bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymmetry in the Jovian auroral Lyman‐α line profile due to thermospheric high‐speed flow
Authors: Chaufray J.‐Y. , Gladstone G. R. , Waite J. H. , Clarke J. T.
Published: May 2010

The presence of a fast wind in the auroral region atmosphere of Jupiter has been detected from the Doppler shift in near‐IR observations of H3+ emissions. The Doppler effect also modifies auroral resonance emission line shapes. We present a new radiative transfer equation for the hydrogen Lyman‐α line in the presence of a horizontal wind and solve it numerically using the Feautrier method. This model allows us to derive the theoretical profile of the Lyman‐α emission line. We apply this code to long slit echelle spectra of Jupiter's auroral Lyman‐α emission obtained by HST‐STIS which exhibit a self‐reversed and asymmetric profile. Using a simple expression for the vertical variation of the horizontal wind velocity, we find the HST‐STIS observations are well reproduced by a velocity profile reaching ∼4–8 km/s near ∼10−5μbar pressure altitude (∼1500 km above the 1 bar level). The velocity is much higher than velocity derived from H3+ emission peaking at ∼550 km and consistent with an increase of the velocity with regards to altitude but reaching larger values than predicted by circulation models at ∼10−5μbar.
Can anomalous diffusion describe depositional fluvial profiles?
Authors: Voller V. R. , Paola C.
Published: May 2010

Diffusion models have been widely applied to describe fluvial long profiles. However, aggrading rivers simulated in laboratory experiments typically display much less profile curvature than a diffusion model would predict, whether aggradation is driven by subsidence or by base‐level rise. Here we explore the possibility that this is due to nonclassical or non‐Fickian, anomalous sediment transport in braided networks, which are known to have fractal planform geometry. We solve a fractional diffusion equation for a steady state aggrading fluvial profile for fractional exponents in the spatial derivative α in the range 1.1 < α + 1 < 2. The domain is bounded at both ends, and a constant sediment sink forces extraction of all of the imposed, constant sediment supply. We assume the fractional behavior is expressed solely by a nonlocal sediment flux term. Using the right‐hand Caputo fractional derivative, we are able to construct a fractional diffusion equation that admits an analytical fluvial profile closely matching the laboratory‐scale physical observations. We show that this solution is also in good agreement with a Monte Carlo simulation obtained using step lengths drawn from a Lévy probability density. However, despite the clear nonlocal behavior, we are unable to establish a direct physical link between the power law statistics of the fluvial transport system and the mathematical ingredients in a fractional diffusion model. In general, we expect the fractional behavior to be most pronounced when the length scale of significant downstream sediment extraction is comparable to the scale range of the fractal channel pattern behavior. This is typically the case for laboratory experiments but not at field scales, which could explain why anomalously flat fluvial long profiles have not been reported from the field. Applying fractional calculus to depositional river profiles, at any scale, exposes problems in applying fractional calculus posed by the bounded domain and the presence of a distributed sink associated with sediment extraction. With present understanding, the benefit of fractional calculus, which is its ability to capture effects of power law statistics in the underlying dynamics, comes at a significant cost in terms of flexibility to handle other physical effects such as complex domains, boundary conditions, and source terms.
MHC class II‐associated proteins in B‐cell exosomes and potential functional implications for exosome biogenesis
Authors: Buschow Sonja I , van Balkom Bas W M , Aalberts Marian , Heck Albert J R , Wauben Marca , Stoorvogel Willem
Published: May 2010

Professional antigen‐presenting cells secrete major histocompatibility complex class II (MHC II) carrying exosomes with unclear physiological function(s). Exosomes are first generated as the intraluminal vesicles (ILVs) of a specific type of multivesicular body, and are then secreted by fusion of this compartment with the plasma membrane. We have previously shown that in contrast to the sorting of MHC II at lysosomally targeted multivesicular bodies, sorting of MHC II into exosomes does not rely on MHC II ubiquitination. In search for proteins that drive the incorporation of MHC II into exosomes or functionally discriminate exosomal from plasma membrane MHC II, we first analyzed the total proteome of highly purified B cell‐derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins, including known and not previously identified constituents. Using quantitative MS, we then identified a small subset of proteins that were specifically co‐immunoprecipitated with MHC II from detergent‐solubilized exosomes. These include HSC71, HSP90, 14‐3‐3ε, CD20 and pyruvate kinase type M2 (PKM2), and we speculate on the functionality of their interaction with exosomal MHC II.
Rapid recruitment and activation of CD8+ T cells after herpes simplex virus type 1 skin infection
Authors: Stock Angus T , Jones Claerwen M , Heath William R , Carbone Francis R
Published: May 2010

