The Design of A High Capacity and Energy Efficient Phase Change Main Memory

Higher energy-efficiency has become essential in servers for a variety of reasons that range from heavy power and thermal constraints, environmental issues and financial savings. With main memory responsible for at least 30% of the energy consumed by a server, a low power main memory is fundamental to achieving this energy efficiency DRAM has been the technology of choice for main memory for the last three decades primarily because it traditionally combined relatively low power, high performance, low cost and high density. However, with DRAM nearing its density limit, alternative low-power memory technologies, such as Phase-change memory (PCM), have become a feasible replacement. PCM limitations, such as limited endurance and low write performance, preclude simple drop-in replacement and require new architectures and algorithms to be developed. A PCM main memory architecture (PMMA) is introduced in this dissertation, utilizing both DRAM and PCM, to create an energy-efficient main memory that is able to replace a DRAM-only memory. PMMA utilizes a number of techniques and architectural changes to achieve a level of performance that is par with DRAM. PMMA achieves gains in energy-delay of up to 65%, with less than 5% of performance loss and extremely high energy gains. To address the other major shortcoming of PCM, namely limited endurance, a novel, low- overhead wear-leveling algorithm that builds on PMMA is proposed that increases the lifetime of PMMA to match the expected server lifetime so that both server and memory subsystems become obsolete at about the same time. We also study how to better use the excess capacity, traditionally available on PCM devices, to obtain the highest lifetime possible. We show that under specific endurance distributions, the naive choice does not achieve the highest lifetime. We devise rules that empower the designer to select algorithms and parameters to achieve higher lifetime or simplify the design knowing the impact on the lifetime. The techniques presented also apply to other storage class memories (SCM) memories that suffer from limited endurance

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Dissertação (Mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico

Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks

Decades of research have disclosed a plethora of alterations in protein glycosylation that decisively impact in all stages of disease and ultimately contribute to more aggressive cell phenotypes. The biosynthesis of cancer-associated glycans and its reflection in the glycoproteome is driven by microenvironmental cues and these events act synergistically toward disease evolution. Such intricate crosstalk provides the molecular foundations for the activation of relevant oncogenic pathways and leads to functional alterations driving invasion and disease dissemination. However, it also provides an important source of relevant glyco(neo)epitopes holding tremendous potential for clinical intervention. Therefore, we highlight the transversal nature of glycans throughout the currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the tumor microenvironment stromal components. Focus is also set on the pressing need to include glycans and glycoconjugates in comprehensive panomics models envisaging molecular-based precision medicine capable of improving patient care. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention

O Significado da Norma Jurídica Sob o Ponto de Vista da Metódica Estruturante e Sua Conexão com a Retórica: a Racionalização por Meio da Comunicação na Judicialização da Saúde

