bluuebunny/crossref_metadata_2025 huggingface dataset:
Length dependence scaling exponent of inverted frustum spring constant
Authors: Mon K. K.
Published: January 2011

Inverted frustums are an important class of fabricated nanostructures and their effective spring constants play an important role in applications. We use an inverted frustum model of particles interacting with springs to probe a recent Euler–Bernoulli theory (EBT) prediction for the length dependence of the effective spring constant. Inverted frustums used in applications have cross sections b(h) that increase as ∼h0.3 and EBT predicts keff will scale as keff∼h−1.8. This is very different from that of a straight-rod with keff∼h−3. In this paper, we have tested this prediction with a model of particles interacting with springs. The scaling exponents from the simulations are consistent with the continuum mechanics EBT predictions.
Defect modification and energy extraction in a one-dimensional terahertz photonic crystal
Authors: Liang Sen , Liu Hai-Ying , Dai Qiao-Feng , Wu Li-Jun , Lan Sheng , Gopal Achanta Venu
Published: January 2011

The modification of the defect mode in a one-dimensional (1D) photonic crystal (PC) in terahertz (THz) spectral region was systematically investigated by using THz time-domain spectroscopy (THz-TDS). The 1D PC was constructed by periodically arranging glass slides into an ordered structure. A defect was created by intentionally increasing the separation (i.e., the air gap) between two neighboring glass slides located in the middle of the PC. The tuning of the defect mode in the band gap was demonstrated by changing the thickness of the air gap. Modification of the defect mode was realized by inserting a silicon wafer into the defect. It was found that the appearance of the defect mode in the band gap depends not only on the relative position of the inserted silicon wafer with respect to the beam center but also on the resistivity of the silicon wafer. For the silicon wafer with a high resistivity, a transition of the defect mode from one frequency to the other was observed. When the front end of the silicon wafer was located exactly at the beam center, two defect modes with lower transmittance are observed. For one of the defect modes, the electromagnetic energy stored in the defect can be effectively coupled to the silicon wafer and eventually extracted out of the cavity. When the silicon wafer with a low resistivity was inserted into the defect, only the attenuation of the defect mode was observed. The defect mode disappeared when the beam was completely blocked by the silicon wafer. The large feature size of THz PCs offers us the opportunity of systematically investigating the modification of defect modes in PCs and its applications in the construction of functional devices. The experimental observations obtained by THz-TDS are in good agreement with the numerical simulation results calculated by finite-difference time-domain technique.
The Role of Occlusion Cues in Apparent Motion
Authors: Ekroll Vebjørn , Borzikowsky Christoph
Published: January 2011

Classical apparent motion stimuli exhibit an inherent ambiguity with respect to the onsets and offsets of the stimulus elements. Sigman and Rock (1974, Perception3 9 – 28) presented evidence suggesting that occlusion cues are used to resolve this ambiguity. We present results from experiments designed to further test predictions of this hypothesis. As expected, we found that the apparent motion of a target stimulus is suppressed when a ‘moving’ occluder is positioned such that it rationalises the onsets and offsets of the stimulus elements constituting the target. Somewhat unexpectedly, though, we also observed a slight tendency for motion suppression under conditions where the target was only partially occluded. The expected motion suppression occurred both with solid occluders and purely virtual Kanizsa-like occluders, although it was not always observed in the latter case. Motion suppression was found to occur over a wide range of stimulus onset asynchronies. Finally, we used binocular disparity cues to test the occlusion account of the motion suppression phenomenon against an alternative explanation in terms of attentional factors. The results are in clear favour of the occlusion account.
Illusory Motion Produced by Dichoptic Stimuli during Saccades
Authors: Mitsudo Hiroyuki , Nakamizo Sachio
Published: January 2011

A new motion illusion is reported in which saccadic eye movements can produce a perceived jump of a static stimulus presented dichoptically. In three experiments, observers made saccades while viewing a stationary stimulus consisting of a disk and random dots presented separately to the two eyes. In experiments 1 and 2, by measuring the strength of the perceived motion and the velocity of binocular eye movements, we found that (a) motion ratings were high for the stimulus that contained a large interocular difference in luminance, and (b) the saccadic strategy of the observer was virtually identical across different stimulus conditions. In experiment 3, by measuring the detectability of a short temporal gap introduced into the stimulus around saccades, we found that saccadic suppression was normal in the dichoptic presentation. We discuss possible mechanisms underlying the illusory motion.
Being surveyed can change later behavior and related parameter estimates
Authors: Zwane Alix Peterson , Zinman Jonathan , Van Dusen Eric , Pariente William , Null Clair , Miguel Edward , Kremer Michael , Karlan Dean S. , Hornbeck Richard , Giné Xavier , Duflo Esther , Devoto Florencia , Crepon Bruno , Banerjee Abhijit
Published: January 2011

