PartsList: a web-based system for dynamically ranking protein folds based on disparate attributes, including whole-genome expression and interaction information

As the number of protein folds is quite limited, a mode of analysis that will be increasingly common in the future, especially with the advent of structural genomics, is to survey and re-survey the finite parts list of folds from an expanding number of perspectives. We have developed a new resource, called PartsList, that lets one dynamically perform these comparative fold surveys. It is available on the web at http://bioinfo.mbb.yale.edu/partslist and http://www.partslist.org. The system is based on the existing fold classifications and functions as a form of companion annotation for them, providing ‘global views’ of many already completed fold surveys. The central idea in the system is that of comparison through ranking; PartsList will rank the approximately 420 folds based on more than 180 attributes. These include: (i) occurrence in a number of completely sequenced genomes (e.g. it will show the most common folds in the worm versus yeast); (ii) occurrence in the structure databank (e.g. most common folds in the PDB); (iii) both absolute and relative gene expression information (e.g. most changing folds in expression over the cell cycle); (iv) protein–protein interactions, based on experimental data in yeast and comprehensive PDB surveys (e.g. most interacting fold); (v) sensitivity to inserted transposons; (vi) the number of functions associated with the fold (e.g. most multi-functional folds); (vii) amino acid composition (e.g. most Cys-rich folds); (viii) protein motions (e.g. most mobile folds); and (ix) the level of similarity based on a comprehensive set of structural alignments (e.g. most structurally variable folds). The integration of whole-genome expression and protein–protein interaction data with structural information is a particularly novel feature of our system. We provide three ways of visualizing the rankings: a profiler emphasizing the progression of high and low ranks across many pre-selected attributes, a dynamic comparer for custom comparisons and a numerical rankings correlator. These allow one to directly compare very different attributes of a fold (e.g. expression level, genome occurrence and maximum motion) in the uniform numerical format of ranks. This uniform framework, in turn, highlights the way that the frequency of many of the attributes falls off with approximate power-law behavior (i.e. according to V–b, for attribute value V and constant exponent b), with a few folds having large values and most having small values.

A power law for cells

Darwin observed that multiple, lowly organized, rudimentary, or exaggerated structures show increased relative variability. However, the cellular basis for these laws has never been investigated. Some animals, such as the nematode Caenorhabditis elegans, are famous for having organs that possess the same number of cells in all individuals, a property known as eutely. But for most multicellular creatures, the extent of cell number variability is unknown. Here we estimate variability in organ cell number for a variety of animals, plants, slime moulds, and volvocine algae. We find that the mean and variance in cell number obey a power law with an exponent of 2, comparable to Taylor's law in ecological processes. Relative cell number variability, as measured by the coefficient of variation, differs widely across taxa and tissues, but is generally independent of mean cell number among homologous tissues of closely related species. We show that the power law for cell number variability can be explained by stochastic branching process models based on the properties of cell lineages. We also identify taxa in which the precision of developmental control appears to have evolved. We propose that the scale independence of relative cell number variability is maintained by natural selection.

Equilibration of the terrestrial water, nitrogen, and carbon cycles

Recent advances in biologically based ecosystem models of the coupled terrestrial, hydrological, carbon, and nutrient cycles have provided new perspectives on the terrestrial biosphere’s behavior globally, over a range of time scales. We used the terrestrial ecosystem model Century to examine relationships between carbon, nitrogen, and water dynamics. The model, run to a quasi-steady-state, shows strong correlations between carbon, water, and nitrogen fluxes that lead to equilibration of water/energy and nitrogen limitation of net primary productivity. This occurs because as the water flux increases, the potentials for carbon uptake (photosynthesis), and inputs and losses of nitrogen, all increase. As the flux of carbon increases, the amount of nitrogen that can be captured into organic matter and then recycled also increases. Because most plant-available nitrogen is derived from internal recycling, this latter process is critical to sustaining high productivity in environments where water and energy are plentiful. At steady-state, water/energy and nitrogen limitation “equilibrate,” but because the water, carbon, and nitrogen cycles have different response times, inclusion of nitrogen cycling into ecosystem models adds behavior at longer time scales than in purely biophysical models. The tight correlations among nitrogen fluxes with evapotranspiration implies that either climate change or changes to nitrogen inputs (from fertilization or air pollution) will have large and long-lived effects on both productivity and nitrogen losses through hydrological and trace gas pathways. Comprehensive analyses of the role of ecosystems in the carbon cycle must consider mechanisms that arise from the interaction of the hydrological, carbon, and nutrient cycles in ecosystems.

Cell cycling and patterned cell proliferation in the Drosophila wing during metamorphosis.

