet, from primary autoimmune hypophysitis. We found evidence for, and proposed that, the slow progression of post‐partum hypopituitarism in Sheehan’s syndrome may have an autoimmune basis. We showed that some cases of idiopathic hypopituitarism are likely autoimmune and concluded that most patients with empty sella syndrome and normal pituitary function are unlikely to have chronic autoimmune hypophysitis. We demonstrated seroconversion time points for pituitary autoantibodies and their persistence in patients with APECED/APS1 from Finland. In a cohort of Polish patients with isolated ACTH deficiency we found 49 kDa autoantibodies in 20% and a novel 36 kDa pituitary autoantigen that correlated with co‐existent Hashimoto’s thyroiditis, strongly supporting a role for autoimmunity in this syndrome. My focus then changed from immunoblotting to immunoscreening of a pituitary cDNA library to identify further autoantigens and develop in‐vitro transcription translation (ITT) assays. We found a number of novel target autoantigens; CHD8, piccolo and CADPS, the latter two involved in dense core vesicle processing, the mechanism for endocrine peptide hormone secretion. Although none was specific in isolation, 8 of 86 patients with hypophysitis, but none of 90 controls reacted to two or more of these proteins (p=0.0093). We were the first to show the corticotroph‐specific transcription factor, TPIT was a target autoantigen in 10% of hypophysitis patients. APS1 (Autoimmune Polyendocrine Syndrome type 1 – also known as APECED) is a rare, monogenic autoimmune disease and hypopituitarism has been reported in up to 7% of patients. Sera from GH‐deficient APS1 patients identified three major, novel target autoantigens: a tudor domain containing protein 6 (TDRD6), a testis specific protein TSGA10 and endothelin converting enzyme‐2 (ECE‐2). The latter was abundantly expressed in endocrine pancreas as well as in the pituitary and brain. Immunostaining of the pituitary showed that it was localized to GH producing cells. In summary, my work in pituitary autoimmunity started with the development of a new diagnostic assay by immunoblotting and extended to the identification of the first target autoantigens. These autoantigens can be enzymes, transcription factors or proteins involved in dense‐core vesicle transport. However, at present pituitary autoantibodies specific for primary autoimmune lymphocytic hypophysitis cannot be differentiated from those secondary to peri‐ tumoural hypophysitis found in a significant percentage of pituitary tumours and hypothalamic tumours (such as germinomas). Therefore, my focus has now shifted to the new paradigm of diagnosis with epigenetics and biomarkers including miRNA profiling. The ultimate aim is to develop minimally invasive diagnostic testing in paediatric endocrinology.
Book chapters on the topic "AP4S1"
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Scharnagl, Hubert, Winfried März, Markus Böhm, Thomas A. Luger, Federico Fracassi, Alessia Diana, Thomas Frieling, et al. "APS1." In Encyclopedia of Molecular Mechanisms of Disease, 135. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_7157.
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Wolff, Anette S. B., Bergithe E. Oftedal, and Eystein S. Husebye. "The Natural History of APS1." In Endocrinology, 1–21. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-319-73082-0_2-1.
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Wolff, Anette S. B., Bergithe E. Oftedal, and Eystein S. Husebye. "The Natural History of APS1." In Endocrinology, 51–70. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-319-89497-3_2.
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Babey, Muriel, and Dolores M. Shoback. "Familial Hypocalciuric Hypercalcaemia Types 1–3 and Neonatal Severe Primary Hyperparathyroidism." In Oxford Textbook of Endocrinology and Diabetes 3e, edited by John A. H. Wass, Wiebke Arlt, and Robert K. Semple, 673–84. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198870197.003.0084.
Full textAbstract:
The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis. The CaSR regulates parathyroid hormone (PTH) secretion and calcium reabsorption by the kidney. Loss-of-function CASR mutations on chromosome 3q21.1 cause familial hypocalciuric hypercalcaemia type 1 (FHH1). FHH1 patients are usually asymptomatic. Biochemically, FHH1 is characterized by mild-to-moderate hypercalcaemia, inappropriately low urinary calcium excretion and a normal or mildly elevated circulating PTH level. Loss-of-function GNA11 mutations on chromosome 19p13.3 lead to FHH2. GNA11 gene encodes Gα-11 which mediates downstream CaSR signalling. Patients with FHH2 mutations display a mild FHH phenotype. Loss-of-function AP2S1 mutations on chromosome 19q.13.3 give rise to FHH3. AP2S1 gene encodes the adaptor-related protein complex 2 sigma (AP2σ) which is crucial for clathrin-mediated endocytosis, CaSR signalling, and trafficking. FHH3 may be a more severe form of FHH that may produce symptomatic hypercalcaemia, low bone mineral density, and cognitive dysfunction. Calcimimetic therapy may be considered for patients with FHH types 1–3.
Conference papers on the topic "AP4S1"
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Wang, Y., F. Valega Mackenzie, B. Ingenhut, and A. Boersma. "AP4.1 - Miniaturized 3D Printed Particulate Matter Sensor for Personal Monitoring." In 17th International Meeting on Chemical Sensors - IMCS 2018. AMA Service GmbH, Von-Münchhausen-Str. 49, 31515 Wunstorf, Germany, 2018. http://dx.doi.org/10.5162/imcs2018/ap4.1.
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Guo, Hong, and Rui Guo. "Manipulation of photon-atom momentum entanglement." In Workshop on Entanglement and Quantum Decoherence. Washington, D.C.: Optica Publishing Group, 2008. http://dx.doi.org/10.1364/weqd.2008.aps1.
Full textAbstract:
We propose some schemes to coherently enhance atom-photon momentum entanglement with either resonant photon scattering or spontaneously induced quantum interference. A novel feature called “phase entanglement” is reported, for which the traditional R-ratio-based entanglement detection becomes inadequate due to the quantum interference.