bluuebunny/crossref_metadata_2025 huggingface dataset:
NMR investigations of structural and dynamics features of natively unstructured drug peptide – salmon calcitonin: implication to rational design of potent sCT analogs
Authors: Rawat Atul , Kumar Dinesh
Published: December 2012

Backbone dynamics and conformational properties of drug peptide salmon calcitonin have been studied in aqueous solution using nuclear magnetic resonance (NMR). Although salmon calcitonin (sCT) is largely unfolded in solution (as has been reported in several circular dichroism studies), the secondary Hα chemical shifts and three bond HN–Hα coupling constants indicated that most of the residues of the peptide are populating the α‐helical region of the Ramachandran (ϕ, ψ) map. Further, the peptide in solution has been found to exhibit multiple conformational states exchanging slowly on the NMR timescale (102–103 s−1), inferred by the multiple chemical shift assignments in the region Leu4–Leu12 and around Pro23 (for residues Gln20–Tyr22 and Arg24). Possibly, these slowly exchanging multiple conformational states might inhibit symmetric self‐association of the peptide and, in part, may account for its reduced aggregation propensity compared with human calcitonin (which lacks this property). The 15N NMR‐relaxation data revealed (i) the presence of slow (microsecond‐to‐millisecond) timescale dynamics in the N‐terminal region (Cys1–Ser5) and core residues His17 and Asn26 and (ii) the presence of high frequency (nanosecond‐to‐picosecond) motions in the C‐terminal arm. Put together, the various results suggested that (i) the flexible C‐terminal of sCT (from Thr25–Thr31) is involved in identification of specific target receptors, (ii) whereas the N‐terminal of sCT (from Cys1–Gln20) in solution – exhibiting significant amount of conformational plasticity and strong bias towards biologically active α‐helical structure – facilitates favorable conformational adaptations while interacting with the intermembrane domains of these target receptors. Thus, we believe that the structural and dynamics features of sCT presented here will be useful guiding attributes for the rational design of biologically active sCT analogs. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
Design parameters for nanowire‐planar tandem solar cells
Authors: Foster Andrew P. , Wilson Luke R.
Published: December 2012

A modified form of detailed balance theory is applied to a tandem semiconductor solar cell formed from a vertical nanowire array on a planar substrate. The concept of an effective packing fraction is introduced to account for the light trapping properties of the nanowire array. Our model provides important design criteria for the nanowire‐planar system, including the requirement for optimum performance of a lower energy nanowire bandgap than in an ideal all‐planar tandem cell. Using realistic design parameters for a III–V nanowire‐silicon bottom cell system we predict an efficiency enhancement of 22–27% relative to a planar silicon cell.
Intermolecular interactions, thermodynamic properties, crystal structure, and detonation performance of HMX/NTO cocrystal explosive
Authors: Lin He , Zhu Shun‐Guan , Zhang Lin , Peng Xin‐Hua , Chen Peng‐Yuan , Li Hong‐Zhen
Published: December 2012

Previous studies have shown that the design of cocrystal explosives is one of the most promising approaches to decrease the sensitivity and maintain the detonation performance of existing explosives. As is well‐known, octahydro‐1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocine (HMX) is a high energy density material (HEDM). But the application of HMX is limited, due to its high sensitivity. Thus, an insensitive explosive 5‐nitro‐1,2,4‐triazol‐3‐one (NTO) is proposed as a cocrystal former (CCF) to cocrystallize with HMX in the present work. The binding energies, heat of formations (HOFs), thermodynamic properties, atoms in molecules, and natural bond orbital analysis of four HMX/NTO complexes have been calculated using density functional theory methods, including meta‐hybrid functional (M062X) and dispersion‐corrected density functionals (B97D, ωB97XD). In addition, the crystal structure of HMX/NTO cocrystal has been investigated using Monte Carlo simulation and first principles methods. The HMX/NTO cocrystal is most likely to crystallize in triclinic crystal system with P1space group, and corresponding cell parameters areZ= 2,a= 9.06 Å,b= 8.19 Å,c= 10.27 Å, α = 81.94°, β = 98.42°, γ = 82.03°, and ρ = 1.92 g/cm3. The detonation velocity and detonation pressure of HMX/NTO cocrystal are 8.73 km/s and 35.14 GPa, respectively, a little lower than those of HMX. Finally, bond dissociation energies (BDEs) of the weakest trigger bond in HMX/NTO complexes are calculated. The results show that HMX/NTO complexes are thermally stable and meet the thermal requirement of HEDMs (BDE > 120 kJ/mol). © 2012 Wiley Periodicals, Inc.
Estimation of covariate effects in generalized linear mixed models with a misspecified distribution of random intercepts and slopes
Authors: Neuhaus John M. , McCulloch Charles E. , Boylan Ross
Published: December 2012