Does completing a household survey change the later behavior of those surveyed? In three field studies of health and two of microlending, we randomly assigned subjects to be surveyed about health and/or household finances and then measured subsequent use of a related product with data that does not rely on subjects' self-reports. In the three health experiments, we find that being surveyed increases use of water treatment products and take-up of medical insurance. Frequent surveys on reported diarrhea also led to biased estimates of the impact of improved source water quality. In two microlending studies, we do not find an effect of being surveyed on borrowing behavior. The results suggest that limited attention could play an important but context-dependent role in consumer choice, with the implication that researchers should reconsider whether, how, and how much to survey their subjects.
Chemical basis of the synergism and antagonism in microbial communities in the nests of leaf-cutting ants
Authors: Schoenian Ilka , Spiteller Michael , Ghaste Manoj , Wirth Rainer , Herz Hubert , Spiteller Dieter
Published: January 2011

Leaf-cutting ants cultivate the fungus
Leucoagaricus gongylophorus
, which serves as a major food source. This symbiosis is threatened by microbial pathogens that can severely infect
L. gongylophorus
. Microbial symbionts of leaf-cutting ants, mainly
Pseudonocardia
and
Streptomyces
, support the ants in defending their fungus gardens against infections by supplying antimicrobial and antifungal compounds. The ecological role of microorganisms in the nests of leaf-cutting ants can only be addressed in detail if their secondary metabolites are known. Here, we use an approach for the rapid identification of established bioactive compounds from microorganisms in ecological contexts by combining phylogenetic data, database searches, and liquid chromatography electrospray ionisation high resolution mass spectrometry (LC-ESI-HR-MS) screening. Antimycins A
1
–A
4
, valinomycins, and actinomycins were identified in this manner from
Streptomyces
symbionts of leaf-cutting ants. Matrix-assisted laser desorption ionization (MALDI) imaging revealed the distribution of valinomycin directly on the integument of
Acromyrmex echinatior
workers. Valinomycins and actinomycins were also directly identified in samples from the waste of
A. echinatior
and
A. niger
leaf-cutting ants, suggesting that the compounds exert their antimicrobial and antifungal potential in the nests of leaf-cutting ants. Strong synergistic effects of the secondary meta-bolites produced by ant-associated
Streptomyces
were observed in the agar diffusion assay against
Escovopsis weberi
. Actinomycins strongly inhibit soil bacteria as well as other
Streptomyces
and
Pseudonocardia
symbionts. The antifungal antimycins are not only active against pathogenic fungi but also the garden fungus
L. gongylophorus
itself. In conclusion, secondary metabolites of microbial symbionts of leaf-cutting ants contribute to shaping the microbial communities within the nests of leaf-cutting ants.
Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis
Authors: Solomon Benjamin D. , Mueller Cynthia , Chae Wook-Jin , Alabanza Leah M. , Bynoe Margaret S.
Published: January 2011

Neuropilin-1 (
Nrp1
) is a cell surface molecule originally identified for its role in neuronal development. Recently,
Nrp1
has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T (T
reg
) cells. In this study, we provide evidence for a central role of
Nrp1
in the regulation of CD4 T-cell immune responses in experimental autoimmune encephalitis (EAE). EAE serves as an animal model for the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated primarily by CD4
+
T cells that migrate to the CNS and mount an inflammatory attack against myelin components, resulting in CNS pathology. Using a tissue-specific deletion system, we observed that the lack of
Nrp1
on CD4
+
T cells results in increased EAE severity. These conditional knockout mice exhibit preferential T
H
-17 lineage commitment and decreased T
reg
-cell functionality. Conversely, CD4
+
T cells expressing
Nrp1
suppress effector T-cell proliferation and cytokine production both in vivo and in vitro independent of T
reg
cells.
Nrp1
-mediated suppression can be inhibited by TGF-β blockade but not by IL-10 blockade. These results suggest that
Nrp1
is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses, leading to diseases like EAE and potentially MS.
Genetic structure and domestication history of the grape
Authors: Myles Sean , Boyko Adam R. , Owens Christopher L. , Brown Patrick J. , Grassi Fabrizio , Aradhya Mallikarjuna K. , Prins Bernard , Reynolds Andy , Chia Jer-Ming , Ware Doreen , Bustamante Carlos D. , Buckler Edward S.
Published: January 2011

