bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary comparison of CloudSAT‐derived microphysical quantities with ground‐based measurements for mixed‐phase cloud research in the Arctic
Authors: de Boer Gijs , Tripoli Gregory J. , Eloranta Edwin W.
Published: September 2008

The omnipresent existence of thin, mixed‐phase clouds in northern polar latitudes presents special challenges to CloudSAT as it attempts to map radiatively relevant cloudiness around the globe. In this work, retrieved cloud properties of Arctic mixed‐phase clouds observed simultaneously in Eureka, Canada by ground‐based cloud radar and lidar, and by the CloudSAT Cloud‐Profiling Radar (CPR) are compared. Through these comparisons, we evaluate the efficacy of identification of precipitation and assignment of cloud type by the 2B‐CLDCLASS product, as well as the accuracy of microphysical retrievals from the 2B‐CWC‐RO product. These preliminary comparisons result in the following findings with regard to the CloudSAT retrievals: (1) The cloud detection algorithm worked well, detecting all clouds observed from surface based sensors. (2) Precipitation was not well identified, and was often mislabeled as cloud. (3) Both liquid and ice particle number densities retrieved by CloudSAT are found to be 1 to 2 orders of magnitude too high when compared to surface‐based retrievals and previous studies of these cloud types. (4) CloudSAT particle effective sizes are often too large, with the exception of the largest particles, which are misidentified as liquid. (5) Water contents show the best agreement between the two retrieval types, as well as with measured values from outside studies. All comparisons were completed for raw liquid and ice retrievals, as well as for “composite” retrievals that partition liquid and ice contributions to measured reflectivity through a temperature‐dependent algorithm. Differences found for these limited cases imply that careful analysis is required for application of these cloud products to mixed‐phase cloud research. Furthermore, these differences help highlight specific assumptions within the CloudSAT algorithms that are in need of improvement to complete mixed‐phase cloud retrievals.
A novel nervous system‐induced factor inducing immune responses in the spleen
Authors: Bakhiet Moiz , Taha Safa
Published: September 2008

This study relates to a novel mediator signaling between the nervous system and the spleen following an immune challenge. Using enzyme‐linked immunospot and cell proliferation assays, we found that supernatants of cultured splenocytes prepared from subcutaneously trypanosome‐inoculated rats and mice spleens obtained immediately after inoculation and added to naive cells significantly stimulate interferon‐γ production and cell proliferation compared to phosphate‐buffered saline‐inoculated animals. This action was abrogated by surgical denervation of the spleen. Using the fluorescent differential display technology, the gene involved in this process was identified and further cloned and its sequence was mapped to chromosome 14 (GenBank accession number:EU552928). Protein expression revealed ∼15 kDa molecule with biological activities similar to the cultured supernatants of splenocytes obtained directly from parasite‐inoculated animals. Antibodies raised against the protein blocked the activities of both the protein and the supernatant and also recognized a band in the active supernatant with the same molecular mass as the protein. Furthermore, the protein was able to reactivate experimentally immunosuppressed cells by regaining their ability to proliferate, suggesting that such a nervous system‐induced immune system‐released activating agent (ISRAA) may have a potential therapeutic benefit in immunocompromised situations and in further understanding the mechanism for innate immunity commencement and action.
Anaerobic glyoxylate cycle activity during simultaneous utilization of glycogen and acetate in uncultured Accumulibacter enriched in enhanced biological phosphorus removal communities
Authors: Burow Luke C , Mabbett Amanda N , Blackall Linda L
Published: September 2008

Enhanced biological phosphorus removal (EBPR) communities protect waterways from nutrient pollution and enrich microorganisms capable of assimilating acetate as polyhydroxyalkanoate (PHA) under anaerobic conditions. Accumulibacter, an important uncultured polyphosphate-accumulating organism (PAO) enriched in EBPR, was investigated to determine the central metabolic pathways responsible for producing PHA. Acetate uptake and assimilation to PHA in Accumulibacter was confirmed using fluorescence in situ hybridization (FISH)-microautoradiography and post-FISH chemical staining. Assays performed with enrichments of Accumulibacter using an inhibitor of glyceraldehyde-3-phosphate dehydrogenase inferred anaerobic glycolysis activity. Significant decrease in anaerobic acetate uptake and PHA production rates were observed using inhibitors targeting enzymes within the glyoxylate cycle. Bioinformatic analysis confirmed the presence of genes unique to the glyoxylate cycle (isocitrate lyase and malate synthase) and gene expression analysis of isocitrate lyase demonstrated that the glyoxylate cycle is likely involved in PHA production. Reduced anaerobic acetate uptake and PHA production was observed after inhibition of succinate dehydrogenase and upregulation of a succinate dehydrogenase gene suggested anaerobic activity. Cytochrome b/b6 activity inferred that succinate dehydrogenase activity in the absence of external electron acceptors may be facilitated by a novel cytochrome b/b6 fusion protein complex that pushes electrons uphill to more electronegative electron carriers. Identification of phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase genes in Accumulibacter demonstrated the potential for interconversion of C3 intermediates of glycolysis and C4 intermediates of the glyoxylate cycle. Our findings along with previous hypotheses from analysis of microbiome data and metabolic models for PAOs were used to develop a model for anaerobic carbon metabolism in Accumulibacter.
Using Trees: Myrmecocystus Phylogeny and Character Evolution and New Methods for Investigating Trait Evolution and Species Delimitation (PhD Dissertation)
Authors: O’Meara Brian
Published: September 2008

