bluuebunny/crossref_metadata_2025 huggingface dataset:
Mathematical Skills in 3- and 5-Year-Olds with Spina Bifida and Their Typically Developing Peers: A Longitudinal Approach
Authors: Barnes Marcia A. , Stubbs Allison , Raghubar Kimberly P. , Agostino Alba , Taylor Heather , Landry Susan , Fletcher Jack M. , Smith-Chant Brenda
Published: March 2011

Preschoolers with spina bifida (SB) were compared to typically developing (TD) children on tasks tapping mathematical knowledge at 36 months (n = 102) and 60 months of age (n = 98). The group with SB had difficulty compared to TD peers on all mathematical tasks except for transformation on quantities in the subitizable range. At 36 months, vocabulary knowledge, visual–spatial, and fine motor abilities predicted achievement on a measure of informal math knowledge in both groups. At 60 months of age, phonological awareness, visual–spatial ability, and fine motor skill were uniquely and differentially related to counting knowledge, oral counting, object-based arithmetic skills, and quantitative concepts. Importantly, the patterns of association between these predictors and mathematical performance were similar across the groups. A novel finding is that fine motor skill uniquely predicted object-based arithmetic abilities in both groups, suggesting developmental continuity in the neurocognitive correlates of early object-based and later symbolic arithmetic problem solving. Models combining 36-month mathematical ability and these language-based, visual–spatial, and fine motor abilities at 60 months accounted for considerable variance on 60-month informal mathematical outcomes. Results are discussed with reference to models of mathematical development and early identification of risk in preschoolers with neurodevelopmental disorder. (JINS, 2011, 17, 431–444)
Disruption of Emotion and Conflict Processing in HIV Infection with and without Alcoholism Comorbidity
Authors: Schulte Tilman , Müller-Oehring Eva M. , Sullivan Edith V. , Pfefferbaum Adolf
Published: March 2011

Alcoholism and HIV-1 infection each affect components of selective attention and cognitive control that may contribute to deficits in emotion processing based on closely interacting fronto-parietal attention and frontal-subcortical emotion systems. Here, we investigated whether patients with alcoholism, HIV-1 infection, or both diseases have greater difficulty than healthy controls in resolving conflict from emotional words with different valences. Accordingly, patients with alcoholism (ALC,n= 20), HIV-1 infection (HIV,n= 20), ALC + HIV comorbidity (n= 22), and controls (CTL,n= 16) performed an emotional Stroop Match-to-Sample task, which assessed the contribution of emotion (happy, angry) to cognitive control (Stroop conflict processing). ALC + HIV showed greater Stroop effects than HIV, ALC, or CTL for negative (ANGRY) but not for positive (HAPPY) words, and also when the cue color did not match the Stroop stimulus color; the comorbid group performed similarly to the others when cue and word colors matched. Furthermore, emotionally salient face cues prolonged color-matching responses in all groups. HIV alone, compared with the other three groups, showed disproportionately slowed color-matching time when trials featured angry faces. The enhanced Stroop effects prominent in ALC + HIV suggest difficulty in exercising attentional top-down control on processes that consume attentional capacity, especially when cognitive effort is required to ignore negative emotions. (JINS, 2011,17, 537–550)
A NOTE ON BUNDLE GERBES AND INFINITE-DIMENSIONALITY
Authors: MURRAY MICHAEL , STEVENSON DANNY
Published: March 2011

Let (P,Y ) be a bundle gerbe over a fibre bundle Y →M. We show that if M is simply connected and the fibres of Y →M are connected and finite-dimensional, then the Dixmier–Douady class of (P,Y ) is torsion. This corrects and extends an earlier result of the first author.
The Keele Congress of 1967: A Paradigm Shift in Anglican Evangelical Attitudes
Authors: Atherstone Andrew
Published: March 2011

The National Evangelical Anglican Congress which took place at Keele University in April 1967 is widely acknowledged as a major watershed for the evangelical movement in the Church of England. This paper offers a fresh analysis of the event, based on detailed archival research. It argues that there was a decisive attitudinal shift at the congress, driven especially by the younger generation – from piety to policy, conservatism to radicalism, homogeneity to diversity, and exclusivism to ecumenism. It shows how in these four areas the Keele Congress established a new agenda for Anglican evangelicalism, a legacy which still continues today.
60 GHz short-range communications: channel measurements, analysis, and modeling
Authors: Garcia Ariza Alexis Paolo , Trautwein Uwe , Müller Robert , Wollenschläger Frank , Thomä Reiner S. , Kunisch Jürgen , de la Torre Itziar , Felbecker Robert , Peter Michael , Keusgen Wilhelm
Published: March 2011

