bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of deviations from optimality in biological systems
Authors: Pérez-Escudero Alfonso , Rivera-Alba Marta , de Polavieja Gonzalo G.
Published: November 2009

Optimization theory has been used to analyze evolutionary adaptation. This theory has explained many features of biological systems, from the genetic code to animal behavior. However, these systems show important deviations from optimality. Typically, these deviations are large in some particular components of the system, whereas others seem to be almost optimal. Deviations from optimality may be due to many factors in evolution, including stochastic effects and finite time, that may not allow the system to reach the ideal optimum. However, we still expect the system to have a higher probability of reaching a state with a higher value of the proposed indirect measure of fitness. In systems of many components, this implies that the largest deviations are expected in those components with less impact on the indirect measure of fitness. Here, we show that this simple probabilistic rule explains deviations from optimality in two very different biological systems. In
Caenorhabditis elegans
, this rule successfully explains the experimental deviations of the position of neurons from the configuration of minimal wiring cost. In
Escherichia coli
, the probabilistic rule correctly obtains the structure of the experimental deviations of metabolic fluxes from the configuration that maximizes biomass production. This approach is proposed to explain or predict more data than optimization theory while using no extra parameters. Thus, it can also be used to find and refine hypotheses about which constraints have shaped biological structures in evolution.
Metabolic evolution of energy-conserving pathways for succinate production in Escherichia coli
Authors: Zhang Xueli , Jantama Kaemwich , Moore Jonathan C. , Jarboe Laura R. , Shanmugam Keelnatham T. , Ingram Lonnie O.
Published: November 2009

During metabolic evolution to improve succinate production in
Escherichia coli
strains, significant changes in cellular metabolism were acquired that increased energy efficiency in two respects. The energy-conserving phosphoenolpyruvate (PEP) carboxykinase (
pck
), which normally functions in the reverse direction (gluconeogenesis; glucose repressed) during the oxidative metabolism of organic acids, evolved to become the major carboxylation pathway for succinate production. Both PCK enzyme activity and gene expression levels increased significantly in two stages because of several mutations during the metabolic evolution process. High-level expression of this enzyme-dominated CO
2
fixation and increased ATP yield (1 ATP per oxaloacetate). In addition, the native PEP-dependent phosphotransferase system for glucose uptake was inactivated by a mutation in
ptsI
. This glucose transport function was replaced by increased expression of the GalP permease (
galP
) and glucokinase (
glk
). Results of deleting individual transport genes confirmed that GalP served as the dominant glucose transporter in evolved strains. Using this alternative transport system would increase the pool of PEP available for redox balance. This change would also increase energy efficiency by eliminating the need to produce additional PEP from pyruvate, a reaction that requires two ATP equivalents. Together, these changes converted the wild-type
E. coli
fermentation pathway for succinate into a functional equivalent of the native pathway that nature evolved in succinate-producing rumen bacteria.
Making evolutionary biology a basic science for medicine
Authors: Nesse Randolph M. , Bergstrom Carl T. , Ellison Peter T. , Flier Jeffrey S. , Gluckman Peter , Govindaraju Diddahally R. , Niethammer Dietrich , Omenn Gilbert S. , Perlman Robert L. , Schwartz Mark D. , Thomas Mark G. , Stearns Stephen C. , Valle David
Published: November 2009

New applications of evolutionary biology in medicine are being discovered at an accelerating rate, but few physicians have sufficient educational background to use them fully. This article summarizes suggestions from several groups that have considered how evolutionary biology can be useful in medicine, what physicians should learn about it, and when and how they should learn it. Our general conclusion is that evolutionary biology is a crucial basic science for medicine. In addition to looking at established evolutionary methods and topics, such as population genetics and pathogen evolution, we highlight questions about why natural selection leaves bodies vulnerable to disease. Knowledge about evolution provides physicians with an integrative framework that links otherwise disparate bits of knowledge. It replaces the prevalent view of bodies as machines with a biological view of bodies shaped by evolutionary processes. Like other basic sciences, evolutionary biology needs to be taught both before and during medical school. Most introductory biology courses are insufficient to establish competency in evolutionary biology. Premedical students need evolution courses, possibly ones that emphasize medically relevant aspects. In medical school, evolutionary biology should be taught as one of the basic medical sciences. This will require a course that reviews basic principles and specific medical applications, followed by an integrated presentation of evolutionary aspects that apply to each disease and organ system. Evolutionary biology is not just another topic vying for inclusion in the curriculum; it is an essential foundation for a biological understanding of health and disease.
PHS1 regulates meiotic recombination and homologous chromosome pairing by controlling the transport of RAD50 to the nucleus
Authors: Ronceret Arnaud , Doutriaux Marie-Pascale , Golubovskaya Inna N. , Pawlowski Wojciech P.
Published: November 2009