1) Rates of phenotypic evolution have changed throughout the history of life, producing variation in levels of morphological, functional, and ecological diversity among groups. Testing for the presence of these rate shifts is a key component of evaluating hypotheses about what causes them. General predictions regarding changes in phenotypic diversity as a function of evolutionary history and rates are developed, and tests are derived to evaluate rate changes. Simulations show that these tests are more powerful than existing tests using standardized contrasts. 2) Species delimitation and species tree inference are difficult problems in the case of recent divergences, especially when different loci have different histories. I quantify the difficulty of the problem and introduce a non-parametric method for simultaneously dividing anonymous samples into different species and inferring a species tree, using individual gene trees as input. This heuristic method seeks to both minimize gene tree – species tree discordance and excess population structure within a species. Analyses suggest that the method may provide useful insights for systematists working at the species level with molecular data.3) The phylogeny of Myrmecocystus ants is estimated using nine loci, finding that none of the three subgenera are monophyletic, implying repeated evolution of foraging times and particular morphologies. A new partitioned likelihood program, MrFisher, is created from MrBayes to aid analysis of multilocus datasets without assuming priors. Simulations show that using a partitioned likelihood approach in the presence of rate heterogeneity and missing data, as is common in supermatrix analyses, can recover correct branch lengths where non-partitioned likelihood gives predictably biased estimates of branch lengths but the correct topology.4) Evolution of foraging time and coevolution of behavior and morphology in Myrmecocystus ants is examined. New models for reconstructing discrete states along branches of a tree and for examining continuous trait evolution and coevolution with discrete traits are developed and implemented. Foraging transitions between diurnal and nocturnal foraging evidently go through crepuscular intermediates. There is some evidence for increased rates of morphological character evolution associated with changes in foraging regime, but little evidence for particular optimum values for morphological traits associated with foraging.
Obesity in Older Adults Is Associated With an Increased Prevalence and Incidence of Pain
Authors: Heim Noor , Snijder Marieke B. , Deeg Dorly J.H. , Seidell Jaap C. , Visser Marjolein
Published: September 2008

Cross‐sectional studies suggest an association between BMI and pain. This prospective study investigated the associations of measured BMI and waist circumference with prevalent and incident pain in older adults. The study included participants of the Longitudinal Aging Study Amsterdam, aged 55–85 years at baseline (1992–1993). Pain was assessed using a subscale of the Nottingham Health Profile at baseline (N = 2,000), after 3 years (N = 1,478) and 6 years (N = 1,271) of follow‐up. The overall prevalence of pain was 32.7% at baseline and increased significantly with higher quartiles of BMI or waist circumference. After adjustment for age, education, depression, smoking, physical activity, and chronic diseases, multiple logistic regression analyses showed odds ratios (ORs (95% confidence interval)) for prevalent pain of 2.16 (1.32–3.54) in men and 1.93 (1.26–2.95) in women comparing the highest with the lowest quartile of BMI. Of the participants without pain at baseline, those in the highest quartile of BMI had a twofold increased odds for incident pain after 3 years of follow‐up. After 6 years of follow‐up, ORs for incident pain were 2.34 (1.17–4.72) in men and 2.78 (1.36–5.70) in women. Additional adjustment for weight change did not change these associations. Similar results were found for the associations between waist circumference and pain. Exploring the reversed causal relation, analyses showed no significant associations between prevalent pain and weight gain. In conclusion, the prevalence of pain is higher among obese older men and women compared to their normal‐weight peers. Furthermore, obese older adults are at increased odds to develop pain.
Toward an Understanding of the Interplay Between Culture, Language, and Augmentative and Alternative Communication
Authors: Huer Mary Blake
Published: September 2008