This article presents measurement and analysis results for 60 GHz short-range wideband radio channels. We consider two scenarios, referred to as “very-high-rate extended-range” (VHR-E) and “ultra-high-rate cordless” (UHR-C). The VHR-E measurements aimed at 60 GHz fixed networks for an Airbus A340 cabin both under static and dynamic (shadowing due to passenger movement) channel conditions. We describe the channel sounder used for the VHR-E measurements and present a simple multipath model derived from the measurements. Furthermore, simulations show the feasibility of the ray-tracing approach for this kind of channel. As a typical UHR-C use case, a data kiosk scenario was investigated. Various propagation conditions are analyzed with respect to channel gain, time dispersion, and frequency selectivity.
siRNA‐induced immunostimulation through TLR7 promotes antitumoral activity against HPV‐driven tumors in vivo
Authors: Khairuddin Norliana , Gantier Michael P , Blake Stephen J , Wu Sherry Y , Behlke Mark A , Williams Bryan RG , McMillan Nigel AJ
Published: March 2011

Oncogene‐specific downregulation mediated by RNA interference (RNAi) is a promising avenue for cancer therapy. In addition to specific gene silencing, in vivo RNAi treatment with short interfering RNAs (siRNAs) can initiate immune activation through innate immune receptors including Toll‐like receptors, (TLRs) 7 and 8. Two recent studies have shown that activation of innate immunity by addition of tri‐phosphate motifs to oncogene‐specific siRNAs, or by co‐treatment with CpG oligos, can potentiate siRNA antitumor effects. To date, there are no reports on applying such approach against human papillomavirus (HPV)‐driven cancers. Here, we characterized the antitumor effects of non‐modified siRNAs that can target a specific oncogene and/or recruit the innate immune system against HPV‐driven tumors. Following the characterization of silencing efficacy and TLR7 immunostimulatory potential of 15 siRNAs targeting the HPV type 16 E6/E7 oncogenes, we identified a bifunctional siRNA sequence that displayed both potent gene silencing and active immunostimulation effect. In vivo systemic administration of this siRNA resulted in reduced growth of established TC‐1 tumors in C57BL/6 mice. Ablation of TLR7 recruitment via 2′O‐methyl modification of the oligo backbone reduced these antitumor effects. Further, a highly immunostimulatory, but non‐HPV targeting siRNA was also able to exert antitumoral effects although for less prolonged time compared with the bifunctional siRNA. Collectively, our work demonstrates for the first time that siRNA‐induced immunostimulation can have antitumoral effects against HPV‐driven tumors in vivo, even independent of gene silencing efficacy.
Distinctive properties of Arabidopsis SUMO paralogues support the in vivo predominant role of AtSUMO1/2 isoforms
Authors: Castaño-Miquel Laura , Seguí Josep , Lois L. Maria
Published: March 2011

Protein modification by SUMO (small ubiquitin-related modifier) has emerged as an essential regulatory mechanism in eukaryotes. Even though the molecular mechanisms of SUMO conjugation/deconjugation are conserved, the number of SUMO machinery components and their degree of conservation are specific to each organism. In the present paper, we show data contributing to the notion that the four expressed Arabidopsis SUMO paralogues, AtSUMO1, 2, 3 and 5, have functionally diverged to a higher extent than their human orthologues. We have explored the degree of conservation of these paralogues and found that the surfaces involved in E1-activating enzyme recognition, and E2-conjugating enzyme and SIM (SUMO-interacting motif) non-covalent interactions are well conserved in AtSUMO1/2 isoforms, whereas AtSUMO3 shows a lower degree of conservation, and AtSUMO5 is the most divergent isoform. These differences are functionally relevant, since AtSUMO3 and 5 are deficient in establishing E2 non-covalent interactions, which has not been reported for any naturally occurring SUMO orthologue. In addition, AtSUMO3 is less efficiently conjugated than AtSUMO1/2, and AtSUMO5 shows the lowest conjugation level. A mutagenesis analysis revealed that decreases in conjugation rate and thioester-bond formation are the result of the non-conserved residues involved in E1-activating enzyme recognition that are present in AtSUMO3 and 5. The results of the present study support a role for the E1-activating enzyme in SUMO paralogue discrimination, providing a new mechanism to favour conjugation of the essential AtSUMO1/2 paralogues.
Slow skeletal muscle myosin-binding protein-C (MyBPC1) mediates recruitment of muscle-type creatine kinase (CK) to myosin
Authors: Chen Zhe , Zhao Tong-Jin , Li Jie , Gao Yan-Song , Meng Fan-Guo , Yan Yong-Bin , Zhou Hai-Meng
Published: March 2011