In metamorphosing wing discs, progression through the cell cycle takes place, as in larval discs, in nonclonally derived clusters of cells synchronized in the same cell cycle stage. Contrary to early discs, there are temporal and spatial heterogeneities in cell proliferation associated with wing margin, vein, intervein, and middle intervein territories. Within these territories, there are no indications of a wave progression of the cell cycle. Mitotic orientations are, as in early discs, at random but there is a preferential allocation of postmitotic cells along the proximodistal axis, thus explaining the elongated shape of the resulting clones along this axis. Shapes of clones in mature discs and in evaginated wings are similar, thus excluding major morphogenetic movements during evagination. After the proliferative period, all the cells are arrested in G1 phase. The final number of cells of the wing is fixed independently of experimental perturbations that alter the cell division schedule. These results are discussed in the context of a model of wing morphogenesis.

Oxidation states of the manganese cluster during the flash-induced S-state cycle of the photosynthetic oxygen-evolving complex.

The Mn K-edge x-ray absorption spectra for the pure S states of the tetranuclear Mn cluster of the oxygen-evolving complex of photosystem II during flash-induced S-state cycling have been determined. The relative S-state populations in samples given 0, 1, 2, 3, 4, or 5 flashes were determined from fitting the flash-induced electron paramagnetic resonance (EPR) multiline signal oscillation pattern to the Kok model. The edge spectra of samples given 0, 1, 2, or 3 flashes were combined with EPR information to calculate the pure S-state edge spectra. The edge positions (defined as the zero-crossing of the second derivatives) are 6550.1, 6551.7, 6553.5, and 6553.8 eV for S0, S1, S2, and S3, respectively. In addition to the shift in edge position, the S0--> S1 and S1--> S2 transitions are accompanied by characteristic changes in the shape of the edge, both indicative of Mn oxidation. The edge position shifts very little (0.3 eV) for the S2--> S3 transition, and the edge shape shows only subtle changes. We conclude that probably no direct Mn oxidation is involved in this transition. The proposed Mn oxidation state assignments are as follows: S0 (II, III, IV, IV) or (III, III, III, IV), S1 (III, III, IV, IV), S2 (III, IV, IV, IV), S3 (III, IV, IV, IV).

Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle.

The basement membrane (BM) extracellular matrix induces differentiation and suppresses apoptosis in mammary epithelial cells, whereas cells lacking BM lose their differentiated phenotype and undergo apoptosis. Addition of purified BM components, which are known to induce beta-casein expression, did not prevent apoptosis, indicating that a more complex BM was necessary. A comparison of culture conditions where apoptosis would or would not occur allowed us to relate inhibition of apoptosis to a complete withdrawal from the cell cycle, which was observed only when cells acquired a three-dimensional alveolar structure in response to BM. In the absence of this morphology, both the GI cyclin kinase inhibitor p21/WAF-1 and positive proliferative signals including c-myc and cyclin DI were expressed and the retinoblastoma protein (Rb) continued to be hyperphosphorylated. When we overexpressed either c-myc in quiescent cells or p21 when cells were still cycling, apoptosis was induced. In the absence of three-dimensional alveolar structures, mammary epithelial cells secrete a number of factors including transforming growth factor alpha and tenascin, which when added exogenously to quiescent cells induced expression of c-myc and interleukin-beta1-converting enzyme (ICE) mRNA and led to apoptosis. These experiments demonstrate that a correct tissue architecture is crucial for long-range homeostasis, suppression of apoptosis, and maintenance of differentiated phenotype.

Cell cycling and patterned cell proliferation in the wing primordium of Drosophila.

The pattern of cell proliferation in the Drosophila imaginal wing primordium is spatially and temporally heterogeneous. Direct visualization of cells in S, G2, and mitosis phases of the cell cycle reveals several features invariant throughout development. The fraction of cells in the disc in the different cell cycle stages is constant, the majority remaining in G1. Cells in the different phases of the cell cycle mainly appear in small synchronic clusters that are nonclonally derived but result from changing local cell-cell interactions. Cluster synchronization occurs before S and in the G2/M phases. Rates of cell division are neither constant nor clonal features. Cell cycle progression is linear rather than concentric. Clusters appear throughout the disc but with symmetries related to presumptive wing patterns, compartment boundaries, and vein clonal restrictions.

Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls.

