Nanoparticles increase the efficacy of cancer chemopreventive agents in cells exposed to cigarette smoke condensate

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery.

Characterization of a monothiol glutaredoxin encoded by Chlorella virus PBCV-1

Annotation of the 330-kb Chlorella virus PBCV-1 genome identified a 237 nucleotide gene (a438l) that codes for a protein with ~35% amino acid identity to glutaredoxins (Grx) found in other organisms. The PBCV-1 protein resembles classical Grxs in both size (9 kDa) and location of the active site (N-terminus). However, the PBCV-1 Grx is unusual because it contains a monothiol active site (CPYS) rather than the typical dithiol active site (CPYC). To examine this unique active site, four sitespecific mutants (CPYC, CPYA, SPYC, and SPYS) were constructed to determine if the N-terminal cysteine is necessary for enzyme activity. Wild type and both mutants containing N-terminal cysteines catalyzed the reduction of disulfides in a coupled system with GSH, NADPH, and glutathione reductase. However, both mutants with an altered N-terminal cysteine were inactive. The grx gene is common in the Chlorella viruses. Molecular phylogenetic analyses of the PBCV-1 enzyme support its relatedness to those from other Chlorella viruses and yet demonstrate the divergence of the Grx molecule.

The Phycodnaviridae: The Story of How Tiny Giants Rule the World

The family Phycodnaviridae encompasses a diverse and rapidly expanding collection of large icosahedral, dsDNA viruses that infect algae. These lytic and lysogenic viruses have genomes ranging from 160 to 560 kb. The family consists of six genera based initially on host range and supported by sequence comparisons. The family is monophyletic with branches for each genus, but the phycodnaviruses have evolutionary roots that connect them with several other families of large DNA viruses, referred to as the nucleocytoplasmic large DNA viruses (NCLDV).The phycodnaviruses have diverse genome structures, some with large regions of noncoding sequence and others with regions of ssDNA. The genomes of members in three genera in the Phycodnaviridae have been sequenced. The genome analyses have revealed more than 1000 unique genes, with only 14 homologous genes in common among the three genera of phycodnaviruses sequenced to date. Thus, their gene diversity far exceeds the number of so-called core genes. Not much is known about the replication of these viruses, but the consequences of these infections on phytoplankton have global affects, including influencing geochemical cycling and weather patterns.

Preface to Lesser Known Large dsDNA Viruses. Current Topics in Microbiology and Immunology 328

Several large dsDNA-containing viruses such as poxviruses (smallpox) and herpes viruses are well known among the scientific community, as well as the general populace, because they cause human diseases. The large dsDNA insect-infecting baculoviruses are also well known in the scientific community because they are used both as biological control agents and as protein expression systems. However, there are other large dsDNA-containing viruses, including the giant 1.2-Mb mimivirus, which are less well known even though all of them play important roles in everyday life. Seven of these virus families are reviewed in this book.

High Resolution Paleoceanography of the Guaymas Basin, Gulf of California, During the Past 15 000 Years

Deep Sea Drilling Project Site 480 (27°54.10’N, 111°39.34’W; 655 m water depth) contains a high resolution record of paleoceanographic change of the past 15 000 years for the Guaymas Basin, a region of very high diatom productivity within the central Gulf of California. Analyses of diatoms and silicoflagellates were completed on samples spaced every 40-50 yr, whereas ICP-AES geochemical analyses were completed on alternate samples (sample spacing 80-100 yr). The Bolling-Allerod interval (14.6-12.9 ka) (note, ka refers to 1000 calendar years BP throughout this report) is characterized by an increase in biogenic silica and a decline in calcium carbonate relative to surrounding intervals, suggesting conditions somewhat similar to those of today. The Younger Dryas event (12.9-11.6 ka) is marked by a major drop in biogenic silica and an increase in calcium carbonate. Increasing relative percentage contributions of Azpeitia nodulifera and Dictyocha perlaevis (a tropical diatom and silicoflagellate, respectively) and reduced numbers of the silicoflagellate Octactis pulchra are supportive of reduced upwelling of nutrient-rich waters. Between 10.6 and 10.0 ka, calcium carbonate and A. nodulifera abruptly decline at DSDP 480, while Roperia tesselata, a diatom indicative of winter upwelling in the modern-day Gulf, increases sharply in numbers. A nearly coincident increase in the silicoflagellate Dictyocha stapedia suggests that waters above DSDP 480 were more similar to the cooler and slightly more saline waters of the northern Gulf during much of the early and middle parts of the Holocene (~10 to 3.2 ka). At about 6.2 ka a stepwise increase in biogenic silica and the reappearance of the tropical diatom A. nodulifera marks a major change in oceanographic conditions in the Gulf. A winter shift to more northwesterly winds may have occurred at this time along with the onset of periodic northward excursions (El Nino-driven?) of the North Equatorial Countercurrent during the summer. Beginning between 2.8 and 2.4 ka, the amplitude of biogenic silica and wt% Fe, Al, and Ti (proxies of terrigenous input) increase, possibly reflecting intensification of ENSO cycles and the establishment of modern oceanographic conditions in the Gulf. Increased numbers of O. pulchra after 2.8 ka suggest enhanced spring upwelling.