The discovery of appropriate forms and function for linguistic competence in augmentative and alternative communication (AAC) is linked to an understanding of the complexity of culture, cultural choices, the impact of acculturation on practices, societal norms and perceptions, and persons' with complex communication needs (PWCCN) basic human rights to full inclusion in social, educational, economic, and personal experiences on an everyday basis. This article focuses on these topics in order to promote further discussion regarding the influence of culture on the practice of AAC.
Linguistic Competence in Aphasia
Authors: LaPointe Leonard L.
Published: September 2008

Loss of implicit linguistic competence assumes a loss of linguistic rules, necessary linguistic computations, or representations. In aphasia, the inherent neurological damage is frequently assumed by some to be a loss of implicit linguistic competence that has damaged or wiped out neural centers or pathways that are necessary for maintenance of the language rules and representations needed to communicate. Not everyone agrees with this view of language use in aphasia. The measurement of implicit language competence, although apparently necessary and satisfying for theoretic linguistics, is complexly interwoven with performance factors. Transience, stimulability, and variability in aphasia language use provide evidence for an access deficit model that supports performance loss. Advances in understanding linguistic competence and performance may be informed by careful study of bilingual language acquisition and loss, the language of savants, the language of feral children, and advances in neuroimaging. Social models of aphasia treatment, coupled with an access deficit view of aphasia, can salve our restless minds and allow pursuit of maximum interactive communication goals even without a comfortable explanation of implicit linguistic competence in aphasia.
When ‘Good Neighbors’ go Bad: Territorial Geographies of Neighborhood Associations
Authors: England Marcia
Published: September 2008

This paper examines the discourses, practices, and spatialities surrounding neighbors and neighborhoods as mobilized by a particular neighborhood association in Seattle, Washington. By examining how this group enacts and encourages territoriality, I provide an analysis of how exclusionary social relations work on the ground through three distinct case studies: the implementation of Good Neighbor Agreements in conjunction with Seattle's newly expanded Alcohol Impact Areas, the Crime Prevention though Environmental Design program, and a community gathering cosponsored by the Mayor's Office and the Seattle Police Department. The effect of these events was the exclusion of those who are seen as outsiders and the reification of narrowly defined ideas of neighbors and neighborhoods.
Family Events and the Residential Mobility of Couples
Authors: Michielin Francesca , Mulder Clara H
Published: September 2008

Using data from retrospective surveys carried out in the Netherlands during the early 1990s, we describe how the residential mobility of couples—that is, short-distance moves—is affected by family events and how fertility is affected by residential mobility. The results show that residential moves are particularly likely to happen in a short period preceding a wedding or during pregnancy, supporting the hypothesis that residential mobility is likely to occur in anticipation of family changes. Anticipation is also suggested by the fact that the likelihood of having a child is greater after a residential move, but only starting from some months after the move. Family events also have a hampering effect on residential moves. Starting from some months after the wedding, being married is associated with a lower propensity of experiencing a short-distance move, while the presence of children is associated with less residential mobility only when children are school-aged.
Multipliers, Markups, and Mobility Rents: In Defense of ‘Chain Models’ in Urban and Regional Analysis
Authors: Persky Joseph , Felsenstein Daniel
Published: September 2008

Social scientists have long used ‘chain’ metaphors, yet their methodological justification remains somewhat hazy. This paper offers a rationale for using chains to measure changes in economic welfare in urban and regional contexts. In contrast to the Marshallian surplus, which well describes situations in which price changes generate rents in a single market, chains are especially useful in markets where changes lead to the transmission of demand or supply through a series of markets characterized by sticky prices and markups. This argument is illustrated by reference to chain-driven analyses of local production, labor, and housing markets. The institutional structures that underpin chain models are stressed.
The Rhetoric and Reality of Urban Policy in the Neoliberal City: Implications for Social Struggle in Over-the-Rhine, Cincinnati
Authors: Jean-Paul D Addie
Published: September 2008

This paper explores the disparities between the ideological discourses and material outcomes of three key urban policies, contextually grounded within the neoliberalised social and institutional spaces of Over-the-Rhine, Cincinnati. Whilst the rhetoric of neoliberal doctrine presents an emancipatory urban imaginary based upon individual freedom and the beneficent role of free markets, the embedding of the policies discussed accentuates the political and economical disenfranchisement of the most marginalised neighbourhood inhabitants. Moreover, the ability of this group to politically mobilise against hostile neoliberalisation and gentrification is undermined by the facilitation of out-migration of stable low-income families and community leaders, and the reproduction of the negative, criminal, and blighted aspects of Over-the-Rhine's environment. Neoliberalisation is seen to operate through material and discursive moments of social exclusion and in perpetuating sociospatial structures which justify the continued implementation of repressive political and regulatory projects. In concluding, I suggest neoliberal hegemony may be undermined through exposing the ways in which it reproduces and exacerbates the phenomena it condemns.
To the West and East of Interstate-35: Obesity, Philanthropic Entrepreneurialism, and the Delineation of Risk in Austin, Texas
Authors: Herrick Clare
Published: September 2008