The discussion about the phenomenon of judicialization of public policies in Brazil, which has as a backdrop the idea of ​​normativity and effectiveness of social constitutional rights, such as the right to health, even at the expense of the budget and fiscal control parameters instituted by the system itself, has instigated questions about the conformation of meaning of the legal norm by the judicial system. Thus, with the intention of obtaining a realistic perception of the process of conformation of meaning of the legal norm and seeking to depart from the conceptions that see in social constitutional rights the ability to transport rational essences, this article, through an analytical perspective of law, aims to promote a critical and reflective study of the theoretical conceptions that endeavored to explain the process of constitution of the legal phenomenon and to share the philosophical and critical point of view of the rhetoric and of the Structuring Theory of Law formulated by Friedrich Müller. This is because the parameters offered by the idealist tradition of law, in any of its aspects, proved to be insufficient to explain how the conformation of meaning of legal discourses actually takes place. Partaking in the point of view of the rhetoric and of the Structuring Method, we understand that the law is rationalized through communication. We affirm, therefore, that, even though it is neither ontological nor essentialist, Friedrich Müller's structuring method is also not rhetorical, but shares several points of contact with this ancient way of understanding the legal phenomenon — in particular, the perception of the indissoluble connection between law and language.    A discussão acerca do fenômeno da judicialização de políticas públicas no Brasil, que tem como pano de fundo a ideia de normatividade e efetividade dos direitos constitucionais sociais, a exemplo do direito à saúde, ainda que ao alvedrio dos parâmetros de controle orçamentário e fiscal instituídos pelo próprio sistema, tem instigado questionamentos acerca da conformação de sentido da norma jurídica pelo Poder Judiciário. Assim, com a pretensão de obter uma percepção realista do processo de conformação de sentido da norma jurídica e procurando se apartar das concepções que enxergam nos direitos constitucionais sociais a aptidão de transportar essências racionais, este artigo, por meio de uma perspectiva analítica do direito, tem por objetivo promover um estudo crítico e reflexivo das concepções teóricas que se empenharam em explicar o processo de constituição do fenômeno jurídico e compartilhar o ponto de vista filosófico e crítico da retórica e da Teoria Estruturante do Direito formulada por Friedrich Müller. Isso porque, os parâmetros ofertados pela tradição idealista do direito, em qualquer se suas vertentes, revelaram-se insuficientes para explicar como efetivamente se dá a conformação de sentido dos discursos jurídicos. Comungando do ponto de vista da retórica e da Metódica Estruturante, compreendemos que o direito é racionalizado por intermédio da comunicação. Afirmamos, portanto, que, mesmo não sendo ontológica ou essencialista, a metódica estruturante de Friedrich Müller também não é retórica, mas possui diversos pontos de contato com essa forma milenar de compreender o fenômeno jurídico —­ em especial, a percepção da indissolúvel conexão entre direito e linguagem

Glycoengineered nanoparticles enhance the delivery of 5-fluoroucil and paclitaxel to gastric cancer cells of high metastatic potential

Gastric cancer is the third leading cause of cancer-related death worldwide, with half of patients developing metastasis within 5 years after curative treatment. Moreover, many patients cannot tolerate or complete systemic treatment due severe side-effects, reducing their effectiveness. Thus, targeted therapeutics are warranted to improve treatment outcomes and reduce toxicity. Herein, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with 5-fluorouracil (5-FU) and paclitaxel were surface-functionalized with a monoclonal antibody targeting sialyl-Lewis A (sLeA), a known glycan mediating hematogenous metastasis. Nanoparticles, ranging from 137 to 330 nm, enabled the controlled release of cytotoxic drugs at neutral and acid pH, supporting potential for intravenous and oral administration. Nanoencapsulation also reduced the initial toxicity of the drugs against gastric cells, suggesting it may constitute a safer administration vehicle. Furthermore, nanoparticle functionalization significantly enhanced targeting to sLeA cells in vitro and ex vivo (over 40% in comparison to non-targeted nanoparticles). In summary, a glycoengineered nano-vehicle was successfully developed to deliver 5-FU and paclitaxel therapeutic agents to metastatic gastric cancer cells. We anticipate that this may constitute an important milestone to establish improved targeted therapeutics against gastric cancer. Given the pancarcinomic nature of the sLeA antigen, the translation of this solution to other models may be also envisaged.publishe

P53 and Cancer-Associated Sialylated Glycans Are Surrogate Markers of Cancerization of the Bladder Associated with Schistosoma haematobium Infection

