Development and application of operational techniques for the inventory and monitoring of resources and uses for the Texas coastal zone

The author has identified the following significant results. Four LANDSAT scenes were analyzed for the Harbor Island area test sites to produce land cover and land use maps using both image interpretation and computer-assisted techniques. When evaluated against aerial photography, the mean accuracy for three scenes was 84% for the image interpretation product and 62% for the computer-assisted classification maps. Analysis of the fourth scene was not completed using the image interpretation technique, because of poor quality, false color composite, but was available from the computer technique. Preliminary results indicate that these LANDSAT products can be applied to a variety of planning and management activities in the Texas coastal zone

PARÂMETROS Clínicos e Parasitológicos de Ovinos Mantidos em Confinamento Infectados Experimentalmente Com Larvas de Haemonchus Sp.

O objetivo deste trabalho foi estabelecer parâmetros parasitológicos que determinem a carga parasitária para intervenção anti-helmíntica, por meio de acompanhamento do comportamento parasitológico de grupos de ovinos mestiços Santa Inês infectados experimentalmente e não infectados (controle) com larvas de Haemonchus sp., mantidos sob sistema de confinamento total. O experimento foi conduzido no período de junho a agosto de 2013. Foram utilizados 14 ovinos machos inteiros, com peso corporal semelhante, livres de nematoides, que foram divididos em dois grupos com 7 animais cada. Posteriormente realizou-se a infecção experimental de um dos grupos com 10.000 larvas de Haemonchus sp., tendo com base os valores e recomendações estabelecidos pela World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.). As avaliações dos parâmetros (Ovos por grama de fezes, Famacha©, peso, proteínas plasmáticas totais e hematócrito) foram semanais, sendo a primeira iniciada 21 dias após a infecção, sendo, portanto os momentos de análise os dias zero (dia infecção) e 21, 28, 35, 42, 49, 56, 63 e 70. Ao término do período experimental, os animais foram abatidos e o trato gastrointestinal coletado para contagem e identificação dos parasitos adultos. Para o parâmetro OPG houve diferença significativa entre os grupos infectado e controle a partir do dia zero para todos os demais momentos analisados. No grupo infectado houve diferença significativa do dia zero para os demais, do dia 21 para os dias 28, 35 e 42 e do dia 35 e 42 para os dias 63 e 70. O hematócrito apresentou diferença significativa entre os grupos nos dias 21, 28, 35, 42, 49 e 63, e entre o dia zero e os dias 28, 35, 42, 56, 63 e 70 no grupo infectado. Para a variável Famacha ambos os grupos se mantiveram classificados como graus 1 e 2, ou seja sem sinais clínicos de anemia. As proteínas plasmáticas não apresentaram alterações entre os momentos ou entre os grupos durante todo o período experimental. Para variável peso também não foram constatadas diferenças entre os grupos em nenhum momento analisado. Os animais do grupo controle não apresentaram diferenças estatisticamente significativas entre os momentos durante todo o período experimental para todas as variáveis analisadas. A correlação entre OPG e número de parasitos adultos foi considerada forte (r = 0,93). A infecção experimental com 10.000 larvas de Haemonchus sp. não foi suficiente para alterar o estado de saúde geral dos animais nas condições estudadas e, portanto animais com OPG até 2500 não necessitam de intervenção anti-helmíntica quando em condições semelhantes as do presente trabalho

Quaternary structure of the specific p53-DNA complex reveals the mechanism of p53 mutant dominance

The p53 tumour suppressor is a transcriptional activator that controls cell fate in response to various stresses. p53 can initiate cell cycle arrest, senescence and/or apoptosis via transactivation of p53 target genes, thus preventing cancer onset. Mutations that impair p53 usually occur in the core domain and negate the p53 sequence-specific DNA binding. Moreover, these mutations exhibit a dominant negative effect on the remaining wild-type p53. Here, we report the cryo electron microscopy structure of the full-length p53 tetramer bound to a DNA-encoding transcription factor response element (RE) at a resolution of 21 Å. While two core domains from both dimers of the p53 tetramer interact with DNA within the complex, the other two core domains remain available for binding another DNA site. This finding helps to explain the dominant negative effect of p53 mutants based on the fact that p53 dimers are formed co-translationally before the whole tetramer assembles; therefore, a single mutant dimer would prevent the p53 tetramer from binding DNA. The structure indicates that the Achilles’ heel of p53 is in its dimer-of-dimers organization, thus the tetramer activity can be negated by mutation in only one allele followed by tumourigenesis