The author draws on a case study of Austin, Texas to argue that the emerging cannon of critical obesity studies should be situated in and interrogated with reference to empirical research undertaken in the urban spaces that enable or constrain healthy behavior. With federal, state and city-scale government departments calling for concerted obesity-prevention efforts, it is suggested that this enterprise has now rendered Austin a space of philanthropic entrepreneurialism. Drawing on stakeholder interviews with those charged with healthy-lifestyle promotion, the author contends that the city's bifurcation by Interstate-35 marks a clear real and imagined socioeconomic and racial divide. Moreover, this divide permits the delineation of East Austin as ‘at risk’ by virtue of its Hispanic population and the assumption that higher prevalent rates of obesity among Hispanic residents are an outcome of certain cultural norms. As a result, East Austin has been legitimized as a strategic place of intervention to help boost the city's image as a healthy, and therefore good, place to live. However, such interventions favor changing personal behavior and therefore neglect to address the environmental and structural factors which, it is asserted, often have far more immediate and profound effects on health.
Calculative Spaces: Cities, Market Relations, and the Commercial Vitalism of the Outdoor Advertising Industry
Authors: Cronin Anne M
Published: September 2008

Based on ethnographic work, this paper examines the market research practices of the outdoor advertising industry in the UK and their commercial production of space. I focus on the role of calculation in the performance of market relations between a range of actors in the field and the use of marketing research's classificatory practices as a currency which enacts those relations. In many accounts of urban governance, city space is produced by various statistical and classificatory devices as calculable and hence governable. But with recent developments in commercial enterprises, the performative quality of market relations engenders calculative space, a nexus of people-in-space, commercial imperatives, and a calculative energy or orientation to calculation. This is understood by the industry as a kind of commercial vitalism—an enlivening of market relations and of objects of commercial calculation—which firms aim to exploit by tapping into and channelling the energy they perceive it generates.
Uninterrupted Views: Real-Estate Advertising and Changing Perspectives on Coastal Property in New Zealand
Authors: Collins Damian , Kearns Robin
Published: September 2008

This paper considers the landscape of coastal property in New Zealand through the lens of real-estate advertising. In analyzing a sample of 236 newspaper advertisements, it connects representations of coastal housing to broader concerns about the development of the coastline. Much public anxiety centres on the notion that coastal residential development and escalating property values signal private gain, but public loss. What is lost, it is claimed, is a landscape that is open, physically but also socially: the presence of imposing holiday homes detracts from the experience of going to the beach, and contributes to the unaffordability of staying at the beach. Such notions do not, of course, feature prominently in advertising. We find that views from private property over the coast are often prioritized in advertising, while the coast itself is typically portrayed as devoid of people. This invites viewers to place themselves in the image—as prospective property owners—and appeals to notions of going to the coast to secure privacy and opportunities for passive relaxation. Advertising for coastal real estate, we conclude, promotes a way of seeing the coastal landscape that is consistent with the ideology of enclosure.
Computer-Supported Cognitive Mapping for Participatory Problem Structuring
Authors: van Kouwen Frank , Dieperink Card , Schot Paul P , Wassen Martin J
Published: September 2008

The environmental management and planning community is struggling with a gap between knowledge and policy making. To bridge this gap, ‘decision support systems’, ‘planning support systems’, and other computer tools have been developed to make knowledge about complex issues more accessible for policy makers. However, the use of these systems in practice is limited. One major reason for this is that these systems are designed for well-defined problems, whereas in practice there is often a lack of stakeholder consensus on the problem structure. The aim of this paper is to present, and explore the potential of, a new approach for decision and planning support. The Quasta tool aims at facilitating participatory problem structuring through computer-supported cognitive mapping. The tool, allowing qualitative exploration of scenarios and simultaneous forecasting and backcasting, is tested in four participatory problem-structuring workshops, in which various environmental issues have been discussed. Evaluations of these workshops show that this approach (1) helps stakeholders to become aware of causal relationships, (2) is useful for a qualitative exploration of scenarios, (3) identifies the need for further (in-depth) knowledge, and (4) has a low threshold for nontechnicians.
Deriving a preliminary breeding objective for commercial ostriches: an overview
Authors: Cloete S. W. P. , Engelbrecht A. , Olivier J. J. , Bunter K. L.
Published: September 2008

