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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
61

Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses

Golebiowski, Diane L. 01 September 2016 (has links)
GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose.
62

Quantitative Imaging of Net Axonal Transport in vivo: A Biomarker for Motor Neuron Health and Disease

Lee, Pin-Tsun Justin 21 December 2021 (has links)
Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disorder that selectively affects both upper and lower motor neurons, leading to muscle weakness, paralysis and death. Despite recent advances in the identification of genes associated with ALS, the quest for a sensitive biomarker for rapid and accurate diagnosis, prognosis, and treatment response monitoring has not been fulfilled. In this thesis, I report a method of quantifying the integrity of motor neurons in vivo using imaging to record uptake and retrograde transport of intramuscularly injected tetanus toxin fragment C (TTC) into spinal motor neurons. This method tracks and profiles progression of disease (transgenic SOD1G93A and PFN1 ALS mice) and detects subclinical perturbations in net transport, as analyzed in C9orf72 transgenic mice. It also defines a progressive reduction in net transport with aging. To address whether our technique enables drug development, I evaluated therapeutic benefits of (1) gene editing and (2) mutant gene silencing (with RNAi targeting SOD1) in SOD1G93A transgenic mice by characterizing their net axonal transport profiles. I constructed a computational model to evaluate key molecular processes affected in net axonal transport in ALS mouse model. The model allows prediction of key parameters affected in a C9ORF72 BAC transgenic mouse line. Prior immunization with tetanus toxoid does not preclude use of this assay, and it can be used repetitively in the same subject. This assay of net axonal transport offers broad clinical application as a diagnostic tool for motor neuron diseases and as a biomarker for rapid detection of benefit from therapies for transport dysfunction in a range of motor neuron diseases.
63

Metabolic adaptation of Staphylococcus aureus pathogenesis and therapeutic approach in diabetic foot ulcers.

Baker, Carol L. 08 August 2023 (has links) (PDF)
37.3 million Americans (11.2% of the US population) currently have Type 2 diabetes mellitus (T2DM) with over 1.5 million new cases being diagnosed each year. The multifactorial etiology of the patient having neuropathy, overweight/obesity, foot deformities, ischemia, and infection leads to a condition called diabetic foot ulcer (DFU). One in six patients with a DFU will require amputation with infected DFUs have a 155-fold increased risk of amputation. Staphylococcus aureus is the most common bacteria isolated from severe DFU infections that require amputation. Interestingly, diabetics are more heavily colonized with S. aureus compared to non-diabetics suggesting a unique advantageous adaptation to diabetes. The specifics of the underlying molecular mechanisms and triggers by which S. aureus adapts and thrives in the T2DM patient that increase its pathogenicity and colonization compared to non-diabetics with skin ulcer infections are not fully elucidated. Thus, our studies aimed to identify the key virulence components in the pathogenesis of S. aureus infected DFUs and using that information to develop therapeutics aimed at disrupting these components to increase the success rate of conservative treatment and prevent non-traumatic lower extremity amputations in T2DM patients. Our studies found that several different elevated sugars in T2DM patients can trigger virulence factor production in S. aureus. We also found by comparing several different clinical DFU S. aureus isolates that there are clear differences in the ability of each isolate to cause necrotic infections. And lastly, we identified a possible therapeutic, the amino acid L-arginine, that can help prevent/treat S. aureus infections in the Tallyho diabetic mouse model. In conclusion, we have increased the understanding of the pathogenesis of S. aureus infected DFU and have proposed a possible therapeutic to add to the conservative treatment regimen.
64

Advancing Treatment and Understanding of Rett Syndrome

Powers, Samantha Lynn January 2020 (has links)
No description available.
65

A Coupled CFD-Lumped Parameter Model of the Human Circulation: Elucidating the Hemodynamics of the Hybrid Norwood Palliative Treatment and Effects of the Reverse Blalock-Taussic Shunt Placement and Diameter