Structure and mechanism of diet specialisation: testing models of individual variation in resource use with sea otters

Studies of consumer-resource interactions suggest that individual diet specialisation is empirically widespread and theoretically important to the organisation and dynamics of populations and communities. We used weighted networks to analyze the resource use by sea otters, testing three alternative models for how individual diet specialisation may arise. As expected, individual specialisation was absent when otter density was low, but increased at high-otter density. A high-density emergence of nested resource-use networks was consistent with the model assuming individuals share preference ranks. However, a density-dependent emergence of a non-nested modular network for core resources was more consistent with the competitive refuge model. Individuals from different diet modules showed predictable variation in rank-order prey preferences and handling times of core resources, further supporting the competitive refuge model. Our findings support a hierarchical organisation of diet specialisation and suggest individual use of core and marginal resources may be driven by different selective pressures.

Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents

We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d] 11,3)dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action. (C) 2012 Elsevier Masson SAS. All rights reserved.

Ascending thoracic aorta dimension and outcomes in acute type B dissection (from the International Registry of Acute Aortic Dissection [IRAD])

It is not well known if the size of the ascending thoracic aorta at presentation predicts features of presentation, management, and outcomes in patients with acute type B aortic dissection. The International Registry of Acute Aortic Dissection (IRAD) database was queried for all patients with acute type B dissection who had documentation of ascending thoracic aortic size at time of presentation. Patients were categorized according to ascending thoracic aortic diameters ≤4.0, 4.1 to 4.5, and ≥4.6 cm. Four hundred eighteen patients met inclusion criteria; 291 patients (69.6%) were men with a mean age of 63.2 ± 13.5 years. Ascending thoracic aortic diameter ≤4.0 cm was noted in 250 patients (59.8%), 4.1 to 4.5 cm in 105 patients (25.1%), and ≥4.6 cm in 63 patients (15.1%). Patients with an ascending thoracic aortic diameter ≥4.6 cm were more likely to be men (p = 0.01) and have Marfan syndrome (p <0.001) and known bicuspid aortic valve disease (p = 0.003). In patients with an ascending thoracic aorta ≥4.1 cm, there was an increased incidence of surgical intervention (p = 0.013). In those with an ascending thoracic aorta ≥4.6 cm, the root, ascending aorta, arch, and aortic valve were more often involved in surgical repair. Patients with an ascending thoracic aorta ≤4.0 were more likely to have endovascular therapy than those with larger ascending thoracic aortas (p = 0.009). There was no difference in overall mortality or cause of death. In conclusion, ascending thoracic aortic enlargement in patients with acute type B aortic dissection is common. Although its presence does not appear to predict an increased risk of mortality, it is associated with more frequent open surgical intervention that often involves replacement of the proximal aorta. Those with smaller proximal aortas are more likely to receive endovascular therapy.

Differential gene and protein expression in abluminal sprouting and intraluminal splitting forms of angiogenesis

In adult skeletal muscle, abluminal sprouting or longitudinal splitting of capillaries can be initiated separately by muscle overload and elevated microcirculation shear stress respectively. In the present study, gene and protein expression patterns associated with the different forms of angiogenesis were examined using a targeted gene array (Superarray), validated by quantitative RT (reverse transcription)-PCR and immunoblots. Sprouting angiogenesis induced large changes in expression levels in genes associated with extracellular matrix remodelling, such as MMP-2 (matrix metalloproteinase-2), TIMP (tissue inhibitor of metalloproteinases), SPARC (secreted protein, acidic and rich in cysteine) and thrombospondin. Changes in neuropilin, midkine and restin levels, which may underpin changes in endothelial morphology, were seen during splitting angiogenesis. Up-regulation of VEGF (vascular endothelial growth factor), Flk-1, angiopoietin-2 and PECAM-1 (platelet/endothelial cell adhesion molecule-1) was seen in both forms of angiogenesis, representing a common angiogenic response of endothelial cells. In conclusion, the present study demonstrates that general angiogenic signals from growth factors can be influenced by the local microenvironment resulting in differing forms of capillary growth to produce a co-ordinated expansion of the vascular bed.

The Geology and Ore Deposits of the Ermont Mines

The Ermont Mines are located sixteen miles northwest of Dillon, Montana, in section 35 of T.6S., R.11W. This is in the central part of Beaverhead County. They are considered to be in the Argenta min­ing district, the town of Argenta lying three miles to the northeast.

A Stereoscopic Volume Rendered Brain Atlas

The anatomy of the human brain is organized as a complex arrangement of interrelated structures in three dimensional space. To facilitate the understanding of both structure and function, we have created a volume rendered brain atlas (VRBA) with an intuitive interface that allows real-time stereoscopic rendering of brain anatomy. The VRBA incorporates 2-dimensional and 3-dimensional texture mapping to display segmented brain anatomy co-registered with a T1 MRI. The interface allows the user to remove and add any of the 62 brain structures, as well as control the display of the MRI dataset. The atlas also contains brief verbal and written descriptions of the different anatomical regions to correlate structure with function. A variety of stereoscopic projection methods are supported by the VRBA and provide an abstract, yet simple, way of visualizing brain anatomy and 3-dimensional relationships between different nuclei.