The grape is one of the earliest domesticated fruit crops and, since antiquity, it has been widely cultivated and prized for its fruit and wine. Here, we characterize genome-wide patterns of genetic variation in over 1,000 samples of the domesticated grape,
Vitis vinifera
subsp.
vinifera
, and its wild relative,
V. vinifera
subsp.
sylvestris
from the US Department of Agriculture grape germplasm collection. We find support for a Near East origin of
vinifera
and present evidence of introgression from local
sylvestris
as the grape moved into Europe. High levels of genetic diversity and rapid linkage disequilibrium (LD) decay have been maintained in
vinifera
, which is consistent with a weak domestication bottleneck followed by thousands of years of widespread vegetative propagation. The considerable genetic diversity within
vinifera
, however, is contained within a complex network of close pedigree relationships that has been generated by crosses among elite cultivars. We show that first-degree relationships are rare between wine and table grapes and among grapes from geographically distant regions. Our results suggest that although substantial genetic diversity has been maintained in the grape subsequent to domestication, there has been a limited exploration of this diversity. We propose that the adoption of vegetative propagation was a double-edged sword: Although it provided a benefit by ensuring true breeding cultivars, it also discouraged the generation of unique cultivars through crosses. The grape currently faces severe pathogen pressures, and the long-term sustainability of the grape and wine industries will rely on the exploitation of the grape's tremendous natural genetic diversity.
Optimal pulse design in quantum control: A unified computational method
Authors: Li Jr-Shin , Ruths Justin , Yu Tsyr-Yan , Arthanari Haribabu , Wagner Gerhard
Published: January 2011

Many key aspects of control of quantum systems involve manipulating a large quantum ensemble exhibiting variation in the value of parameters characterizing the system dynamics. Developing electromagnetic pulses to produce a desired evolution in the presence of such variation is a fundamental and challenging problem in this research area. We present such robust pulse designs as an optimal control problem of a continuum of bilinear systems with a common control function. We map this control problem of infinite dimension to a problem of polynomial approximation employing tools from geometric control theory. We then adopt this new notion and develop a unified computational method for optimal pulse design using ideas from pseudospectral approximations, by which a continuous-time optimal control problem of pulse design can be discretized to a constrained optimization problem with spectral accuracy. Furthermore, this is a highly flexible and efficient numerical method that requires low order of discretization and yields inherently smooth solutions. We demonstrate this method by designing effective broadband
π
/2 and
π
pulses with reduced rf energy and pulse duration, which show significant sensitivity enhancement at the edge of the spectrum over conventional pulses in 1D and 2D NMR spectroscopy experiments.
From polariton condensates to highly photonic quantum degenerate states of bosonic matter
Authors: Aßmann Marc , Tempel Jean-Sebastian , Veit Franziska , Bayer Manfred , Rahimi-Iman Arash , Löffler Andreas , Höfling Sven , Reitzenstein Stephan , Worschech Lukas , Forchel Alfred
Published: January 2011

Bose–Einstein condensation (BEC) is a thermodynamic phase transition of an interacting Bose gas. Its key signatures are remarkable quantum effects like superfluidity and a phonon-like Bogoliubov excitation spectrum, which have been verified for atomic BECs. In the solid state, BEC of exciton–polaritons has been reported. Polaritons are strongly coupled light-matter quasiparticles in semiconductor microcavities and composite bosons. However, they are subject to dephasing and decay and need external pumping to reach a steady state. Accordingly the polariton BEC is a nonequilibrium process of a degenerate polariton gas in self-equilibrium, but out of equilibrium with the baths it is coupled to and therefore deviates from the thermodynamic phase transition seen in atomic BECs. Here we show that key signatures of BEC can even be observed without fulfilling the self-equilibrium condition in a highly photonic quantum degenerate nonequilibrium system.
Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming
Authors: McLaughlin-Drubin Margaret E. , Crum Christopher P. , Münger Karl
Published: January 2011

Despite the availability of vaccines, human papillomavirus (HPV) infections remain a cause of significant cancer morbidity and mortality. We have previously shown that HPV16 E7 associates with and diminishes E2F6-containing polycomb repressive complexes. Here, we show that repressive trimethyl marks on lysine 27 of histone 3, which are necessary for binding of polycomb repressive complexes, are decreased in HPV16 E7-expressing cells and HPV16-positive cervical lesions. This is caused by transcriptional induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases. HPV16 E7-mediated KDM6B induction accounts for expression of the cervical cancer biomarker, p16
INK4A
. Moreover, KDM6A- and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells. These effects are independent of the ability of E7 to inhibit the retinoblastoma tumor suppressor protein. Most importantly, these effects are reversed when E7 expression is silenced, indicating that this pathway may have prognostic and/or therapeutic significance.
Correlated genotypes in friendship networks
Authors: Fowler James H. , Settle Jaime E. , Christakis Nicholas A.
Published: January 2011