Ceballos, Andres 01 January 2015 (has links)
The Hybrid Norwood (HN) is a relatively new first stage procedure for neonates with Hypoplastic Left Heart Syndrome (HLHS), in which a sustainable univentricular circulation is established in a less invasive manner than with the standard procedure. A computational multiscale model of such HLHS circulation following the HN procedure was used to obtain detailed hemodynamics. Implementation of a reverse-BT shunt (RBTS), a synthetic bypass from the main pulmonary to the innominate artery placed to counteract aortic arch stenosis, and its effects on local and global hemodynamics were studied. A synthetic and a 3D reconstructed, patient derived anatomy after the HN procedure were utilized, with varying degrees of distal arch obstruction, or stenosis, (nominal and 90% reduction in lumen) and varying RBTS diameters (3.0, 3.5, 4.0 mm). A closed lumped parameter model (LPM) for the peripheral or distal circulation coupled to a 3D Computational Fluid Dynamics (CFD) model that allows detailed description of the local hemodynamics was created for each anatomy. The implementation of the RBTS in any of the chosen diameters under severe stenosis resulted in a restoration of arterial perfusion to near-nominal levels. Shunt flow velocity, vorticity, and overall wall shear stress levels are inverse functions of shunt diameter, while shunt perfusion and systemic oxygen delivery correlates positively with diameter. No correlation of shunt diameter with helicity was recorded. In the setting of the hybrid Norwood circulation, our results suggest: (1) the 4.0mm RBTS may be more thrombogenic when implemented in the absence of severe arch stenosis and (2) the 3.0mm and 3.5mm RBTS may be a more suitable alternative, with preference to the latter since it provides similar hemodynamics at lower levels of wall shear stress.
66

Gastrointestinal-Sparing Effects of Novel NSAIDs in Rats with Compromised Mucosal Defence

Blackler, Rory William 10 1900 (has links)
<p>Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high-risk human users, leading to an underestimate of the true toxicity of these drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, hypertensive rats, and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.</p> / Master of Science (MSc)
67

Deciphering The Contribution Of Microglia To Neurodegeneration In Friedreich's Ataxia

Gillette, Sydney N 01 June 2024 (has links) (PDF)
Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia, affecting one in every 50,000 individuals in the United States. This hereditary condition is caused by an abnormal GAA trinucleotide repeat expansion within the first intron of the frataxin gene resulting in decreased levels of the frataxin protein (FXN). Insufficient cellular frataxin levels results in iron accumulation, increased reactive oxygen species production and mitochondrial dysfunction. Tissues most heavily impacted are those most dependent on oxidative phosphorylation as an energy source and include the nervous system and muscle tissue. This is evident in the clinical phenotype which includes muscle weakness, ataxia, neurodegeneration and cardiomyopathy. However, there has been a lack of data regarding the cell type specific contributions in FRDA pathogenesis. We generated a cohort of induced pluripotent stem cells (iPSCs) consisting of FRDA patient lines, CRISPR-Cas9 edited controls, carriers and non-related controls. Our preliminary data identified a hyperinflammatory microglial phenotype with extensive defects in mitochondrial function; since microglia are the primary innate immune cell of the brain, we hypothesized microglia may decrease neuronal viability which contributes to FRDA pathology. To investigate this, the iPSC cohort was utilized to generate microglia (iMGs) and neurons to better understand microglia-mediated neurodegeneration and how this contributes to pathology. An in vitro co-culture model composed of neurons, astrocytes and microglia was employed to better understand microglia-neuronal communication in FRDA. Healthy neurons co-cultured with FRDA iMG or with FRDA iMG-conditioned media demonstrated higher incidences of caspase-3 mediated apoptosis. These findings were recapitulated in vivo as xenotransplantation of FRDA microglia progenitors into a murine model resulted in reduced Purkinje cell survival in the cerebellum. Previous research has demonstrated the therapeutic potential of wildtype microglia to rescue the FRDA phenotype in the Y8GR mouse model of FRDA. To further explore the potential mechanisms behind this rescue, the delivery of mitochondria and FXN to FRDA microglia and neurons was investigated. CRISPR-Cas9 edited microglia demonstrated transfer of healthy mitochondria to FRDA microglia and neurons in an in vitro co-culture model. To investigate the transfer of frataxin protein, an FRDA iPSC line was transduced with an FXN-GFP lentivirus. Restoring FXN expression was demonstrated to rescue the FRDA microglial morphological phenotype. FXN-GFP microglia demonstrated transfer of frataxin protein to FRDA microglia suggesting the potential role of microglia as a therapeutic vehicle in FRDA. Together these findings show that FRDA microglia have a deleterious effect on neuronal viability, while healthy microglia may work as a therapeutic vehicle through the delivery of mitochondria and frataxin to FRDA cells.
68