Generalized linear mixed models with random intercepts and slopes provide useful analyses of clustered and longitudinal data and typically require the specification of the distribution of the random effects. Previous work for models with only random intercepts has shown that misspecifying the shape of this distribution may bias estimates of the intercept, but typically leads to little bias in estimates of covariate effects. Very few papers have examined the effects of misspecifying the joint distribution of random intercepts and slopes. However, simulation results in a recent paper suggest that misspecifying the shape of the random slope distribution can yield severely biased estimates of all model parameters. Using analytic results, simulation studies and fits to example data, this paper examines the bias in parameter estimates due to misspecification of the shape of the joint distribution of random intercepts and slopes. Consistent with results for models with only random intercepts, and contrary to the claims of severe bias in a recent paper, we show that misspecification of the joint distribution typically yields little bias in estimates of covariate effects and is restricted to covariates associated with the misspecified random effects distributions. We also show that misspecification of the distribution of random effects has little effect on confidence interval performance. Coverage rates based on the model‐based standard errors from fitted likelihoods were generally quite close to nominal. Copyright © 2012 John Wiley & Sons, Ltd.
A semiparametric marginal mixture cure model for clustered survival data
Authors: Niu Yi , Peng Yingwei
Published: December 2012

We consider a marginal model for the regression analysis of clustered failure time data with a cure fraction. We propose to use novel generalized estimating equations in an expectation–maximization algorithm to estimate regression parameters in a semiparametric proportional hazards mixture cure model. The dependence among the cure statuses and among the survival times of uncured patients within clusters are modeled by working correlation matrices in the estimating equations. We use a bootstrap method to obtain the variances of the estimates. We report a simulation study to demonstrate a substantial efficiency gain of the proposed method over an existing marginal method. Finally, we apply the model and the proposed method to a set of data from a multi‐institutional study of tonsil cancer patients treated with a radiation therapy. Copyright © 2012 John Wiley & Sons, Ltd.
Household and Living Arrangement Projections at the Subnational Level: An Extended Cohort-Component Approach
Authors: Zeng Yi , Land Kenneth C. , Wang Zhenglian , Gu Danan
Published: December 2012

This article presents the core methodological ideas and empirical assessments of an extended cohort-component approach (known as the “ProFamy model”), and applications to simultaneously project household composition, living arrangements, and population sizes–gender structures at the subnational level in the United States. Comparisons of projections from 1990 to 2000 using this approach with census counts in 2000 for each of the 50 states and Washington, DC show that 68.0 %, 17.0 %, 11.2 %, and 3.8 % of the absolute percentage errors are <3.0 %, 3.0 % to 4.99 %, 5.0 % to 9.99 %, and ≥10.0 %, respectively. Another analysis compares average forecast errors between the extended cohort-component approach and the still widely used classic headship-rate method, by projecting number-of-bedrooms–specific housing demands from 1990 to 2000 and then comparing those projections with census counts in 2000 for each of the 50 states and Washington, DC. The results demonstrate that, compared with the extended cohort-component approach, the headship-rate method produces substantially more serious forecast errors because it cannot project households by size while the extended cohort-component approach projects detailed household sizes. We also present illustrative household and living arrangement projections for the five decades from 2000 to 2050, with medium-, small-, and large-family scenarios for each of the 50 states; Washington, DC; six counties of southern California; and the Minneapolis–St. Paul metropolitan area. Among many interesting numerical outcomes of household and living arrangement projections with medium, low, and high bounds, the aging of American households over the next few decades across all states/areas is particularly striking. Finally, the limitations of the present study and potential future lines of research are discussed.
Writing for Justice: An Activist Beginning of the Cult of Female Chastity in Late Imperial China
Authors: Fei Siyen
Published: December 2012

This article examines the rise of the chastity cult—the quintessential symbol of patriarchal suppression of female agency for modern reformers—during the sixteenth century. Despite the resultant stricter control over female sexuality, the growing dominance of the chastity cult cannot be simply construed as a product of top-down imposition. What made possible the penetrative power of chastity practice, this article argues, was a state indoctrination working in reverse. That is, the fast ascendance of the chastity cult in the late Ming was powered by various strains of activism that sought to protest and repair the failing system of chastity awards. The activist impetus greatly enhanced the centrality and influence of chastity practice in social life and, in doing so, opened the notion of chastity to contentious and sometimes subversive negotiations.
Bellingshausen's first accounts of his Antarctic voyage of 1819–1821
Authors: Bulkeley Rip
Published: December 2012

In 1949 a reassessment of the Imperial Russian Navy's Antarctic expedition of 1819–1821 was promulgated in the Soviet Union. The contention was that Russian seamen had made the first discovery of the mainland of Antarctica, two or three days before the northern tip of the Antarctic Peninsula was sighted by a British expedition, under William Smith and Edward Bransfield, sent to take formal possession of the South Shetland Islands. The new Soviet line apparently required that an important passage in a report which Captain Bellingshausen had sent from Australia in 1820 should, as far as possible, be overlooked or downplayed. Nineteenth century editions of the report and its covering letter are translated, the contemporary ice vocabulary in which they were phrased is explained, and the practice of discounting parts of them in the past and continuing to ignore those passages today is discussed.
Is the law of occupation applicable to the invasion phase?
Authors: Zwanenburg Marten , Bothe Michael , Sassòli Marco
Published: December 2012

The ‘debate’ section of theReviewaims at contributing to the reflection on current ethical, legal, or practical controversies around humanitarian issues.