From 2-methylimidazole to 1,2,3-triazole: a topological transformation of ZIF-8 and ZIF-67 by post-synthetic modification

Bridging ligand replacement in zeolitic imidazolate frameworks, ZIF-8 and ZIF-67, by 1,2,3-triazole was investigated. A complete substitution of 2-methylimidazole by 1,2,3-triazole resulted in a topological transformation of the parent framework from a sodalite (SOD) network to a diamond (DIA) network

CP-31398, a putative p53-stabilizing molecule tested in mammalian cells and in yeast for its effects on p53 transcriptional activity

BACKGROUND: CP-31398 is a small molecule that has been reported to stabilize the DNA-binding core domain of the human tumor suppressor protein p53 in vitro. The compound was also reported to function as a potential anti-cancer drug by rescuing the DNA-binding activity and, consequently, the transcription activation function of mutant p53 protein in mammalian tissue culture cells and in mice. RESULTS: We performed a series of gene expression experiments to test the activity of CP-31398 in yeast and in human cell cultures. With these cell-based assays, we were unable to detect any specific stimulation of mutant p53 activity by this compound. Concentrations of CP-31398 that were reported to be active in the published work were highly toxic to the human H1299 lung carcinoma and Saos-2 cell lines in our experiments. CONCLUSION: In our experiments, the small molecule CP-31398 was unable to reactivate mutant p53 protein. The results of our in vivo experiments are in agreement with the recently published biochemical analysis of CP-31398 showing that this molecule does not bind p53 as previously claimed, but intercalates into DNA

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Automated Analysis of Risk Factors for Postictal Generalized EEG Suppression

Rationale: Currently, there is some ambiguity over the role of postictal generalized electro-encephalographic suppression (PGES) as a biomarker in sudden unexpected death in epilepsy (SUDEP). Visual analysis of PGES, known to be subjective, may account for this. In this study, we set out to perform an analysis of PGES presence and duration using a validated signal processing tool, specifically to examine the association between PGES and seizure features previously reported to be associated with visually analyzed PGES. Methods: This is a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of SUDEP in adult patients with intractable epilepsy. We studied videoelectroencephalogram (vEEG) recordings of generalized convulsive seizures (GCS) in a cohort of patients in whom respiratory and vEEG recording were carried out during the evaluation in the epilepsy monitoring unit. A validated automated EEG suppression detection tool was used to determine presence and duration of PGES. Results: We studied 148 GCS in 87 patients. PGES occurred in 106/148 (71.6%) seizures in 70/87 (80.5%) of patients. PGES mean duration was 38.7 ± 23.7 (37; 1–169) seconds. Presence of tonic phase during GCS, including decerebration, decortication and hemi-decerebration, were 8.29 (CI 2.6–26.39, p = 0.0003), 7.17 (CI 1.29–39.76, p = 0.02), and 4.77 (CI 1.25–18.20, p = 0.02) times more likely to have PGES, respectively. In addition, presence of decerebration (p = 0.004) and decortication (p = 0.02), older age (p = 0.009), and hypoxemia duration (p = 0.03) were associated with longer PGES durations. Conclusions: In this study, we confirmed observations made with visual analysis, that presence of tonic phase during GCS, longer hypoxemia, and older age are reliably associated with PGES. We found that of the different types of tonic phase posturing, decerebration has the strongest association with PGES, followed by decortication, followed by hemi-decerebration. This suggests that these factors are likely indicative of seizure severity and may or may not be associated with SUDEP. An automated signal processing tool enables objective metrics, and may resolve apparent ambiguities in the role of PGES in SUDEP and seizure severity studies

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer