bluuebunny/crossref_metadata_2025 huggingface dataset:
Using spatial principles to optimize distributed computing for enabling the physical science discoveries
Authors: Yang Chaowei , Wu Huayi , Huang Qunying , Li Zhenlong , Li Jing
Published: March 2011

Contemporary physical science studies rely on the effective analyses of geographically dispersed spatial data and simulations of physical phenomena. Single computers and generic high-end computing are not sufficient to process the data for complex physical science analysis and simulations, which can be successfully supported only through distributed computing, best optimized through the application of spatial principles. Spatial computing, the computing aspect of a spatial cyberinfrastructure, refers to a computing paradigm that utilizes spatial principles to optimize distributed computers to catalyze advancements in the physical sciences. Spatial principles govern the interactions between scientific parameters across space and time by providing the spatial connections and constraints to drive the progression of the phenomena. Therefore, spatial computing studies could better position us to leverage spatial principles in simulating physical phenomena and, by extension, advance the physical sciences. Using geospatial science as an example, this paper illustrates through three research examples how spatial computing could (
i
) enable data intensive science with efficient data/services search, access, and utilization, (
ii
) facilitate physical science studies with enabling high-performance computing capabilities, and (
iii
) empower scientists with multidimensional visualization tools to understand observations and simulations. The research examples demonstrate that spatial computing is of critical importance to design computing methods to catalyze physical science studies with better data access, phenomena simulation, and analytical visualization. We envision that spatial computing will become a core technology that drives fundamental physical science advancements in the 21st century.
Rapid, global demographic expansions after the origins of agriculture
Authors: Gignoux Christopher R. , Henn Brenna M. , Mountain Joanna L.
Published: March 2011

The invention of agriculture is widely assumed to have driven recent human population growth. However, direct genetic evidence for population growth after independent agricultural origins has been elusive. We estimated population sizes through time from a set of globally distributed whole mitochondrial genomes, after separating lineages associated with agricultural populations from those associated with hunter-gatherers. The coalescent-based analysis revealed strong evidence for distinct demographic expansions in Europe, southeastern Asia, and sub-Saharan Africa within the past 10,000 y. Estimates of the timing of population growth based on genetic data correspond neatly to dates for the initial origins of agriculture derived from archaeological evidence. Comparisons of rates of population growth through time reveal that the invention of agriculture facilitated a fivefold increase in population growth relative to more ancient expansions of hunter-gatherers.
Phenotypic integration emerges from aposematism and scale in poison frogs
Authors: Santos Juan C. , Cannatella David C.
Published: March 2011

Complex phenotypes can be modeled as networks of component traits connected by genetic, developmental, or functional interactions. Aposematism, which has evolved multiple times in poison frogs (Dendrobatidae), links a warning signal to a chemical defense against predators. Other traits are involved in this complex phenotype. Most aposematic poison frogs are ant specialists, from which they sequester defensive alkaloids. We found that aposematic species have greater aerobic capacity, also related to diet specialization. To characterize the aposematic trait network more fully, we analyzed phylogenetic correlations among its hypothesized components: conspicuousness, chemical defense, diet specialization, body mass, active and resting metabolic rates, and aerobic scope. Conspicuous coloration was correlated with all components except resting metabolism. Structural equation modeling on the basis of trait correlations recovered “aposematism” as one of two latent variables in an integrated phenotypic network, the other being scaling with body mass and physiology (“scale”). Chemical defense and diet specialization were uniquely tied to aposematism whereas conspicuousness was related to scale. The phylogenetic distribution of the aposematic syndrome suggests two scenarios for its evolution: (i) chemical defense and conspicuousness preceded greater aerobic capacity, which supports the increased resource-gathering abilities required of ant–mite diet specialization; and (ii) assuming that prey are patchy, diet specialization and greater aerobic capacity evolved in tandem, and both traits subsequently facilitated the evolution of aposematism.
Urban growth, climate change, and freshwater availability
Authors: McDonald Robert I. , Green Pamela , Balk Deborah , Fekete Balazs M. , Revenga Carmen , Todd Megan , Montgomery Mark
Published: March 2011

Nearly 3 billion additional urban dwellers are forecasted by 2050, an unprecedented wave of urban growth. While cities struggle to provide water to these new residents, they will also face equally unprecedented hydrologic changes due to global climate change. Here we use a detailed hydrologic model, demographic projections, and climate change scenarios to estimate per-capita water availability for major cities in the developing world, where urban growth is the fastest. We estimate the amount of water physically available near cities and do not account for problems with adequate water delivery or quality. Modeled results show that currently 150 million people live in cities with perennial water shortage, defined as having less than 100 L per person per day of sustainable surface and groundwater flow within their urban extent. By 2050, demographic growth will increase this figure to almost 1 billion people. Climate change will cause water shortage for an additional 100 million urbanites. Freshwater ecosystems in river basins with large populations of urbanites with insufficient water will likely experience flows insufficient to maintain ecological process. Freshwater fish populations will likely be impacted, an issue of special importance in regions such as India's Western Ghats, where there is both rapid urbanization and high levels of fish endemism. Cities in certain regions will struggle to find enough water for the needs of their residents and will need significant investment if they are to secure adequate water supplies and safeguard functioning freshwater ecosystems for future generations.
Exploring transcription regulation through cell-to-cell variability
Authors: Rinott Ruty , Jaimovich Ariel , Friedman Nir
Published: March 2011