After localized infection, naive antigen‐specific T cells must localize to those lymph nodes (LNs) draining the site of infection before engaging antigen‐bearing dendritic cells. Given that naive precursors are initially distributed randomly throughout the secondary lymphoid compartment, it is unclear how long it takes most antigen‐specific precursors to mobilize to draining LNs and become recruited into the primary T cell response. Here, we have examined the kinetics of these events, measuring the period over which naive precursors are recruited into the primary T cell response after cutaneous infection with herpes simplex virus type 1 (HSV‐1). We show that despite prolonged MHC class‐I‐restricted antigen presentation, most naive HSV‐specific precursors were recruited from the circulation in the first 4 days after inoculation. Furthermore, this prolonged presentation was also not essential for memory development, as truncating the period of antigen presentation to around 4 days did not affect the level of contraction, or long‐term stability of the HSV‐specific CD8+ memory T cell pool. Thus, despite initially being dispersed throughout the entire circulation, the recruitment of naive precursors is achieved quite quickly, even when priming is restricted to a small number of draining LNs.
Metabolomic and transcriptomic stress response of Escherichia coli
Authors: Jozefczuk Szymon , Klie Sebastian , Catchpole Gareth , Szymanski Jedrzej , Cuadros‐Inostroza Alvaro , Steinhauser Dirk , Selbig Joachim , Willmitzer Lothar
Published: May 2010

Environmental fluctuations lead to a rapid adjustment of the physiology of Escherichia coli, necessitating changes on every level of the underlying cellular and molecular network. Thus far, the majority of global analyses of E. coli stress responses have been limited to just one level, gene expression. Here, we incorporate the metabolite composition together with gene expression data to provide a more comprehensive insight on system level stress adjustments by describing detailed time‐resolved E. coli response to five different perturbations (cold, heat, oxidative stress, lactose diauxie, and stationary phase). The metabolite response is more specific as compared with the general response observed on the transcript level and is reflected by much higher specificity during the early stress adaptation phase and when comparing the stationary phase response to other perturbations. Despite these differences, the response on both levels still follows the same dynamics and general strategy of energy conservation as reflected by rapid decrease of central carbon metabolism intermediates coinciding with downregulation of genes related to cell growth. Application of co‐clustering and canonical correlation analysis on combined metabolite and transcript data identified a number of significant condition‐dependent associations between metabolites and transcripts. The results confirm and extend existing models about co‐regulation between gene expression and metabolites demonstrating the power of integrated systems oriented analysis.
Chromosomal periodicity and positional networks of genes in Escherichia coli
Authors: Mathelier Anthony , Carbone Alessandra
Published: May 2010

The structure of dynamic folds in microbial chromosomes is largely unknown. Here, we find that genes with a highly biased codon composition and characterizing a functional core in Escherichia coli K12 show to be periodically distributed along the arcs, suggesting an encoded three‐dimensional genomic organization helping functional activities among which are translation and, possibly, transcription. This extends to functional classes of genes that are shown to systematically organize into two independent positional gene networks, one driven by metabolic genes and the other by genes involved in cellular processing and signaling. We conclude that functional reasons justify periodic gene organization. This finding generates new questions on evolutionary pressures imposed on the chromosome. Our methodological approach is based on single genome analysis. Given either core genes or genes organized in functional classes, we analyze the detailed distribution of distances between pairs of genes through a parameterized model based on signal processing and find that these groups of genes tend to be separated by a regular integral distance. The methodology can be applied to any set of genes and can be taken as a footprint for large‐scale bacterial and archaeal analysis.
Transgene effects on rhizodeposition: Evidence from molecular-chemical screening by Pyrolysis-Field Ionisation Mass Spectrometry (Py-FIMS)
Authors: Schlichting Andre , Baum Christel , Zimmer Dana , Leinweber Peter
Published: May 2010

Rhizodeposition plays an important role in the C and N cycle of ecosystems, since it essentially reflects the interaction between plant, soil and soil microorganisms. The molecular-chemical characterisation of rhizodeposition is often limited to selected compound classes (e.g., carbohydrates and amino acids). A more comprehensive analytical approach is based on the molecular-chemical “fingerprint” revealed by Pyrolysis-Field Ionisation Mass Spectrometry (Py-FIMS).The presented results give evidence of specific effects in conjunction with soil type, crop, variety, transgenes and mycorrhizal colonisation on the molecular-chemical composition of rhizodeposition. The experiments included various crops (maize, potato, vetch, willow and poplar), which were grown in leaching vessels under controlled environmental conditions on different soil types. The experimental design covered different varieties for maize, trangenes (vetch and potato) and inoculation with mycorrhizal fungi (poplar). All rhizodeposits were leached at defined growth stages and analysed by Py-FIMS.The Py-FIMS data evaluation by multivariate statistics enabled a clear discrimination by all factors. Among these factors soil type and the crop had the largest effect on the molecular-chemical composition. By contrast, variety and transgene effects were subordinated.The results of the multivariate statistics for crops, grown on the same soil (maize, potato, vetch), revealed 23 mass signals with highest discriminating power (P<0.001, multiple F-test). About 90 % of those signals can be assigned to known substances, based on our mass spectrometric in-house library and/or the literature. Further investigation will be focused on structural elucidation of the previously unassigned mass signals.
Transition paths in molecules at finite temperature
Authors: Pinski F. J. , Stuart A. M.
Published: May 2010