BACKGROUND: Bladder cancer is a significant health problem in rural areas of Africa and the Middle East where Schistosoma haematobium is prevalent, supporting an association between malignant transformation and infection by this blood fluke. Nevertheless, the molecular mechanisms linking these events are poorly understood. Bladder cancers in infected populations are generally diagnosed at a late stage since there is a lack of non-invasive diagnostic tools, hence enforcing the need for early carcinogenesis markers. METHODOLOGY/PRINCIPAL FINDINGS: Forty-three formalin-fixed paraffin-embedded bladder biopsies of S. haematobium-infected patients, consisting of bladder tumours, tumour adjacent mucosa and pre-malignant/malignant urothelial lesions, were screened for bladder cancer biomarkers. These included the oncoprotein p53, the tumour proliferation rate (Ki-67>17%), cell-surface cancer-associated glycan sialyl-Tn (sTn) and sialyl-Lewisa/x (sLea/sLex), involved in immune escape and metastasis. Bladder tumours of non-S. haematobium etiology and normal urothelium were used as controls. S. haematobium-associated benign/pre-malignant lesions present alterations in p53 and sLex that were also found in bladder tumors. Similar results were observed in non-S. haematobium associated tumours, irrespectively of their histological nature, denoting some common molecular pathways. In addition, most benign/pre-malignant lesions also expressed sLea. However, proliferative phenotypes were more prevalent in lesions adjacent to bladder tumors while sLea was characteristic of sole benign/pre-malignant lesions, suggesting it may be a biomarker of early carcionogenesis associated with the parasite. A correlation was observed between the frequency of the biomarkers in the tumor and adjacent mucosa, with the exception of Ki-67. Most S. haematobium eggs embedded in the urothelium were also positive for sLea and sLex. Reinforcing the pathologic nature of the studied biomarkers, none was observed in the healthy urothelium. CONCLUSION/SIGNIFICANCE: This preliminary study suggests that p53 and sialylated glycans are surrogate biomarkers of bladder cancerization associated with S. haematobium, highlighting a missing link between infection and cancer development. Eggs of S. haematobium express sLea and sLex antigens in mimicry of human leukocytes glycosylation, which may play a role in the colonization and disease dissemination. These observations may help the early identification of infected patients at a higher risk of developing bladder cancer and guide the future development of non-invasive diagnostic tests

Glycan affinity magnetic nanoplatforms for urinary glycobiomarkers discovery in bladder cancer

Bladder Cancer (BC) presents one of the highest recurrence rates amongst solid tumours and constitutes the second deadliest disease of the genitourinary track. Non-invasive identification of patients facing disease recurrence and/or progression remains one of the most critical and challenging aspects in disease management. To contribute to this goal, we demonstrate the potential of glycan-affinity glycoproteomics nanoplatforms for urinary biomarkers discovery in bladder cancer. Briefly, magnetic nanoprobes (MNP) coated with three broad-spectrum lectins, namely Concanavalin A (ConA; MNP@ConA), Wheat Germ Agglutinin (WGA; MNP@WGA), and Sambucus nigra (SNA; MNP@SNA), were used to selectively capture glycoproteins from the urine of low-grade and high-grade non-muscle invasive as well as muscle-invasive BC patients. Proteins were identified by nano-LC MALDI-TOF/TOF and data was curated using bioinformatics tools (UniProt, NetOGlyc, NetNGlyc, ClueGO app for Cytoscape and Oncomine) to highlight clinically relevant species. Accordingly, 63 glycoproteins were exclusively identified in cancer samples compared with healthy controls matching in age and gender. Specific glycoprotein sets exclusively found in low-grade non-muscle invasive bladder tumours may aid early diagnosis, while those only found in high-grade non-invasive and muscle-invasive tumours hold potential for accessing progression. Amongst these proteins is bladder cancer stem-cell marker CD44, which has been associated with poor prognosis. Orthogonal validation studies by slot-blotting demonstrated an elevation in urine CD44 levels of high-grade patients, which became more pronounced upon muscle-invasion, in mimicry of the primary tumour. These observations demonstrate the potential of MNP@lectins for identification of clinically relevant glycoproteomics signatures in bladder cancer. Future clinical validation in a larger and well characterized patient subset is required envisaging clinical translation of the results.publishe

P53 and cancer-associated sialylated glygans are surrogate markers of cancerization of the bladder associated with \u3ci\u3eSchistosoma haematobium\u3c/i\u3e infection