Recombination and pairing of homologous chromosomes are critical for bivalent formation in meiotic prophase. In many organisms, including yeast, mammals, and plants, pairing and recombination are intimately interconnected. The
POOR HOMOLOGOUS SYNAPSIS1
(
PHS1
) gene acts in coordination of chromosome pairing and early recombination steps in plants, ensuring pairing fidelity and proper repair of meiotic DNA double-strand-breaks. In
phs1
mutants, chromosomes exhibit early recombination defects and frequently associate with non-homologous partners, instead of pairing with their proper homologs. Here, we show that the product of the
PHS1
gene is a cytoplasmic protein that functions by controlling transport of RAD50 from cytoplasm to the nucleus. RAD50 is a component of the MRN protein complex that processes meiotic double-strand-breaks to produce single-stranded DNA ends, which act in the homology search and recombination. We demonstrate that PHS1 plays the same role in homologous pairing in both Arabidopsis and maize, whose genomes differ dramatically in size and repetitive element content. This suggests that PHS1 affects pairing of the gene-rich fraction of the genome rather than preventing pairing between repetitive DNA elements. We propose that PHS1 is part of a system that regulates the progression of meiotic prophase by controlling entry of meiotic proteins into the nucleus. We also document that in
phs1
mutants in Arabidopsis, centromeres interact before pairing commences along chromosome arms. Centromere coupling was previously observed in yeast and polyploid wheat while our data suggest that it may be a more common feature of meiosis.
Dissecting the expression dynamics of RNA-binding proteins in posttranscriptional regulatory networks
Authors: Mittal Nitish , Roy Nilanjan , Babu M. Madan , Janga Sarath Chandra
Published: November 2009

In eukaryotic organisms, gene expression requires an additional level of coordination that links transcriptional and posttranslational processes. Messenger RNAs have traditionally been viewed as passive molecules in the pathway from transcription to translation. However, it is now clear that RNA-binding proteins (RBPs) play an important role in cellular homeostasis by controlling gene expression at the posttranscriptional level. Here, we show that RBPs, as a class of proteins, show distinct gene expression dynamics compared to other protein coding genes in the eukaryote
Sacchoromyces cerevisiae
. We find that RBPs generally exhibit high protein stability, translational efficiency, and protein abundance but their encoding transcripts tend to have a low half-life. We show that RBPs are also most often posttranslationally modified, indicating their potential for regulation at the protein level to control diverse cellular processes. Further analysis of the RBP-RNA interaction network showed that the number of distinct targets bound by an RBP (connectivity) is strongly correlated with its protein stability, translational efficiency, and abundance. We also note that RBPs show less noise in their expression in a population of cells, with highly connected RBPs showing significantly lower noise. Our results indicate that highly connected RBPs are likely to be tightly regulated at the protein level as significant changes in their expression may bring about large-scale changes in global expression levels by affecting their targets. These observations might explain the molecular basis behind the cause of a number of disorders associated with misexpression or mutation in RBPs. Future studies uncovering the posttranscriptional networks in higher eukaryotes can help our understanding of the link between different levels of regulation and their role in pathological conditions.
An adenosine nucleoside inhibitor of dengue virus
Authors: Yin Zheng , Chen Yen-Liang , Schul Wouter , Wang Qing-Yin , Gu Feng , Duraiswamy Jeyaraj , Kondreddi Ravinder Reddy , Niyomrattanakit Pornwaratt , Lakshminarayana Suresh B. , Goh Anne , Xu Hao Ying , Liu Wei , Liu Boping , Lim Joanne Y. H. , Ng Chuan Young , Qing Min , Lim Chin Chin , Yip Andy , Wang Gang , Chan Wai Ling , Tan Hui Pen , Lin Kai , Zhang Bo , Zou Gang , Bernard Kristen A. , Garrett Christine , Beltz Karen , Dong Min , Weaver Margaret , He Handan , Pichota Arkadius , Dartois Veronique , Keller Thomas H. , Shi Pei-Yong
Published: November 2009

Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections.
GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo
Authors: Hu Neng-Wei , Klyubin Igor , Anwyl Roger , Rowan Michael J.
Published: November 2009

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-β protein (Aβ) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Aβ in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Aβ
1–42
-mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFα mediates this deleterious action of Aß was provided by the ability of TNFα antagonists to prevent Aβ
1–42
inhibition of plasticity and the abrogation of a similar disruptive effect of TNFα using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFα, Aβ
1–42
did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease.
Different cross-presentation pathways in steady-state and inflammatory dendritic cells
Authors: Segura Elodie , Albiston Anthony L. , Wicks Ian P. , Chai Siew Yeen , Villadangos José A.
Published: November 2009