In the zero temperature limit, it is well known that in systems evolving via Brownian dynamics, the most likely transition path between reactant and product may be found as a minimizer of the Freidlin–Wentzell action functional. An analog for finite temperature transitions is given by the Onsager–Machlup functional. The purpose of this work is to investigate properties of Onsager–Machlup minimizers. We study transition paths for thermally activated molecules governed by the Langevin equation in the overdamped limit of Brownian dynamics. Using gradient descent in pathspace, we minimize the Onsager–Machlup functional for a range of model problems in one and two dimensions and then for some simple atomic models including Lennard-Jones seven-atom and 38-atom clusters, as well as for a model of vacancy diffusion in a planar crystal. Our results demonstrate interesting effects, which can occur at nonzero temperature, showing transition paths that could not be predicted on the basis of the zero temperature limit. However the results also demonstrate unphysical features associated with such Onsager–Machlup minimizers. As there is a growing literature that addresses transition path sampling by related techniques, these insights add a potentially useful perspective into the interpretation of this body of work.
Unusual elastic behavior of ultrathin polymer films: Confinement-induced/molecular stiffening and surface tension effects
Authors: Xu Shanhong , O’Connell Paul A. , McKenna Gregory B.
Published: May 2010

Prior experiments of membrane inflation (biaxial extension) on ultrathin polymer films have evidenced a dramatic stiffening in the rubbery regime whose origins remain unclear. Here, we describe results from bubble inflation measurements on ultrathin films of a previously unexamined material [poly (n-butyl methacrylate) (PBMA)] and show that the observed rubbery stiffening behavior can be attributed to a mixture of “molecular or confinement-induced stiffening” and surface tension effects. The results suggest that the molecular stiffening contribution is significant, with the macroscopic surface tension being unchanged even for films as thin as 20 nm. It is also found that PBMA exhibits a significantly different behavior from both poly(vinyl acetate) and polystyrene, illustrating that the magnitude of the molecular or confinement-induced stiffening in ultrathin films depends on the polymer repeat unit structure.
Communications: High-pressure dielectric scaling study of a monohydroxy alcohol
Authors: Reiser Andreas , Kasper Gernot , Gainaru Catalin , Böhmer Roland
Published: May 2010

Glass forming monohydroxy alcohols show an exponential Debye-type dielectric relaxation, which proceeds slower than the structural relaxation. Dielectric high-pressure measurements of 2-ethyl-1-hexanol reveal that isochronal scaling is violated. Temperature-volume scaling was found to be valid separately for the Debye-type and for the structural relaxation, yielding a scaling exponent of γ≈1.8.
On ternary nitride substrates for visible semiconductor light-emitters
Authors: Sharma T. K. , Towe E.
Published: May 2010

No nitride or other substrate material exists for growing lattice-matched nitride device structures. Use of bulk GaN or sapphire substrates is complicated by lattice and thermal mismatches that lead to defect and dislocation generation. To alleviate this problem, we recently proposed ternary nitride substrates on which lattice-matched structures could be grown for lasers within specified spectral bands. These proposed application-oriented nitride substrates have one drawback: several would be required to cover the visible spectrum. By taking advantage of the complex (but feature-rich) valence band structure of nitrides, we have determined that a single substrate (In0.15Ga0.85N) could be used for the development of efficient blue, green, and red laser diodes.
Influence of the As2/As4 growth modes on the formation of quantum dot-like InAs islands grown on InAlGaAs/InP (100)
Authors: Gilfert C. , Pavelescu E.-M. , Reithmaier J. P.
Published: May 2010

The formation process of InAs quantum dashes and quantum dots (QDs) grown on quaternary InAlGaAs surfaces lattice-matched to n-type InP(100) are investigated. A clear trend of the InAs to form dashes or dots depending on the species of supplied arsenic could be demonstrated. Using As4, elongated quantum dashes can be observed. Changing the growth mode to As2 molecules enables a shape transition from dashes to dome-shaped QDs. The dot ensembles exhibit improved photoluminescence (PL) intensity and linewidth over their elongated counterparts. With this basic concept, low temperature PL linewidths as low as 23 meV have been achieved.
Structural and dynamical anomalies of a Gaussian core fluid: A mode-coupling theory study
Authors: Shall Lindsey Ann , Egorov S. A.
Published: May 2010