The regulation of cellular protein levels is a complex process involving many regulatory mechanisms, each introducing stochastic events, leading to variability of protein levels between isogenic cells. Previous studies have shown that perturbing genes involved in transcription regulation affects the amount of cell-to-cell variability in protein levels, but to date there has been no systematic characterization of variability in expression as a phenotype. In this research, we use single-cell expression levels of two fluorescent reporters driven by two different promoters under a wide range of genetic perturbations in
Saccharomyces cerevisiae
, to identify proteins that affect variability in the expression of these reporters. We introduce computational methodology to determine the variability caused by each perturbation and distinguish between global variability, which affects both reporters in a coordinated manner (e.g., due to cell size variability), and local variability, which affects the individual reporters independently (e.g., due to stochastic events in transcription initiation). Classifying genes by their variability phenotype (the effect of their deletion on reporter variability) identifies functionally coherent groups, which broadly correlate with the different stages of transcriptional regulation. Specifically, we find that most processes whose perturbation affects global variability are related to protein synthesis, protein transport, and cell morphology, whereas most processes whose perturbations affect local variability are related to DNA maintenance, chromatin regulation, and RNA synthesis. Moreover, we demonstrate that the variability phenotypes of different protein complexes provide insights into their cellular functions. Our results establish the utility of variability phenotype for dissecting the regulatory mechanisms involved in gene expression.
Transition from a plasmid to a chromosomal mode of replication entails additional regulators
Authors: Venkova-Canova Tatiana , Chattoraj Dhruba K.
Published: March 2011

Plasmid origins of replication are rare in bacterial chromosomes, except in multichromosome bacteria. The replication origin of
Vibrio cholerae
chromosome II (chrII) closely resembles iteron-bearing plasmid origins. Iterons are repeated initiator binding sites in plasmid origins and participate both in replication initiation and its control. The control is mediated primarily by coupling of iterons via the bound initiators (“handcuffing”), which causes steric hindrance to the origin. The control in chrII must be different, since the timing of its replication is cell cycle-specific, whereas in plasmids it is random. Here we show that chrII uses, in addition to iterons, another kind of initiator binding site, named 39-mers. The 39-mers confer stringent control by increasing handcuffing of iterons, presumably via initiator remodeling. Iterons, although potential inhibitors of replication themselves, restrain the 39-mer–mediated inhibition, possibly by direct coupling (“heterohandcuffing”). We propose that the presumptive transition of a plasmid to a chromosomal mode of control requires additional regulators to increase the stringency of control, and as will be discussed, to gain the capacity to modulate the effectiveness of the regulators at different stages of the cell cycle.
Arginine methylation of BCL-2 antagonist of cell death (BAD) counteracts its phosphorylation and inactivation by Akt
Authors: Sakamaki Jun-ichi , Daitoku Hiroaki , Ueno Katsuya , Hagiwara Ayano , Yamagata Kazuyuki , Fukamizu Akiyoshi
Published: March 2011

Protein arginine methylation is a common posttranslational modification catalyzed by a family of the protein arginine methyltransferases (PRMTs). We have previously reported that PRMT1 methylates Forkhead box O transcription factors at two arginine residues within an Akt consensus phosphorylation motif (RxRxxS/T), and that this methylation blocks Akt-mediated phosphorylation of the transcription factors. These findings led us to hypothesize that the functional crosstalk between arginine methylation and phosphorylation could be extended to other Akt target proteins as well as Forkhead box O proteins. Here we identify BCL-2 antagonist of cell death (BAD) as an additional substrate for PRMT1 among several Akt target proteins. We show that PRMT1 specifically binds and methylates BAD at Arg-94 and Arg-96, both of which comprise the Akt consensus phosphorylation motif. Consistent with the hypothesis, PRMT1-mediated methylation of these two arginine residues inhibits Akt-mediated phosphorylation of BAD at Ser-99 in vitro and in vivo. We also demonstrate that the complex formation of BAD with 14-3-3 proteins, which occurs subsequent to Akt-mediated phosphorylation, is negatively regulated by PRMT1. Furthermore, PRMT1 knockdown prevents mitochondrial localization of BAD and its binding to the antiapoptotic BCL-X
L
protein. BAD overexpression causes an increase in apoptosis with concomitant activation of caspase-3, whereas PRMT1 knockdown significantly suppresses these apoptotic processes. Taken together, our results add a new dimension to the complexity of posttranslational BAD regulation and provide evidence that arginine methylation within an Akt consensus phosphorylation motif functions as an inhibitory modification against Akt-dependent survival signaling.
Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding
Authors: Moscoso Carlos G. , Sun Yide , Poon Selina , Xing Li , Kan Elaine , Martin Loïc , Green Dominik , Lin Frank , Vahlne Anders G. , Barnett Susan , Srivastava Indresh , Cheng R. Holland
Published: March 2011

The human immunodeficiency virus envelope protein is the key element mediating entry into host cells. Conformational rearrangement of Env upon binding to the host CD4 receptor and chemokine coreceptor drives membrane fusion. We elucidated the quaternary arrangement of the soluble Env trimeric immunogen o-gp140ΔV2TV1, in both its native (unliganded) and CD4-induced (liganded) states by cryoelectron microscopy and molecular modeling. The liganded conformation was elicited by binding gp140 to the synthetic CD4-mimicking miniprotein CD4m. Upon CD4m binding, an outward domain shift of the three gp120 subunits diminishes gp120–gp41 interactions, whereas a “flat open” concave trimer apex is observed consequent to gp120 tilting away from threefold axis, likely juxtaposing the fusion peptide with the host membrane. Additional features observed in the liganded conformation include rotations of individual gp120 subunits that may release gp41 for N- and C-helix refolding and also may lead to optimal exposure of the elicited coreceptor binding site. Such quaternary arrangements of gp140 lead to the metastable liganded conformation, with putative locations of exposed epitopes contributing to a description of sequential events occurring prior to membrane fusion. Our observations imply a mechanism whereby a soluble Env trimeric construct, as opposed to trimers extracted from virions, may better expose crucial epitopes such as the CD4 binding site and V3, as well as epitopes in the vicinity of gp41, subsequent to conjugation with CD4m. Structural features gleaned from our studies should aid the design of Env-based immunogens for inducement of potent broadly neutralizing antibodies against exposed conformational epitopes.
Dimensional crossover in the coalescence dynamics of viscous drops confined in between two plates
Authors: Yokota Maria , Okumura Ko
Published: March 2011

Coalescence of liquid drops is a daily phenomenon familiar to everybody and is related to many fields from biology to astronomy and also related to a variety of practical problems in industry. However, the detailed physical understanding of the dynamics has been revealed only recently with the aid of high-speed camera, high-performance computer, and scaling analysis. In this study, coalescence of a viscous drop to a bath of the same liquid is studied in a confined space. This is because dealing with a small amount of liquid drops becomes increasingly important (e.g., in industrial and biological applications). Here, the aqueous drop and bath are surrounded by low-viscosity oil and sandwiched by two parallel plates of the cell. We quantify experimentally the width of a neck that bridges the drop and the bath during coalescence. As a result, we find that the neck width increases linearly with time at short times, but the dynamics slows down significantly at longer times. Thanks to simple and original scaling arguments, we clearly show that this transition of the dynamics with time in a single coalescence event is brought about by a crossover from a three-dimensional viscous dynamics for a spherical drop to a quasi two-dimensional one for a disk drop. In addition, we report an unusual type of coalescence that is possibly caused by naturally accumulated electric charge in the confined geometry and whose dynamics seems self-similar.
Prosody guides the rapid mapping of auditory word forms onto visual objects in 6-mo-old infants
Authors: Shukla Mohinish , White Katherine S. , Aslin Richard N.
Published: March 2011

Human infants are predisposed to rapidly acquire their native language. The nature of these predispositions is poorly understood, but is crucial to our understanding of how infants unpack their speech input to recover the fundamental word-like units, assign them referential roles, and acquire the rules that govern their organization. Previous researchers have demonstrated the role of general distributional computations in prelinguistic infants’ parsing of continuous speech. We extend these findings to more naturalistic conditions, and find that 6-mo-old infants can simultaneously segment a nonce auditory word form from prosodically organized continuous speech and associate it to a visual referent. Crucially, however, this mapping occurs only when the word form is aligned with a prosodic phrase boundary. Our findings suggest that infants are predisposed very early in life to hypothesize that words are aligned with prosodic phrase boundaries, thus facilitating the word learning process. Further, and somewhat paradoxically, we observed successful learning in a more complex context than previously studied, suggesting that learning is enhanced when the language input is well matched to the learner's expectations.
Radiation damage in protein crystals is reduced with a micron-sized X-ray beam
Authors: Sanishvili Ruslan , Yoder Derek W. , Pothineni Sudhir Babu , Rosenbaum Gerd , Xu Shenglan , Vogt Stefan , Stepanov Sergey , Makarov Oleg A. , Corcoran Stephen , Benn Richard , Nagarajan Venugopalan , Smith Janet L. , Fischetti Robert F.
Published: March 2011