Presentation of exogenous antigens on MHC class I molecules, termed cross-presentation, is essential for the induction of CD8 T-cell responses and is carried out by specialized dendritic cell (DC) subsets. The mechanisms involved remain unclear. It has been proposed that antigens could be transported by endocytic receptors, such as the mannose receptor (MR) in the case of soluble ovalbumin, into early endosomes in which the cross-presentation machinery would be recruited. In these endosomal compartments, peptides would be trimmed by the aminopeptidase IRAP before loading onto MHC class I molecules. Here, we have investigated the contribution of this pathway to cross-presentation by steady-state CD8
+
DC and inflammatory monocyte-derived DC (moDC) generated in vivo. We demonstrate that IRAP and MR are dispensable for cross-presentation by CD8
+
DC and for cross-priming. Moreover, we could not find any evidence for diversion of endocytosed antigen into IRAP-containing endosomes in these cells. However, cross-presentation was impaired in moDC deficient in IRAP or MR, confirming the role of these two molecules in inflammatory DC. These results demonstrate that the mechanisms responsible for cross-priming by steady-state and inflammatory DC are different, which has important implications for vaccine design.
Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling
Authors: Pflegerl Pamina , Vesely Paul , Hantusch Brigitte , Schlederer Michaela , Zenz Rainer , Janig Elke , Steiner Günter , Meixner Arabella , Petzelbauer Peter , Wolf Peter , Soleiman Afschin , Egger Gerda , Moriggl Richard , Kishimoto Tadamitsu , Wagner Erwin F. , Kenner Lukas
Published: November 2009

Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting various tissues. Involvement of B and T cells as well as increased cytokine levels have been associated with disease manifestation. Recently, we demonstrated that mice with epidermal loss of JunB (JunB
Δep
) develop a myeloproliferative syndrome (MPS) due to high levels of G-CSF which are secreted by JunB-deficient keratinocytes. In addition, we show that JunB
Δep
mice develop a SLE phenotype linked to increased epidermal interleukin 6 (IL-6) secretion. Intercrosses with IL-6-deficient mice could rescue the SLE phenotype. Furthermore, we show that JunB binds to the IL-6 promoter and transcriptionally suppresses IL-6. Facial skin biopsies of human SLE patients similarly revealed low JunB protein expression and high IL-6, activated Stat3, Socs-1, and Socs-3 levels within lupus lesions. Thus, keratinocyte-induced IL-6 secretion can cause SLE and systemic autoimmunity. Our results support trials to use α-IL-6 receptor antibody therapy for treatment of SLE.
Enhanced dendritic activity in awake rats
Authors: Murayama Masanori , Larkum Matthew E.
Published: November 2009

Almost nothing is known about dendritic activity in awake animals and even less about its relationship to behavior. The tuft dendrites of layer 5 (L5) pyramidal neurons lie in layer 1, where long-range axons from secondary thalamic nuclei and higher cortical areas arrive. This class of input is very dependent on active thalamo-cortical loops and activity in higher brain areas and so is likely to be heavily influenced by the conscious state of the animal. If, as has been suggested, the dendrites of pyramidal neurons actively participate in this process, dendritic activity should greatly increase in the awake state. Here, we measured calcium activity in L5 pyramidal neuron dendrites using the “periscope” fiberoptic system. Recordings were made in the sensorimotor cortex of awake and anesthetized rats following sensory stimulation of the hindlimb. Bi-phasic dendritic responses evoked by hindlimb stimulation were extremely dependent on brain state. In the awake state, there was a prominent slow, delayed response whose integral was on average 14-fold larger than in the anesthetized state. Moreover, the dramatic increases in dendritic activity closely correlated to the strength of subsequent hindlimb movement. These changes were confined to L5 pyramidal dendrites and were not reflected in the response of layer 2/3 (L2/3) neurons to air-puff stimuli in general (which actually decreased in the awake state). The results demonstrate that the activity of L5 pyramidal dendrites is a neural correlate of awake behavior.
A structural basis for H-NOX signaling in
Shewanella oneidensis
by trapping a histidine kinase inhibitory conformation
Authors: Erbil W. Kaya , Price Mark S. , Wemmer David E. , Marletta Michael A.
Published: November 2009

Heme nitric oxide/oxygen (H-NOX) proteins are found in eukaryotes where they are typically part of a larger protein such as soluble guanylate cyclase and in prokaryotes where they are often found in operons with a histidine kinase, suggesting that H-NOX proteins serve as sensors for NO and O
2
in signaling pathways. The Fe(II)–NO complex of the H-NOX protein from
Shewanella oneidensis
inhibits the autophosphorylation of the operon-associated histidine kinase, whereas the ligand-free H-NOX has no effect on the kinase. NMR spectroscopy was used to determine the structures of the Fe(II)–CO complex of the
S. oneidensis
H-NOX and the Fe(II)–CO complex of the H103G H-NOX mutant as a mimic of the ligand-free and kinase-inhibitory Fe(II)–NO H-NOX, respectively. The results provide a molecular glimpse into the ligand-induced conformational changes that may underlie kinase inhibition and the subsequent control of downstream signaling.
HIV-1 Gag-specific immunity induced by a lentivector-based vaccine directed to dendritic cells
Authors: Dai Bingbing , Yang Lili , Yang Haiguang , Hu Biliang , Baltimore David , Wang Pin
Published: November 2009