Ostrich farmers rely on skins and meat as their most important sources of revenue, with feathers being of secondary importance. This paper provides a summary of parameter estimates (heritabilities and genetic correlations) estimated from the resource flock held at the Oudtshoorn Research Farm. Traits considered were egg production, chick production, mature liveweight, offspring slaughter weight and skin traits. Feather weight of mature breeding birds was not included, as revenue received for this commodity is comparatively low, and mostly reliant on quality. All the traits considered were moderately to highly heritable, and reproduction traits in particular were highly variable. No substantial unfavourable genetic correlations were noted, and worthwhile gains in all traits appear to be achievable within a selection objective based on economic principles. Economic weights for key traits were obtained from a bio-economical input–output simulation model that was prepared for the industry. A simple preliminary selection index including chick production (as a hen reproductive trait) and slaughter weight (as a measure of growth) appears to be adequate for the present needs, given the limited availability of routinely recorded traits. A key performance trait that is currently missing from the economic assessment is chick survival, which is known to be low and highly variable among ostrich flocks. Further information will be added as it becomes available.
Combinatorics of least-squares trees
Authors: Mihaescu Radu , Pachter Lior
Published: September 2008

A recurring theme in the least-squares approach to phylogenetics has been the discovery of elegant combinatorial formulas for the least-squares estimates of edge lengths. These formulas have proved useful for the development of efficient algorithms, and have also been important for understanding connections among popular phylogeny algorithms. For example, the selection criterion of the neighbor-joining algorithm is now understood in terms of the combinatorial formulas of Pauplin for estimating tree length. We highlight a phylogenetically desirable property that weighted least-squares methods should satisfy, and provide a complete characterization of methods that satisfy the property. The necessary and sufficient condition is a multiplicative four-point condition that the variance matrix needs to satisfy. The proof is based on the observation that the Lagrange multipliers in the proof of the Gauss–Markov theorem are tree-additive. Our results generalize and complete previous work on ordinary least squares, balanced minimum evolution, and the taxon-weighted variance model. They also provide a time-optimal algorithm for computation.
Natural selection of
FLT1
alleles and their association with malaria resistance
in utero
Authors: Muehlenbachs Atis , Fried Michal , Lachowitzer Jeff , Mutabingwa Theonest K. , Duffy Patrick E.
Published: September 2008

Placental malaria (PM) caused by
Plasmodium falciparum
contributes significantly to infant mortality in sub-Saharan Africa and is associated with pregnancy loss. We hypothesized that fetal genes that modify PM would be associated with fetal fitness. During PM, placental trophoblasts produce soluble
fms
-like tyrosine kinase 1 (sFlt1), also known as soluble VEGF receptor 1, an angiogenesis inhibitor associated with preeclampsia. Here we present a study examining the genotype of the
fms
-related tyrosine kinase 1 (
FLT1
) 3′ UTR in Tanzanian mother–infant pairs. First-time mothers suffer the most PM, and newborn FLT1 genotype distribution differed by birth order, with newborns of first-time mothers outside of Hardy–Weinberg equilibrium (HWE) during peak PM season. Among first-time but not other mothers, maternal
FLT1
genotype was associated with a history of prior pregnancy loss. During PM, newborn
FLT1
genotype was associated with low birth weight and placental inflammatory gene expression.
FLT1
genotype was also associated with Flt1 levels among study subjects and
in vitro
. Thus, FLT1 variants confer fetal fitness
in utero
and are associated with the maternal immune response during PM. This indicates that
FLT1
is under natural selection in a malaria endemic area and that human exposure to malaria can influence the evolutionary genetics of the maternal-fetal relationship.
Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons
Authors: Zhang Dao-Qi , Wong Kwoon Y. , Sollars Patricia J. , Berson David M. , Pickard Gary E. , McMahon Douglas G.
Published: September 2008

Retinal dopaminergic amacrine neurons (DA neurons) play a central role in reconfiguring retinal function according to prevailing illumination conditions, yet the mechanisms by which light regulates their activity are poorly understood. We investigated the means by which sustained light responses are evoked in DA neurons. Sustained light responses were driven by cationic currents and persisted
in vitro
and
in vivo
in the presence of L-AP4, a blocker of retinal ON-bipolar cells. Several characteristics of these L-AP4-resistant light responses suggested that they were driven by melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), including long latencies, marked poststimulus persistence, and a peak spectral sensitivity of 478 nm. Furthermore, sustained DA neuron light responses, but not transient DA neuron responses, persisted in rod/cone degenerate retinas, in which ipRGCs account for virtually all remaining retinal phototransduction. Thus, ganglion-cell photoreceptors provide excitatory drive to DA neurons, most likely by way of the coramification of their dendrites and the processes of DA neurons in the inner plexiform layer. This unprecedented centrifugal outflow of ganglion-cell signals within the retina provides a novel basis for the restructuring of retinal circuits by light.
Neanderthal brain size at birth provides insights into the evolution of human life history
Authors: Ponce de León Marcia S. , Golovanova Lubov , Doronichev Vladimir , Romanova Galina , Akazawa Takeru , Kondo Osamu , Ishida Hajime , Zollikofer Christoph P. E.
Published: September 2008