Radiation damage is a major limitation in crystallography of biological macromolecules, even for cryocooled samples, and is particularly acute in microdiffraction. For the X-ray energies most commonly used for protein crystallography at synchrotron sources, photoelectrons are the predominant source of radiation damage. If the beam size is small relative to the photoelectron path length, then the photoelectron may escape the beam footprint, resulting in less damage in the illuminated volume. Thus, it may be possible to exploit this phenomenon to reduce radiation-induced damage during data measurement for techniques such as diffraction, spectroscopy, and imaging that use X-rays to probe both crystalline and noncrystalline biological samples. In a systematic and direct experimental demonstration of reduced radiation damage in protein crystals with small beams, damage was measured as a function of micron-sized X-ray beams of decreasing dimensions. The damage rate normalized for dose was reduced by a factor of three from the largest (15.6 μm) to the smallest (0.84 μm) X-ray beam used. Radiation-induced damage to protein crystals was also mapped parallel and perpendicular to the polarization direction of an incident 1-μm X-ray beam. Damage was greatest at the beam center and decreased monotonically to zero at a distance of about 4 μm, establishing the range of photoelectrons. The observed damage is less anisotropic than photoelectron emission probability, consistent with photoelectron trajectory simulations. These experimental results provide the basis for data collection protocols to mitigate with micron-sized X-ray beams the effects of radiation damage.
Glasses crystallize rapidly at free surfaces by growing crystals upward
Authors: Sun Ye , Zhu Lei , Kearns Kenneth L. , Ediger Mark D. , Yu Lian
Published: March 2011

The crystallization of glasses and amorphous solids is studied in many fields to understand the stability of amorphous materials, the fabrication of glass ceramics, and the mechanism of biomineralization. Recent studies have found that crystal growth in organic glasses can be orders of magnitude faster at the free surface than in the interior, a phenomenon potentially important for understanding glass crystallization in general. Current explanations differ for surface-enhanced crystal growth, including released tension and enhanced mobility at glass surfaces. We report here a feature of the phenomenon relevant for elucidating its mechanism: Despite their higher densities, surface crystals rise substantially above the glass surface as they grow laterally, without penetrating deep into the bulk. For indomethacin (IMC), an organic glass able to grow surface crystals in two polymorphs (α and γ), the growth front can be hundreds of nanometers above the glass surface. The process of surface crystal growth, meanwhile, is unperturbed by eliminating bulk material deeper than some threshold depth (
ca.
300 nm for α IMC and less than 180 nm for γ IMC). As a growth strategy, the upward-lateral growth of surface crystals increases the system’s surface energy, but can effectively take advantage of surface mobility and circumvent slow growth in the bulk.
Label-free live brain imaging and targeted patching with third-harmonic generation microscopy
Authors: Witte Stefan , Negrean Adrian , Lodder Johannes C. , de Kock Christiaan P. J. , Testa Silva Guilherme , Mansvelder Huibert D. , Louise Groot Marie
Published: March 2011

The ability to visualize neurons inside living brain tissue is a fundamental requirement in neuroscience and neurosurgery. Especially the development of a noninvasive probe of brain morphology with micrometer-scale resolution is highly desirable, as it would provide a noninvasive approach to optical biopsies in diagnostic medicine. Two-photon laser-scanning microscopy (2PLSM) is a powerful tool in this regard, and has become the standard for minimally invasive high-resolution imaging of living biological samples. However, while 2PLSM-based optical methods provide sufficient resolution, they have been hampered by the requirement for fluorescent dyes to provide image contrast. Here we demonstrate high-contrast imaging of live brain tissue at cellular resolution, without the need for fluorescent probes, using optical third-harmonic generation (THG). We exploit the specific geometry and lipid content of brain tissue at the cellular level to achieve partial phase matching of THG, providing an alternative contrast mechanism to fluorescence. We find that THG brain imaging allows rapid, noninvasive label-free imaging of neurons, white-matter structures, and blood vessels simultaneously. Furthermore, we exploit THG-based imaging to guide micropipettes towards designated neurons inside live tissue. This work is a major step towards label-free microscopic live brain imaging, and opens up possibilities for the development of laser-guided microsurgery techniques in the living brain.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration
Authors: Zhang Kang , Hopkins Jill J. , Heier Jeffrey S. , Birch David G. , Halperin Lawrence S. , Albini Thomas A. , Brown David M. , Jaffe Glenn J. , Tao Weng , Williams George A.
Published: March 2011

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (
P
= 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (
P
= 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.
Maternal investment, life histories, and the costs of brain growth in mammals
Authors: Barton Robert A. , Capellini Isabella
Published: March 2011

Brain size variation in mammals correlates with life histories: larger-brained species have longer gestations, mature later, and have increased lifespans. These patterns have been explained in terms of developmental costs (larger brains take longer to grow) and cognitive benefits (large brains enhance survival and increase lifespan). In support of the developmental cost hypothesis, we show that evolutionary changes in pre- and postnatal brain growth correlate specifically with duration of the relevant phases of maternal investment (gestation and lactation, respectively). We also find support for the hypothesis that the rate of fetal brain growth is related to the energy turnover of the mother. In contrast, we find no support for hypotheses proposing that costs are accommodated through direct tradeoffs between brain and body growth, or between brain growth and litter size. When the duration of maternal investment is taken into account, adult brain size is uncorrelated with other life history traits such as lifespan. Hence, the general pattern of slower life histories in large-brained species appears to be a direct consequence of developmental costs.
Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model
Authors: Simons David L. , Boye Sanford L. , Hauswirth William W. , Wu Samuel M.
Published: March 2011

