bluuebunny/crossref_metadata_2025 huggingface dataset:
Probing DNA shape and methylation state on a genomic scale with DNase I
Authors: Lazarovici Allan , Zhou Tianyin , Shafer Anthony , Dantas Machado Ana Carolina , Riley Todd R. , Sandstrom Richard , Sabo Peter J. , Lu Yan , Rohs Remo , Stamatoyannopoulos John A. , Bussemaker Harmen J.
Published: April 2013

DNA binding proteins find their cognate sequences within genomic DNA through recognition of specific chemical and structural features. Here we demonstrate that high-resolution DNase I cleavage profiles can provide detailed information about the shape and chemical modification status of genomic DNA. Analyzing millions of DNA backbone hydrolysis events on naked genomic DNA, we show that the intrinsic rate of cleavage by DNase I closely tracks the width of the minor groove. Integration of these DNase I cleavage data with bisulfite sequencing data for the same cell type’s genome reveals that cleavage directly adjacent to cytosine-phosphate-guanine (CpG) dinucleotides is enhanced at least eightfold by cytosine methylation. This phenomenon we show to be attributable to methylation-induced narrowing of the minor groove. Furthermore, we demonstrate that it enables simultaneous mapping of DNase I hypersensitivity and regional DNA methylation levels using dense in vivo cleavage data. Taken together, our results suggest a general mechanism by which CpG methylation can modulate protein–DNA interaction strength via the remodeling of DNA shape.
Sex-biased gene expression at homomorphic sex chromosomes in emus and its implication for sex chromosome evolution
Authors: Vicoso Beatriz , Kaiser Vera B. , Bachtrog Doris
Published: April 2013

Sex chromosomes originate from autosomes. The accumulation of sexually antagonistic mutations on protosex chromosomes selects for a loss of recombination and sets in motion the evolutionary processes generating heteromorphic sex chromosomes. Recombination suppression and differentiation are generally viewed as the default path of sex chromosome evolution, and the occurrence of old, homomorphic sex chromosomes, such as those of ratite birds, has remained a mystery. Here, we analyze the genome and transcriptome of emu (
Dromaius novaehollandiae
) and confirm that most genes on the sex chromosome are shared between the Z and W. Surprisingly, however, levels of gene expression are generally sex-biased for all sex-linked genes relative to autosomes, including those in the pseudoautosomal region, and the male-bias increases after gonad formation. This expression bias suggests that the emu sex chromosomes have become masculinized, even in the absence of ZW differentiation. Thus, birds may have taken different evolutionary solutions to minimize the deleterious effects imposed by sexually antagonistic mutations: some lineages eliminate recombination along the protosex chromosomes to physically restrict sexually antagonistic alleles to one sex, whereas ratites evolved sex-biased expression to confine the product of a sexually antagonistic allele to the sex it benefits. This difference in conflict resolution may explain the preservation of recombining, homomorphic sex chromosomes in other lineages and illustrates the importance of sexually antagonistic mutations driving the evolution of sex chromosomes.
Structural ensemble and microscopic elasticity of freely diffusing DNA by direct measurement of fluctuations
Authors: Shi Xuesong , Herschlag Daniel , Harbury Pehr A. B.
Published: April 2013

Significance

Deformation of the double helix is a ubiquitous feature of the protein–DNA interactions that regulate, replicate, repair, and pack DNA in cells. Understanding the energetics of DNA deformation is therefore of central importance. DNA is generally modeled as a linear elastic rod, but it has not been possible to test this directly by observing the nanometer-scale bending and twisting of the helix. Using an X-ray interferometry technique, we measured the structural fluctuations of a short B-form duplex. The results expose a potential nonlinearity of DNA elasticity and illustrate how to measure the structural ensemble of a freely diffusing macromolecule.
Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice
Authors: Joseph Anu , Tang Mingxi , Mamiya Takayoshi , Chen Qian , Yang Ling-Ling , Jiao Jianwei , Yu Na , Tang Ya-Ping
Published: April 2013

Adolescent trauma (AT) is a common risk factor for adult-onset posttraumatic stress disorder (PTSD). However, the vulnerability to AT among different individuals varies dramatically, indicating that other cofactors are important. Despite extensive studies, the identification of those cofactors has had little success. Here, we found that after subjected to traumatic stress at postnatal day 25 (P25), a stage that is comparable to the human adolescent period, inducible/reversible forebrain-specific cholecystokinin receptor-2 transgenic (IF-
CCKR-2
tg) mice exhibited a significantly higher level of PTSD-like behavior at a later life (adult) stage compared with their wild-type littermates. Moreover, in these traumatized IF-
CCKR-2
tg mice, both the glucocorticoid negative feedback inhibition and spatial learning and memory were impaired. Interestingly, if the
CCKR-2
transgene was specifically suppressed during the time of AT exposure, these observations were largely diminished, indicating that a temporal association of the elevated CCKergic tone and AT is pathogenically critical. Treatment of traumatized IF-
CCKR-2
tg mice with fluoxetine, a selective serotonin reuptake inhibitor, for a period of 4 wk significantly attenuated the PTSD-like behavior and the impaired glucocorticoid negative feedback inhibition, but not the memory deficit, implying that the memory deficit is an independent post-AT clinical entity and not a consequence of PTSD. Taken together, these results reveal a dynamic role of the CCKergic system in the development of post-AT psychopathologies and suggest that a timely antagonism of CCKR-2 activity during AT exposure is a potential preventive strategy for post-AT psychopathologies including PTSD and cognitive dysfunction.
Shaping organs by a wingless-int/Notch/nonmuscle myosin module which orients feather bud elongation
Authors: Li Ang , Chen Meng , Jiang Ting-Xin , Wu Ping , Nie Qing , Widelitz Randall , Chuong Cheng-Ming
Published: April 2013