The definition of occupation under international humanitarian law (IHL) is rather vague, and IHL instruments provide no clear standard for determining the beginning of occupation. Derived from the wording of Article 42 of the 1907 Hague Regulations, occupation may be defined as the effective control of a foreign territory by hostile armed forces. It is not always easy to determine when an invasion has become an occupation. This raises the question whether or not the law of occupation could already be applied during the invasion phase. In this regard, two main positions are usually put forward in legal literature. Generally it is held that the provisions of occupation law only apply once the elements underpinning the definition set out in Article 42 of the 1907 Hague Regulations are met. However, the so-called ‘Pictet theory’, as formulated by Jean S. Pictet in the ICRC's Commentary on the Geneva Conventions, proposes that no intermediate phase between invasion and occupation exists and that certain provisions of occupation law already apply during an invasion.

The collapse of essential public facilities such as hospitals and water-supply installations, partly due to the large-scale looting and violence that came along with the progress of the coalition forces, in Iraq in 2003 demonstrates that this discussion is not simply a theoretical one. Invading armed forces need clarity as to what rules they need to apply.

Three experts in the field of occupation law – Marten Zwanenburg, Michael Bothe, and Marco Sassòli – have agreed to participate in this debate and to defend three approaches.Marten Zwanenburgmaintains that for determining when an invasion turns into an occupation the only test is the one set out in Article 42 of the 1907 Hague Regulations, and therefore rejects the ‘Pictet theory’.Michael Bothe, while also rejecting the ‘Pictet theory’, argues that a possible intermediate situation between invasion and occupation, if there is any at all, would be very short and that, once an invader has gained control over a part of an invaded territory, the law of occupation applies. Finally,Marco Sassòlidefends the ‘Pictet theory’ and argues that, in order to avoid legal vacuums, there is no distinction between an invasion phase and an occupation phase for applying the rules of the Fourth Geneva Convention.

The debaters have simplified their complex legal reasoning for the sake of clarity and brevity. Readers of theReviewshould bear in mind that the debaters’ actual legal positions may be more nuanced than they may appear in this debate.
Carbonate dissolution rates at the deep ocean floor
Authors: Boudreau Bernard P.
Published: December 2012

This paper reexamines experimental data on the seawater dissolution of CaCO3‐bearing sediment beds to establish that the dependence of the calcite dissolution rate is linearly dependent on the calcite saturation state of the overlying water. This linearity is inherent to the original data and is not the result of an error in the solubility product for calcite. A comparison between these linear kinetics and the rate of solute transport across the benthic boundary layer further reveals that the overall rate of dissolution at ocean depths below the saturation horizon is controlled by boundary layer transfer. A carbonate mass‐balance model for the sediment‐water interface, which includes both kinetics and boundary layer effects, predictively reproduces the currently observed CaCO3depth distribution for two test areas in the oceans. These findings allow important simplifications in modeling CO2neutralization in the oceans.
Climatic impact of the Millennium eruption of Changbaishan volcano in China: New insights from high‐precision radiocarbon wiggle‐match dating
Authors: Xu Jiandong , Pan Bo , Liu Tanzhuo , Hajdas Irka , Zhao Bo , Yu Hongmei , Liu Ruoxin , Zhao Ping
Published: December 2012

Changbaishan volcano in northeast China, previously dated to have erupted around the mid‐10th century A.D., is renowned for producing one of the largest eruptions in history (magnitude 6.8) and thus speculated to have substantial climatic impact. Here we report a new high‐precision 14C wiggle‐match age of A.D. 946 ± 3 obtained from a 264 year old tree trunk (with bark) killed during the eruption, using the OxCal's Bayesian modeling approach with 27 sequentially sampled annual rings of decadal intervals. The new chronology conforms well to the calendar date of A.D. 946 for the eruption inferred from historical documentary evidence. We find no stratospherically loaded sulfate spike that might be associated with the A.D. 946 eruption in the global volcanism record from the GISP2 ice core, suggesting the stratospheric sulfate aerosols produced during the eruption were not transported to the arctic region, due probably to its relatively low stratospheric sulfur emission and the seasonal effects of the atmospheric circulation at the time of the eruption that likely occurred in the winter of A.D. 946–947. Since the stratospheric volcanic sulfates are the main cause of large‐scale climate perturbations, this finding indicates that the Millennium eruption of Changbaishan volcano might have limited regional climatic effects, rather than global or hemispheric impact as implied by its magnitude.
Two‐dimensional hybrid simulations of quasi‐perpendicular collisionless shock dynamics: Gyrating downstream ion distributions
Authors: Ofman L. , Gedalin M.
Published: December 2012