It is well known that humans tend to associate with other humans who have similar characteristics, but it is unclear whether this tendency has consequences for the distribution of genotypes in a population. Although geneticists have shown that populations tend to stratify genetically, this process results from geographic sorting or assortative mating, and it is unknown whether genotypes may be correlated as a consequence of nonreproductive associations or other processes. Here, we study six available genotypes from the National Longitudinal Study of Adolescent Health to test for genetic similarity between friends. Maps of the friendship networks show clustering of genotypes and, after we apply strict controls for population stratification, the results show that one genotype is positively correlated (homophily) and one genotype is negatively correlated (heterophily). A replication study in an independent sample from the Framingham Heart Study verifies that
DRD2
exhibits significant homophily and that
CYP2A6
exhibits significant heterophily. These unique results show that homophily and heterophily obtain on a genetic (indeed, an allelic) level, which has implications for the study of population genetics and social behavior. In particular, the results suggest that association tests should include friends’ genes and that theories of evolution should take into account the fact that humans might, in some sense, be metagenomic with respect to the humans around them.
Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis
Authors: Rosenbluth Jennifer M. , Mays Deborah J. , Jiang Aixiang , Shyr Yu , Pietenpol Jennifer A.
Published: January 2011

The transcription factor p73 plays critical roles during development and tumorigenesis. It exhibits sequence identity and structural homology with p53, and can engage p53-like tumor-suppressive programs. However, different pathways regulate p53 and p73, and p73 is not mutated in human tumors. Therefore, p73 represents a therapeutic target, and there is a critical need to understand genes and noncoding RNAs regulated by p73 and how they change during treatment regimens. Here, we define the p73 genomic binding profile and demonstrate its modulation by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) and inducer of p73. Rapamycin selectively increased p73 occupancy at a subset of its binding sites. In addition, multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR. We generated an mTOR-p73 signature that is enriched for p73 target genes and miRNAs that are involved in mesenchymal differentiation and tumorigenesis, can classify rhabdomyosarcomas by clinical subtype, and can predict patient outcome.
Dynamic histone acetylation is critical for cotranscriptional spliceosome assembly and spliceosomal rearrangements
Authors: Gunderson Felizza Q. , Merkhofer Evan C. , Johnson Tracy L.
Published: January 2011

Assembly of the spliceosome onto pre-mRNA is a dynamic process involving the ordered exchange of snRNPs to form the catalytically active spliceosome. These ordered rearrangements have recently been shown to occur cotranscriptionally, while the RNA polymerase is still actively engaged with the chromatin template. We previously demonstrated that the histone acetyltransferase Gcn5 is required for U2 snRNP association with the branchpoint. Here we provide evidence that histone acetylation and deacetylation facilitate proper cotranscriptional association of spliceosomal snRNPs. As with
GCN5
, mutation or deletion of Gcn5-targeted histone H3 residues leads to synthetic lethality when combined with deletion of the genes encoding the U2 snRNP components Lea1 or Msl1. Gcn5 associates throughout intron-containing genes and, in the absence of the histone deacetylases Hos3 and Hos2, enhanced histone H3 acetylation is observed throughout the body of genes. Deletion of histone deacetylaces also results in persistent association of the U2 snRNP and a severe defect in the association of downstream factors. These studies show that cotranscriptional spliceosome rearrangements are driven by dynamic changes in the acetylation state of histones and provide a model whereby yeast spliceosome assembly is tightly coupled to histone modification.
Activation of IFN-β expression by a viral mRNA through RNase L and MDA5
Authors: Luthra Priya , Sun Dengyun , Silverman Robert H. , He Biao
Published: January 2011

IFNs play a critical role in innate immunity against viral infections. Melanoma differentiation-associated protein 5 (MDA5), an RNA helicase, is a key component in activating the expression of type I IFNs in response to certain types of viral infection. MDA5 senses noncellular RNA and triggers the signaling cascade that leads to IFN production. Synthetic double-stranded RNAs are known activators of MDA5. Natural single-stranded RNAs have not been reported to activate MDA5, however. We have serendipitously identified a viral mRNA from parainfluenza virus 5 (PIV5) that activates IFN expression through MDA5. We provide evidence that the signaling pathway includes the antiviral enzyme RNase L. The L mRNA of PIV5 activated expression of IFN-β. We have mapped the RNA to a region of 430 nucleotides within the L mRNA of PIV5. Our results indicate that a viral mRNA, with 5′-cap and 3′-poly (A), can activate IFN expression through an RNase L-MDA5 pathway.
Outcrossing, mitotic recombination, and life-history trade-offs shape genome evolution in
Saccharomyces cerevisiae
Authors: Magwene Paul M. , Kayıkçı Ömür , Granek Joshua A. , Reininga Jennifer M. , Scholl Zackary , Murray Debra
Published: January 2011