Patients with Bardet-Biedl syndrome (BBS) experience severe retinal degeneration as a result of impaired photoreceptor transport processes that are not yet fully understood. To date, there is no effective treatment for BBS-associated retinal degeneration, and blindness is imminent by the second decade of life. Here we report the development of an adeno-associated viral (AAV) vector that rescues rhodopsin mislocalization, maintains nearly normal-appearing rod outer segments, and prevents photoreceptor death in theBbs4-null mouse model. Analysis of the electroretinogram a-wave indicates that rescued rod cells are functionally indistinguishable from wild-type rods. These results demonstrate that gene therapy can prevent retinal degeneration in a mammalian BBS model.
Local kinetics of morphogen gradients
Authors: Gordon Peter V. , Sample Christine , Berezhkovskii Alexander M. , Muratov Cyrill B. , Shvartsman Stanislav Y.
Published: March 2011

Some aspects of pattern formation in developing embryos can be described by nonlinear reaction–diffusion equations. An important class of these models accounts for diffusion and degradation of a locally produced single chemical species. At long times, solutions of such models approach a steady state in which the concentration decays with distance from the source of production. We present analytical results that characterize the dynamics of this process and are in quantitative agreement with numerical solutions of the underlying nonlinear equations. The derived results provide an explicit connection between the parameters of the problem and the time needed to reach a steady state value at a given position. Our approach can be used for the quantitative analysis of tissue patterning by morphogen gradients, a subject of active research in biophysics and developmental biology.
Sex pheromone desaturase functioning in a primitive
Ostrinia
moth is cryptically conserved in congeners’ genomes
Authors: Fujii Takeshi , Ito Katsuhiko , Tatematsu Mitsuko , Shimada Toru , Katsuma Susumu , Ishikawa Yukio
Published: March 2011

(
E
)-11- and (
Z
)-11-tetradecenyl acetate are the most common female sex pheromone components in
Ostrinia
moths. The Δ11-desaturase expressed in the pheromone gland (PG) of female moths is a key enzyme that introduces a double bond into pheromone molecules. A single Δ11-desaturase of
Ostrinia nubilalis
, OnubZ/E11, has been shown to produce an ∼7:3 mixture of (
E
)-11- and (
Z
)-11-tetradecenoate from the substrate tetradecanoate. In contrast, the sex pheromone of
Ostrinia latipennis
, a primitive species of
Ostrinia,
is (
E
)-11-tetradecenol. This pheromone is unique in that it is not acetylated, and includes no
Z
isomer. In the present study, through the cloning and functional analysis of a PG-specific Δ11-desaturase in
O. latipennis
, we showed that the absence of the
Z
isomer in the pheromone is attributable to the strict product specificity of the Δ11-desaturase in this species, LATPG1. Phylogenetic analysis revealed that LATPG1 was not closely related to OnubZ/E11. Rather, it was closely related to retroposon-linked cryptic Δ11-desaturases (
ezi
-Δ11) found in the genomes of
O. nubilalis
and
Ostrinia furnacalis
. Taken together, the results showed that an unusual Δ11-desaturase is functionally expressed in
O. latipennis
, although the genes encoding this enzyme appear to be cryptic in congeners.
Roles of transactivating functions 1 and 2 of estrogen receptor-α in bone
Authors: Börjesson A. E. , Windahl S. H. , Lagerquist M. K. , Engdahl C. , Frenkel B. , Movérare-Skrtic S. , Sjögren K. , Kindblom J. M. , Stubelius A. , Islander U. , Antal M. C. , Krust A. , Chambon P. , Ohlsson C.
Published: March 2011

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα
−/−
), ERα AF-1 (ERαAF-1
0
), or ERα AF-2 (ERαAF-2
0
). Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WT mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ERα
−/−
or OVX ERαAF-2
0
mice. OVX ERαAF-1
0
mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ERα
−/−
or OVX ERαAF-2
0
mice. The effect of E2 in OVX ERαAF-1
0
mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.
Characterization of a unique [FeS] cluster in the electron transfer chain of the oxygen tolerant [NiFe] hydrogenase from
Aquifex aeolicus
Authors: Pandelia Maria-Eirini , Nitschke Wolfgang , Infossi Pascale , Giudici-Orticoni Marie-Thérèse , Bill Eckhard , Lubitz Wolfgang
Published: March 2011

Iron-sulfur clusters are versatile electron transfer cofactors, ubiquitous in metalloenzymes such as hydrogenases. In the oxygen-tolerant Hydrogenase I from
Aquifex aeolicus
such electron “wires” form a relay to a diheme cyt
b
, an integral part of a respiration pathway for the reduction of O
2
to water. Amino acid sequence comparison with oxygen-sensitive hydrogenases showed conserved binding motifs for three iron-sulfur clusters, the nature and properties of which were unknown so far. Electron paramagnetic resonance spectra exhibited complex signals that disclose interesting features and spin-coupling patterns; by redox titrations three iron-sulfur clusters were identified in their usual redox states, a [3Fe4S] and two [4Fe4S], but also a unique high-potential (HP) state was found. On the basis of
57
Fe Mössbauer spectroscopy we attribute this HP form to a superoxidized state of the [4Fe4S] center proximal to the [NiFe] site. The unique environment of this cluster, characterized by a surplus cysteine coordination, is able to tune the redox potentials and make it compliant with the [4Fe4S]
3+
state. It is actually the first example of a biological [4Fe4S] center that physiologically switches between 3+, 2+, and 1+ oxidation states within a very small potential range. We suggest that the (1 + /2+) redox couple serves the classical electron transfer reaction, whereas the superoxidation step is associated with a redox switch against oxidative stress.
Integrated soil–crop system management for food security
Authors: Chen Xin-Ping , Cui Zhen-Ling , Vitousek Peter M. , Cassman Kenneth G. , Matson Pamela A. , Bai Jin-Shun , Meng Qing-Feng , Hou Peng , Yue Shan-Chao , Römheld Volker , Zhang Fu-Suo
Published: March 2011