From birth to adulthood, the human brain expands by a factor of 3.3, compared with 2.5 in chimpanzees [DeSilva J and Lesnik J (2006) Chimpanzee neonatal brain size: Implications for brain growth in
Homo erectus. J Hum Evol
51: 207–212]. How the required extra amount of human brain growth is achieved and what its implications are for human life history and cognitive development are still a matter of debate. Likewise, because comparative fossil evidence is scarce, when and how the modern human pattern of brain growth arose during evolution is largely unknown. Virtual reconstructions of a Neanderthal neonate from Mezmaiskaya Cave (Russia) and of two Neanderthal infant skeletons from Dederiyeh Cave (Syria) now provide new comparative insights: Neanderthal brain size at birth was similar to that in recent
Homo sapiens
and most likely subject to similar obstetric constraints. Neanderthal brain growth rates during early infancy were higher, however. This pattern of growth resulted in larger adult brain sizes but not in earlier completion of brain growth. Because large brains growing at high rates require large, late-maturing, mothers [Leigh SR and Blomquist GE (2007) in Campbell CJ
et al.
Primates in perspective; pp 396–407], it is likely that Neanderthal life history was similarly slow, or even slower-paced, than in recent
H. sapiens
.
Hierarchical folding mechanism of apomyoglobin revealed by ultra-fast H/D exchange coupled with 2D NMR
Authors: Uzawa Takanori , Nishimura Chiaki , Akiyama Shuji , Ishimori Koichiro , Takahashi Satoshi , Dyson H. Jane , Wright Peter E.
Published: September 2008

The earliest steps in the folding of proteins are complete on an extremely rapid time scale that is difficult to access experimentally. We have used rapid-mixing quench-flow methods to extend the time resolution of folding studies on apomyoglobin and elucidate the structural and dynamic features of members of the ensemble of intermediate states that are populated on a submillisecond time scale during this process. The picture that emerges is of a continuum of rapidly interconverting states. Even after only 0.4 ms of refolding time a compact state is formed that contains major parts of the A, G, and H helices, which are sufficiently well folded to protect amides from exchange. The B, C, and E helix regions fold more slowly and fluctuate rapidly between open and closed states as they search docking sites on this core; the secondary structure in these regions becomes stabilized as the refolding time is increased from 0.4 to 6 ms. No further stabilization occurs in the A, G, H core at 6 ms of folding time. These studies begin to time-resolve a progression of compact states between the fully unfolded and native folded states and confirm the presence an ensemble of intermediates that interconvert in a hierarchical sequence as the protein searches conformational space on its folding trajectory.
IL-21 signaling is critical for the development of type I diabetes in the NOD mouse
Authors: Spolski Rosanne , Kashyap Mohit , Robinson Constance , Yu Zuxi , Leonard Warren J.
Published: September 2008

IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor γ chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated
Idd3
locus is at the
Il2
/
Il21
locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes,
Il21r
-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans.
A fast randomized algorithm for overdetermined linear least-squares regression
Authors: Rokhlin Vladimir , Tygert Mark
Published: September 2008

We introduce a randomized algorithm for overdetermined linear least-squares regression. Given an arbitrary full-rank
m
×
n
matrix
A
with
m
≥
n
, any
m
× 1 vector
b
, and any positive real number ε, the procedure computes an
n
× 1 vector
x
such that
x
minimizes the Euclidean norm ‖
Ax
−
b
‖ to relative precision ε. The algorithm typically requires 𝒪((log(
n
)+log(1/ε))
mn
+
n
3
) floating-point operations. This cost is less than the 𝒪(
mn
2
) required by the classical schemes based on
QR
-decompositions or bidiagonalization. We present several numerical examples illustrating the performance of the algorithm.
Spatial organization of a replicating bacterial chromosome
Authors: Berlatzky Idit Anna , Rouvinski Alex , Ben-Yehuda Sigal
Published: September 2008

Emerging evidence indicates that the global organization of the bacterial chromosome is defined by its physical map. This architectural understanding has been gained mainly by observing the localization and dynamics of specific chromosomal loci. However, the spatial and temporal organization of the entire mass of newly synthesized DNA remains elusive. To visualize replicated DNA within living cells, we developed an experimental system in the bacterium
Bacillus subtilis
whereby fluorescently labeled nucleotides are incorporated into the chromosome as it is being replicated. Here, we present the first visualization of replication morphologies exhibited by the bacterial chromosome. At the start of replication, newly synthesized DNA is translocated via a helical structure from midcell toward the poles, where it accumulates. Next, additionally synthesized DNA forms a second, visually distinct helix that interweaves with the original one. In the final stage of replication, the space between the two helices is filled up with the very last synthesized DNA. This striking geometry provides insight into the three-dimensional conformation of the replicating chromosome.
A scale of greatness and causal classification of mass extinctions: Implications for mechanisms
Authors: Şengör A. M. Celâl , Atayman Saniye , Özeren Sinan
Published: September 2008