We present a theoretical study of transport properties of a liquid comprised of particles interacting via Gaussian core pair potential. Shear viscosity and self-diffusion coefficients are computed on the basis of the mode-coupling theory, with required structural input obtained from integral equation theory. Both the self-diffusion coefficient and the viscosity display anomalous density dependence, with diffusivity increasing and viscosity decreasing and with density within a particular density range along several isotherms below a certain temperature. Our theoretical results for both transport coefficients are in good agreement with the simulation data.
Bacterial ratchet motors
Authors: Di Leonardo R. , Angelani L. , Dell’Arciprete D. , Ruocco G. , Iebba V. , Schippa S. , Conte M. P. , Mecarini F. , De Angelis F. , Di Fabrizio E.
Published: May 2010

Self-propelling bacteria are a nanotechnology dream. These unicellular organisms are not just capable of living and reproducing, but they can swim very efficiently, sense the environment, and look for food, all packaged in a body measuring a few microns. Before such perfect machines can be artificially assembled, researchers are beginning to explore new ways to harness bacteria as propelling units for microdevices. Proposed strategies require the careful task of aligning and binding bacterial cells on synthetic surfaces in order to have them work cooperatively. Here we show that asymmetric environments can produce a spontaneous and unidirectional rotation of nanofabricated objects immersed in an active bacterial bath. The propulsion mechanism is provided by the self-assembly of motile
Escherichia coli
cells along the rotor boundaries. Our results highlight the technological implications of active matter’s ability to overcome the restrictions imposed by the second law of thermodynamics on equilibrium passive fluids.
External and internal constraints on eukaryotic chemotaxis
Authors: Fuller Danny , Chen Wen , Adler Micha , Groisman Alex , Levine Herbert , Rappel Wouter-Jan , Loomis William F.
Published: May 2010

Chemotaxis, the chemically guided movement of cells, plays an important role in several biological processes including cancer, wound healing, and embryogenesis. Chemotacting cells are able to sense shallow chemical gradients where the concentration of chemoattractant differs by only a few percent from one side of the cell to the other, over a wide range of local concentrations. Exactly what limits the chemotactic ability of these cells is presently unclear. Here we determine the chemotactic response of
Dictyostelium
cells to exponential gradients of varying steepness and local concentration of the chemoattractant cAMP. We find that the cells are sensitive to the steepness of the gradient as well as to the local concentration. Using information theory techniques, we derive a formula for the mutual information between the input gradient and the spatial distribution of bound receptors and also compute the mutual information between the input gradient and the motility direction in the experiments. A comparison between these quantities reveals that for shallow gradients, in which the concentration difference between the back and the front of a 10-μm-diameter cell is <5%, and for small local concentrations (<10 nM) the intracellular information loss is insignificant. Thus, external fluctuations due to the finite number of receptors dominate and limit the chemotactic response. For steeper gradients and higher local concentrations, the intracellular information processing is suboptimal and results in a smaller mutual information between the input gradient and the motility direction than would have been predicted from the ligand–receptor binding process.
Chemically rich seaweeds poison corals when not controlled by herbivores
Authors: Rasher Douglas B. , Hay Mark E.
Published: May 2010

Coral reefs are in dramatic global decline, with seaweeds commonly replacing corals. It is unclear, however, whether seaweeds harm corals directly or colonize opportunistically following their decline and then suppress coral recruitment. In the Caribbean and tropical Pacific, we show that, when protected from herbivores, ~40 to 70% of common seaweeds cause bleaching and death of coral tissue when in direct contact. For seaweeds that harmed coral tissues, their lipid-soluble extracts also produced rapid bleaching. Coral bleaching and mortality was limited to areas of direct contact with seaweeds or their extracts. These patterns suggest that allelopathic seaweed-coral interactions can be important on reefs lacking herbivore control of seaweeds, and that these interactions involve lipid-soluble metabolites transferred via direct contact. Seaweeds were rapidly consumed when placed on a Pacific reef protected from fishing but were left intact or consumed at slower rates on an adjacent fished reef, indicating that herbivory will suppress seaweeds and lower frequency of allelopathic damage to corals if reefs retain intact food webs. With continued removal of herbivores from coral reefs, seaweeds are becoming more common. This occurrence will lead to increasing frequency of seaweed-coral contacts, increasing allelopathic suppression of remaining corals, and continuing decline of reef corals.
Pitx2
prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification
Authors: Wang Jun , Klysik Elzbieta , Sood Subeena , Johnson Randy L. , Wehrens Xander H. T. , Martin James F.
Published: May 2010

Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, often coexists with the related arrhythmia atrial flutter (AFL). Limitations in effectiveness and safety of current therapies make an understanding of the molecular mechanism underlying AF more urgent. Genome-wide association studies implicated a region of human chromosome 4q25 in familial AF and AFL, ≈150 kb distal to the
Pitx2
homeobox gene, a developmental left–right asymmetry (LRA) gene. To investigate the significance of the 4q25 variants, we used mouse models to investigate
Pitx2
in atrial arrhythmogenesis directly. When challenged by programmed stimulation,

