43 research outputs found
Talk2Me
No full textThis paper describes an interactive installation work set in a large dome space. The installation is an audio and physical re-rendition of an interactive writing work. In the original work, the user interacted via keyboard and screen while online. This rendition of the work retains the online interaction, but also places the interaction within a physical space, where the main 'conversation' takes place by the participant-audience speaking through microphones and listening through headphones. The work now also includes voice and SMS input, using speech-to-text and text-to-speech conversion technologies, and audio and displayed text for output. These additions allow the participant-audience to co-author the work while they participate in audible conversation with keyword-triggering characters (bots). Communication in the space can be person-to-computer via microphone, keyboard, and phone; person-to-person via machine and within the physical space; computer-to- computer; and computer-to-person via audio and projected text. Copyright 2006 ACM
Interferon stimulation creates chromatin marks and establishes transcriptional memory
No full textEpigenetic memory for signal-dependent transcription has remained elusive. So far, the concept of epigenetic memory has been largely limited to cell-autonomous, preprogrammed processes such as development and metabolism. Here we show that IFN beta stimulation creates transcriptional memory in fibroblasts, conferring faster and greater transcription upon restimulation. The memory was inherited through multiple cell divisions and led to improved antiviral protection. Of similar to 2,000 IFN beta-stimulated genes (ISGs), about half exhibited memory, which we define as memory ISGs. The rest, designated nonmemory ISGs, did not show memory. Surprisingly, mechanistic analysis showed that IFN memory was not due to enhanced IFN signaling or retention of transcription factors on the ISGs. We demonstrated that this memory was attributed to accelerated recruitment of RNA polymerase II and transcription/chromatin factors, which coincided with acquisition of the histone H3.3 and H3K36me3 chromatin marks on memory ISGs. Similar memory was observed in bone marrow macrophages after IFN. stimulation, suggesting that IFN stimulation modifies the shape of the innate immune response. Together, external signals can establish epigenetic memory in mammalian cells that imparts lasting adaptive performance upon various somatic cells
The etiology of esophageal cancer in high- and low- risk areas of Jiangsu province, China
No full text [Background]Esophageal cancer (EC) remains one of the most common and fatal malignancies worldwide. The geographic variation in EC occurrence is striking, and China is an area with one of the highest incidences of EC. A number of epidemiological studies have been conducted toward EC in the past decades, results suggested that tobacco smoking, alcohol drinking, unhealthy dietary factors and chronic injuries of the esophageal mucosa are important in the development of this disease. Genetic polymorphisms in enzymes involved in metabolism of carcinogens may also influence individual susceptibility. However, the effects of major lifestyle and hereditary risk factors on the development of EC remain poorly understood in China. Moreover, little attention has been paid to the etiological heterogeneity between similar areas with great risk gradient. [Methods]From 2003 to 2007, a large population-based case-control study of EC has been conducted in a selected high-risk area and a selected low-risk area of Jiangsu Province, one of the highest cancer incidence areas in China. In total, 1,520 cases and 3,879 controls were recruited. In this thesis, we evaluated the role of major lifestyle factors such as tobacco smoking, alcohol drinking and dietary factors, as well as inherited determinants including family history of cancer and genetic polymorphisms of alcohol-metabolizing related genes on the risk of EC. In addition, we investigated how much of the risk gradient between two areas could be explained by variation in the distributions of major risk factors. [Results] Tobacco smoking and alcohol drinking moderately increased the risk of EC, while the positive associations were only found among men but not among women. Dietary factors were observed to play important roles in the development of EC. Specific dietary habits i.e., fast eating speed, and hot eating and/or drinking substantially elevated EC risk and could explain more than 20% of EC cases each. High intake of salty foods and fried foods, low consumption of raw garlic were also observed to increase the risk of EC. In addition to environmental and lifestyle factors, we confirmed that a positive family history can significantly increase EC risk, and found the inheritance may modify the effect of some unhealthy lifestyles. Moreover, we further explored the relationship between EC and single nucleotide polymorphismsof ADH1B, ADH1C and ALDH2 genes. Results showed that the slow metabolizing ADH1B G