CHRONIC PANCREATITIS, PAIN, AND ANXIETY IN AN ALCOHOL AND HIGH FAT MOUSE MODEL

Clinkinbeard, Tiffanie 01 January 2016 (has links)
Homeodynamic space (HDS) shrinks as vulnerability increases with aging and repeated damage to the cells. HDS is lost in alcoholic pancreatitis patients due to overconsumption of alcohol, smoking, and high fat diets. Etiologically relevant animal models for study of chronic pancreatitis (CP) are needed. In order to begin filling this gap a central purpose of this dissertation research was to examine relationships between the alcohol and high fat diet (AHF) and pancreatitis with attention to hypersensitivity and anxiety-like behaviors. The AHF diet induced pancreatitis described here etiologically mimics human risk factors of AHF consumption for advancement to alcoholic CP. In this study one group of mice was fed long term with a diet of high fat and alcohol for comparison with a group fed normal chow. Mice consumed a liquid diet containing 6% alcohol and a high fat supplement ad libitum over a period of five months. Each group was evaluated for heat and mechanical hypersensitivity, and histology indicative of CP. The association of pancreatitis pathology with anxiety has been understudied. Anxiety, like pain, is useful as a transient state but when anxiety is prolonged it is termed a disorder. Anxiety is often comorbid with pain and depression. Therefore, it is important to determine anxiety in mice with CP histology. This model was characterized for the interaction of pancreatitis histology, as well as persisting pain-, anxiety-, and fear-like behaviors. The AHF diet mice developed hypersensitivity, demonstrated anxiety-like behaviors, and showed concurrent histology consistent with CP. Nontransgenic mouse models where pancreatitis is induced only by a combination of ad libitum liquid food with added alcohol and lard supplementation do not currently exist, nor has an in-depth study of anxiety-like behaviors been conducted in this mouse model. This dissertation research addresses this knowledge gap.
69

Analysis of the Role of Astrocyte Elevated Gene-1 in Normal Liver Physiology and in the Onset and Progression of Hepatocellular Carcinoma

Robertson, Chadia L 01 January 2014 (has links)
First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction pathways such as mitogen-activated protein extracellular kinase (MEK)/ extracellular signal-regulated kinase (ERK), phosphotidyl-inositol-3-kinase (PI3K)/Akt/mTOR, NF-κB and Wnt/β-catenin pathway. In addition, studies show that AEG-1 not only alters global gene and protein expression profiles, it also modulates fundamental intracellular processes, such as transcription, translation and RNA interference in cancer cells most likely by functioning as a scaffold protein. The mechanisms by which AEG-1 is overexpressed in cancer have been studied extensively and it is clear that multiple layers of regulation including genomic amplification, transcriptional, posttranscriptional, and posttranslational controls are involved however; the mechanism by which AEG 1 itself induces its oncogenic effects is still poorly understood. Just as questions remain about the exact role of AEG-1 in carcinogenesis, very little is known about the role of AEG-1 in regulating normal physiological functions in the liver. With the help of the Massey Cancer Center Transgenic/Knockout Mouse Core, our lab has successfully created a germline-AEG-1 knockout mouse (AEG-1-/-) as a model to interrogate AEG-1 function in vivo. Here I present the insights gained from efforts to analyze this novel AEG-1-/- mouse model. Aspects of the physiological functions of AEG-1 will be covered in chapter two wherein details of the characterization of the AEG-1-/- mouse are described including the role of AEG-1 in lipid metabolism. Chapter three discusses novel discoveries about the specific role of AEG-1 in mediating hepatocarcinogenesis by modulating NF-κB, a critical inflammatory pathway. First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction pathways such as mitogen-activated protein extracellular kinase (MEK)/ extracellular signal-regulated kinase (ERK), phosphotidyl-inositol-3-kinase (PI3K)/Akt/mTOR, NF-κB and Wnt/β-catenin pathway. In addition, studies show that AEG-1 not only alters global gene and protein expression profiles, it also modulates fundamental intracellular processes, such as transcription, translation and RNA interference in cancer cells most likely by functioning as a scaffold protein. The mechanisms by which AEG-1 is overexpressed in cancer have been studied extensively and it is clear that multiple layers of regulation including genomic amplification, transcriptional, posttranscriptional, and posttranslational controls are involved however; the mechanism by which AEG 1 itself induces its oncogenic effects is still poorly understood. Just as questions remain about the exact role of AEG-1 in carcinogenesis, very little is known about the role of AEG-1 in regulating normal physiological functions in the liver. With the help of the Massey Cancer Center Transgenic/Knockout Mouse Core, our lab has successfully created a germline-AEG-1 knockout mouse (AEG-1-/-) as a model to interrogate AEG-1 function in vivo. Here I present the insights gained from efforts to analyze this novel AEG-1-/- mouse model. Aspects of the physiological functions of AEG-1 will be covered in chapter two wherein details of the characterization of the AEG-1-/- mouse are described including the role of AEG-1 in lipid metabolism. Chapter three discusses novel discoveries about the specific role of AEG-1 in mediating hepatocarcinogenesis by modulating NF-κB, a critical inflammatory pathway.
70