Quasi‐perpendicular collisionless shocks undergo structural changes with the increase of the Mach number. These changes are related to the increasing role of the reflected ions, which have a highly nongyrotropic distribution. Eventually, it is expected that the shock front becomes nonstationary. At low and moderate Mach numbers, the fraction of reflected ions is small, yet recent observations show the existence of a well‐pronounced structure of the postshock magnetic field in the close vicinity of the transition layer. Large amplitude oscillations were earlier interpreted as waves generated by the shock front or passing through the shock in the downstream direction. Here we show, using two‐dimensional hybrid simulations of quasi‐perpendicular shocks, that the gyration of the directly transmitted ions downstream of the ramp produces the spatial pressure variations, which are accompanied with the observed magnetic oscillations due to the momentum conservation. In a wide range of the upstream ion temperatures, the low and moderate‐Mach‐number shocks remain stationary and one‐dimensional, so that the magnetic and electric field depend only on the coordinate along the shock normal. The downstream ion distributions gradually gyrotropize due to the collisionless mixing of gyrophases. Nonstationary effects in these shocks do not affect noticeably the ion dynamics. However, we find that with the increase of the Mach number, shocks form rippled fronts in the low‐β and moderate‐β regimes.
Circulation in Drake Passage revisited using new current time series and satellite altimetry: 2. The Ona Basin
Authors: Ferrari Ramiro , Provost Christine , Sennéchael Nathalie , Lee Jae‐Hak
Published: December 2012

Time series of horizontal velocities were obtained at four mooring sites across the Ona Basin, southern Drake Passage, during 26 months (February 2006 to April 2008). The moorings were located under the Jason satellite ground‐track #104, allowing precise comparisons with various other altimetry products. Velocities as high as 0.5 m s–1 at 500 m depth were observed during current pulses. Mean velocity amplitudes at 500 m reached 0.22 m s–1 at 58.5°S and 0.15 m s–1 at 60°S, but were smaller at 59°S and 60.5°S. Mean velocities at 2500 m depth varied between 0.05 and 0.10 m s–1 and were westward on two of the moorings, suggesting recirculation in the center of the basin. Mean velocities were consistent with a general cyclonic circulation in the Ona Basin. The mean velocity vectors were observed to rotate with depth, the sense of rotation depending upon mooring sites. Standard deviation ellipses were close to circular except on the continental slope (60.5°S) where they were stretched in the direction of isobaths. The southernmost mooring was under sea ice in winter, and velocity variations were reduced in amplitude during that period. The horizontal velocities were highly coherent in the vertical. Altimetrically derived surface geostrophic velocities compared well with the in situ velocities and were used to investigate further the flow over the West Scotia Ridge and in the center of the Ona Basin to the East of the highest part of the Shackleton Ridge, which provides some shelter from the eastward flowing Antarctic Circumpolar Current.
A two‐phase model for sheet flow regime based on dense granular flow rheology
Authors: Revil‐Baudard T. , Chauchat J.
Published: December 2012

A two‐phase model having a μ(I) rheology for the intergranular stresses and a mixing length approach for the turbulent stresses is proposed to describe the sheet flow regime of sediment transport. In the model, two layers are considered: a dilute suspension layer and a dense sediment bed layer. The concentration profile is obtained from the dilatancy law ϕ(I) in the sediment bed layer and from a Rouse profile in the suspension layer. The comparison of velocity profile, concentration profile, and macroscopic parameters (sediment transport rate, thickness, and roughness) with experimental data shows a good agreement. These comparisons demonstrate that the dense granular rheology is relevant to describe intense bed‐load transport in turbulent regime (sheet flow). The transition from the dense static bed to the dilute suspension is well described by the present model. Also, the different regimes of the dense granular rheology seems to be able to capture the transition between collision‐dominant and turbulent‐fluctuations‐dominant sheet flows, depending on the particle's characteristics.
A new stochastic particle‐tracking approach for fractured sedimentary formations
Authors: Willmann M. , Lanyon G. W. , Marschall P. , Kinzelbach W.
Published: December 2012

Key Points

Explicit particle tracking in fractures and background matrix

Direct comparison of advection and diffusion in fractured sedimentary aquifers
Effective conductivity of isotropic highly heterogeneous formations: Numerical and theoretical issues
Authors: Jankovic Igor , Fiori Aldo , Dagan Gedeon
Published: December 2012

Key Points

Effective conductivity is studies through accurate 3D numerical simulations

Kef is similar to the one predicted by the self‐consistent approximation

Kef may depend on the higher order correlations of K
Numerical study of the impact response of woodpecker's head
Authors: Zhu Zhao Dan , Ma Guo Jun , Wu Cheng Wei , Chen Zhen
Published: December 2012

Woodpecker can beat trees 20-25 times per second and lasts for several seconds, with a 1200 g deceleration, but it appears that they never get brain concussion. How does the stress wave propagate from the beak tip to brain and how does a woodpecker protect itself from brain damage? In this paper, we establish a finite element model of typical woodpecker head based on its X-ray tomography images and conduct the numerical analysis of the impact response of the woodpecker's head by using a viscoelasticity material model. Especially, the woodpecker head response to an impact speed of 7 m/s is investigated to explore the stress concentration zone and how the stress wave propagates in its head. The numerical results show that the stress wave in the head propagates from the upper beak to back skull and is reduced by the specific structure of hyoid and viscoelasticity of biomaterials. The maximum stresses in skull and brain are both below the safe level. The stress in skull almost disappears before the next impact. The stress in brain lasts for a little longer but shows smaller value with little variation. The stress is impossible to accumulate in the limited pecking time, so the brain damage can be avoided.
Effect of gap width on enhanced magnetic optical fields in metallic split ring resonators
Authors: Shen Qi , Hou Bo , Chen Zhuo , Wang Zhen-Lin
Published: December 2012