allele, ADH1C G allele and ALDH2 A allele significantly increased EC risk among moderate-to-heavy alcohol drinkers, and a significant interaction was observed between ALDH2 gene and alcohol consumption. Lastly, we found that more than 60% of EC cases could be attributable to major lifestyle risk factors in the study population; furthermore, dissimilar distribution of several lifestyle factors, together with variations of hereditary factors may be largely responsible for the incidence difference between two study areas. [Conclusion]The findings in this thesis confirm that unhealthy lifestyles including smoking, alcohol drinking and some dietary factors are the predominant risk factors of EC in China, and a large proportion of incidence difference between regions at varying risk could be attributed to the different prevalence of lifestyle factors. As most of the identified risk factors are modifiable, these could be translated into risk reduction prevention programs in China, and a substantial proportion of new EC cases are expected to be prevented by eliminating or avoiding these risk factors in the population. </p
Investigação de alterações no nível e na ativação de proteínas cinases no neocórtex e no hipocampo de camundongos submetidos ao modelo de kindling por pentilenotetrazol
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Neurociências, Florianópolis, 2014.A epileptogênese é um processo que envolve a sinalização celular e a neuroplasticidade. As proteínas cinases ativadas por mitógenos, MAPKs (subfamílias ERK1/2, JNK1/2 e p38MAPK), a fosfatidil-inositol 3-cinase (PI3K)/Akt (PKB ou Akt) e a glicogênio sintase cinase-3? (GSK-3?) regulam uma variedade de eventos intracelulares envolvidos na diferenciação, sobrevivência e morte celular e na plasticidade sináptica. Nós quantificamos através de western blotting, os níveis de MAPKs (ERK1/2, JNK1/2 e p38MAPK), Akt e GSK-3? totais e fosforiladas no neocórtex e no hipocampo de camundongos Swiss machos, 48 h após a última injeção do modelo de kindling por pentilenotetrazol (PTZ, 35 mg/kg, i.p., em dias alternados, total de 8 injeções). Os níveis totais das proteínas cinases nas estruturas estudadas não foram afetados pelo kindling por PTZ. Os níveis de MAPKs fosforiladas permaneceram inalterados nos animais que não apresentaram crises convulsivas. Os níveis de JNK2 fosforilada, mas não de JNK1 fosforilada, aumentaram no hipocampo dos animais que apresentaram poucos dias com crise convulsiva (1 a 3 dias), e permaneceram semelhantes aos controles nos animais que apresentaram mais de três dias com crise convulsiva. Os níveis de ERK1/2 fosforiladas diminuíram no neocórtex e aumentaram no hipocampo de animais com 1 a 4 dias com crise convulsiva, e permaneceram inalterados nos animais que tiveram mais de 4 dias com crise convulsiva. Já a GSK-3? teve os seus níveis de fosforilação aumentados no neocórtex, mas não no hipocampo, nos animais que tiveram de 0 a 3 dias com crise convulsiva, caindo drasticamente para níveis inferiores ao controle nos animais que apresentaram 4 ou mais dias com crise convulsiva. Uma regressão linear múltipla mostrou que 85% da variação na progressão do kindling por PTZ foi explicada pela latência para a ocorrência da crise no primeiro e no último dia de estimulação e pelos níveis de GSK-3? fosforilada no neocórtex. A análise também mostrou que 87% da variação na latência para a ocorrência da última crise convulsiva é explicada pela latência para a ocorrência da primeira crise convulsiva, progressão do kindling, níveis de GSK-3? fosforilada no neocórtex e de Akt fosforilada no hipocampo. Utilizando apenas os animais que evoluíram para o kindling evidenciou-se que os níveis de ERK1 fosforilada, JNK2 fosforilada, JNK1 total e JNK1 fosforilada no hipocampo estiveram independentemente associados negativa ou positivamente ao número de dias com crise convulsiva. No mesmo grupo de animais, apenas o nível de p38MAPK fosforilada no neocórtex esteve associado, positivamente, à latência para a ocorrência da crise convulsiva na última estimulação com PTZ. Os resultados do presente estudo sugerem uma dissociação entre os níveis cerebrais regionais de MAPKs, GSK-3? e Akt associados à epileptogênese (progressão do kindling) e ao limiar (latência) para a ocorrência da crise convulsiva em animais sensibilizados pelo PTZ. Esta dissociação pode contribuir para o entendimento da ausência de efeito anti-epileptogênico clinicamente relevante dos fármacos utilizados para o controle das crises epilépticas.Abstract : Epileptogenesis is a process that involves neuroplasticity and cellular signaling. The mitogen-activated protein kinases, MAPKs (subfamilies ERK1/2, JNK1/2, and p38MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt (PKB or Akt) and glycogen synthase kinase-3? (GSK-3?) regulate a variety of intracellular events involved in the cell differentiation, survival and death and synaptic plasticity. Herein we quantified by Western blotting the phosphorylation and total levels of MAPKs (ERK1/2, JNK1/2, and p38MAPK), Akt and GSK-3? in the neocortex and hippocampus from