China and other rapidly developing economies face the dual challenge of substantially increasing yields of cereal grains while at the same time reducing the very substantial environmental impacts of intensive agriculture. We used a model-driven integrated soil–crop system management approach to develop a maize production system that achieved mean maize yields of 13.0 t ha
−1
on 66 on-farm experimental plots—nearly twice the yield of current farmers’ practices—with no increase in N fertilizer use. Such integrated soil–crop system management systems represent a priority for agricultural research and implementation, especially in rapidly growing economies.
Intermediate states of the Kv1.2 voltage sensor from atomistic molecular dynamics simulations
Authors: Delemotte Lucie , Tarek Mounir , Klein Michael L. , Amaral Cristiano , Treptow Werner
Published: March 2011

The response of a membrane-bound Kv1.2 ion channel to an applied transmembrane potential has been studied using molecular dynamics simulations. Channel deactivation is shown to involve three intermediate states of the voltage sensor domain (VSD), and concomitant movement of helix S4 charges 10–15 Å along the bilayer normal; the latter being enabled by zipper-like sequential pairing of S4 basic residues with neighboring VSD acidic residues and membrane-lipid head groups. During the observed sequential transitions S4 basic residues pass through the recently discovered charge transfer center with its conserved phenylalanine residue, F
233
. Analysis indicates that the local electric field within the VSD is focused near the F
233
residue and that it remains essentially unaltered during the entire process. Overall, the present computations provide an atomistic description of VSD response to hyperpolarization, add support to the sliding helix model, and capture essential features inferred from a variety of recent experiments.
Macromolecular structural dynamics visualized by pulsed dose control in 4D electron microscopy
Authors: Kwon Oh-Hoon , Ortalan Volkan , Zewail Ahmed H.
Published: March 2011

Macromolecular conformation dynamics, which span a wide range of time scales, are fundamental to the understanding of properties and functions of their structures. Here, we report direct imaging of structural dynamics of helical macromolecules over the time scales of conformational dynamics (ns to subsecond) by means of four-dimensional (4D) electron microscopy in the single-pulse and stroboscopic modes. With temporally controlled electron dosage, both diffraction and real-space images are obtained without irreversible radiation damage. In this way, the order-disorder transition is revealed for the organic chain polymer. Through a series of equilibrium-temperature and temperature-jump dependencies, it is shown that the metastable structures and entropy of conformations can be mapped in the nonequilibrium region of a “funnel-like” free-energy landscape. The
T
-jump is introduced through a substrate (a “hot plate” type arrangement) because only the substrate is made to absorb the pulsed energy. These results illustrate the promise of ultrafast 4D imaging for other applications in the study of polymer physics as well as in the visualization of biological phenomena.
Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH)
Authors: Shang Shiying , Tan Zhongping , Danishefsky Samuel J.
Published: March 2011

The power of chemical synthesis of large cysteine-free polypeptides has been significantly enhanced through the use of nonproteogenic constructs which bear strategically placed thiol groups, enabling native chemical ligation. Central to these much expanded capabilities is the specific, radical-induced, metal-free dethiolation, which can be accomplished in aqueous medium.
Homeostatic adaptation to endoplasmic reticulum stress depends on Ire1 kinase activity
Authors: Rubio Claudia , Pincus David , Korennykh Alexei , Schuck Sebastian , El-Samad Hana , Walter Peter
Published: March 2011

Accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). Ire1, an ER-resident transmembrane kinase/RNase, senses the protein folding status inside the ER. When activated, Ire1 oligomerizes and trans-autophosphorylates, activating its RNase and initiating a nonconventional mRNA splicing reaction. Splicing results in production of the transcription factor Hac1 that induces UPR target genes; expression of these genes restores ER homeostasis by increasing its protein folding capacity and allows abatement of UPR signaling. Here, we uncouple Ire1’s RNase from its kinase activity and find that cells expressing kinase-inactive Ire1 can regulate Ire1’s RNase, splice HAC1 mRNA, produce Hac1 protein, and induce UPR target genes. Unlike wild-type IRE1, kinase-inactive Ire1 cells display defects in Ire1 deactivation. Failure to properly inactivate Ire1 causes chronic ER stress and reduces cell survival under UPR-inducing conditions. Thus, Ire1-catalyzed phosphoryl-transfer aids disassembly of Ire1 signaling complexes and is a critical component of the UPR homeostatic feedback loop.
Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis
Authors: Jewell Jenna L. , Oh Eunjin , Ramalingam Latha , Kalwat Michael A. , Tagliabracci Vincent S. , Tackett Lixuan , Elmendorf Jeffrey S. , Thurmond Debbie C.
Published: March 2011