Lentivectors (LVs) have attracted considerable interest for their potential as a vaccine delivery vehicle. In this study, we evaluate in mice a dendritic cell (DC)-directed LV system encoding the Gag protein of human immunodeficiency virus (HIV) (LV-Gag) as a potential vaccine for inducing an anti-HIV immune response. The DC-directed specificity is achieved through pseudotyping the vector with an engineered Sindbis virus glycoprotein capable of selectively binding to the DC-SIGN protein. A single immunization by this vector induces a durable HIV Gag-specific immune response. We investigated the antigen-specific immunity and T-cell memory generated by a prime/boost vaccine regimen delivered by either successive LV-Gag injections or a DNA prime/LV-Gag boost protocol. We found that both prime/boost regimens significantly enhance cellular and humoral immune responses. Importantly, a heterologous DNA prime/LV-Gag boost regimen results in superior Gag-specific T-cell responses as compared with a DNA prime/adenovector boost immunization. It induces not only a higher magnitude response, as measured by Gag-specific tetramer analysis and intracellular IFN-γ staining, but also a better quality of response evidenced by a wider mix of cytokines produced by the Gag-specific CD8
+
and CD4
+
T cells. A boosting immunization with LV-Gag also generates T cells reactive to a broader range of Gag-derived epitopes. These results demonstrate that this DC-directed LV immunization is a potent modality for eliciting anti-HIV immune responses.
The secondary contact phase of allopatric speciation in Darwin's finches
Authors: Grant Peter R. , Grant B. Rosemary
Published: November 2009

Speciation, the process by which two species form from one, involves the development of reproductive isolation of two divergent lineages. Here, we report the establishment and persistence of a reproductively isolated population of Darwin's finches on the small Galápagos Island of Daphne Major in the secondary contact phase of speciation. In 1981, an immigrant medium ground finch (
Geospiza fortis
) arrived on the island. It was unusually large, especially in beak width, sang an unusual song, and carried some
Geospiza scandens
alleles. We followed the fate of this individual and its descendants for seven generations over a period of 28 years. In the fourth generation, after a severe drought, the lineage was reduced to a single brother and sister, who bred with each other. From then on this lineage, inheriting unusual song, morphology, and a uniquely homozygous marker allele, was reproductively isolated, because their own descendants bred with each other and with no other member of the resident
G. fortis
population. These observations agree with some expectations of an ecological theory of speciation in that a barrier to interbreeding arises as a correlated effect of adaptive divergence in morphology. However, the important, culturally transmitted, song component of the barrier appears to have arisen by chance through an initial imperfect copying of local song by the immigrant. The study reveals additional stochastic elements of speciation, in which divergence is initiated in allopatry; immigration to a new area of a single male hybrid and initial breeding with a rare hybrid female.
Getting Disadvantaged Parents into Employment: The Working for Families Fund in Scotland
Authors: Bond Sue , McQuaid Ronald , Fuertes Vanesa
Published: November 2009

Between 2004 and 2008, the Scottish Government's Working for Families Fund (WFF) in Scotland offered support to parents seeking to move into, within or towards employment, education or training. Focused on disadvantaged parents, the programme had registered a total of over 25,000 clients by April 2008, with 66 per cent of these having achieved a significant outcome during the life of the programme. In this paper, we examine the policy background from which the WFF programme emerged. The paper outlines key features of the programme that are distinct from other programmes (particularly the New Deal for Lone Parents) as well as setting out the key outcomes of the programme. The paper identifies some lessons concerning how WFF operated, and, finally, it outlines the key conclusions.
Local Economic Development in Area-based Urban Regeneration in Germany
Authors: Weck Sabine
Published: November 2009

The article is intended to give insight into the state of the art of local economic development in area-based urban regeneration in Germany. The impor-tance of local economic development has been widely recognised and a series of workshops, evaluation reports and programmes has been initiated to promote this policy area. A set of policy programmes has been developed to support integrated action in distressed urban areas. There are no radical changes in the different programme designs, but rather subsequent adaptations and amplifications through time. Policy learning has taken place in a process cutting across all levels of government. The state of the art of local economic development is illustrated using the example of the city of Gelsenkirchen in order to see how different funding programmes on the national and/or Länder (federal states) level are applied and combined on the local level, and how they help to formulate an integrated urban renewal approach. A range of policy challenges remains. The challenges on the local level include, for example, the development of strategic capacity in designing and implementing local-economic development measures.
A Critical Review of Public Borrowing by Turkish Municipalities: 1960–2006
Authors: Yakar-Onal Aysegul
Published: November 2009

This paper offers an analysis of municipal borrowing in Turkey during 1960–2006 in two sub-periods: 1960–79 and 1980–2006. These sub-periods are distinguished from each other as different regimes of capital accumulation, taking 1980 as the breaking point. In this framework, the capital accumulation model of the import substitution era of 1960–79 is assessed in the context of the national developmental state, while the financial capital accumulation regime in the post-1980 period is studied in the context of financial globalisation. The impacts of these two regimes on the debt structures of municipalities are compared using period-specific indices of indebtedness. It is found that indebtedness in real terms increased significantly in the post-1980 sub-period, which can be attributed to the adoption of the financial capital accumulation regime.
When Motor Attention Improves Selective Attention: The Dissociating Role of Saliency
Authors: Symes Ed , Ottoboni Giovanni , Tucker Mike , Ellis Rob , Tessari Alessia
Published: November 2009