The human hepatitis B virus (HBV) HBx protein is a small transcriptional activator that is essential for virus infection. HBx is thought to be involved in viral hepatocarcinogenesis because it promotes tumorigenesis in transgenic mice. HBx activates the RAS-RAF-mitogen-activated protein (MAP) kinase signaling cascade, through which it activates transcription factors AP-1 and NF-kappa B, and stimulates cell DNA synthesis. We show that HBx stimulates cell cycle progression, shortening the emergence of cells from quiescence (G0) and entry into S phase by at least 12 h, and accelerating transit through checkpoint controls at G0/G1 and G2/M. Compared with serum stimulation, HBx was found to strongly increase the rate and level of activation of the cyclin-dependent kinases CDK2 and CDC2, and their respective active association with cyclins E and A or cyclin B. HBx is also shown to override or greatly reduce serum dependence for cell cycle activation. Both HBx and serum were found to require activation of RAS to stimulate cell cycling, but only HBx could shorten checkpoint intervals. HBx therefore stimulates cell proliferation by activating RAS and a second unknown effector, which may be related to its reported ability to induce prolonged activation of JUN or to interact with cellular p53 protein. These data suggest a molecular mechanism by which HBx likely contributes to viral carcinogenesis. By deregulating checkpoint controls, HBx could participate in the selection of cells that are genetically unstable, some of which would accumulate unrepaired transforming mutations.

The BCL2 major breakpoint region is a sequence- and cell-cycle-specific binding site of the Ku antigen.

The majority of translocations involving BCL2 are very narrowly targeted to three breakpoint clusters evenly spaced over a 100-bp region of the gene's terminal exon. We have recently shown that the immediate upstream boundary of this major breakpoint region (mbr) is a specific recognition site for single-strand DNA (ssDNA) binding proteins on the sense and antisense strands. The downstream flank of the mbr is a helicase binding site. In this report we demonstrate that the helicase and ssDNA binding proteins show reciprocal changes in binding activity over the cell cycle. The helicase is maximally active in G1 and early S phases; the ssDNA binding proteins are maximally active in late S and G2/M phases. An inhibitor of helicase binding appears in late S and G2/M. Finally, at least one component of the helicase binding complex is the Ku antigen. Thus, a protein with helicase activity implicated in repair of double-strand breaks, variable (diversity) joining recombination, and, potentially, cell-cycle regulation is targeted to the BCL2 mbr.

EIA-RIMA insuficiente como avaliação de impactos ambientais enquanto busca de sustentabilidade urbana: o caso de São Sebastião

O presente trabalho comprova que o atual instrumento EIA-RIMA - Estudo de Impacto Ambiental e seu respectivo Relatório de Impacto Ambiental, é insuficiente enquanto busca de sustentabilidade urbana no Litoral Norte do Estado de São Paulo, especificamente no município de São Sebastião. O método de analise dos EIA-RIMA sempre enfatizam os ganhos econômicos e atenuam os impactos negativos, apesar das fragilidades naturais, estruturais e restrições legais incidentes. A tese comprova que os instrumentos utilizados no âmbito do processo de licenciamento ambiental dos empreendimentos, como a ampliação do porto comercial de São Sebastião, estão pouco comprometidos com o real desenvolvimento sustentável da cidade e região. As especificidades geográficas, sobretudo as facilidades de interface do território terrestre com o marítimo, proporcionadas pelas características naturais do Canal de São Sebastião, sempre ofereceram condições privilegiadas para o abrigo de embarcações, característica decisiva na escolha do lugar como cidade portuária, vinculada aos mais importantes ciclos econômicos do país. Agora, em 2015, está prestes a entrar em um novo ciclo, principalmente com a ampliação do porto comercial, duplicação da rodovia dos Tamoios e da SP-055 e a exploração da camada pré-sal na Bacia de Santos. A região já apresenta todos os problemas de uma ocupação acelerada em um território ambientalmente frágil, localizado em estreita faixa litorânea, composta de um lado pela Serra do Mar e do outro pelo Oceano Atlântico. Se não houver um planejamento urbano e regional que considere as características e capacidade de suporte deste território, a zona costeira entrará em colapso. Saber dosar o uso de suas potencialidades sem esgotá-las será o desafio de nossa geração. Os Estudos de Impactos Ambientais precisam ser aperfeiçoados para que ações mitigadoras alcancem muito mais do que o mínimo, alinhadas a investimentos, tecnologias inovadoras, infraestruturas necessárias e obrigatórias que sejam pensadas de maneira conjunta e cumulativa nas diversas esferas do poder, com efetiva participação pública, caso contrário, o crescente interesse econômico e político tenderá à destruição irreversível do patrimônio histórico e natural deste território. O EIA está se transformando em um poderoso instrumento político de ordenamento territorial que acaba por definir critérios e parâmetros de uso e ocupação, desempenhando uma função que não lhe compete, além de aprofundar o desencontro entre uma vida urbana de qualidade e um ambiente equilibrado em nome do desenvolvimento econômico e a serviço dos interesses privados.

Entropy production and thermodynamic power of the squeezed thermal reservoir

We analyze the entropy production and the maximal extractable work from a squeezed thermal reservoir. The nonequilibrium quantum nature of the reservoir induces an entropy transfer with a coherent contribution while modifying its thermal part, allowing work extraction from a single reservoir, as well as great improvements in power and efficiency for quantum heat engines. Introducing a modified quantum Otto cycle, our approach fully characterizes operational regimes forbidden in the standard case, such as refrigeration and work extraction at the same time, accompanied by efficiencies equal to unity.