male Swiss mice, 48 hours after the last injection of the kindling pentylenetetrazol procedure (PTZ, 35 mg/kg, i.p., on alternate days, in a total of 8 injections). The total levels of such protein kinases in the investigated structures were not altered by PTZ kindling. The total levels of MAPKs were unchanged in animals that did not develop convulsive seizures. The levels of JNK2 phosphorylation, but not JNK1 phosphorylation, increased in the hippocampus of animals with fewer days with convulsive seizures (1-3 days), and remained similar to controls in animals that had more than three days with convulsive seizures. The levels of ERK1/2 phosphorylation decreased in the neocortex and increased in the hippocampus of animals with 1 to 4 days with convulsive seizures and remained unchanged in animals that had more than 4 days with convulsive seizures. The phosphorylation levels of GSK-3? was increased in the neocortex, but not in the hippocampus, in animals with 0-3 days with convulsive seizures, and reduced drastically in animals with 4 or more days with convulsive seizures. A multiple linear regression analysis showed that 85% of the kindling progression variance is explained by the latencies for the first and the last days with convulsive seizures and the neocortical levels of GSK-3? phosphorylation. This analysis also showed that 87% of the variance in the latency for the last day with convulsive seizure is explained by the latency for the first days with convulsive seizure, kindling progression, neocortical GSK-3? phosphorylation and hippocampal Akt phosphorylation. Analyzing only the animals that developed kindling, we showed that the levels of total ERK1, total JNK1, ERK1 phosphorylation and JNK1 phosphorylation in the hippocampus were independently associated with the number of days with convulsive seizures. In the same group of animals, only the level of p38MAPK phosphorylation in the neocortex was positvely or negatively associated with the latency to the occurrence of convulsive seizure in the last stimulation day with PTZ. These findings suggest dissociation between the MAPKs, GSK-3? and Akt regional brain levels and the seizure threshold and kindling progression in mice. These results may contribute to explain the absence of clinically relevant anti-epileptogenic effects of drugs currently used to treat seizures
Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity
No full text(Cell Stem Cell 20, 518–532.e1–e9; April 6, 2017) In the originally published version of this manuscript, Caroline Hendry was inadvertently excluded from the author list. Her contributions to the work included the following: the development of SOPs for the relatively novel Sendai virus infection method for reprogramming; the design and implementation of studies to assess the variation among lines derived from a single donor (which included up to 14 lines per donor and analyses at both the iPSC stage and post-differentiation); and, together with S.L.D. and P.C., contributing to the development of an optimized workflow for the characterization of a large library of human iPSC lines, the creation and isolation of iPSCs, the performance of quality control for pluripotency markers, the serial passaging of each line for at least 12 passages, the verification that said lines were Sendai-free, the freezing down of cells at every split, the active maintenance of databases to catalogue the large number of lines and splits, and the preparation of these cells for RNA-seq analysis to be performed by members of the E.E.S. lab. All of these studies were performed to optimize the workflow that underpinned the project, and hence, the paper. All of the authors on the original author list, excluding those who are unable to be contacted and those who are deceased, have given their consent for Dr. Hendry's addition. The corrected author list is now included with this statement and the original manuscript online
Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass:Findings from the LACE sarcopenia trial
No full textIntroduction: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722–9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. Methods: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants’ blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. Results: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9–1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019).Conclusion: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass
Colorectal cancer: a comparative study of models of health care delivery in two adjacent trusts in South Wales
No full textIntroduction
Survival in colorectal cancer patients is dependant on the stage of the cancer at diagnosis. Referral via an appropriate pathway to a specialist service is vital to the early detection of colorectal cancer but there is neither a standard referral system nor a nationally agreed referral pathway in the UK. Though studies have compared individual components of different models of health care in colorectal cancer, this is the first study comparing two models in their entirety.