Pitx2
null+/−

adult mice had atrial arrhythmias, including AFL and atrial tachycardia, indicating that
Pitx2
haploinsufficiency predisposes to atrial arrhythmias. Microarray and in situ studies indicated that
Pitx2
suppresses sinoatrial node (SAN)-specific gene expression, including
Shox2
, in the left atrium of embryos and young adults. In vivo ChIP and transfection experiments indicated that Pitx2 directly bound
Shox2
in vivo, supporting the notion that Pitx2 directly inhibits the SAN-specific genetic program in left atrium. Our findings implicate
Pitx2
and
Pitx2
-mediated LRA-signaling pathways in prevention of atrial arrhythmias.
RNPC1, an RNA-binding protein and a target of the p53 family, regulates p63 expression through mRNA stability
Authors: Zhang Jin , Jun Cho Seong , Chen Xinbin
Published: May 2010

P63, a p53 family tumor suppressor, is involved in many cellular processes, including growth suppression and differentiation. Thus, p63 activity needs to be tightly controlled. Here, we found that RNPC1, a RNA-binding protein and a target of the p53 family, regulates p63 mRNA stability and consequently p63 activity. Specifically, we showed that overexpression of RNPC1 decreases, whereas knockdown of RNPC1 increases, the half-life of p63 transcript, which leads to altered p63 expression. Consistent with this, we showed that RNPC1 binds the AU-/U-rich elements in p63 3′ UTR in vitro and in vivo and the RRM domain in RNPC1 is required for binding, and regulating the stability of, p63 transcript. Furthermore, we showed that RNPC1 promotes keratinocyte differentiation by repressing p63 expression. Together, we uncovered a previously undetected mechanism by which p63 expression is regulated via mRNA stability and a novel regulatory feedback loop between RNPC1 and p63.
A molecular mechanism underlying the neural-specific defect in torsinA mutant mice
Authors: Kim Connie E. , Perez Alex , Perkins Guy , Ellisman Mark H. , Dauer William T.
Published: May 2010

A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion (“ΔE”) in the widely expressed gene
TOR1A
. Disease mutant knockin mice (
Tor1a
ΔE/ΔE
) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in
Tor1a
ΔE/ΔE
nonneuronal cells. The
Tor1a
ΔE/ΔE
neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.
Viral fibroblast growth factor, matrix metalloproteases, and caspases are associated with enhancing systemic infection by baculoviruses
Authors: Means John C. , Passarelli A. Lorena
Published: May 2010

Most arthropod-borne and invertebrate viruses are orally ingested and commence infection in cells of the invertebrate intestine. Infection of secondary sites and eventual transmission to other hosts is hindered by basal lamina, a tightly interwoven and virus-impenetrable noncellular layer, lining the intestine and other organ cell layers. The mechanisms for viral escape across basal laminae are unknown. We describe an elegant mechanism mediated by a baculovirus-encoded fibroblast growth factor (vFGF) that signals a previously undescribed stepwise cascade of protease activation wherein matrix metalloproteases activate effector caspases, leading to remodeling of basal lamina lining tracheal cells associated with the intestine and culminating in the establishment of efficient systemic infections. Because FGFs coordinate diverse functions during development, metabolic processes, and tissue repair, it is plausible that the vFGF-mediated pathway described here is widely used during developmental and pathogenic processes that involve basal lamina remodeling.
Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy
Authors: Ulanet Danielle B. , Ludwig Dale L. , Kahn C. Ronald , Hanahan Douglas
Published: May 2010

The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic β cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti–IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti–IGF-1R therapies.
Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome
Authors: Simon Anna , Park Heiyoung , Maddipati Ravikanth , Lobito Adrian A. , Bulua Ariel C. , Jackson Adrianna J. , Chae Jae Jin , Ettinger Rachel , de Koning Heleen D. , Cruz Anthony C. , Kastner Daniel L. , Komarow Hirsh , Siegel Richard M.
Published: May 2010

TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade.
Phytophthora infestans
effector AVR3a is essential for virulence and manipulates plant immunity by stabilizing host E3 ligase CMPG1
Authors: Bos Jorunn I. B. , Armstrong Miles R. , Gilroy Eleanor M. , Boevink Petra C. , Hein Ingo , Taylor Rosalind M. , Zhendong Tian , Engelhardt Stefan , Vetukuri Ramesh R. , Harrower Brian , Dixelius Christina , Bryan Glenn , Sadanandom Ari , Whisson Stephen C. , Kamoun Sophien , Birch Paul R. J.
Published: May 2010