Background Bladder cancer is a significant health problem in rural areas of Africa and the Middle East where Schistosoma haematobium is prevalent, supporting an association between malignant transformation and infection by this blood fluke. Nevertheless, the molecular mechanisms linking these events are poorly understood. Bladder cancers in infected populations are generally diagnosed at a late stage since there is a lack of non-invasive diagnostic tools, hence enforcing the need for early carcinogenesis markers. Methodology/Principal Findings Forty-three formalin-fixed paraffin-embedded bladder biopsies of S. haematobium-infected patients, consisting of bladder tumours, tumour adjacent mucosa and pre-malignant/malignant urothelial lesions, were screened for bladder cancer biomarkers. These included the oncoprotein p53, the tumour proliferation rate (Ki-67\u3e17%), cell-surface cancer-associated glycan sialyl-Tn (sTn) and sialyl-Lewisa/x (sLea/sLex), involved in immune escape and metastasis. Bladder tumours of non-S. haematobium etiology and normal urothelium were used as controls. S. haematobium-associated benign/pre-malignant lesions present alterations in p53 and sLex that were also found in bladder tumors. Similar results were observed in non-S. haematobium associated tumours, irrespectively of their histological nature, denoting some common molecular pathways. In addition, most benign/pre-malignant lesions also expressed sLea. However, proliferative phenotypes were more prevalent in lesions adjacent to bladder tumors while sLea was characteristic of sole benign/pre-malignant lesions, suggesting it may be a biomarker of early carcionogenesis associated with the parasite. A correlation was observed between the frequency of the biomarkers in the tumor and adjacent mucosa, with the exception of Ki-67. Most S. haematobium eggs embedded in the urothelium were also positive for sLea and sLex. Reinforcing the pathologic nature of the studied biomarkers, none was observed in the healthy urothelium. Conclusion/Significance This preliminary study suggests that p53 and sialylated glycans are surrogate biomarkers of bladder cancerization associated with S. haematobium, highlighting a missing link between infection and cancer development. Eggs of S. haematobium express sLea and sLex antigens in mimicry of human leukocytes glycosylation, which may play a role in the colonization and disease dissemination. These observations may help the early identification of infected patients at a higher risk of developing bladder cancer and guide the future development of non-invasive diagnostic tests

Target Score-A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness

Esophageal cancer (EC) is a life-threatening disease, demanding the discovery of new biomarkers and molecular targets for precision oncology. Aberrantly glycosylated proteins hold tremendous potential towards this objective. In the current study, a series of esophageal squamous cell carcinomas (ESCC) and EC-derived circulating tumor cells (CTCs) were screened by immunoassays for the sialyl-Tn (STn) antigen, a glycan rarely expressed in healthy tissues and widely observed in aggressive gastrointestinal cancers. An ESCC cell model was glycoengineered to express STn and characterized in relation to cell proliferation and invasion in vitro. STn was found to be widely present in ESCC (70% of tumors) and in CTCs in 20% of patients, being associated with general recurrence and reduced survival. Furthermore, STn expression in ESCC cells increased invasion in vitro, while reducing cancer cells proliferation. In parallel, an ESCC mass spectrometry-based proteomics dataset, obtained from the PRIDE database, was comprehensively interrogated for abnormally glycosylated proteins. Data integration with the Target Score, an algorithm developed in-house, pinpointed the glucose transporter type 1 (GLUT1) as a biomarker of poor prognosis. GLUT1-STn glycoproteoforms were latter identified in tumor tissues in patients facing worst prognosis. Furthermore, healthy human tissues analysis suggested that STn glycosylation provided cancer specificity to GLUT1. In conclusion, STn is a biomarker of worst prognosis in EC and GLUT1-STn glycoforms may be used to increase its specificity on the stratification and targeting of aggressive ESCC forms