Dispers?o da febre amarela entre primatas n?o-humanos durante epizootia no Rio Grande do Sul : entendendo o papel de fatores abi?ticos, da paisagem e da presen?a de animais imunes para propor cen?rios futuros de reemerg?ncia da doen?a

Almeida, Marco Ant?nio Barreto de 22 March 2018 (has links)
Submitted by PPG Zoologia (zoologia-pg@pucrs.br) on 2018-08-01T18:22:00Z No. of bitstreams: 1 Almeida MAB___TESE___VERS?O FINAL.pdf: 2953118 bytes, checksum: 99cbefa9c38c7969abce4bafc4b20d54 (MD5) / Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2018-08-02T17:55:11Z (GMT) No. of bitstreams: 1 Almeida MAB___TESE___VERS?O FINAL.pdf: 2953118 bytes, checksum: 99cbefa9c38c7969abce4bafc4b20d54 (MD5) / Made available in DSpace on 2018-08-02T18:39:41Z (GMT). No. of bitstreams: 1 Almeida MAB___TESE___VERS?O FINAL.pdf: 2953118 bytes, checksum: 99cbefa9c38c7969abce4bafc4b20d54 (MD5) Previous issue date: 2018-03-22 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Nonhuman primates (NHP) are susceptible to many arboviruses, including the yellow fever (YF) virus. Although native to Africa, this virus found susceptible NHP and competent mosquito vectors for maintaining its transmission in American forests. A high sensitivity of NHP to YF led health agencies to monitor these animals as a way of monitoring the disease in Brazil. The State of Rio Grande do Sul (RS) began this surveillance in 2002, which has detected the arboviruses Oropouche and Saint Louis (SLEV) and a YF epizootic that killed more than 2,000 NHP (Alouatta caraya and A. guariba clamitans) between 2008 and 2009. The objectives of this PhD thesis research were to generate models of niche suitability for YF based on that epizootic and prospect arboviruses in NHP in northwestern RS. The maximum entropy algorithm - Maxent was used to generate distribution models of Alouatta spp. and the mosquito vector Haemagogus leucocelaenus. Together with climatic, topographic and vegetative variables, these models served as predictor layers to model the occurrence of the disease based on the points of death of NHP of YF. The most influential variables in the YF models were the variation in air humidity, distribution of Alouatta spp. and maximum wind speed followed by mean annual rainfall and maximum temperature. Therefore, support for the influence of the rainfall regime and the ambient temperature on the cycle of jungle YF was found. Wind speed and direction can play an important role in the dispersal of infected mosquitoes and, consequently, the virus. The models based on the occurrence of dead NHP in the first months of the epizootic identified suitable areas to where the disease spread a few months later. In addition, 19 arboviruses were prospected in 40 blood (viral isolation and PCR) and serum (hemagglutination inhibition and neutralization tests [NT]) samples collected from 26 black howler monkeys (A. caraya) belonging to three populations in four field campaigns in the municipality of Santo Ant?nio das Miss?es, RS, between 2014 and 2016. There was no detection of circulating virus, but antibodies to Flavivirus SLEV and Ilh?us and Phlebovirus Icoaraci was found by NT. Evidence of the contact with Ilh?us and Icoaraci are the southernmost records in Brazilian NHP. An increase in antibodies to SLEV detected between two consecutive captures of the same individual is compatible with a