Fungal and oomycete plant pathogens translocate effector proteins into host cells to establish infection. However, virulence targets and modes of action of their effectors are unknown. Effector AVR3a from potato blight pathogen
Phytophthora infestans
is translocated into host cells and occurs in two forms: AVR3a
KI
, which is detected by potato resistance protein R3a, strongly suppresses infestin 1 (INF1)-triggered cell death (ICD), whereas AVR3a
EM
, which evades recognition by R3a, weakly suppresses host ICD. Here we show that AVR3a interacts with and stabilizes host U-box E3 ligase CMPG1, which is required for ICD. In contrast, AVR3a
KI/Y147del
, a mutant with a deleted C-terminal tyrosine residue that fails to suppress ICD, cannot interact with or stabilize CMPG1. CMPG1 is stabilized by the inhibitors MG132 and epoxomicin, indicating that it is degraded by the 26S proteasome. CMPG1 is degraded during ICD. However, it is stabilized by mutations in the U-box that prevent its E3 ligase activity. In stabilizing CMPG1, AVR3a thus modifies its normal activity. Remarkably, given the potential for hundreds of effector genes in the
P. infestans
genome, silencing
Avr3a
compromises
P. infestans
pathogenicity, suggesting that AVR3a is essential for virulence. Interestingly,
Avr3a
silencing can be complemented by
in planta
expression of

Avr3a
KI

or

Avr3a
EM

but not the

Avr3a
KI/Y147del

mutant. Our data provide genetic evidence that AVR3a is an essential virulence factor that targets and stabilizes the plant E3 ligase CMPG1, potentially to prevent host cell death during the biotrophic phase of infection.
Engineering of an alternative electron transfer path in photosystem II
Authors: Larom Shirley , Salama Faris , Schuster Gadi , Adir Noam
Published: May 2010

The initial steps of oxygenic photosynthetic electron transfer occur within photosystem II, an intricate pigment/protein transmembrane complex. Light-driven electron transfer occurs within a multistep pathway that is efficiently insulated from competing electron transfer pathways. The heart of the electron transfer system, composed of six linearly coupled redox active cofactors that enable electron transfer from water to the secondary quinone acceptor QB, is mainly embedded within two proteins called D1 and D2. We have identified a sitein silico, poised in the vicinity of the QAintermediate quinone acceptor, which could serve as a potential binding site for redox active proteins. Here we show that modification of Lysine 238 of the D1 protein to glutamic acid (Glu) in the cyanobacteriumSynechocystissp. PCC 6803, results in a strain that grows photautotrophically. The Glu thylakoid membranes are able to perform light-dependent reduction of exogenous cytochrome c with water as the electron donor. Cytochrome c photoreduction by the Glu mutant was also shown to significantly protect the D1 protein from photodamage when isolated thylakoid membranes were illuminated. We have therefore engineered a novel electron transfer pathway from water to a soluble protein electron carrier without harming the normal function of photosystem II.
Single-base resolution mapping of H1–nucleosome interactions and 3D organization of the nucleosome
Authors: Syed Sajad Hussain , Goutte-Gattat Damien , Becker Nils , Meyer Sam , Shukla Manu Shubhdarshan , Hayes Jeffrey J. , Everaers Ralf , Angelov Dimitar , Bednar Jan , Dimitrov Stefan
Published: May 2010

Despite the key role of the linker histone H1 in chromatin structure and dynamics, its location and interactions with nucleosomal DNA have not been elucidated. In this work we have used a combination of electron cryomicroscopy, hydroxyl radical footprinting, and nanoscale modeling to analyze the structure of precisely positioned mono-, di-, and trinucleosomes containing physiologically assembled full-length histone H1 or truncated mutants of this protein. Single-base resolution •OH footprinting shows that the globular domain of histone H1 (GH1) interacts with the DNA minor groove located at the center of the nucleosome and contacts a 10-bp region of DNA localized symmetrically with respect to the nucleosomal dyad. In addition, GH1 interacts with and organizes about one helical turn of DNA in each linker region of the nucleosome. We also find that a seven amino acid residue region (121–127) in the COOH terminus of histone H1 was required for the formation of the stem structure of the linker DNA. A molecular model on the basis of these data and coarse-grain DNA mechanics provides novel insights on how the different domains of H1 interact with the nucleosome and predicts a specific H1-mediated stem structure within linker DNA.
KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation
Authors: Hsia Datsun A. , Tepper Clifford G. , Pochampalli Mamata R. , Hsia Elaine Y. C. , Izumiya Chie , Huerta Steve B. , Wright Michael E. , Chen Hong-Wu , Kung Hsing-Jien , Izumiya Yoshihiro
Published: May 2010