Hypothesis
The distinct model of service delivery in Trust A picks up a higher percentage of early colorectal cancers than the model of service delivery in Trust B.
Method
The study compares colorectal cancers diagnosed from two adjacent Trusts in Wales during a three year period. The samples obtained after rigid exclusions correlate the two models of health care with the stage of cancer at diagnosis.
Results
Trust A has a higher emergency and urgent workload. The overall pick up of early cancers is similar in both Trusts. However, there is a higher pick up rate of early colorectal cancer in Trust A, when GPs accessed the specialist service using an urgent referral through the elective route. Trust A had lower overall waiting times for the first clinic appointment but there was no difference for urgent cases between the two Trusts. Specialists in Trust B had a higher rate of re-prioritisation of urgent GP referrals to the non urgent category.
Conclusion
There appears to be no significant difference in the overall pick-up rate of modified Dukes’ A colorectal cancers between the two models of health care delivery. The higher pick up rate of early colorectal cancer in Trust A was achieved only where GPs sent patients into the specialist service using an urgent referral through the elective route
Modelagem de sistema de conhecimento para apoio a decisão sentencial na justiça estadual
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia e Gestão do Conhecimento, Florianópolis, 2012O papel de manutenção do estado de direito exercido pelo poder judiciário, guardando a constituição e suas leis, julgando conflitos de interesses e mantendo a ordem social, deve ser prestado de forma a atender o cidadão e empresas de forma adequada. Um dos principais pontos a ser considerado é a luta contra a morosidade do judiciário, ou seja, alcançar celeridade razoável nos processos. O processo eletrônico diminuiu o tempo de trâmite judicial diminuindo tempo "morto", como por exemplo, montagem da pasta do processo, numeração de páginas e, principalmente com o trânsito físico das peças processuais. Observa-se que, para uma maior diminuição do tempo de trâmite dessas ações, é necessário uso adequado dos recursos do tribunal e aumento de desempenho no processo decisório sentencial, atividades intensivas de conhecimento. Esse trabalho tem como objetivo levantar o contexto organizacional, identificando as atividades intensivas de conhecimento e definir modelagem de Sistema de Conhecimento para auxiliar o processo decisório, no âmbito da justiça estadual. Foram levantadas aplicações de engenharia de conhecimento aplicadas ao judiciário e a partir desta revisão de literatura, gerar base para modelo de sistema de conhecimento. Para modelagem do sistema organizacional "Tribunal de Justiça do Estado do Amazonas" foi aplicado modelo CESM, de modo a estabelecer componentes, estrutura, ambiente e mecanismos deste, para entendimento de sua complexidade. A metodologia CommomKADS foi aplicada de forma a levantar o contexto organizacional, assim como os conceitos a serem concebidos para a resolução dos problemas e aproveitamento de oportunidade, bem como definições do projeto do artefato, ou seja, do Sistema de Conhecimento. A partir da metodologia foram estabelecidos modelo de organização, onde podem ser definidos os problemas e oportunidades, que podem ou não ser relacionadas a atividades intensivas de conhecimento, identificando, portanto, ativos de conhecimento aplicados. O Modelo de Tarefa descreve os processos do TJ/AM, identificando o uso do conhecimento e uma crítica com relação a sua aplicação correta. O modelo de agente oferece levantamento dos agentes, humanos ou de software. Com base nesses modelos é apresentado o contexto e definido o conceito do sistema de conhecimento, através dos modelos de conhecimento, que descreve a aplicação do mesmo nas tarefas, e os modelos de comunicação, que define a interação entre os agentes. A partir disto é definido o projeto do software, definindo um artefato. Desta forma, este trabalho contribui com a academia demonstrando quais atividades intensivas de conhecimento carecem de melhorias para melhorar o desempenho do judiciário, a aplicação de técnicas de engenharia de conhecimento para tal identificação, bem como apresenta uma sistemática de recuperação de documentos aplicada ao judiciário, de modo a melhorar o processo decisório e impactar positivamente com a diminuição temporal do trâmite judicial.Abstract : The duty of maintaining the rule of law applied by the judiciary board, watching the constitution and its laws, judging conflicts of interest and maintaining the social order, must be provided to meet the citizens and businesses needs properly. One of the main points to be considered is the fight against the slowness of the judiciary; in