recent contact with the virus. An adult male captured in one of the areas presented concomitant infection by the Oropouche, SLEV and YF viruses by NT. Further studies are necessary to understand the role played by NHP and other vertebrates in the circulation of arboviruses in the region, to assess potential risks to NHP and public health, and to identify the driving forces responsible for the dispersal of the YF virus during epizootics in wildlife populations. / Os primatas n?o-humanos (PNH) s?o suscet?veis a diversos arbov?rus, incluindo o v?rus da febre amarela (FA). Embora origin?rio da ?frica, esse v?rus encontrou PNH suscet?veis e mosquitos vetores competentes para sua transmiss?o em matas nas Am?ricas. Uma alta sensibilidade dos PNH ? FA levou ?rg?os de sa?de a monitorar esses animais como forma de vigiar a doen?a no Brasil. O Estado do Rio Grande do Sul (RS) iniciou essa vigil?ncia em 2002, a qual detectou os arbov?rus Oropouche e Saint Louis (SLEV) e uma epizootia de FA que matou mais de 2000 PNH (Alouatta caraya e A. guariba clamitans) entre 2008 e 2009. A presente tese de doutorado teve como objetivos gerar modelos de adequabilidade ambiental para FA com base nessa epizootia e prospectar arbov?rus em PNH no noroeste do RS. Foi utilizado o algoritmo de m?xima entropia ? Maxent para gerar modelos de distribui??o de Alouatta spp. e do mosquito vetor Haemagogus leucocelaenus. Esses modelos serviram como camadas preditoras para, junto a vari?veis clim?ticas, topogr?ficas e vegetacionais, modelar a ocorr?ncia da doen?a baseada nos pontos de morte de PNH por FA. As vari?veis mais influentes nos modelos da FA foram a varia??o na umidade do ar, a distribui??o de Alouatta spp. e a velocidade m?xima dos ventos, seguidas pela precipita??o m?dia anual e a temperatura m?xima. Portanto, foi confirmado suporte para a influ?ncia do regime de chuvas e da temperatura ambiente no ciclo da FA silvestre. A velocidade e a dire??o do vento devem desempenhar um importante papel na dispers?o de mosquitos infectados e, consequentemente, do v?rus. Os modelos baseados na distribui??o espacial de PNH mortos nos primeiros meses da epizootia identificaram ?reas adequadas para onde a doen?a avan?ou poucos meses mais tarde. Tamb?m foram prospectados 19 arbov?rus em 40 amostras de sangue (isolamento viral e PCR) e soro (inibi??o da hemaglutina??o e testes de neutraliza??o [NT]) coletadas em quatro campanhas de campo entre 2014 e 2016 de 26 bugios-pretos (A. caraya) de tr?s popula??es no munic?pio de Santo Ant?nio das Miss?es, RS. N?o houve detec??o de v?rus circulante, mas sim de anticorpos para os Flavivirus SLEV e Ilh?us e o Phlebovirus Icoaraci por NT. As evid?ncias de contato com Ilh?us e Icoaraci s?o as primeiras em PNH no extremo sul do Brasil. Um aumento de anticorpos para SLEV detectado entre duas capturas consecutivas do mesmo indiv?duo ? compat?vel com um contato recente com o v?rus. Um macho adulto capturado em uma das ?reas apresentou infec??o concomitante pelos v?rus Oropouche, SLEV e FA por NT. Mais estudos s?o necess?rios para compreender o papel de PNH e outros vertebrados na circula??o de arbov?rus na regi?o, avaliar poss?veis riscos para PNH e a sa?de humana e identificar as for?as motrizes respons?veis pela dispers?o do v?rus da FA durante epizootias em popula??es selvagens.

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