We analyze the U-shaped metallic split-ring resonators (SRRs) aimed at creating highly confined and enhanced magnetic field in the near-infrared frequency range. At the magnetic resonance, the induced circulating current of the SRRs could lead to a strong enhancement of the surrounding magnetic field. Such a magnetic field enhancement is found to be dominated by the gap width between two SRR arms. By decreasing the gap width to 10 nm, the SRR is predicted to have a 3790-fold enhancement of the magnetic field at the resonance wavelength of 1340 nm.
RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition
Authors: Lipinski Simone , Grabe Nils , Jacobs Gunnar , Billmann-Born Susanne , Till Andreas , Häsler Robert , Aden Konrad , Paulsen Maren , Arlt Alexander , Kraemer Lars , Hagemann Nina , Erdmann Kai Sven , Schreiber Stefan , Rosenstiel Philip
Published: December 2012

The intracellular nucleotide-binding oligomerization domain-2 (NOD2) receptor detects bacteria-derived muramyl dipeptide (MDP) and activates the transcription factor NF-κB. Here we describe the regulatome of NOD2 signaling using a systematic RNAi screen. Using three consecutive screens, we identified a set of 20 positive NF-κB regulators including the known pathway members RIPK2, RELA, and BIRC4 (XIAP) as well as FRMPD2 (FERM and PDZ domain-containing 2). FRMPD2 interacts with NOD2 via leucine-rich repeats and forms a complex with the membrane-associated protein ERBB2IP. We demonstrate that FRMPD2 spatially assembles the NOD2-signaling complex, hereby restricting NOD2-mediated immune responses to the basolateral compartment of polarized intestinal epithelial cells. We show that genetic truncation of the NOD2 leucine-rich repeat domain, which is associated with Crohn disease, impairs the interaction with FRMPD2, and that intestinal inflammation leads to down-regulation of
FRMPD2
. These results suggest a structural mechanism for how polarity of epithelial cells acts on intestinal NOD-like receptor signaling to mediate spatial specificity of bacterial recognition and control of immune responses.
Possible role of pineal allopregnanolone in Purkinje cell survival
Authors: Haraguchi Shogo , Hara Sakurako , Ubuka Takayoshi , Mita Masatoshi , Tsutsui Kazuyoshi
Published: December 2012

It is believed that neurosteroids are produced in the brain and other nervous systems. Here, we show that allopregnanolone (ALLO), a neurosteroid, is exceedingly produced in the pineal gland compared with the brain and that pineal ALLO acts on the Purkinje cell, a principal cerebellar neuron, to prevent apoptosis in the juvenile quail. We first demonstrated that the pineal gland is a major organ of neurosteroidogenesis. A series of experiments using molecular and biochemical techniques has further demonstrated that the pineal gland produces a variety of neurosteroids de novo from cholesterol in the juvenile quail. Importantly, ALLO was far more actively produced in the pineal gland than in the brain. Pinealectomy (Px) decreased ALLO concentration in the cerebellum and induced apoptosis of Purkinje cells, whereas administration of ALLO to Px quail chicks prevented apoptosis of Purkinje cells. We further found that Px significantly increased the number of Purkinje cells that expressed active caspase-3, a key protease in apoptotic pathway, and daily injection of ALLO to Px quail chicks decreased the number of Purkinje cells expressing active caspase-3. These results indicate that the neuroprotective effect of pineal ALLO is associated with the decrease in caspase-3 activity during the early stage of neuronal development. We thus provide evidence that the pineal gland is an important neurosteroidogenic organ and that pineal ALLO may be involved in Purkinje cell survival during development. This is an important function of the pineal gland in the formation of neuronal circuits in the developing cerebellum.
Efficient associative memory storage in cortical circuits of inhibitory and excitatory neurons
Authors: Chapeton Julio , Fares Tarec , LaSota Darin , Stepanyants Armen
Published: December 2012

Many features of synaptic connectivity are ubiquitous among cortical systems. Cortical networks are dominated by excitatory neurons and synapses, are sparsely connected, and function with stereotypically distributed connection weights. We show that these basic structural and functional features of synaptic connectivity arise readily from the requirement of efficient associative memory storage. Our theory makes two fundamental predictions. First, we predict that, despite a large number of neuron classes, functional connections between potentially connected cells must be realized with <50% probability if the presynaptic cell is excitatory and >50% probability if the presynaptic cell is inhibitory. Second, we establish a unique relation between probability of connection and coefficient of variation in connection weights. These predictions are consistent with a dataset of 74 published experiments reporting connection probabilities and distributions of postsynaptic potential amplitudes in various cortical systems. What is more, our theory explains the shapes of the distributions obtained in these experiments.
A legacy of contrasting spatial genetic structure on either side of the Atlantic–Mediterranean transition zone in a marine protist
Authors: Lowe Chris D. , Martin Laura E. , Montagnes David J. S. , Watts Phillip C.
Published: December 2012