Significance

How are specific organs shaped? To convert organ primordia from small domes to polarized, thin, conical structures, the orientation and duration of the elongation process must be carefully regulated. Using a feather bud elongation model, we identify a molecular module that directs precisely oriented elongation by converting a chemical gradient into a sharp boundary zone, which mediates mechanical processes. The module involves wingless-int (Wnt)7a,
β
-catenin, and nonmuscle myosin IIB and is modulated by Notch activity. Our mathematical simulations confirm the module’s effect on reducing variations and fluctuations in the system via gradient-threshold conversion.
Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer
Authors: Magnani Luca , Stoeck Alexander , Zhang Xiaoyang , Lánczky András , Mirabella Anne C. , Wang Tian-Li , Gyorffy Balázs , Lupien Mathieu
Published: April 2013

Significance

Resistance to treatment with endocrine therapy occurs in ∼50% of all breast cancer patients. The pathway(s) leading to drug resistance is ill-defined. We show that accessibility to the genome is altered in drug-resistant compared with responsive breast cancer cells. This coincides with the overactivation of the NOTCH pathway in drug-resistant compared with responsive cancer cells. The transcription factor PBX1, a known NOTCH target gene, is required for the growth of endocrine therapy-resistant breast cancer cells. Accordingly, a gene expression signature based on NOTCH-PBX1 activity can discriminate a priori breast cancer patients that are responsive or not to endocrine therapy.
Neural progenitors organize in small-world networks to promote cell proliferation
Authors: Malmersjö Seth , Rebellato Paola , Smedler Erik , Planert Henrike , Kanatani Shigeaki , Liste Isabel , Nanou Evanthia , Sunner Hampus , Abdelhady Shaimaa , Zhang Songbai , Andäng Michael , El Manira Abdeljabbar , Silberberg Gilad , Arenas Ernest , Uhlén Per
Published: April 2013

Significance

Synchronized activity among groups of interconnected cells is essential for diverse functions in the brain. Most studies on neuronal networks have been performed in the mature brain when chemical synapses have been established. However, less is known about networking during embryonic development. We have studied neural progenitors and found that they form gap junction-mediated small-world networks, which, via electrical depolarization, drive spontaneous calcium activity to stimulate cell proliferation. Our data underscore the critical role of intricate cell signaling during embryonic development and show that complex networks of immature cells exist in the brain before birth.
Transitions to catalytically inactive conformations in EGFR kinase
Authors: Shan Yibing , Arkhipov Anton , Kim Eric T. , Pan Albert C. , Shaw David E.
Published: April 2013

The epidermal growth factor receptor (EGFR) is a key protein in cellular signaling, and its kinase domain (EGFR kinase) is an intensely pursued target of small-molecule drugs. Although both catalytically active and inactive conformations of EGFR kinase have been resolved crystallographically, experimental characterization of the transitions between these conformations remains difficult. Using unbiased, all-atom molecular dynamics simulations, we observed EGFR kinase spontaneously transition from the active to the so-called “Src-like inactive” conformation by way of two sets of intermediate conformations: One corresponds to a previously identified locally disordered state and the other to previously undescribed “extended” conformations, marked by the opening of the ATP-binding site between the two lobes of the kinase domain. We also simulated the protonation-dependent transition of EGFR kinase to another [“Asp-Phe-Gly-out” (“DFG-out”)] inactive conformation and observed similar intermediate conformations. A key element observed in the simulated transitions is local unfolding, or “cracking,” which supports a prediction of energy landscape theory. We used hydrogen–deuterium (H/D) exchange measurements to corroborate our simulations and found that the simulated intermediate conformations correlate better with the H/D exchange data than existing active or inactive EGFR kinase crystal structures. The intermediate conformations revealed by our simulations of the transition process differ significantly from the existing crystal structures and may provide unique possibilities for structure-based drug discovery.
Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells
Authors: Choi Paul J. , Mitchison Timothy J.
Published: April 2013

Cytotoxic lymphocytes eliminate virus-infected and cancerous cells by immune recognition and killing through the perforin-granzyme pathway. Traditional killing assays measure average target cell lysis at fixed times and high effector:target ratios. Such assays obscure kinetic details that might reveal novel physiology. We engineered target cells to report on granzyme activity, used very low effector:target ratios to observe potential serial killing, and performed low magnification time-lapse imaging to reveal time-dependent statistics of natural killer (NK) killing at the single-cell level. Most kills occurred during serial killing, and a single NK cell killed up to 10 targets over a 6-h assay. The first kill was slower than subsequent kills, especially on poor targets, or when NK signaling pathways were partially inhibited. Spatial analysis showed that sequential kills were usually adjacent. We propose that NK cells integrate signals from the previous and current target, possibly by simultaneous contact. The resulting burst kinetics and spatial coordination may control the activity of NK cells in tissues.
T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy
Authors: Zhong Shi , Malecek Karolina , Johnson Laura A. , Yu Zhiya , Vega-Saenz de Miera Eleazar , Darvishian Farbod , McGary Katelyn , Huang Kevin , Boyer Josh , Corse Emily , Shao Yongzhao , Rosenberg Steven A. , Restifo Nicholas P. , Osman Iman , Krogsgaard Michelle
Published: April 2013

T cells expressing antigen-specific T-cell receptors (TCRs) can mediate effective tumor regression, but they often also are accompanied by autoimmune responses. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo,we used a unique self-antigen system comprising seven human melanoma gp100(209–217)-specific TCRs spanning physiological affinities (1–100 μM). We found that in vitro and in vivo T-cell responses are determined by TCR affinity, except in one case that was compensated by substantial CD8 involvement. Strikingly, we found that T-cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Together, these results suggest that a relatively low-affinity threshold is necessary for the immune system to avoid self-damage, given the close relationship between antitumor activity and autoimmunity. The low threshold, in turn, indicates that adoptive T-cell therapy treatment strategies using in vitro-generated high-affinity TCRs do not necessarily improve efficacy.
Why glass elasticity affects the thermodynamics and fragility of supercooled liquids
Authors: Yan Le , Düring Gustavo , Wyart Matthieu
Published: April 2013

Supercooled liquids are characterized by their fragility: The slowing down of the dynamics under cooling is more sudden and the jump of specific heat at the glass transition is generally larger in fragile liquids than in strong ones. Despite the importance of this quantity in classifying liquids, explaining what aspects of the microscopic structure controls fragility remains a challenge. Surprisingly, experiments indicate that the linear elasticity of the glass—a purely local property of the free energy landscape—is a good predictor of fragility. In particular, materials presenting a large excess of soft elastic modes, the so-called boson peak, are strong. This is also the case for network liquids near the rigidity percolation, known to affect elasticity. Here we introduce a model of the glass transition based on the assumption that particles can organize locally into distinct configurations that are coupled spatially via elasticity. The model captures the mentioned observations connecting elasticity and fragility. We find that materials presenting an abundance of soft elastic modes have little elastic frustration: Energy is insensitive to most directions in phase space, leading to a small jump of specific heat. In this framework strong liquids turn out to lie the closest to a critical point associated with a rigidity or jamming transition, and their thermodynamic properties are related to the problem of number partitioning and to Hopfield nets in the limit of small memory.
Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways
Authors: Rardin Matthew J. , Newman John C. , Held Jason M. , Cusack Michael P. , Sorensen Dylan J. , Li Biao , Schilling Birgit , Mooney Sean D. , Kahn C. Ronald , Verdin Eric , Gibson Bradford W.
Published: April 2013

Large-scale proteomic approaches have identified numerous mitochondrial acetylated proteins; however in most cases, their regulation by acetyltransferases and deacetylases remains unclear. Sirtuin 3 (SIRT3) is an NAD
+
-dependent mitochondrial protein deacetylase that has been shown to regulate a limited number of enzymes in key metabolic pathways. Here, we use a rigorous label-free quantitative MS approach (called MS1 Filtering) to analyze changes in lysine acetylation from mouse liver mitochondria in the absence of SIRT3. Among 483 proteins, a total of 2,187 unique sites of lysine acetylation were identified after affinity enrichment. MS1 Filtering revealed that lysine acetylation of 283 sites in 136 proteins was significantly increased in the absence of SIRT3 (at least twofold). A subset of these sites was independently validated using selected reaction monitoring MS. These data show that SIRT3 regulates acetylation on multiple proteins, often at multiple sites, across several metabolic pathways including fatty acid oxidation, ketogenesis, amino acid catabolism, and the urea and tricarboxylic acid cycles, as well as mitochondrial regulatory proteins. The widespread modification of key metabolic pathways greatly expands the number of known substrates and sites that are targeted by SIRT3 and establishes SIRT3 as a global regulator of mitochondrial protein acetylation with the capability of coordinating cellular responses to nutrient status and energy homeostasis.
Gene expression-based modeling of human cortical synaptic density
Authors: Goyal Manu S. , Raichle Marcus E.
Published: April 2013