There is evidence that preparing and maintaining a motor plan (“motor attention”) can bias visual selective attention. For example, a motor attended grasp biases visual attention to select appropriately graspable object features (Symes, Tucker, Ellis, Vainio, & Ottoboni, 2008). According to the biased competition model of selective attention, the relative weightings of stimulus-driven and goal-directed factors determine selection. The current study investigated how the goal-directed bias of motor attention might operate when the stimulus-driven salience of the target was varied. Using a change detection task, two almost identical photographed scenes of simplistic graspable objects were presented flickering back and forth. The target object changed visually, and this change was either high or low salience. Target salience determined whether or not the motor attended grasp significantly biased visual selective attention. Specifically, motor attention only had a reliable influence on target detection times when the visual salience of the target was low.
Environmental context change affects memory for performed actions
Authors: Sahakyan Lili
Published: November 2009

The current study investigated the effect of environmental context change between the study and test on the recall of action phrases that either were performed during encoding (subject-performed tasks, SPTs) or were verbally encoded (verbal tasks, VTs). Both SPTs and VTs showed the same magnitude of impaired recall when the study and test contexts mismatched. Furthermore, changing the context between the two study lists reduced cross-list intrusion errors compared to encoding the lists in the same context. Both SPTs and VTs benefited from studying the lists in different contexts as evidenced by reduced intrusions. Taken together, the results suggest that SPTs are integrated with their context because they suffered when context changed between the study and test, and they also benefited when they were performed in two environments versus the same environment.
Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells
Authors: Halle Stephan , Dujardin Hélène C. , Bakocevic Nadja , Fleige Henrike , Danzer Heike , Willenzon Stefanie , Suezer Yasemin , Hämmerling Günter , Garbi Natalio , Sutter Gerd , Worbs Tim , Förster Reinhold
Published: November 2009

Mucosal vaccination via the respiratory tract can elicit protective immunity in animal infection models, but the underlying mechanisms are still poorly understood. We show that a single intranasal application of the replication-deficient modified vaccinia virus Ankara, which is widely used as a recombinant vaccination vector, results in prominent induction of bronchus-associated lymphoid tissue (BALT). Although initial peribronchiolar infiltrations, characterized by the presence of dendritic cells (DCs) and few lymphocytes, can be found 4 d after virus application, organized lymphoid structures with segregated B and T cell zones are first observed at day 8. After intratracheal application, in vitro–differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently activate antigen-specific T cells, as revealed by two-photon microscopy. Furthermore, the lung-specific depletion of DCs in mice that express the diphtheria toxin receptor under the control of the CD11c promoter interferes with BALT maintenance. Collectively, these data identify BALT as tertiary lymphoid structures supporting the efficient priming of T cell responses directed against unrelated airborne antigens while crucially requiring DCs for its sustained presence.
TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones
Authors: Hwang Il-Young , Park Chung , Harrison Kathleen , Kehrl John H.
Published: November 2009

B lymphocyte–intrinsic Toll-like receptor (TLR) signals amplify humoral immunity and can exacerbate autoimmune diseases. We identify a new mechanism by which TLR signals may contribute to autoimmunity and chronic inflammation. We show that TLR4 signaling enhances B lymphocyte trafficking into lymph nodes (LNs), induces B lymphocyte clustering and interactions within LN follicles, leads to sustained in vivo B cell proliferation, overcomes the restriction that limits the access of nonantigen-activated B cells to germinal center dark zones, and enhances the generation of memory and plasma cells. Intravital microscopy and in vivo tracking studies of B cells transferred to recipient mice revealed that TLR4-activated, but not nonstimulated, B cells accumulated within the dark zones of preexisting germinal centers even when transferred with antigen-specific B cells. The TLR4-activated cells persist much better than nonstimulated cells, expanding both within the memory and plasma cell compartments. TLR-mediated activation of B cells may help to feed and stabilize the spontaneous and ectopic germinal centers that are so commonly found in autoimmune individuals and that accompany chronic inflammation.
The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus
Authors: Zamisch Monica , Tian Linhua , Grenningloh Roland , Xiong Yumei , Wildt Kathryn F. , Ehlers Marc , Ho I-Cheng , Bosselut Rémy
Published: November 2009

The transcription factor Ets1 contributes to the differentiation of CD8 lineage cells in the thymus, but how it does so is not understood. In this study, we demonstrate that Ets1 is required for the proper termination of CD4 expression during the differentiation of major histocompatability class 1 (MHC I)–restricted thymocytes, but not for other events associated with their positive selection, including the initiation of cytotoxic gene expression, corticomedullary migration, or thymus exit. We further show that Ets1 promotes expression of Runx3, a transcription factor important for CD8 T cell differentiation and the cessation of Cd4 gene expression. Enforced Runx3 expression in Ets1-deficient MHC I–restricted thymocytes largely rescued their impaired Cd4 silencing, indicating that Ets1 is not required for Runx3 function. Finally, we document that Ets1 binds at least two evolutionarily conserved regions within the Runx3 gene in vivo, supporting the possibility that Ets1 directly contributes to Runx3 transcription. These findings identify Ets1 as a key player during CD8 lineage differentiation and indicate that it acts, at least in part, by promoting Runx3 expression.
Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity
Authors: Du Jianyang , Xie Jia , Yue Lixia
Published: November 2009