The mechanisms that underpin the varied spatial genetic structures exhibited by free-living marine microorganisms remain controversial, with most studies emphasizing a high dispersal capability that should redistribute genetic diversity in contrast to most macroorganisms whose populations often retain a genetic signature of demographic response to historic climate fluctuations. We quantified the European phylogeographic structure of the marine flagellate
Oxyrrhis marina
and found a marked difference in spatial genetic structure, population demography, and genetic diversity between the northwest Atlantic and Mediterranean Sea that reflects the persistent separation of these regions as well as context-dependent population responses to contrasting environments. We found similar geographic variation in the level of genetic diversity in the sister species
Oxyrrhis maritima
. Because the capacity for wide dispersal is not always realized, historic genetic footprints of range expansion and contraction persist in contemporary populations of marine microbes, as they do in larger species. Indeed, the well-described genetic effects of climatic variation on macroorganisms provide clear, testable hypotheses about the processes that drive genetic divergence in marine microbes and thus about the response to future environmental change.
Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA
Authors: Ma Junhe , Edlich Frank , Bermejo Guillermo A. , Norris Kristi L. , Youle Richard J. , Tjandra Nico
Published: December 2012

The human protein Bax sits at a critical regulatory junction of apoptosis, or programmed cell death. Bax exists in equilibrium between cytosolic and mitochondria-associated forms that shifts toward the latter when Bax is activated by proapoptotic proteins. Activated Bax changes conformation, inserts into the mitochondrial outer membrane (MOM), oligomerizes, and induces MOM permeabilization, causing the release of cytochrome
c
, which effectively commits the cell to die. Because apoptosis is also a basic defense mechanism against invading pathogens, many viruses have developed counteractive measures. Such is the case of human cytomegalovirus, the replication of which hinges on vMIA (viral mitochondria-localized inhibitor of apoptosis), a virus-encoded protein with a unique, albeit poorly understood antiapoptotic activity by which it binds and recruits Bax to mitochondria. Here we show, via the structure determination of the complex between Bax and a peptide comprising vMIA’s Bax-binding domain, that vMIA contacts Bax at a previously unknown regulatory site. Notably, using full-length vMIA, the structure is independently confirmed by assays in human cells that measure Bax subcellular localization and cytochrome
c
release. Mutants that disrupt key intermolecular interactions disfavor vMIA’s mitochondrial recruitment of Bax, and increase cytochrome
c
release upon apoptosis induction. In a more stringent test, an engineered binding interface that achieves wild-type–like charge complementarity, although in a reversed fashion, recovers wild-type behavior. The structure suggests that by stabilizing key elements in Bax needed to unravel for its MOM insertion and oligomerization, vMIA prevents these important steps in apoptosis.
Contribution of active hair-bundle motility to nonlinear amplification in the mammalian cochlea
Authors: Nin Fumiaki , Reichenbach Tobias , Fisher Jonathan A. N. , Hudspeth A. J.
Published: December 2012

The cochlea’s high sensitivity stems from the active process of outer hair cells, which possess two force-generating mechanisms: active hair-bundle motility elicited by Ca
2+
influx and somatic motility mediated by the voltage-sensitive protein prestin. Although interference with prestin has demonstrated a role for somatic motility in the active process, it remains unclear whether hair-bundle motility contributes in vivo. We selectively perturbed the two mechanisms by infusing substances into the endolymph or perilymph of the chinchilla’s cochlea and then used scanning laser interferometry to measure vibrations of the basilar membrane. Blocking somatic motility, damaging the tip links of hair bundles, or depolarizing hair cells eliminated amplification. While reducing amplification to a lesser degree, pharmacological perturbation of active hair-bundle motility diminished or eliminated the nonlinear compression underlying the broad dynamic range associated with normal hearing. The results suggest that active hair-bundle motility plays a significant role in the amplification and compressive nonlinearity of the cochlea.
Coding perceptual discrimination in the somatosensory thalamus
Authors: Camarillo Liliana , Luna Rogelio , Nácher Verónica , Romo Ranulfo
Published: December 2012

The sensory thalamus is classically viewed as a relay station of sensory information to cortex, but recent studies suggest that it is sensitive to cognitive demands. There are, however, few experiments designed to test whether this is so. We addressed this problem by analyzing the responses of single neurons recorded in the somatosensory thalamus while trained monkeys reported a decision based on the comparison of two mechanical vibration frequencies applied sequentially to one fingertip. In this task, monkeys must hold the first stimulus frequency (f1) in working memory and compare it to the current sensory stimulus (f2) and must postpone the decision report until a cue triggers the decision motor report, i.e., whether f2 > f1 or f2 < f1. We found that thalamic somatosensory neurons encoded the stimulus frequency either in their periodicity and firing-rate responses, but only during the stimulus periods and not during the working memory and decision components of this task. Furthermore, correlation analysis between behavior and stimulus coding showed that only the firing rate modulations accounted for the overall psychophysical performance. However, these responses did not predict the animal’s decision reports on individual trials. Moreover, the sensitivity to changes in stimulus frequency was similar when the monkeys performed the vibrotactile discrimination task and when they were not required to report discrimination. These results suggest that the somatosensory thalamus behaves as a relay station of sensory information to the cortex and that it is insensitive to the cognitive demands of the task used here.
Mobility of the SecA 2-helix-finger is not essential for polypeptide translocation via the SecYEG complex
Authors: Whitehouse Sarah , Gold Vicki A.M. , Robson Alice , Allen William J. , Sessions Richard B. , Collinson Ian
Published: December 2012