Postnatal cortical synaptic development is characterized by stages of exuberant growth, pruning, and stabilization during adulthood. How gene expression orchestrates these stages of synaptic development is poorly understood. Here we report that synaptic growth-related gene expression alone does not determine cortical synaptic density changes across the human lifespan, but instead, the dynamics of cortical synaptic density can be accurately simulated by a first-order kinetic model of synaptic growth and elimination that incorporates two separate gene expression patterns. Surprisingly, modeling of cortical synaptic density is optimized when genes related to oligodendrocytes are used to determine synaptic elimination rates. Expression of synaptic growth and oligodendrocyte genes varies regionally, resulting in different predictions of synaptic density among cortical regions that concur with previous regional data in humans. Our analysis suggests that modest rates of synaptic growth persist in adulthood, but that this is counterbalanced by increasing rates of synaptic elimination, resulting in stable synaptic number and ongoing synaptic turnover in the human adult cortex. Our approach provides a promising avenue for exploring how complex interactions among genes may contribute to neurobiological phenomena across the human lifespan.
Cytochrome
c
causes pore formation in cardiolipin-containing membranes
Authors: Bergstrom Chris L. , Beales Paul A. , Lv Yang , Vanderlick T. Kyle , Groves John T.
Published: April 2013

The release of cytochrome
c
from mitochondria is a key signaling mechanism in apoptosis. Although extramitochondrial proteins are thought to initiate this release, the exact mechanisms remain unclear. Cytochrome
c
(cyt
c
) binds to and penetrates lipid structures containing the inner mitochondrial membrane lipid cardiolipin (CL), leading to protein conformational changes and increased peroxidase activity. We describe here a direct visualization of a fluorescent cyt
c
crossing synthetic, CL-containing membranes in the absence of other proteins. We observed strong binding of cyt
c
to CL in phospholipid vesicles and bursts of cyt
c
leakage across the membrane. Passive fluorescent markers such as carboxyfluorescein and a 10-kDa dextran polymer crossed the membrane simultaneously with cyt
c
, although larger dextrans did not. The data show that these bursts result from the opening of lipid pores formed by the cyt
c
–CL conjugate. Pore formation and cyt
c
leakage were significantly reduced in the presence of ATP. We suggest a model, consistent with these findings, in which the formation of toroidal lipid pores is driven by initial cyt
c
-induced negative spontaneous membrane curvature and subsequent protein unfolding interactions. Our results suggest that the CL–cyt
c
interaction may be sufficient to allow cyt
c
permeation of mitochondrial membranes and that cyt
c
may contribute to its own escape from mitochondria during apoptosis.
Single-crystal structure determination of (Mg,Fe)SiO3postperovskite
Authors: Zhang Li , Meng Yue , Dera Przemyslaw , Yang Wenge , Mao Wendy L. , Mao Ho-kwang
Published: April 2013

Knowledge of the structural properties of mantle phases is critical for understanding the enigmatic seismic features observed in the Earth’s lower mantle down to the core–mantle boundary. However, our knowledge of lower mantle phase equilibria at high pressure (P) and temperature (T) conditions has been based on limited information provided by powder X-ray diffraction technique and theoretical calculations. Here, we report the in situ single-crystal structure determination of (Mg,Fe)SiO3postperovskite (ppv) at highPand after temperature quenching in a diamond anvil cell. Using a newly developed multigrain single-crystal X-ray diffraction analysis technique in a diamond anvil cell, crystallographic orientations of over 100 crystallites were simultaneously determined at highPin a coarse-grained polycrystalline sample containing submicron ppv grains. Conventional single-crystal structural analysis and refinement methods were applied for a few selected ppv crystallites, which demonstrate the feasibility of the in situ study of crystal structures of submicron crystallites in a multiphase polycrystalline sample contained within a highPdevice. The similarity of structural models for single-crystal Fe-bearing ppv (∼10 mol% Fe) and Fe-free ppv from previous theoretical calculations suggests that the Fe content in the mantle has a negligible effect on the crystal structure of the ppv phase.
Hippocampal damage impairs recognition memory broadly, affecting both parameters in two prominent models of memory
Authors: Dede Adam J. O. , Wixted John T. , Hopkins Ramona O. , Squire Larry R.
Published: April 2013

Declarative memory is thought to rely on two processes: recollection and familiarity. Recollection involves remembering specific details about the episode in which an item was encountered, and familiarity involves simply knowing that an item was presented even when no information can be recalled about the episode itself. There has been debate whether the hippocampus supports only recollection or whether it supports both processes. We approached this issue in a relatively theory-neutral way by fitting two prominent models that have been used to describe recognition memory: dual process signal detection and unequal variance signal detection. Both models yield two parameters of interest when fit to recognition memory data. The dual process signal detection model yields estimates of recollection (
r
) and familiarity (
d′
). The unequal variance signal detection model yields estimates of the ratio of the variance of target and foil memory strength distributions (σ
target
/σ
foil
) and the difference in the means of the two distributions (
d
). We asked how the two parameters of each model were affected by hippocampal damage. We tested five patients with well-characterized bilateral lesions thought to be limited to the hippocampus and age-matched controls. The patients exhibited a broad memory deficit that markedly reduced the value of both parameters in both models. In addition, the pattern of results exhibited by the patients was recapitulated in healthy controls as the delay between learning and testing was extended. Thus, hippocampal damage impairs both component processes of recognition memory.
Genetic Population Structure of Bull Trout in the East Fork Bitterroot River Drainage, Montana
Authors: Nyce Leslie G. , Eby Lisa , Clancy Christopher G. , Painter Sally , Leary Robb F.
Published: April 2013