A quantitative scale for measuring greatness,G, of mass extinctions is proposed on the basis of rate of biodiversity diminution expressed as the product of the loss of biodiversity, called magnitude (M), and the inverse of time in which that loss occurs, designated as intensity (I). On this scale, the catastrophic Cretaceous–Tertiary (K-T) extinction appears as the greatest since the Ordovician and the only one with a probable extraterrestrial cause. The end-Permian extinction was less great but with a large magnitude (M) and smaller intensity (I); only some of its individual episodes involved some semblance of catastrophe. Other extinctions during the Phanerozoic, with the possible exception of the end-Silurian diversity plunge, were parts of a forced oscillatory phenomenon and seem caused by marine- and land-habitat destruction during continental assemblies that led to elimination of shelves and (after the Devonian) rain forests and enlargement of deserts. Glaciations and orogenies that shortened and thickened the continental crust only exacerbated these effects. During the Mesozoic and Cainozoic, the evolution of life was linearly progressive, interrupted catastrophically only at the K-T boundary. The end-Triassic extinction was more like the Paleozoic extinctions in nature and probably also in its cause. By contrast, the current extinction resembles none of the earlier ones and may end up being the greatest of all.
Experience versus talent shapes the structure of the Web
Authors: Kong Joseph S. , Sarshar Nima , Roychowdhury Vwani P.
Published: September 2008

We use sequential large-scale crawl data to empirically investigate and validate the dynamics that underlie the evolution of the structure of the web. We find that the overall structure of the web is defined by an intricate interplay between experience or entitlement of the pages (as measured by the number of inbound hyperlinks a page already has), inherent talent or fitness of the pages (as measured by the likelihood that someone visiting the page would give a hyperlink to it), and the continual high rates of birth and death of pages on the web. We find that the web is conservative in judging talent and the overall fitness distribution is exponential, showing low variability. The small variance in talent, however, is enough to lead to experience distributions with high variance: The preferential attachment mechanism amplifies these small biases and leads to heavy-tailed power-law (PL) inbound degree distributions over all pages, as well as over pages that are of the same age. The balancing act between experience and talent on the web allows newly introduced pages with novel and interesting content to grow quickly and surpass older pages. In this regard, it is much like what we observe in high-mobility and meritocratic societies: People with entitlement continue to have access to the best resources, but there is just enough screening for fitness that allows for talented winners to emerge and join the ranks of the leaders. Finally, we show that the fitness estimates have potential practical applications in ranking query results.
Crystal structure of the β-finger domain of Prp8 reveals analogy to ribosomal proteins
Authors: Yang Kui , Zhang Lingdi , Xu Tao , Heroux Annie , Zhao Rui
Published: September 2008

Prp8 stands out among hundreds of splicing factors as a key regulator of spliceosome activation and a potential cofactor of the splicing reaction. We present here the crystal structure of a 274-residue domain (residues 1,822–2,095) near the C terminus of
Saccharomyces cerevisiae
Prp8. The most striking feature of this domain is a β-hairpin finger protruding out of the protein (hence, this domain will be referred to as the β-finger domain), resembling many globular ribosomal proteins with protruding extensions. Mutations throughout the β-finger change the conformational equilibrium between the first and the second catalytic step. Mutations at the base of the β-finger affect U4/U6 unwinding-mediated spliceosome activation. Prp8 may insert its β-finger into the first-step complex (U2/U5/U6/pre-mRNA) or U4/U6.U5 tri-snRNP and stabilize these complexes. Mutations on the β-finger likely alter these interactions, leading to the observed mutant phenotypes. Our results suggest a possible mechanism of how Prp8 regulates spliceosome activation. These results also demonstrate an analogy between a spliceosomal protein and ribosomal proteins that insert extensions into folded rRNAs and stabilize the ribosome.
Accelerated evolution of resistance in multidrug environments
Authors: Hegreness Matthew , Shoresh Noam , Damian Doris , Hartl Daniel , Kishony Roy
Published: September 2008

The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions—synergy or antagonism—between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds ofEscherchia colipopulations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clinical settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.
Decyanation of vitamin B
12
by a trafficking chaperone
Authors: Kim Jihoe , Gherasim Carmen , Banerjee Ruma
Published: September 2008