We carried out a population genomic survey of
Saccharomyces cerevisiae
diploid isolates and find that many budding yeast strains have high levels of genomic heterozygosity, much of which is likely due to outcrossing. We demonstrate that variation in heterozygosity among strains is correlated with a life-history trade-off that involves how readily yeast switch from asexual to sexual reproduction under nutrient stress. This trade-off is reflected in a negative relationship between sporulation efficiency and pseudohyphal development and correlates with variation in the expression of
RME1
, a transcription factor with pleiotropic effects on meiosis and filamentous growth. Selection for alternate life-history strategies in natural versus human-associated environments likely contributes to differential maintenance of genomic heterozygosity through its effect on the frequency that yeast lineages experience sexual cycles and hence the opportunity for inbreeding. In addition to elevated levels of heterozygosity, many strains exhibit large genomic regions of loss-of-heterozygosity (LOH), suggesting that mitotic recombination has a significant impact on genetic variation in this species. This study provides new insights into the roles that both outcrossing and mitotic recombination play in shaping the genome architecture of
Saccharomyces cerevisiae
. This study also provides a unique case where stark differences in the genomic distribution of genetic variation among individuals of the same species can be largely explained by a life-history trade-off.
Determinants of lemming outbreaks
Authors: Ims Rolf A. , Yoccoz Nigel G. , Killengreen Siw T.
Published: January 2011

Population outbreaks in tundra rodents have intrigued scientists for a century as a result of their spectacular appearances and their general lessons in ecology. One outstanding question that has led to competing hypotheses is why sympatric lemmings and voles differ in regularity and shape of their outbreaks. Lemming outbreaks may be lost for decades while vole populations maintain regular population cycles. Moreover, when lemming populations eventually irrupt, they do so more steeply than the vole populations. Norwegian lemmings exhibited a large-scale outbreak synchronously with gray-sided voles in Finnmark, northern Fennoscandia, during 2006 to 2007 for the first time in two decades. Analyses of spatial variability of this outbreak across altitudinal gradients allowed us to identify determinants of the contrasting lemming and vole dynamics. The steeper lemming outbreak trajectories were caused by breeding and population growth during winter, when nonbreeding vole populations consistently declined. The differently shaped lemming and vole outbreaks appear to result from a particular demographic tactic of lemmings that evolved as an adaptation to the long and cold Arctic–Alpine winters. The lemming outbreak amplitude increased with altitude and vole density, indicating that lemming outbreaks are jointly facilitated by low temperatures and apparent mutualism with voles mediated by shared predators. High sensitivity to variation in climate and predation is likely to be the reasons why lemmings have more erratic population dynamics than sympatric voles. The combination of continued climatic warming and dampened vole cycles is expected to further decrease the frequency, amplitude, and geographic range of lemming outbreaks in tundra ecosystems.
Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation
Authors: Denoble Anna E. , Huffman Kim M. , Stabler Thomas V. , Kelly Susan J. , Hershfield Michael S. , McDaniel Gary E. , Coleman R. Edward , Kraus Virginia B.
Published: January 2011

Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1β. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1β. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1β was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1β) known to be produced by uric acid-activated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.
Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease
Authors: James Terrence W. , Frias-Staheli Natalia , Bacik John-Paul , Levingston Macleod Jesica M. , Khajehpour Mazdak , García-Sastre Adolfo , Mark Brian L.
Published: January 2011

The attachment of ubiquitin (Ub) and the Ub-like (Ubl) molecule interferon-stimulated gene 15 (ISG15) to cellular proteins mediates important innate antiviral responses. Ovarian tumor (OTU) domain proteases from nairoviruses and arteriviruses were recently found to remove these molecules from host proteins, which inhibits Ub and ISG15-dependent antiviral pathways. This contrasts with the Ub-specific activity of known eukaryotic OTU-domain proteases. Here we describe crystal structures of a viral OTU domain from the highly pathogenic Crimean–Congo haemorrhagic fever virus (CCHFV) bound to Ub and to ISG15 at 2.5-Å and 2.3-Å resolution, respectively. The complexes provide a unique structural example of ISG15 bound to another protein and reveal the molecular mechanism of an ISG15 cross-reactive deubiquitinase. To accommodate structural differences between Ub and ISG15, the viral protease binds the β-grasp folds of Ub and C-terminal Ub-like domain of ISG15 in an orientation that is rotated nearly 75° with respect to that observed for Ub bound to a representative eukaryotic OTU domain from yeast. Distinct structural determinants necessary for binding either substrate were identified and allowed the reengineering of the viral OTU protease into enzymes with increased substrate specificity, either for Ub or for ISG15. Our findings now provide the basis to determine in vivo the relative contributions of deubiquitination and deISGylation to viral immune evasion tactics, and a structural template of a promiscuous deubiquitinase from a haemorrhagic fever virus that can be targeted for inhibition using small-molecule-based strategies.
LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+T cells
Authors: Summers deLuca Leslie , Ng Dennis , Gao Yunfei , Wortzman Michael E. , Watts Tania H. , Gommerman Jennifer L.
Published: January 2011