Investigation of the genetic population structure of Bull Trout Salvelinus confluentus is useful for developing biologically sound conservation and management strategies. We focused on the East Fork Bitterroot River (hereafter, East Fork), Montana, because it is a relatively undisturbed, connected watershed that contains a migratory life history form of Bull Trout. Fin clips were collected from 17 sites: nine East Fork tributaries, the main-stem East Fork, and seven other tributaries across the Bitterroot River drainage. Considering all the population samples, principal components analysis of allele frequencies at 15 microsatellite loci indicated that the East Fork samples formed a cluster that was distinct from the other Bitterroot River tributary samples. Within the East Fork, there was significant divergence among population samples, with pairwise FST ranging from 0.016 to 0.188 and a global FST of 0.063. Relative to other Bull Trout studies, levels of genetic variation within our samples were typically higher, while the overall level of differentiation among samples was lower. Based on ONCOR analyses of multiple-locus genotypes, most individuals in the East Fork basin were assigned to their water body of capture, with an average probability of 88%. Within the East Fork, 16 fish that were collected in the main stem were assigned to tributary populations; 26 individuals sampled from seven tributaries were assigned to the main-stem population. In addition, there were five tributaries in which sampled individuals were assigned to tributary populations other than the water body of capture. Based on GeneClass2 analysis, 76 individuals were identified as first-generation migrants. These observations suggest movement and potential gene flow between the main-stem East Fork and its tributaries and between tributaries via the main stem. The main-stem East Fork therefore appears to be an integral component for maintaining the migratory form of Bull Trout in the drainage and may serve as an important vehicle for genetic exchange among tributary populations.

Received May 18, 2012; accepted January 9, 2013
Anxiety experiences of male psychotherapists: A hermeneutic phenomenological study
Authors: Kierski Werner
Published: April 2013

Aims: There is currently a lack of clarity surrounding how men experience anxiety. This is caused by epistemological limitations with the perspectives employed to explore male anxiety, but equally by a lack of empirical research and uncertainty of how to define masculinity. In order to explain male anxiety more effectively this study needed to overcome these limitations by both incorporating the notion that there are multiple masculinities, through which men experience specific anxieties, and allowing men to talk directly about their experiences. This study focused on one kind of masculine identity: that of male psychotherapists. Research design: A hermeneutic phenomenological method was employed. Eight male psychotherapists of various modalities were interviewed who work in a number of therapeutic contexts. Results: Anxiety patterns are complex and comprise of feelings that are very difficult to deal with. Yet, anxiety is also an impetus for learning and improvement. Conclusions: The few existing ideas of male anxiety fail to capture the complexity of how men experience anxiety. Concepts of male anxiety need to be defined with more accuracy.
Sparing Fish Oil with Soybean Oil in Feeds for White Seabass: Effects of Inclusion Rate and Soybean Oil Composition
Authors: Trushenski Jesse , Mulligan Bonnie , Jirsa David , Drawbridge Mark
Published: April 2013

Fish oil sparing has proven difficult for some fish species, especially marine carnivores like White Seabass Atractoscion nobilis that require one or more long-chain polyunsaturated fatty acids (LC-PUFAs). Recent studies have suggested that the use of saturated fatty acid (SFA)–rich lipids instead of C18 polyunsaturated fatty acid–rich (C18 PUFA) lipids may be advantageous in maintaining tissue levels of LC-PUFAs; SFA-rich lipids may also offer a strategic advantage in terms of meeting the LC-PUFA requirements of marine carnivores while minimizing dietary fish oil inclusion. Accordingly, we assessed the performance and tissue fatty acid composition of White Seabass (3.8 ± 0.2 g [mean ± SE]) fed diets containing fish oil or graded levels of C18 PUFA–rich standard soy oil or SFA-rich hydrogenated soy oil (replacing 25, 50, 75, or 100% of dietary fish oil) for 8 weeks. Feed conversion ratio, weight gain, and specific growth rate were not impaired by partial or complete replacement of dietary fish oil with hydrogenated soy oil; however, fish oil sparing with standard soy oil was associated with declining performance. The tissue fatty acid profiles of fish fed the hydrogenated soy oil–based diets were very similar to those of fish fed the fish oil–based feed, but the standard soy oil–based feeds resulted in concomitant loss of n-3 fatty acids and LC-PUFAs. In all cases, the magnitude of the dietary effect was greater among liver and fillet tissues than among brain and eye tissues. These data suggest a limitation, potentially related to LC-PUFA deficiency, associated with replacing fish oil with standard soybean oil, but not with hydrogenated soybean oil. Our data suggest that the LC-PUFA requirements of White Seabass can be effectively reduced by feeding SFA-rich alternative lipids, allowing for a greater level of fish oil sparing without growth impairment or tissue profile modification than is possible with C18 PUFA–rich lipids.
Evaluation of the Effects of Menhaden Oil and Soybean Oil Levels in Purified Diets on Growth and Gonad Production in Adult Sea Urchin Lytechinus variegatus
Authors: Gibbs Victoria K , Powell Mickie L , Hammer Hugh S , Jones Warren T , Watts Stephen A , Lawrence Addison L , Lawrence John M
Published: April 2013