The mystery of how the cyanide group in vitamin B
12
or cyanocobalamin, discovered 60 years ago, is removed, has been solved by the demonstration that the trafficking chaperone, MMACHC, catalyzes a reductive decyanation reaction. Electrons transferred from NADPH via cytosolic flavoprotein oxidoreductases are used to cleave the cobalt–carbon bond with reductive elimination of the cyanide ligand. The product, cob(II)alamin, is a known substrate for assimilation into the active cofactor forms, methylcobalamin and 5′-deoxyadenosylcobalamin, and is bound in the “base-off” state that is needed by the two B
12
-dependent target enzymes, methionine synthase and methylmalonyl-CoA mutase. Defects in MMACHC represent the most common cause of inborn errors of B
12
metabolism, and our results explain the observation that fibroblasts from these patients are poorly responsive to vitamin B
12
but show some metabolic correction with aquocobalamin, a cofactor form lacking the cyanide ligand, which is mirrored by patients showing poorer clinical responsiveness to cyano- versus aquocobalamin.
Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice
Authors: Menconi Francesca , Monti Maria C. , Greenberg David A. , Oashi Taiji , Osman Roman , Davies Terry F. , Ban Yoshiyuki , Jacobson Eric M. , Concepcion Erlinda S. , Li Cheuk Wun , Tomer Yaron
Published: September 2008

Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT (P= 6.18 × 10−5, OR = 3.73). Lys-71 showed the strongest association (P= 1.7 × 10−8, OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT (P= 3.66 × 10−4). In mice, the I-E pocket amino acids Val-28, Phe-86, and Asn-88 were strongly associated with EAT. Structural modeling studies demonstrated that pocket P4 was critical for the development of HT, and pockets P1 and P4 influenced susceptibility to EAT. Surprisingly, the structures of the HT- and EAT-susceptible pockets were different. We conclude that specific MHC II pocket amino acid signatures determine susceptibility to HT and EAT by causing structural changes in peptide-binding pockets that may influence peptide binding, selectivity, and presentation. Because the HT- and EAT-associated pockets are structurally different, it is likely that distinct antigenic peptides are associated with HT and EAT.
TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3
Authors: Samanta Arabinda , Li Bin , Song Xiaomin , Bembas Kathryn , Zhang Geng , Katsumata Makoto , Saouaf Sandra J. , Wang Qiang , Hancock Wayne W. , Shen Yuan , Greene Mark I.
Published: September 2008

Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown. Although TGF-β is known to induce murine FOXP3
+
Treg cells, TGF-β in combination with IL-6 attenuates the induction of FOXP3 functional activities. Here we show that TCR stimuli and TGF-β signals modulate the disposition of FOXP3 into different subnuclear compartments, leading to enhanced chromatin binding in human CD4
+
CD25
+
regulatory T cells. TGF-β treatment increases the level of acetylated FOXP3 on chromatin and site-specific recruitment of FOXP3 on the human IL-2 promoter. However, the proinflammatory cytokine IL-6 down-regulates FOXP3 binding to chromatin in the presence of TGF-β. Moreover, histone deacetylation inhibitor (HDACi) treatment abrogates the down-regulating effects of IL-6 and TGF-β. These studies indicate that HDACi can enhance regulatory T cell function via promoting FOXP3 binding to chromatin even in a proinflammatory cellular microenvironment. Collectively, our data provide a framework of how different signals affect intranuclear redistribution, posttranslational modifications, and chromatin binding patterns of FOXP3.
A fluorescent reporter of caspase activity for live imaging
Authors: Bardet Pierre-Luc , Kolahgar Golnar , Mynett Anita , Miguel-Aliaga Irene , Briscoe James , Meier Pascal , Vincent Jean-Paul
Published: September 2008

There is a growing interest in the mechanisms that control the apoptosis cascade during development and adult life. To investigate the regulatory events that trigger apoptosis in whole tissues, we have devised a genetically encoded caspase sensor that can be detected in live and fixed tissue by standard confocal microscopy. The sensor comprises two fluorophores, mRFP, monomeric red fluorescent protein (mRFP) and enhanced green fluorescent protein (eGFP), that are linked by an efficient and specific caspase-sensitive site. Upon caspase activation, the sensor is cleaved and eGFP translocates to the nucleus, leaving mRFP at membranes. This is detected before other markers of apoptosis, including anti–cleaved caspase 3 immunoreactivity. Moreover, the sensor does not perturb normal developmental apoptosis and is specific, as cleavage does not occur in
Drosophila
embryos that are unable to activate the apoptotic cascade. Importantly, dying cells can be recognized in live embryos, thus opening the way for
in vivo
imaging. As expected from the high conservation of caspases, it is also cleaved in dying cells of chick embryos. It is therefore likely to be generally useful to track the spatiotemporal pattern of caspase activity in a variety of species.