Localized chromatin modifications of histone tails play an important role in regulating gene transcription, and aberration of these processes leads to carcinogenesis. Methylated histone lysine residues, a key player in chromatin remodeling, are demethylated by the JmjC class of enzymes. Here we show that JMJD5 (now renamed KDM8), a JmjC family member, demethylates H3K36me2 and is required for cell cycle progression. Chromatin immunoprecipitation assays applied to human genome tiling arrays in conjunction with RNA microarray revealed that KDM8 occupies the coding region of cyclin A1 and directly regulates transcription. Mechanistic analyses showed that KDM8 functioned as a transcriptional activator by inhibiting HDAC recruitment via demethylation of H3K36me2, an epigenetic repressive mark. Tumor array experiments revealed KDM8 is overexpressed in several types of cancer. In addition, loss-of-function studies in MCF7 cells leads to cell cycle arrest. These studies identified KDM8 as an important cell cycle regulator.
A fossil primate of uncertain affinities from the earliest late Eocene of Egypt
Authors: Seiffert Erik R. , Simons Elwyn L. , Boyer Doug M. , Perry Jonathan M. G. , Ryan Timothy M. , Sallam Hesham M.
Published: May 2010

Paleontological work carried out over the last 3 decades has established that three major primate groups were present in the Eocene of Africa—anthropoids, adapiforms, and advanced strepsirrhines. Here we describe isolated teeth of a previously undocumented primate from the earliest late Eocene (≈37 Ma) of northern Egypt,
Nosmips aenigmaticus
, whose phylogenetic placement within Primates is unclear.
Nosmips
is smaller than the sympatric adapiform
Afradapis
but is considerably larger than other primate taxa known from the same paleocommunity. The species bears an odd mosaic of dental features, combining enlarged, elongate, and molariform premolars with simple upper molars that lack hypocones. Phylogenetic analysis across a series of different assumption sets variously places
Nosmips
as a stem anthropoid, a nonadapiform stem strepsirrhine, or even among adapiforms. This phylogenetic instability suggests to us that
Nosmips
likely represents a highly specialized member of a previously undocumented, and presumably quite ancient, endemic African primate lineage, the subordinal affinities of which have been obscured by its striking dental autapomorphies. Discriminant functions based on measurements of lower molar size and topography reliably classify extant prosimian primates into their correct dietary groups and identify
Nosmips
and
Afradapis
as omnivores and folivores, respectively. Although
Nosmips
currently defies classification, this strange and unexpected fossil primate nevertheless provides additional evidence for high primate diversity in northern Africa ≈37 million years ago and further underscores the fact that our understanding of early primate evolution on that continent remains highly incomplete.
Functional connectivity density mapping
Authors: Tomasi Dardo , Volkow Nora D.
Published: May 2010

Brain networks with energy-efficient hubs might support the high cognitive performance of humans and a better understanding of their organization is likely of relevance for studying not only brain development and plasticity but also neuropsychiatric disorders. However, the distribution of hubs in the human brain is largely unknown due to the high computational demands of comprehensive analytical methods. Here we propose a 10
3
times faster method to map the distribution of the local functional connectivity density (lFCD) in the human brain. The robustness of this method was tested in 979 subjects from a large repository of MRI time series collected in resting conditions. Consistently across research sites, a region located in the posterior cingulate/ventral precuneus (BA 23/31) was the area with the highest lFCD, which suggest that this is the most prominent functional hub in the brain. In addition, regions located in the inferior parietal cortex (BA 18) and cuneus (BA 18) had high lFCD. The variability of this pattern across subjects was <36% and within subjects was 12%. The power scaling of the lFCD was consistent across research centers, suggesting that that brain networks have a “scale-free” organization.
Nickel-borate oxygen-evolving catalyst that functions under benign conditions
Authors: Dincă Mircea , Surendranath Yogesh , Nocera Daniel G.
Published: May 2010

Thin catalyst films with electrocatalytic water oxidation properties similar to those of a recently reported Co-based catalyst can be electrodeposited from dilute Ni2+solutions in borate electrolyte at pH 9.2 (Bi). The Ni-Bifilms can be prepared with precise thickness control and operate at modest overpotential providing an alternative to the Co catalyst for applications in solar energy conversion.
N-cadherin-dependent neuron–neuron interaction is required for the maintenance of activity-induced dendrite growth
Authors: Tan Zhu-Jun , Peng Yun , Song He-Ling , Zheng Jing-Jing , Yu Xiang
Published: May 2010