Development of a standardized reference diet will facilitate the determination of nutritional requirements for sea urchins. A purified diet, containing only chemically defined ingredients, provides consistency in diet formulations for reproducibility across different laboratories. In the present study, the growth performance of small Lytechinus variegatus (11.9 ± 1.3 g [mean ± SD] wet weight, 28.4 ± 1.1 mm test diameter; 16 per treatment) fed ad libitum daily (16 weeks) one of seven purified diets differing in the level (0, 2.4, or 4.8% as fed) and source of neutral lipid (refined menhaden oil and soy oil) was compared with the growth performance of individuals fed a semipurified diet previously shown to support high growth rates and gonad production. Survival was ≥88% for all dietary treatments, and the growth rates of individuals fed the 1.2% menhaden oil and 1.2% soybean oil purified diet (215% wet weight gain) were approximately 65% of those for individuals fed the semipurified diet (326% wet weight gain). The growth rates and wet organ weights for individuals fed purified diets were not significantly affected by lipid source. However, increased total dietary lipid resulted in higher dry gut weights. Ovary weight was higher than testis weight for all treatments. Although no significant differences were detected among the purified diet treatments, qualitative performance (survival, weight gain, and gonad production) for individuals fed the purified diet containing 1.2% menhaden oil and 1.2% soybean oil was best under the conditions of this study. The purified diet used in this study is adequate to evaluate specific nutrients on sea urchin weight gain and organ production.
Effects of Increasing Docosahexaenoic Acid (DHA) and Arachidonic Acid (ARA) in Brood Diets of Monodactylus sebae on Fecundity, Egg and Larval Quality, and Egg Fatty Acid Composition
Authors: Ohs C L , DiMaggio M A , Grabe S W , Broach J S , Watson C A , Breen N E , Barrows F T
Published: April 2013

The Guinean Fingerfish Monodactylus sebae is a popular euryhaline ornamental fish species with limited aquaculture production. One of the bottlenecks to commercial production is lack of knowledge of the nutritional requirements for broodstock. Therefore, three broodfish diets were formulated and fed to Guinean Fingerfish broodstock to determine their quantitative and qualitative effects on egg production and egg and larval morphology. The dietary treatments consisted of a control, a diet with increased docosahexaenoic acid (DHA), and a diet with increased DHA and arachidonic acid (DHA + ARA). Broodfish fed the DHA + ARA diet spawned more frequently than broodfish fed the DHA diet and those fed the control diet. The greatest egg production was also observed from broodfish fed the DHA + ARA diet. The mean hatching success of floating eggs was not significantly different among diets. The mean egg and oil globule diameters for both floating and sinking eggs were significantly smaller for broodfish fed the DHA + ARA diet rather than the other diets. At both 24 and 48 h, survival was significantly greater for fish fed the control diet than for those fed the DHA and DHA + ARA diets. At both 24 and 48 h posthatch, notochord length was significantly shorter for larvae from broodfish fed the DHA + ARA diet than for larvae from fish fed the control diet. The fatty acid profiles of the eggs closely resembled the fatty acid profiles of the diets with respect to DHA and ARA levels. Guinean Fingerfish females appear to have the ability to regulate the levels of DHA and ARA assimilated into developing eggs, although there is not clear evidence that they can elongate and desaturate C18 fatty acids into DHA and ARA.
The Time-Course of Lexical Activation in Japanese Morphographic Word Recognition: Evidence for a Character-Driven Processing Model
Authors: Miwa Koji , Libben Gary , Dijkstra Ton , Baayen Harald
Published: April 2013