When Wells Run Dry: Water and Tourism Along the Western Coast of Nicaragua

This dissertation uses a political ecology approach to examine the relationship between tourism development and groundwater in southwest Nicaragua. Tourism in Nicaragua is a booming industry bolstered by ‘unspoiled’ natural beauty, low crime rates, and government incentives. This growth has led to increased infrastructure, revenue, and employment opportunities for many local communities along the Pacific coast. Not surprisingly, it has also brought concomitant issues of deeper poverty, widening gaps between rich and poor, and competition over natural resources. Adequate provisions of freshwater are necessary to sustain the production and reproduction of tourism; however, it remains uncertain if groundwater supplies can keep pace with demand. The objective of this research is to assess water supply availability amidst tourism development in the Playa Gigante area. It addresses the questions: 1) are local groundwater supplies sufficient to sustain the demand for freshwater imposed by increased tourism development? and 2) is there a power relationship between tourism development and control over local freshwater that would prove inequitable to local populations? Integrating the findings of groundwater monitoring, geological mapping, and ethnographic and survey research from a representative stretch of Pacific coastline, this dissertation shows that diminishing recharge and increased groundwater consumption is creating conflict between stakeholders with various levels of knowledge, power, and access. Although national laws are structured to protect the environment and ensure equitable access to groundwater, the current scramble to secure water has powerful implications on social relations and power structures associated with tourism development. This dissertation concludes that marginalization due to environmental degradation is attributable to the nexus of a political promotion of tourism, poorly enforced state water policies, insufficient water research, and climate change. Greater technical attention to hydrological dynamics and collaboration amongst stakeholders are necessary for equitable access to groundwater, environmental sustainability, and profitability of tourism.

Clinical validation of an algorithm to correct the error in the keratometric estimation of corneal power for normal eyes

To validate clinically an algorithm for correcting the error in the keratometric estimation of corneal power by using a variable keratometric index of refraction (nk) in a normal healthy population.

PCDD/F Emissions from Light-Duty Diesel Vehicles Operated under Highway Conditions and a Diesel-Engine Based Power Generator

PCDD/F emissions from three light-duty diesel vehicles–two vans and a passenger car–have been measured in on-road conditions. We propose a new methodology for small vehicles: a sample of exhaust gas is collected by means of equipment based on United States Environmental Protection Agency (U.S. EPA) method 23A for stationary stack emissions. The concentrations of O2, CO, CO2, NO, NO2 and SO2 have also been measured. Six tests were carried out at 90-100 km/h on a route 100 km long. Two additional tests were done during the first 10 minutes and the following 60 minutes of the run to assess the effect of the engine temperature on PCDD/F emissions. The emission factors obtained for the vans varied from 1800 to 8400 pg I-TEQ/Nm3 for a 2004 model year van and 490-580 pg I-TEQ/Nm3 for a 2006 model year van. Regarding the passenger car, one run was done in the presence of a catalyst and another without, obtaining emission factors (330-880 pg I-TEQ/Nm3) comparable to those of the modern van. Two other tests were carried out on a power generator leading to emission factors ranging from 31 to 78 pg I-TEQ/Nm3. All the results are discussed and compared with literature.

Minimizing the IOL Power Error Induced by Keratometric Power

Purpose. To evaluate theoretically in normal eyes the influence on IOL power (PIOL) calculation of the use of a keratometric index (nk) and to analyze and validate preliminarily the use of an adjusted keratometric index (nkadj) in the IOL power calculation (PIOLadj). Methods. A model of variable keratometric index (nkadj) for corneal power calculation (Pc) was used for IOL power calculation (named PIOLadj). Theoretical differences ($PIOL) between the new proposed formula (PIOLadj) and which is obtained through Gaussian optics (PIOL Gauss) were determined using Gullstrand and Le Grand eye models. The proposed new formula for IOL power calculation (PIOLadj) was prevalidated clinically in 81 eyes of 81 candidates for corneal refractive surgery and compared with Haigis, HofferQ, Holladay, and SRK/T formulas. Results. A theoretical PIOL underestimation greater than 0.5 diopters was present in most of the cases when nk = 1.3375 was used. If nkadj was used for Pc calculation, a maximal calculated error in $PIOL of T0.5 diopters at corneal vertex in most cases was observed independently from the eye model, r1c, and the desired postoperative refraction. The use of nkadj in IOL power calculation (PIOLadj) could be valid with effective lens position optimization nondependent of the corneal power. Conclusions. The use of a single value of nk for Pc calculation can lead to significant errors in PIOL calculation that may explain some IOL power overestimations with conventional formulas. These inaccuracies can be minimized by using the new PIOLadj based on the algorithm of nkadj.