During an immune response, antigen-bearing dendritic cells (DCs) migrate to the local draining lymph node and present antigen to CD4+helper T cells. Antigen-activated CD4+T cells then up-regulate TNF superfamily members including CD40 ligand and lymphotoxin (LT)αβ. Although it is well-accepted that CD40 stimulation on DCs is required for DC licensing and cross-priming of CD8+T-cell responses, it is likely that other signals are integrated into a comprehensive DC activation program. Here we show that a cognate interaction between LTαβ on CD4+helper T cells and LTβ receptor on DCs results in unique signals that are necessary for optimal CD8+T-cell expansion via a type I IFN-dependent mechanism. In contrast, CD40 signaling appears to be more critical for CD8+T-cell IFNγ production. Therefore, different TNF family members provide integrative signals that shape the licensing potential of antigen-presenting DCs.
Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria
Authors: Das Soumita , Owen Katherine A. , Ly Kim T. , Park Daeho , Black Steven G. , Wilson Jeffrey M. , Sifri Costi D. , Ravichandran Kodi S. , Ernst Peter B. , Casanova James E.
Published: January 2011

Bacterial recognition by host cells is essential for initiation of infection and the host response. Bacteria interact with host cells via multiple pattern recognition receptors that recognize microbial products or pathogen-associated molecular patterns. In response to this interaction, host cell signaling cascades are activated that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Brain angiogenesis inhibitor 1 (BAI1) is a receptor that recognizes apoptotic cells through its conserved type I thrombospondin repeats and triggers their engulfment through an ELMO1/Dock/Rac1 signaling module. Because thrombospondin repeats in other proteins have been shown to bind bacterial surface components, we hypothesized that BAI1 may also mediate the recognition and clearance of pathogenic bacteria. We found that preincubation of bacteria with recombinant soluble BAI1 ectodomain or knockdown of endogenous BAI1 in primary macrophages significantly reduced binding and internalization of the Gram-negative pathogen
Salmonella typhimurium
. Conversely, overexpression of BAI1 enhanced attachment and engulfment of
Salmonella
in macrophages and in heterologous nonphagocytic cells. Bacterial uptake is triggered by the BAI1-mediated activation of Rac through an ELMO/Dock-dependent mechanism, and inhibition of the BAI1/ELMO1 interaction prevents both Rac activation and bacterial uptake. Moreover, inhibition of ELMO1 or Rac function significantly impairs the proinflammatory response to infection. Finally, we show that BAI1 interacts with a variety of Gram-negative, but not Gram-positive, bacteria through recognition of their surface lipopolysaccharide. Together these findings identify BAI1 as a pattern recognition receptor that mediates nonopsonic phagocytosis of Gram-negative bacteria by macrophages and directly affects the host response to infection.
Dynamically tunable hemispherical electronic eye camera system with adjustable zoom capability
Authors: Jung Inhwa , Xiao Jianliang , Malyarchuk Viktor , Lu Chaofeng , Li Ming , Liu Zhuangjian , Yoon Jongseung , Huang Yonggang , Rogers John A.
Published: January 2011

Imaging systems that exploit arrays of photodetectors in curvilinear layouts are attractive due to their ability to match the strongly nonplanar image surfaces (i.e., Petzval surfaces) that form with simple lenses, thereby creating new design options. Recent work has yielded significant progress in the realization of such “eyeball” cameras, including examples of fully functional silicon devices capable of collecting realistic images. Although these systems provide advantages compared to those with conventional, planar designs, their fixed detector curvature renders them incompatible with changes in the Petzval surface that accompany variable zoom achieved with simple lenses. This paper describes a class of digital imaging device that overcomes this limitation, through the use of photodetector arrays on thin elastomeric membranes, capable of reversible deformation into hemispherical shapes with radii of curvature that can be adjusted dynamically, via hydraulics. Combining this type of detector with a similarly tunable, fluidic plano-convex lens yields a hemispherical camera with variable zoom and excellent imaging characteristics. Systematic experimental and theoretical studies of the mechanics and optics reveal all underlying principles of operation. This type of technology could be useful for night-vision surveillance, endoscopic imaging, and other areas that require compact cameras with simple zoom optics and wide-angle fields of view.
HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation
Authors: Burr Marian L. , Cano Florencia , Svobodova Stanislava , Boyle Louise H. , Boname Jessica M. , Lehner Paul J.
Published: January 2011

The assembly of MHC class I molecules is governed by stringent endoplasmic reticulum (ER) quality control mechanisms. MHC class I heavy chains that fail to achieve their native conformation in complex with β2-microglobulin (β2m) and peptide are targeted for ER-associated degradation. This requires ubiquitination of the MHC class I heavy chain and its dislocation from the ER to the cytosol for proteasome-mediated degradation, although the cellular machinery involved in this process is unknown. Using an siRNA functional screen in β2m-depleted cells, we identify an essential role for the E3 ligase HRD1 (Synoviolin) together with the E2 ubiquitin-conjugating enzyme UBE2J1 in the ubiquitination and dislocation of misfolded MHC class I heavy chains. HRD1 is also required for the ubiquitination and degradation of the naturally occurring hemochromatosis-associated HFE-C282Y mutant, which is unable to bind β2m. In the absence of HRD1, misfolded HLA-B27 accumulated in cells with a normal MHC class I assembly pathway, and HRD1 depletion prevented the appearance of low levels of cytosolic unfolded MHC I heavy chains. HRD1 and UBE2J1 associate in a complex together with non-β2m bound MHC class I heavy chains, Derlin 1, and p97 and discriminate misfolded MHC class I from conformational MHC I-β2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression.
miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells
Authors: Kuhn Stephanie , Johnson Stuart L. , Furness David N. , Chen Jing , Ingham Neil , Hilton Jennifer M. , Steffes Georg , Lewis Morag A. , Zampini Valeria , Hackney Carole M. , Masetto Sergio , Holley Matthew C. , Steel Karen P. , Marcotti Walter
Published: January 2011