How the Sec1/Munc18–syntaxin complex might transition to form the SNARE core complex remains unclear. Toward this, Munc18c tyrosine phosphorylation has been correlated with its dissociation from syntaxin 4. Using 3T3-L1 adipocytes subjected to small interfering ribonucleic acid reduction of Munc18c as a model of impaired insulin-stimulated GLUT4 vesicle exocytosis, we found that coordinate expression of Munc18c–wild type or select phosphomimetic Munc18c mutants, but not phosphodefective mutants, restored GLUT4 vesicle exocytosis, suggesting a requirement for Munc18c tyrosine phosphorylation at Tyr219 and Tyr521. Surprisingly, the insulin receptor (IR) tyrosine kinase was found to target Munc18c at Tyr521 in vitro, rapidly binding and phosphorylating endogenous Munc18c within adipocytes and skeletal muscle. IR, but not phosphatidylinositol 3-kinase, activation was required. Altogether, we identify IR as the first known tyrosine kinase for Munc18c as part of a new insulin-signaling step in GLUT4 vesicle exocytosis, exemplifying a new model for the coordination of SNARE assembly and vesicle mobilization events in response to a single extracellular stimulus.
Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase
Authors: Chawla Aditi , Chakrabarti Sutapa , Ghosh Gourisankar , Niwa Maho
Published: March 2011

The unfolded protein response (UPR) activates Ire1, an endoplasmic reticulum (ER) resident transmembrane kinase and ribonuclease (RNase), in response to ER stress. We used an in vivo assay, in which disappearance of the UPR-induced spliced HAC1 messenger ribonucleic acid (mRNA) correlates with the recovery of the ER protein-folding capacity, to investigate the attenuation of the UPR in yeast. We find that, once activated, spliced HAC1 mRNA is sustained in cells expressing Ire1 carrying phosphomimetic mutations within the kinase activation loop, suggesting that dephosphorylation of Ire1 is an important step in RNase deactivation. Additionally, spliced HAC1 mRNA is also sustained after UPR induction in cells expressing Ire1 with mutations in the conserved DFG kinase motif (D828A) or a conserved residue (F842) within the activation loop. The importance of proper Ire1 RNase attenuation is demonstrated by the inability of cells expressing Ire1-D828A to grow under ER stress. We propose that the activity of the Ire1 kinase domain plays a role in attenuating its RNase activity when ER function is recovered.
System analysis shows distinct mechanisms and common principles of nuclear envelope protein dynamics
Authors: Zuleger Nikolaj , Kelly David A. , Richardson A. Christine , Kerr Alastair R. W. , Goldberg Martin W. , Goryachev Andrew B. , Schirmer Eric C.
Published: March 2011

The nuclear envelope contains >100 transmembrane proteins that continuously exchange with the endoplasmic reticulum and move within the nuclear membranes. To better understand the organization and dynamics of this system, we compared the trafficking of 15 integral nuclear envelope proteins using FRAP. A surprising 30-fold range of mobilities was observed. The dynamic behavior of several of these proteins was also analyzed after depletion of ATP and/or Ran, two functions implicated in endoplasmic reticulum–inner nuclear membrane translocation. This revealed that ATP- and Ran-dependent translocation mechanisms are distinct and not used by all inner nuclear membrane proteins. The Ran-dependent mechanism requires the phenylalanine-glycine (FG)-nucleoporin Nup35, which is consistent with use of the nuclear pore complex peripheral channels. Intriguingly, the addition of FGs to membrane proteins reduces FRAP recovery times, and this also depends on Nup35. Modeling of three proteins that were unaffected by either ATP or Ran depletion indicates that the wide range in mobilities could be explained by differences in binding affinities in the inner nuclear membrane.
A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells
Authors: Peyre Elise , Jaouen Florence , Saadaoui Mehdi , Haren Laurence , Merdes Andreas , Durbec Pascale , Morin Xavier
Published: March 2011