This lexical decision study with eye tracking of Japanese two-kanji-character words investigated the order in which a whole two-character word and its morphographic constituents are activated in the course of lexical access, the relative contributions of the left and the right characters in lexical decision, the depth to which semantic radicals are processed, and how nonlinguistic factors affect lexical processes. Mixed-effects regression analyses of response times and subgaze durations (i.e., first-pass fixation time spent on each of the two characters) revealed joint contributions of morphographic units at all levels of the linguistic structure with the magnitude and the direction of the lexical effects modulated by readers' locus of attention in a left-to-right preferred processing path. During the early time frame, character effects were larger in magnitude and more robust than radical and whole-word effects, regardless of the font size and the type of nonwords. Extending previous radical-based and character-based models, we propose a task/decision-sensitive character-driven processing model with a level-skipping assumption: Connections from the feature level bypass the lower radical level and link up directly to the higher character level.
Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27–CD70 pathway
Authors: Coquet Jonathan M. , Ribot Julie C. , Bąbała Nikolina , Middendorp Sabine , van der Horst Gerda , Xiao Yanling , Neves Joana F. , Fonseca-Pereira Diogo , Jacobs Heinz , Pennington Daniel J. , Silva-Santos Bruno , Borst Jannie
Published: April 2013

CD4+Foxp3+ regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27–CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4+Foxp3− T cell numbers. The CD27–CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire− and Aire+ medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α+ subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27–CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.
Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin
Authors: Curran Michael A. , Geiger Theresa L. , Montalvo Welby , Kim Myoungjoo , Reiner Steven L. , Al-Shamkhani Aymen , Sun Joseph C. , Allison James P.
Published: April 2013

4-1BB agonist antibody treatment induces a population of KLRG1+ T cells that infiltrate melanoma tumors. We investigated the origin and function of these cells, as well as their place within established T cell paradigms. We find that these T cells, particularly the CD4 lineage, represent a novel phenotype characterized by enhanced, multipotent cytotoxicity. Distinct from described polarities, this T cell phenotype is driven by the T-box transcription factor Eomesodermin. Formation of this phenotype requires 4-1BB signaling on both T and antigen-presenting cells and the resulting production of the cytokines IL-27, IL-15, and IL-10. Furthermore, we find CD4+ T cells bearing the signature features of this phenotype in the livers of mice infected with both bacterial and viral intracellular pathogens, suggesting a role for these cells in infectious immunity. These T cells constitute a novel phenotype that resolves multiple questions associated with 4-1BB activation, including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity.
Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance
Authors: Soroosh Pejman , Doherty Taylor A. , Duan Wei , Mehta Amit Kumar , Choi Heonsik , Adams Yan Fei , Mikulski Zbigniew , Khorram Naseem , Rosenthal Peter , Broide David H. , Croft Michael
Published: April 2013

Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3+ iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3+ Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma.
Parametrizations of some Teichmüller spaces by trace functions
Authors: Nakamura Gou , Nakanishi Toshihiro
Published: April 2013

We show a tuple of trace functions which give a global parametrization of the Teichmüller space

T

(
g
,
m
)

{\mathcal T}(g,m)

of types

(
1
,
2
)

(1,2)

and

(
2
,
0
)

(2,0)

. We also show that the mapping class group acting on these Teichmüller spaces can be represented by a group of rational transformations in seven variables.
Histamine 4 receptor plays an important role in auto-antibody-induced arthritis
Authors: Nent Elisa , Frommholz David , Gajda Mieczyslaw , Bräuer Rolf , Illges Harald
Published: April 2013

Rheumatoid arthritis is a widespread autoimmune disease. In the murine K/B×N arthritis model, anti-GPI (anti-glucose 6-phosphate isomerase) antibodies lead to the formation of immune complexes. In the course of pathogenesis, these complexes activate the immune system and induce degranulation of mast cells, which are essential in this model of rheumatoid arthritis. A major mediator in mast cell granules is histamine, which is proven to be indispensable for joint inflammation in K/B×N mice. Histamine is known to bind to four different receptors (HR1–4), which have different expression profiles and exert a variety of different functions, including activation of the immune system. To analyze the contribution of the different histamine receptors, we employed histamine receptor antagonists (cetirizine, ranitidine, thioperamide and clozapine) blocking the receptors in C57BL/6 mice. Arthritis was induced via K/B×N serum injection. The results demonstrated that mice treated with all four histamine receptor antagonists simultaneously showed no arthritic symptoms, while positive control mice injected with K/B×N serum and vehicle suffered from severe symptoms. When antagonists specific for HR1–4 were applied individually, only the HR4 antagonist clozapine could protect mice from arthritis, reflecting its expression and functionality in the immune system.
Microscopic Colitis in Children With Chronic Diarrhea
Authors: Singh Prashant , Das Prasenjit , Jain A.K. , Mathan Minnie , Mathur Meera , Bhat Abdus Sami , Varma Sharat , Chaturvedi Mona K. , Gupta Siddhartha Datta , Bhatnagar Shinjini
Published: April 2013

Objective:

The aim of the present study was to study microscopic colitis (MC) in children with special reference to its role in chronic diarrhea and changes in mucosal biopsies.

Methods:

A total of 100 consecutive children ages 3 to 12 years, with nonbloody diarrhea (passage of ≥3 loose stools per day) of >12 weeks' duration were screened and 26 were enrolled in the study in which no specific etiology could be found and colonoscopy did not reveal any mucosal abnormality. Colonic biopsies were evaluated for the presence of lymphocytic colitis or collagenous colitis and those with the characteristic changes were defined to have MC (group A). Colonic biopsies from patients with MC were compared with biopsies from patients with chronic diarrhea but no evidence of MC (group B). One hundred children ages 3 to 12 years with bleeding per rectum were screened and colonic biopsies from 45 patients (group C) who had colonic mucosal changes but no vascular or polyp lesion were compared with patients with MC.