MicroRNAs (miRNAs) are small noncoding RNAs able to regulate a broad range of protein-coding genes involved in many biological processes. miR-96 is a sensory organ-specific miRNA expressed in the mammalian cochlea during development. Mutations in miR-96 cause nonsyndromic progressive hearing loss in humans and mice. The mouse mutant diminuendo has a single base change in the seed region of the
Mir96
gene leading to widespread changes in the expression of many genes. We have used this mutant to explore the role of miR-96 in the maturation of the auditory organ. We found that the physiological development of mutant sensory hair cells is arrested at around the day of birth, before their biophysical differentiation into inner and outer hair cells. Moreover, maturation of the hair cell stereocilia bundle and remodelling of auditory nerve connections within the cochlea fail to occur in miR-96 mutants. We conclude that miR-96 regulates the progression of the physiological and morphological differentiation of cochlear hair cells and, as such, coordinates one of the most distinctive functional refinements of the mammalian auditory system.
ORGAN BOUNDARY1
defines a gene expressed at the junction between the shoot apical meristem and lateral organs
Authors: Cho Euna , Zambryski Patricia C.
Published: January 2011

We identify a gene,
ORGAN BOUNDARY1
(
OBO1
), by its unique pattern of enhancer- driven GFP expression at the boundaries between the apical meristems and lateral organs in
Arabidopsis
embryos, seedlings, and mature plants.
OBO1
also is expressed at the root apical meristem and in distinct cell files surrounding this area.
OBO1
is one of a 10-member plant-specific gene family encoding a single small domain (133 amino acids) with unknown function. One member of this gene family,
OBO2
, is identical to a previously studied gene,
LIGHT-SENSITIVE HYPOCOTYL1
. Overexpression of
OBO1
causes an abnormal number and size of petals and petal–stamen fusions. The patterns of
OBO1
gene expression are distinct but overlap with other genes involved in boundary formation in the
Arabidopsis
shoot apical meristem, including
CUP-SHAPED COTYLEDON
,
LATERAL ORGAN BOUNDARIES
,
BLADE-ON-PETIOLE
,
ASYMMETRIC LEAVES
, and
LATERAL ORGAN FUSION.
Nuclear localization of
OBO1
suggests that it might act with one or more of the transcription factors encoded by the foregoing genes. Ablation of the specific cells expressing
OBO1
leads to loss of the shoot apical meristem and lateral organs. Thus, the cells expressing
OBO1
are important for meristem maintenance and organogenesis in
Arabidopsis
.
mut-16
and other
mutator
class genes modulate 22G and 26G siRNA pathways in
Caenorhabditis elegans
Authors: Zhang Chi , Montgomery Taiowa A. , Gabel Harrison W. , Fischer Sylvia E. J. , Phillips Carolyn M. , Fahlgren Noah , Sullivan Christopher M. , Carrington James C. , Ruvkun Gary
Published: January 2011

Argonaute-associated siRNAs and Piwi-associated piRNAs have overlapping roles in silencing mobile genetic elements in animals. In
Caenorhabditis elegans
,
mutator
(
mut
) class genes mediate siRNA-guided repression of transposons as well as exogenous RNAi, but their roles in endogenous RNA silencing pathways are not well-understood. To characterize the endogenous small RNAs dependent on
mut
class genes, small RNA populations from a null allele of
mut-16
as well as a regulatory
mut-16
(
mg461
) allele that disables only somatic RNAi were subjected to deep sequencing. Additionally, each of the
mut
class genes was tested for a requirement in 26G siRNA pathways. The results indicate that
mut-16
is an essential factor in multiple endogenous germline and somatic siRNA pathways involving several distinct Argonautes and RNA-dependent RNA polymerases. The results also reveal essential roles for
mut-2
and
mut-7
in the ERGO-1 class 26G siRNA pathway and less critical roles for
mut-8
,
mut-14
, and
mut-15
. We show that transposons are hypersusceptible to
mut-16
–dependent silencing and identify a requirement for the siRNA machinery in piRNA biogenesis from Tc1 transposons. We also show that the soma-specific
mut-16
(
mg461
) mutant allele is present in multiple
C. elegans
laboratory strains.
Simultaneous single-molecule measurements of phage T7 replisome composition and function reveal the mechanism of polymerase exchange
Authors: Loparo Joseph J. , Kulczyk Arkadiusz W. , Richardson Charles C. , van Oijen Antoine M.
Published: January 2011