TRPM2 is a Ca2+-permeable nonselective cation channel that plays important roles in oxidative stress–mediated cell death and inflammation processes. However, how TRPM2 is regulated under physiological and pathological conditions is not fully understood. Here, we report that both intracellular and extracellular protons block TRPM2 by inhibiting channel gating. We demonstrate that external protons block TRPM2 with an IC50 of pHo = 5.3, whereas internal protons inhibit TRPM2 with an IC50 of pHi = 6.7. Extracellular protons inhibit TRPM2 by decreasing single-channel conductance. We identify three titratable residues, H958, D964, and E994, at the outer vestibule of the channel pore that are responsible for pHo sensitivity. Mutations of these residues reduce single-channel conductance, decrease external Ca2+ ([Ca2+]o) affinity, and inhibit [Ca2+]o-mediated TRPM2 gating. These results support the following model: titration of H958, D964, and E994 by external protons inhibits TRPM2 gating by causing conformation change of the channel, and/or by decreasing local Ca2+ concentration at the outer vestibule, therefore reducing [Ca2+]o permeation and inhibiting [Ca2+]o-mediated TRPM2 gating. We find that intracellular protons inhibit TRPM2 by inducing channel closure without changing channel conductance. We identify that D933 located at the C terminus of the S4-S5 linker is responsible for intracellular pH sensitivity. Replacement of Asp933 by Asn933 changes the IC50 from pHi = 6.7 to pHi = 5.5. Moreover, substitution of Asp933 with various residues produces marked changes in proton sensitivity, intracellular ADP ribose/Ca2+ sensitivity, and gating profiles of TRPM2. These results indicate that D933 is not only essential for intracellular pH sensitivity, but it is also crucial for TRPM2 channel gating. Collectively, our findings provide a novel mechanism for TRPM2 modulation as well as molecular determinants for pH regulation of TRPM2. Inhibition of TRPM2 by acidic pH may represent an endogenous mechanism governing TRPM2 gating and its physiological/pathological functions.
Powers of large random unitary matrices and Toeplitz determinants
Authors: Duits Maurice , Johansson Kurt
Published: November 2009

We study the limiting behavior of

Tr
⁡

U

k
(
n
)

\operatorname {Tr}U^{k(n)}

, where

U
U

is an

n
×
n

n\times n

random unitary matrix and

k
(
n
)

k(n)

is a natural number that may vary with

n
n

in an arbitrary way. Our analysis is based on the connection with Toeplitz determinants. The central observation of this paper is a strong Szegö limit theorem for Toeplitz determinants associated to symbols depending on

n
n

in a particular way. As a consequence of this result, we find that for each fixed

m
∈

N

m\in \mathbb {N}

, the random variables

Tr
⁡

U

k
j

(
n
)

/

min
(

k
j

(
n
)
,
n
)

\operatorname {Tr}U^{k_j(n)}/\sqrt {\min (k_j(n),n)}

,

j
=
1
,
…
,
m

j=1,\ldots ,m

, converge to independent standard complex normals.
The second closed geodesic on Finsler spheres of dimension 𝑛>2
Authors: Rademacher Hans-Bert
Published: November 2009

We show the existence of at least two geometrically distinct closed geodesics on an

n
n

-dimensional sphere with a bumpy and non-reversible Finsler metric for

n
>
2.

n > 2.
Almost all elliptic curves are Serre curves
Authors: Jones Nathan
Published: November 2009

Using a multidimensional large sieve inequality, we obtain a bound for the mean-square error in the Chebotarev theorem for division fields of elliptic curves that is as strong as what is implied by the Generalized Riemann Hypothesis. As an application we prove that, according to height, almost all elliptic curves are Serre curves, where a Serre curve is an elliptic curve whose torsion subgroup, roughly speaking, has as much Galois symmetry as possible.
Telescope conjecture, idempotent ideals, and the transfinite radical
Authors: Šťovíček Jan
Published: November 2009

We show that for an artin algebra

Λ
\Lambda

, the telescope conjecture for module categories is equivalent to certain idempotent ideals of

mod
⁡
Λ

\operatorname {mod}\Lambda

being generated by identity morphisms. As a consequence, we prove the conjecture for domestic standard selfinjective algebras and domestic special biserial algebras. We achieve this by showing that in any Krull-Schmidt category with local d.c.c. on ideals, any idempotent ideal is generated by identity maps and maps from the transfinite radical.
Dyadic-like maximal operators on integrable functions and Bellman functions related to Kolmogorov’s inequality
Authors: Melas Antonios , Nikolidakis Eleftherios
Published: November 2009

For each

q
>
1

q>1

we precisely evaluate the main Bellman functions associated with the behavior of dyadic maximal operators on