The bacterial ATPase SecA and protein channel complex SecYEG form the core of an essential protein translocation machinery. The nature of the conformational changes induced by each stage of the hydrolytic cycle of ATP and how they are coupled to protein translocation are not well understood. The structure of the SecA–SecYEG complex revealed a 2-helix-finger (2HF) of SecA in an ideal position to contact the substrate protein and push it through the membrane. Surprisingly, immobilization of this finger at the edge of the protein channel had no effect on translocation, whereas its imposition inside the channel blocked transport. This analysis resolves the stoichiometry of the active complex, demonstrating that after the initiation process translocation requires only one copy each of SecA and SecYEG. The results also have important implications on the mechanism of energy transduction and the power stroke driving transport. Evidently, the 2HF is not a highly mobile transducing element of polypeptide translocation.
Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling
Authors: Rai Vivek , Touré Fatouma , Chitayat Seth , Pei Renjun , Song Fei , Li Qing , Zhang Jinghua , Rosario Rosa , Ramasamy Ravichandran , Chazin Walter J. , Schmidt Ann Marie
Published: December 2012

The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA–RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
Distinct requirements for T-bet in gut innate lymphoid cells
Authors: Sciumé Giuseppe , Hirahara Kiyoshi , Takahashi Hayato , Laurence Arian , Villarino Alejandro V. , Singleton Kentner L. , Spencer Sean P. , Wilhelm Christoph , Poholek Amanda C. , Vahedi Golnaz , Kanno Yuka , Belkaid Yasmine , O'Shea John J.
Published: December 2012

Interleukin (IL)-22–producing innate lymphoid cells (ILCs; ILC22) comprise a heterogeneous population of cells that are dependent on the transcription factor retinoid-related orphan γt (RORγt) and are critical for barrier function of the intestinal mucosa. A distinct ILC22 subset expresses the natural cytotoxicity receptor NKp46 (NKp46+ ILC22); however, the factors that contribute to the generation of this population versus other subsets are largely unknown. Herein, we show that T-bet (encoded by Tbx21) was highly expressed in NKp46+ ILC22, a feature shared by all NKp46+ cells present in the intestine but not by other IL-22–producing populations. Accordingly, the absence of T-bet resulted in loss of NKp46+ ILC22 in the intestinal lamina propria. The residual NKp46+ ILC22 present in Tbx21−/− mice showed a marked reduction of Rorγt expression and impairment in IL-22 production. Generation and functions of gut NK1.1+ cells were also altered. Bone marrow chimera experiments revealed a cell-intrinsic requirement for T-bet in these subsets and competitive reconstitution experiments revealed roles for T-bet in multiple ILC subsets. Thus, T-bet has a general importance for ILC in the gut and plays a selective and critical role in the generation of NKp46+ ILC22.
Contractors for flows
Authors: Garijo Delia , Goodall Andrew , Nešetřil Jaroslav
Published: December 2012

We answer a question raised by Lovász and B. Szegedy [Contractors and connectors in graph algebras, J. Graph Theory 60:1 (2009)] asking for a contractor for the graph parameter counting the number of

B
B

-flows of a graph, where

B
B

is a subset of a finite Abelian group closed under inverses. We prove our main result using the duality between flows and tensions and finite Fourier analysis.
Degree formula for the Euler characteristic
Authors: Haution Olivier
Published: December 2012

We give a proof of the degree formula for the Euler characteristic previously obtained by Kirill Zainoulline. The arguments used here are considerably simpler and allow us to remove all restrictions on the characteristic of the base field.
Influence of the Type of Sagittal Profile on Clinical Results of Lumbar Total Disk Replacement After a Mean Follow-Up of 39 Months
Authors: Strube Patrick , Hoff Eike K. , Perka Carsten F. , Gross Christian , Putzier Michael
Published: December 2012

Study Design:

Retrospective analysis of clinical and radiologic data of a prospective cohort study.

Objective:

To research the clinical differences after lumbar total disk replacement (TDR) with respect to the preoperative global and the adaptation at the local sagittal profile (SP) of the spine.

Summary of Background Data:

It was suggested that facet loads and degeneration are dependent on epidemiologically defined types of SP. Moreover, the success of TDR was related to segmental facet joint loads. The influences of the preoperative SP or of the changes of the local SP after TDR on the clinical outcome after TDR remain unclear.

Methods:

Fifty-two patients included in a prospective cohort study regarding lumbar single-level TDR L4/5 (n=22) or L5/S1 (n=30) because of degenerative disk disease (Modic ≤2 degrees) were clinically (visual analog scale for back, leg, and overall pain; Oswestry Disability Index) and radiologically (extension-flexion radiographs, plain-spine, and whole-spine lateral radiographs in upright standing position) reevaluated after a minimum follow-up of 24 (24–69) months. On the basis of preoperative plain radiographs in upright standing position, patients were retrospectively assigned to 4 groups according to the individual sagittal profile type (SPT). In patients with persistent back pain, a facet infiltration at the index level was performed.