A complete understanding of the molecular mechanisms underlying the functioning of large, multiprotein complexes requires experimental tools capable of simultaneously visualizing molecular architecture and enzymatic activity in real time. We developed a novel single-molecule assay that combines the flow-stretching of individual DNA molecules to measure the activity of the DNA-replication machinery with the visualization of fluorescently labeled DNA polymerases at the replication fork. By correlating polymerase stoichiometry with DNA synthesis of T7 bacteriophage replisomes, we are able to quantitatively describe the mechanism of polymerase exchange. We find that even at relatively modest polymerase concentration (∼2 nM), soluble polymerases are recruited to an actively synthesizing replisome, dramatically increasing local polymerase concentration. These excess polymerases remain passively associated with the replisome through electrostatic interactions with the T7 helicase for ∼50 s until a stochastic and transient dissociation of the synthesizing polymerase from the primer-template allows for a polymerase exchange event to occur.
Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart
Authors: Tao Zhengxian , Chen Bo , Tan Xiao , Zhao Yingming , Wang Liansheng , Zhu Tiebing , Cao Kejiang , Yang Zhijian , Kan Yuet Wai , Su Hua
Published: January 2011

VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.
Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory
Authors: Sindreu Carlos , Palmiter Richard D. , Storm Daniel R.
Published: January 2011

The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus-dependent memory.
Membrane lipidome of an epithelial cell line
Authors: Sampaio Julio L. , Gerl Mathias J. , Klose Christian , Ejsing Christer S. , Beug Hartmut , Simons Kai , Shevchenko Andrej
Published: January 2011

Tissue differentiation is an important process that involves major cellular membrane remodeling. We used Madin–Darby canine kidney cells as a model for epithelium formation and investigated the remodeling of the total cell membrane lipidome during the transition from a nonpolarized morphology to an epithelial morphology and vice versa. To achieve this, we developed a shotgun-based lipidomics workflow that enabled the absolute quantification of mammalian membrane lipidomes with minimal sample processing from low sample amounts. Epithelial morphogenesis was accompanied by a major shift from sphingomyelin to glycosphingolipid, together with an increase in plasmalogen, phosphatidylethanolamine, and cholesterol content, whereas the opposite changes took place during an epithelial-to-mesenchymal transition. Moreover, during polarization, the sphingolipids became longer, more saturated, and more hydroxylated as required to generate an apical membrane domain that serves as a protective barrier for the epithelial sheet.
Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16
INK4A
and p14
ARF
expression
Authors: Maruo Seiji , Zhao Bo , Johannsen Eric , Kieff Elliott , Zou James , Takada Kenzo
Published: January 2011

Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) and EBNA3A are each essential for EBV conversion of primary human B lymphocytes into continuously proliferating lymphoblast cell lines (LCLs) and for maintaining LCL growth. We now find that EBNA3C and EBNA3A's essential roles are to repress p16
INK4A
and p14
ARF
. In the absence of EBNA3C or EBNA3A, p16
INK4A
and p14
ARF
expression increased and cell growth ceased. EBNA3C inactivation did not alter

p16
INK4A

promoter CpG methylation, but reduced already low H3K27me3, relative to resting B cells, and increased H3K4me3 and H3-acetylation, linking EBNA3C inactivation to histone modifications associated with increased transcription. Importantly, knockdown of p16
INK4A
or p14
ARF
partially rescued LCLs from EBNA3C or EBNA3A inactivation-induced growth arrest and knockdown of both rescued LCL growth, confirming central roles for p16
INK4A
and p14
ARF
in LCL growth arrest following EBNA3C or EBNA3A inactivation. Moreover, blockade of p16
INK4A
and p14
ARF
effects on pRb and p53 by human papilloma virus type 16 E7 and E6 expression, sustained LCL growth after EBNA3C or EBNA3A inactivation. These data indicate that EBNA3C and EBNA3A joint repression of
CDKN2A
p16
INK4A
and p14
ARF
is essential for LCL growth.
The Lithium Excretion Test: I. Clinical Application and Interpretation
Authors: Serry Maurice
Published: January 2011

The clinical and research applications of the Lithium Excretion Test (L.E.T.) are described. With a 4-hour test it is possible to differentiate manic patients who respond to lithium from those who do not. Significant applications for a small but important group of patients with personality disorders are discussed, as well as the findings in depression and schizophrenia.
The Lithium Excretion Test
Authors: Serry Maurice , Andrews Shirley
Published: January 2011

The ward technique, practical problems and biochemical methods of the Lithium Excretion Test (L.E.T.) are described. The procedures for the estimation of plasma, urinary and erythrocyte levels of lithium are given in detail.