R

n

\mathbb {R}^{n}

on integrable functions. Actually we do that in the more general setting of tree-like maximal operators. These are related to and refine the corresponding Kolmogorov inequality, which we show is actually sharp. For this we use the effective linearization introduced by the first author in 2005 for such maximal operators on an adequate set of functions.
Structures having o-minimal open core
Authors: Dolich Alfred , Miller Chris , Steinhorn Charles
Published: November 2009

The open core of an expansion of a dense linear order is its reduct, in the sense of definability, generated by the collection of all of its open definable sets. In this paper, expansions of dense linear orders that have o-minimal open core are investigated, with emphasis on expansions of densely ordered groups. The first main result establishes conditions under which an expansion of a densely ordered group has an o-minimal open core. Specifically, the following is proved:

Let

R

\mathfrak R

be an expansion of a densely ordered group

(
R
,
>
,
∗
)

(R,>,*)

that is definably complete and satisfies the uniform finiteness property. Then the open core of 

R

\mathfrak R

is o-minimal.

Two examples of classes of structures that are not o-minimal yet have o-minimal open core are discussed: dense pairs of o-minimal expansions of ordered groups, and expansions of o-minimal structures by generic predicates. In particular, such structures have open core interdefinable with the original o-minimal structure. These examples are differentiated by the existence of definable unary functions whose graphs are dense in the plane, a phenomenon that can occur in dense pairs but not in expansions by generic predicates. The property of having no dense graphs is examined and related to uniform finiteness, definable completeness, and having o-minimal open core.
Weighted averages of modular 𝐿-values
Authors: Knightly Andrew , Li Charles
Published: November 2009

Using an explicit relative trace formula on

GL
⁡
(
2
)

\operatorname {GL}(2)

, we derive a formula for averages of modular

L
L

-values in the critical strip, weighting by Fourier coefficients, Hecke eigenvalues, and Petersson norms. As an application we show that a GRH holds for these averages as the weight or the level goes to

∞
\infty

. We also use the formula to give explicit zero-free regions of the form

|

Im
⁡
(
s
)

|

≤

τ
0

|\operatorname {Im}(s)|\le \tau _0

for some particular modular

L
L

-functions.
The behavior of the spectral gap under growing drift
Authors: Franke B. , Hwang C.-R. , Pai H.-M. , Sheu S.-J.
Published: November 2009

We analyze the behavior of the spectral gap of the Laplace- Beltrami operator on a compact Riemannian manifold when a divergence-free drift vector field is added. We increase the drift by multiplication with a large constant

c
c

and ask the question how the spectral gap behaves as

c
c

goes to infinity. It turns out that the spectral gap stays bounded if and only if the drift-vector field has eigenfunctions in

H
1

H^1

. In that case the spectral gaps converge and we determine the limit.
Asymptotic curvature decay and removal of singularities of Bach-flat metrics
Authors: Streets Jeffrey
Published: November 2009

We prove a removal of singularities result for Bach-flat metrics in dimension

4
4

under the assumption of bounded

L
2

L^2

-norm of curvature, bounded Sobolev constant and a volume growth bound. This result extends the removal of singularities result for special classes of Bach-flat metrics obtained by Tian and Viaclovsby. For the proof we emulate Cheeger and Tian and analyze the decay rates of solutions to the Bach-flat equation linearized around a flat metric. This classification is used to prove that Bach-flat cones are in fact ALE of order

2
2

. This result is then used to prove the removal of singularities theorem.
Orbit of the diagonal in the power of a nilmanifold
Authors: Leibman A.
Published: November 2009

Let

X
X

be a nilmanifold, that is, a compact homogeneous space of a nilpotent Lie group

G
G

, and let

a
∈
G

a\in G

. We study the closure of the orbit of the diagonal of

X

r

X^{r}

under the action

(

a

p

1

(
n
)

,
…
,

a

p

r

(
n
)

)

(a^{p_{1}(n)},\ldots ,a^{p_{r}(n)})

, where

p

i

p_{i}

are integer-valued polynomials in

m
m

integer variables. (Knowing this closure is crucial for finding limits of the form
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="limit Subscript upper N right-arrow normal infinity Baseline StartFraction 1 Over upper N Superscript m Baseline EndFraction sigma-summation Underscript n element-of left-brace 1 comma ellipsis comma upper N right-brace Superscript m Endscripts mu left-parenthesis upper T Superscript p 1 left-parenthesis n right-parenthesis Baseline upper A 1 intersection ellipsis intersection upper T Superscript p Super Subscript r Superscript left-parenthesis n right-parenthesis Baseline upper A Subscript r Baseline right-parenthesis">

lim

N
→
∞

1

N

m

∑

n
∈
{
1
,
…
,
N

}

m

μ
(

T

p

1

(
n
)

A

1

∩
…
∩

T

p

r

(
n
)

A

r

)

\hbox {lim}_{N\rightarrow \infty }\frac {1}{N^{m}}\sum _{n\in \{1,\ldots ,N\}^{m}} \mu (T^{p_{1}(n)}A_{1}\cap \ldots \cap T^{p_{r}(n)}A_{r})