Results:

Of the 26 patients with chronic diarrhea, MC was found in 5 (3 lymphocytic colitis and 2 collagenous colitis). Significantly higher polymorphonuclear infiltration was seen in group A as compared with group B (13.8 [5.4–20.6] vs 7.2 [0–19.6]; P = 0.03) or group C (13.8 [5.4–20.6] vs 4 [0–13.4]; P = 0.007). Intraepithelial lymphocytes (12 [4–32] vs 4 [0–24]; P = 0.008) and basement membrane thickening (3.5 [2.9–10.6] vs 2.5 [1.6–5.86]; P = 0.008) were also significantly higher in group A as compared with group C.

Conclusions:

MC was found to be present in children with nonbloody chronic diarrhea in children. Further multicentric studies may provide adequate data on its prevalence.
Anti‐inflammatory Effect of Obestatin and Ghrelin in Dextran Sulfate Sodium–Induced Colitis in Rats
Authors: Pamukcu Ozge , Kumral Zarife Nigar Ozdemir , Ercan Feriha , Yegen Berrak Ç. , Ertem Deniz
Published: April 2013

Background and Objectives:

Obestatin and ghrelin are hormones derived from the same gene but have opposing effects. Ghrelin has anti‐inflammatory activities; however, the role of obestatin in the inflammatory processes has not been clearly demonstrated yet. The aim of the study was to analyse and compare the anti‐inflammatory effect of exogenous ghrelin and obestatin in a rat model of colitis.

Methods:

Acute and chronic colitis was induced in 96 rats by adding 3% dextran sulfate sodium to the drinking water for 5 and 10 days, respectively. Intraperitoneal pretreatment with ghrelin or obestatin was started before the induction of colitis, and continued for 5 and 10 days. Clinical signs of the disease and histopathological changes were evaluated. By‐products of neutrophil activation, lipid peroxidation, and inflammatory and anti‐inflammatory cytokines were measured in colonic tissues.

Results:

Obestatin and ghrelin significantly ameliorated clinical and histopathological severity of chronic colitis, whereas they were less effective in the acute form. Therapeutic effect of ghrelin and obestatin in acute colitis was associated with reduced lipid peroxidation and TH1‐induced inflammatory response, whereas obestatin in chronic colitis was protective via the suppression of polymorphonuclear leukocyte infiltration and enhancement of glutathione synthesis. Moreover, therapeutic effects of ghrelin and obestatin in chronic colitis appear to be associated with inhibition of inflammatory and activation of anti‐inflammatory cytokines.

Conclusions:

This study demonstrated the novel anti‐inflammatory effect of obestatin and ghrelin in an experimental model of colitis. Although both obestatin and ghrelin exerted anti‐inflammatory effects in chronic colitis, they were less effective in acute colitis.
On reflection symmetry and its application to the Euler–Lagrange equations in fractional mechanics
Authors: Klimek Małgorzata
Published: April 2013

We study the properties of fractional differentiation with respect to the reflection symmetry in a finite interval. The representation and integration formulae are derived for symmetric and anti-symmetric fractional derivatives, both of the Riemann–Liouville and Caputo type. The action dependent on the left-sided Caputo derivatives of orders in the range (1,2) is considered and we derive the Euler–Lagrange equations for the symmetric and anti-symmetric part of the trajectory. The procedure is illustrated with an example of the action dependent linearly on fractional velocities. For the obtained Euler–Lagrange system, we discuss its localization resulting from the subsequent symmetrization of the action.
CRONE control system design toolbox for the control engineering community: tutorial and case study
Authors: Lanusse Patrick , Malti Rachid , Melchior Pierre
Published: April 2013

Fractional-order differentiation offers new degrees of freedom that simplify the design of high-performance dynamic controllers. The CRONE control system design (CSD) methodology proposes the design of robust controllers by using fractional-order operators. A software toolbox has been developed based on this methodology and is freely available for the international scientific and industrial communities. This paper presents both the CRONE CSD methodology and its implementation using the toolbox. The design of two robust controllers for irrigation canals shows how to use the toolbox.
Application of the principal fractional meta-trigonometric functions for the solution of linear commensurate-order time-invariant fractional differential equations
Authors: Lorenzo C. F. , Hartley T. T. , Malti R.
Published: April 2013

A new and simplified method for the solution of linear constant coefficient fractional differential equations of any commensurate order is presented. The solutions are based on the
R
-function and on specialized Laplace transform pairs derived from the principal fractional meta-trigonometric functions. The new method simplifies the solution of such fractional differential equations and presents the solutions in the form of real functions as opposed to fractional complex exponential functions, and thus is directly applicable to real-world physics.