To maintain tissue architecture, epithelial cells divide in a planar fashion, perpendicular to their main polarity axis. As the centrosome resumes an apical localization in interphase, planar spindle orientation is reset at each cell cycle. We used three-dimensional live imaging of GFP-labeled centrosomes to investigate the dynamics of spindle orientation in chick neuroepithelial cells. The mitotic spindle displays stereotypic movements during metaphase, with an active phase of planar orientation and a subsequent phase of planar maintenance before anaphase. We describe the localization of the NuMA and LGN proteins in a belt at the lateral cell cortex during spindle orientation. Finally, we show that the complex formed of LGN, NuMA, and of cortically located Gαi subunits is necessary for spindle movements and regulates the dynamics of spindle orientation. The restricted localization of LGN and NuMA in the lateral belt is instructive for the planar alignment of the mitotic spindle, and required for its planar maintenance.
DISCOVERY AND COSMOLOGICAL IMPLICATIONS OF SPT-CL J2106-5844, THE MOST MASSIVE KNOWN CLUSTER AT z>1
Authors: Foley R. J. , Andersson K. , Bazin G. , de Haan T. , Ruel J. , Ade P. A. R. , Aird K. A. , Armstrong R. , Ashby M. L. N. , Bautz M. , Benson B. A. , Bleem L. E. , Bonamente M. , Brodwin M. , Carlstrom J. E. , Chang C. L. , Clocchiatti A. , Crawford T. M. , Crites A. T. , Desai S. , Dobbs M. A. , Dudley J. P. , Fazio G. G. , Forman W. R. , Garmire G. , George E. M. , Gladders M. D. , Gonzalez A. H. , Halverson N. W. , High F. W. , Holder G. P. , Holzapfel W. L. , Hoover S. , Hrubes J. D. , Jones C. , Joy M. , Keisler R. , Knox L. , Lee A. T. , Leitch E. M. , Lueker M. , Luong-Van D. , Marrone D. P. , McMahon J. J. , Mehl J. , Meyer S. S. , Mohr J. J. , Montroy T. E. , Murray S. S. , Padin S. , Plagge T. , Pryke C. , Reichardt C. L. , Rest A. , Ruhl J. E. , Saliwanchik B. R. , Saro A. , Schaffer K. K. , Shaw L. , Shirokoff E. , Song J. , Spieler H. G. , Stalder B. , Stanford S. A. , Staniszewski Z. , Stark A. A. , Story K. , Stubbs C. W. , Vanderlinde K. , Vieira J. D. , Vikhlinin A. , Williamson R. , Zenteno A.
Published: March 2011

Using the South Pole Telescope (SPT), we have discovered the most massive known galaxy cluster at z>1, SPT-CL J2106-5844. In addition to producing a strong Sunyaev–Zel'dovich (SZ) effect signal, this system is a luminous X-ray source and its numerous constituent galaxies display spatial and color clustering, all indicating the presence of a massive galaxy cluster. Very Large Telescope and Magellan spectroscopy of 18 member galaxies shows that the cluster is at z = 1.132+0.002
−0.003. Chandra observations obtained through a combined HRC-ACIS GTO program reveal an X-ray spectrum with an Fe K line redshifted by z = 1.18 ± 0.03. These redshifts are consistent with the galaxy colors found in optical, near-infrared, and mid-infrared imaging. SPT-CL J2106-5844 displays extreme X-ray properties for a cluster having a core-excluded temperature of TX
= 11.0+2.6
−1.9 keV and a luminosity (within r
500) of LX
(0.5–2.0 keV) = (13.9 ± 1.0) × 1044 erg s−1. The combined mass estimate from measurements of the SZ effect and X-ray data is M
200 = (1.27 ± 0.21) × 1015 h
−1
70 
M
☉. The discovery of such a massive gravitationally collapsed system at high redshift provides an interesting laboratory for galaxy formation and evolution, and is a probe of extreme perturbations of the primordial matter density field. We discuss the latter, determining that, under the assumption of ΛCDM cosmology with only Gaussian perturbations, there is only a 7% chance of finding a galaxy cluster similar to SPT-CL J2106-5844 in the 2500 deg2 SPT survey region and that only one such galaxy cluster is expected in the entire sky.
In situ study of spin waves in thin films deposited onto compliant substrates submitted to external stresses
Authors: Karboul-Trojet W , Faurie D , Roussigné Y , Chérif S M , Renault P-O , Goudeau Ph
Published: March 2011

We have developed a new methodology to study the effect of mechanical stress on spin waves in thin films deposited onto compliant substrates. It is based on micro-tensile tests combined with Brillouin light-scattering spectroscopy, which allows in situ probing of the magnetization dynamics of the studied film upon deformation. This paper shows from both theoretical and experimental approaches that the magneto-elastic coupling in the saturation regime leads to a simple linear relationship between the spin waves' frequency and the stress applied to the magnetic film. The linear part of the experimental data can be reproduced theoretically, assuming a complete strain transfer through the metallic film–compliant substrate interface.
Bismuth-sensitized efficient near-infrared luminescence from ytterbium in zeolites
Authors: Bai Zhenhua , Sun Hong-Tao , Fujii Minoru , Miwa Yuji , Hasegawa Takashi , Mizuhata Minoru , Hayashi Shinji
Published: March 2011

Yb–Bi co-doped zeolites are prepared by a method consisting of a simple ion-exchange process and subsequent high-temperature annealing. We observe two strong near-infrared (NIR) emission bands overlapping in the range 930–1480 nm, corresponding to the electronic transitions of bismuth-related active centres (BiRAC) and Yb3+ ions, respectively. In the obtained products, the excitation wavelength of Yb3+ is extended to the range 420–850 nm, and the lifetime reaches 665 µs. In the zeolite matrix, Bi ions exist as BiRAC and Bi compound agglomerates. The former act as a sensitizer of Yb3+ ions, and the latter act as a blockage to seal the pores of zeolites, which enables Yb3+ ions to show efficient NIR emission even if the zeolites contain a large amount of coordinated water. The excellent optical and structural properties make these NIR-emitting nanoparticles promising in applications as biological probes.