, where

T
T

is a measure-preserving transformation of a finite measure space

(
Y
,
μ
)

(Y,\mu )

and

A

i

A_{i}

are subsets of

Y
Y

, and limits of the form
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="limit Subscript upper N right-arrow normal infinity Baseline StartFraction 1 Over upper N Superscript m Baseline EndFraction sigma-summation Underscript n element-of left-brace 1 comma ellipsis comma upper N right-brace Superscript m Endscripts d left-parenthesis left-parenthesis upper A 1 plus p 1 left-parenthesis n right-parenthesis right-parenthesis intersection ellipsis intersection left-parenthesis upper A Subscript r Baseline plus p Subscript r Baseline left-parenthesis n right-parenthesis right-parenthesis right-parenthesis">

lim

N
→
∞

1

N

m

∑

n
∈
{
1
,
…
,
N

}

m

d
(
(

A

1

+

p

1

(
n
)
)
∩
…
∩
(

A

r

+

p

r

(
n
)
)
)

\hbox {lim}_{N\rightarrow \infty }\frac {1}{N^{m}}\sum _{n\in \{1,\ldots ,N\}^{m}} d((A_{1}+p_{1}(n))\cap \ldots \cap (A_{r}+p_{r}(n)))

, where

A

i

A_{i}

are subsets of Z and

d
(
A
)

d(A)

is the density of

A
A

in Z.) We give a simple description of the closure of the orbit of the diagonal in the case that all

p

i

p_{i}

are linear, in the case that

G
G

is connected, and in the case that the identity component of

G
G

is commutative; in the general case our description of the orbit is not explicit.
A relative Seidel morphism and the Albers map
Authors: Hu Shengda , Lalonde François
Published: November 2009

In this note, we introduce a relative (or Lagrangian) version of the Seidel homomorphism that assigns to each homotopy class of paths in

Ham

(
M
)

\textrm {Ham}(M)

, starting at the identity and ending on the subgroup that preserves a given Lagrangian submanifold

L
L

, an element in the Floer homology of

L
L

. We show that these elements are related to the absolute Seidel elements by the Albers map. We also study, for later use, the effect of reversing the signs of the symplectic structure as well as the orientations of the generators and of the operations on the Floer homologies.
Sublethal effects of catch-and-release fishing: measuring capture stress, fish impairment, and predation risk using a condition index
Authors: Campbell Matthew D. , Patino Reynaldo , Tolan James , Strauss Richard , Diamond Sandra L.
Published: November 2009

Campbell, M. D., Patino, R., Tolan, J., Strauss, R., and Diamond, S. L. 2010. Sublethal effects of catch-and-release fishing: measuring capture stress, fish impairment, and predation risk using a condition index. – ICES Journal of Marine Science, 67: 513–521. The sublethal effects of simulated capture of red snapper (Lutjanus campechanus) were analysed using physiological responses, condition indexing, and performance variables. Simulated catch-and-release fishing included combinations of depth of capture and thermocline exposure reflective of environmental conditions experienced in the Gulf of Mexico. Frequency of occurrence of barotrauma and lack of reflex response exhibited considerable individual variation. When combined into a single condition or impairment index, individual variation was reduced, and impairment showed significant increases as depth increased and with the addition of thermocline exposure. Performance variables, such as burst swimming speed (BSS) and simulated predator approach distance (AD), were also significantly different by depth. BSSs and predator ADs decreased with increasing depth, were lowest immediately after release, and were affected for up to 15 min, with longer recovery times required as depth increased. The impairment score developed was positively correlated with cortisol concentration and negatively correlated with both BSS and simulated predator AD. The impairment index proved to be an efficient method to estimate the overall impairment of red snapper in the laboratory simulations of capture and shows promise for use in field conditions, to estimate release mortality and vulnerability to predation.
Getting a Better Grip on Research: A Simple System that Works
Authors: Maskrey Neal , Underhill Jonathan , Hutchinson Andy , Shaughnessy Allen , Slawson Dave
Published: November 2009

This is the third paper in a series of five describing the use of evidence to support decisions made in clinical practice.
Enumerating periodic patterns of synchrony via finite bidirectional networks
Authors: Dias Ana Paula S. , Pinho Eliana Manuel
Published: November 2009

Periodic patterns of synchrony are lattice networks whose cells are coloured according to a local rule, or balanced colouring, and such that the overall system has spatial periodicity. These patterns depict the finite-dimensional flow-invariant subspaces for all the lattice dynamical systems, in the given lattice network, that exhibit those periods. Previous results relate the existence of periodic patterns of synchrony, in
n
-dimensional Euclidean lattice networks with nearest neighbour coupling architecture, with that of finite coupled cell networks that follow the same colouring rule and have all the couplings bidirectional. This paper addresses the relation between periodic patterns of synchrony and finite bidirectional coloured networks. Given an
n
-dimensional Euclidean lattice network with nearest neighbour coupling architecture, and a colouring rule with
k
colours, we enumerate all the periodic patterns of synchrony generated by a given finite network, or graph. This enumeration is constructive and based on the automorphisms group of the graph.