Results:

For all patients, an SPT could be defined. Global SP did not change compared with the preoperative state. All groups improved clinically over follow-up. At the last follow-up, types 1 and 4 demonstrated significantly inferior scores for pain and function. TDR-induced changes at the superior adjacent segment and the posterior disk height at the index level were also correlated to inferior clinical results. Infiltration test was positive in type 1–4: 67%, 40%, 33%, and 75%, respectively, of the symptomatic patients.

Conclusions:

We suggest SPTs 1 and 4 to represent a contraindication for lumbar TDR of levels L4/5 or L5/S1. Local adaptation in the adjacent segment to TDR may influence the clinical outcome as well.
Effects of Anterior Plating on Clinical Outcomes of Anterior Lumbar Interbody Fusion
Authors: Snyder Laura A. , Kalb Samuel , Kakarla Udaya K. , Porter Randall W. , Kaibara Taro , Dickman Curtis A. , Theodore Nicholas
Published: December 2012

Study Design:

Retrospective review.

Objective:

To compare surgical outcomes of patients who have undergone anterior lumbar interbody fusion (ALIF) with and without plating.

Summary of Background Data:

In biomechanical testing, ALIF constructs supplemented with plating (ALIFP) reduce range of motion and increase construct stiffness compared with ALIF alone. However, whether ALIFP constructs translate into improved clinical outcomes over ALIF alone is unknown.

Methods:

From 2004 through 2010, 231 patients underwent ALIF with (146) or without (85) plating. Eight patients lost to follow up were excluded from final evaluation. Patients’ records were evaluated retrospectively for demographics, complications, and outcomes.

Results:

At a mean follow-up of 13.7 months (range, 1–108 mo), the mean Economic, Functional, and Total Prolo scores for ALIF patients were 4.23, 3.63, and 7.87, respectively. The mean Oswestry Disability Index (ODI) was 24%. At a mean follow-up of 11.2 months (range, 1–93 mo), the mean Economic, Functional, and Total Prolo scores for ALIFP patients were 4.28, 3.67, and 7.95, respectively. The mean ODI was 22.9%. There was no significant difference between rate of complications or Prolo scores or ODI between the 2 groups (t test). Neither diabetes, hypertension, smoking, sex, nor age older than 55 years was significantly related to whether patients had higher Prolo scores with or without plating. Patients with a normal body mass index and ALIF had significantly better Prolo Economic scores and total scores than patients with a normal body mass index and ALIFP (P=0.04 and 0.02, independent samples t test). Patients were also stratified by surgical indication for surgery, and there was no significant difference in Prolo scores or ODI for patients who underwent ALIF alone versus ALIFP.

Conclusions:

Even when stratified by indication for surgery, anterior plating does not seem to improve Prolo scores or ODI, suggesting that not all patients undergoing ALIF require plating.
Evolutionary rescue by beneficial mutations in environments that change in space and time
Authors: Kirkpatrick Mark , Peischl Stephan
Published: December 2012

A factor that may limit the ability of many populations to adapt to changing conditions is the rate at which beneficial mutations can become established. We study the probability that mutations become established in changing environments by extending the classic theory for branching processes. When environments change in time, under quite general conditions, the establishment probability is approximately twice the ‘effective selection coefficient’, whose value is an average that gives most weight to a mutant's fitness in the generations immediately after it appears. When fitness varies along a gradient in a continuous habitat, increased dispersal generally decreases the chance a mutation establishes because mutations move out of areas where they are most adapted. When there is a patch of favourable habitat that moves in time, there is a maximum speed of movement above which mutations cannot become established, regardless of when and where they first appear. This critical speed limit, which is proportional to the mutation's maximum selective advantage, represents an absolute constraint on the potential of locally adapted mutations to contribute to evolutionary rescue.
Limited evolutionary rescue of locally adapted populations facing climate change
Authors: Schiffers Katja , Bourne Elizabeth C. , Lavergne Sébastien , Thuiller Wilfried , Travis Justin M. J.
Published: December 2012

Dispersal is a key determinant of a population's evolutionary potential. It facilitates the propagation of beneficial alleles throughout the distributional range of spatially outspread populations and increases the speed of adaptation. However, when habitat is heterogeneous and individuals are locally adapted, dispersal may, at the same time, reduce fitness through increasing maladaptation. Here, we use a spatially explicit, allelic simulation model to quantify how these equivocal effects of dispersal affect a population's evolutionary response to changing climate. Individuals carry a diploid set of chromosomes, with alleles coding for adaptation to non-climatic environmental conditions and climatic conditions, respectively. Our model results demonstrate that the interplay between gene flow and habitat heterogeneity may decrease effective dispersal and population size to such an extent that substantially reduces the likelihood of evolutionary rescue. Importantly, even when evolutionary rescue saves a population from extinction, its spatial range following climate change may be strongly narrowed, that is, the rescue is only partial. These findings emphasize that neglecting the impact of non-climatic, local adaptation might lead to a considerable overestimation of a population's evolvability under rapid environmental change.