other words, achieve reasonable quickness in the processes. The electronic process reduced the judicial proceeding time, allowing to diminish "dead time", for example, assembly the process files, page numbering, and mainly with the physical transit of procedural parts. Notice that, to a greater reduction in length of these pending actions, it is necessary a correct use of resources of the court and increase the performance in decisionmaking judgment, intensive knowledge activities. This essay aims to raise the organizational context, identifying the intensive knowledge activities and define the Knowledge System pattern to support the decision-making process within the state courts. It has brought up engineering applications expertise applied to the judiciary and from this literature review, to generate a pattern to the knowledge system model. For the organizational system pattern "Court of justice of the State of Amazonas" the CESM model was applied in order to establish the components, structure, and mechanisms of this environment to understand its complexity. The CommomKADS methodology was applied to raise the organizational context as well as the concepts to be designed to solve problems and exploit opportunities, as well as the design definitions of the artifact, in other words, the Knowledge System. From this methodology, it was established organization models, where it can define problems and opportunities, which may or may not be related to knowledge intensive activities, so identifying applied knowledge assets. The task model describes the processes of the CJ/AM, identifying the use of knowledge and a review about its correct application. The instrument model provides a study about the human agents or software. Based on these models the context is presented and it is defined the concept of the knowledge system, through the knowledge systems models, which describes its application during the tasks, as well as the communication models that define the interaction between the agents. Thenceforth, it is defined the software design, outlining an artifact. Thus, this study contributes to the academy demonstrating which intensive knowledge activities need to be improved to enhance the performance of the judiciary, and the application of engineering knowledge techniques to such identification, even as presents systematic document retrieval applied to the judiciary to improve decision-making processes and impacting positively with the decrease in length of pending actions
Erratum: The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma (Cell Reports (2018) 23(1) (313–326.e5) (S2211124718304364) (10.1016/j.celrep.2018.03.075))
No full text(Cell Reports 23, 313–326; April 3, 2018) In the originally published version of this article, the author list contained two errors. Specifically, David J. Kwiatkowski was misspelled as David J. Kwaitkowski, and William Y. Kim was inadvertently written as William T. Kim. Both names have been corrected online. The authors regret this error
The interferon alpha receptor utilises T-cell receptor-associated proteins for signalling
No full textThe interferon alpha receptor (IFNAR) and T-cell receptor (TCR) are expressed upon the T-cell surface. The dimeric Class I interferon receptor is a cytokine receptor that recognises interferons such as IFNα. Interferons (IFNs) are pluripotent, antiviral cytokines that causes
antiproliferative effects, primarily through Jak/STAT signalling. The T-cell receptor is an antigenic receptor that recognises antigenically-derived peptides in the context of the MHC complex located on an antigen presenting cell, resulting in a cellular proliferation.
Although both receptors elicit opposing cellular outcomes, both the TCR and IFNAR activate the ERK MAPK signalling pathway, albeit with a different time course.
Furthermore, studies have shown that the IFNAR and TCR utilise an overlapping subset of proteins for this pathway to occur such as CD45, Lck and Zap70.
In this study evidence is presented to show that two further TCR-associated proteins are phosphorylated in response to the IFNAR; the 95kDa guanosine nucleotide exchange factor, Vav, and the 76kDa adaptor protein Slp76. This proceeds in a similar manner to that observed at the TCR. Furthermore, the absence of either protein impairs IFNAR-induced ERK MAPK signalling. The similarities between TCR and IFNAR signalling led to questioning of whether crosstalk occurs between the two receptors. To address this
possibility a TCRβ deficient cell line, which lacks functional TCR expression, was utilised.
It was demonstrated that the absence of the TCR completely abrogates the ERK MAPK response emanating from the IFNAR yet Jak/STAT signalling is unaffected. These results
highlight for the first time an intimate connection between the TCR and IFNAR