Formation of neural circuits depends on stable contacts between neuronal processes, mediated by interaction of cell adhesion molecules, including N-cadherin. In the present study, we found that activity-dependent dendrite arborization specifically requires N-cadherin–mediated extracellular neuron–neuron interaction, because the enhancement did not occur for neurons cultured in isolation or plated on an astrocyte monolayer and was abolished by a recombinant soluble N-cadherin ectodomain. Furthermore, depolarization elevated the level of membrane-associated cadherin/catenin complexes and surface N-cadherin. Importantly, surface N-cadherin elevation is specifically required for the maintenance of nascent dendrite arbors. Through loss- and gain-of-function approaches, we showed that N-cadherin-mediated dendrite growth requires association of the cadherin/catenin complex with the actin cytoskeleton. In summary, these results identify a previously unexplored and specific function for activity-induced, N-cadherin–mediated neuron–neuron contacts in the maintenance of dendrite arbors.
Function of human Rh based on structure of RhCG at 2.1 Å
Authors: Gruswitz Franz , Chaudhary Sarika , Ho Joseph D. , Schlessinger Avner , Pezeshki Bobak , Ho Chi-Min , Sali Andrej , Westhoff Connie M. , Stroud Robert M.
Published: May 2010

In humans, NH
3
transport across cell membranes is facilitated by the Rh (rhesus) family of proteins. Human Rh C glycoprotein (RhCG) forms a trimeric complex that plays an essential role in ammonia excretion and renal pH regulation. The X-ray crystallographic structure of human RhCG, determined at 2.1 Å resolution, reveals the mechanism of ammonia transport. Each monomer contains 12 transmembrane helices, one more than in the bacterial homologs. Reconstituted into proteoliposomes, RhCG conducts NH
3
to raise internal pH. Models of the erythrocyte Rh complex based on our RhCG structure suggest that the erythrocytic Rh complex is composed of stochastically assembled heterotrimers of RhAG, RhD, and RhCE.
Positive regulation by small RNAs and the role of Hfq
Authors: Soper Toby , Mandin Pierre , Majdalani Nadim , Gottesman Susan , Woodson Sarah A.
Published: May 2010

Bacterial small noncoding RNAs carry out both positive and negative regulation of gene expression by pairing with mRNAs; in
Escherichia coli
, this regulation often requires the RNA chaperone Hfq. Three small regulatory RNAs (sRNAs), DsrA, RprA, and ArcZ, positively regulate translation of the sigma factor RpoS, each pairing with the 5′ leader to open up an inhibitory hairpin. In vitro,
rpoS
interaction with sRNAs depends upon an (AAN)
4
Hfq-binding site upstream of the pairing region. Here we show that both Hfq and this Hfq binding site are required for RprA or ArcZ to act in vivo and to form a stable complex with
rpoS
mRNA in vitro; both were partially dispensable for DsrA at 37 °C. ArcZ sRNA is processed from 121 nt to a stable 56 nt species that contains the pairing region; only the 56 nt ArcZ makes a strong Hfq-dependent complex with
rpoS
. For each of these sRNAs, the stability of the sRNA•mRNA complexes, rather than their rate of formation, best predicted in vivo activity. These studies demonstrate that binding of Hfq to the
rpoS
mRNA is critical for sRNA regulation under normal conditions, but if the stability of the sRNA•mRNA complex is sufficiently high, the requirement for Hfq can be bypassed.
Sugar binding induces the same global conformational change in purified LacY as in the native bacterial membrane
Authors: Nie Yiling , Kaback H. Ronald
Published: May 2010

Many independent lines of evidence indicate that the lactose permease of
Escherichia coli
(LacY) is highly dynamic and that sugar binding causes closing of a large inward-facing cavity with opening of a wide outward-facing hydrophilic cavity. Therefore, lactose/H
+
symport catalyzed by LacY very likely involves a global conformational change that allows alternating access of single sugar- and H
+
-binding sites to either side of the membrane (the alternating access model). The x-ray crystal structures of LacY, as well as the majority of spectroscopic studies, use purified protein in detergent micelles. By using site-directed alkylation, we now demonstrate that sugar binding induces virtually the same global conformational change in LacY whether the protein is in the native bacterial membrane or is solubilized and purified in detergent. The results also indicate that the x-ray crystal structure reflects the structure of wild-type LacY in the native membrane in the absence of sugar.
Hemispherical anisotropic patterns of the Earth’s inner core
Authors: Mattesini Maurizio , Belonoshko Anatoly B. , Buforn Elisa , Ramírez María , Simak Sergei I. , Udías Agustín , Mao Ho-Kwang , Ahuja Rajeev
Published: May 2010

It has been shown that the Earth’s inner core has an axisymmetric anisotropic structure with seismic waves traveling ∼3% faster along polar paths than along equatorial directions. Hemispherical anisotropic patterns of the solid Earth’s core are rather complex, and the commonly used hexagonal-close-packed iron phase might be insufficient to account for seismological observations. We show that the data we collected are in good agreement with the presence of two anisotropically specular east and west core hemispheres. The detected travel-time anomalies can only be disclosed by a lattice-preferred orientation of a body-centered-cubic iron aggregate, having a fraction of their [111] crystal axes parallel to the Earth’s rotation axis. This is compelling evidence for the presence of a body-centered-cubic Fe phase at the top of the Earth’s inner core.