Muscle contraction requires high energy fluxes, which are supplied by MM-CK (muscle-type creatine kinase) which couples to the myofibril. However, little is known about the detailed molecular mechanisms of how MM-CK participates in and is regulated during muscle contraction. In the present study, MM-CK is found to physically interact with the slow skeletal muscle-type MyBPC1 (myosin-binding protein C1). The interaction between MyBPC1 and MM-CK depended on the creatine concentration in a dose-dependent manner, but not on ATP, ADP or phosphocreatine. The MyBPC1–CK interaction favoured acidic conditions, and the two molecules dissociated at above pH 7.5. Domain-mapping experiments indicated that MM-CK binds to the C-terminal domains of MyBPC1, which is also the binding site of myosin. The functional coupling of myosin, MyBPC1 and MM-CK is further corroborated using an ATPase activity assay in which ATP expenditure accelerates upon the association of the three proteins, and the apparent Km value of myosin is therefore reduced. The results of the present study suggest that MyBPC1 acts as an adaptor to connect the ATP consumer (myosin) and the regenerator (MM-CK) for efficient energy metabolism and homoeostasis.
Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney
Authors: Pearce Laura R. , Sommer Eeva M. , Sakamoto Kei , Wullschleger Stephan , Alessi Dario R.
Published: March 2011

The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth and is a key target for therapeutic intervention in cancer. Two complexes of mTOR have been identified: complex 1 (mTORC1), consisting of mTOR, Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1 or Protor-2. Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members: mTORC1 phosphorylates S6K (S6 kinase), whereas mTORC2 regulates phosphorylation of Akt, PKCα (protein kinase Cα) and SGK1 (serum- and glucocorticoid-induced protein kinase 1). To investigate the roles of the Protor isoforms, we generated single as well as double Protor-1- and Protor-2-knockout mice and studied how activation of known mTORC2 substrates was affected. We observed that loss of Protor-1 and/or Protor-2 did not affect the expression of the other mTORC2 components, nor their ability to assemble into an active complex. Moreover, Protor knockout mice display no defects in the phosphorylation of Akt and PKCα at their hydrophobic or turn motifs. Strikingly, we observed that Protor-1 knockout mice displayed markedly reduced hydrophobic motif phosphorylation of SGK1 and its physiological substrate NDRG1 (N-Myc downregulated gene 1) in the kidney. Taken together, these results suggest that Protor-1 may play a role in enabling mTORC2 to efficiently activate SGK1, at least in the kidney.
RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation
Authors: Kim Jung Ha , Kim Kabsun , Youn Bang Ung , Jin Hye Mi , Kim Ji-Young , Moon Jang Bae , Ko Aeran , Seo Sang-Beom , Lee Kwang-Youl , Kim Nacksung
Published: March 2011

NFATc1 (nuclear factor of activated T-cells c1), a key transcription factor, plays a role in regulating expression of osteoclast-specific downstream target genes such as TRAP (tartrate-resistant acid phosphatase) and OSCAR (osteoclast-associated receptor). It has been shown that RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] induces NFATc1 expression during osteoclastogenesis at a transcriptional level. In the present study, we demonstrate that RANKL increases NFATc1 protein levels by post-translational modification. RANKL stimulates NFATc1 acetylation via HATs (histone acetyltransferases), such as p300 and PCAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor], thereby stabilizing NFATc1 proteins. PCAF physically interacts with NFATc1 and directly induces NFATc1 acetylation and stability, subsequently increasing the transcriptional activity of NFATc1. In addition, RANKL-mediated NFATc1 acetylation is increased by the HDAC (histone deacetylase) inhibitors sodium butyrate and scriptaid. Overexpression of HDAC5 reduces RANKL- or PCAF-mediated NFATc1 acetylation, stability and transactivation activity, suggesting that the balance between HAT and HDAC activities might play a role in the regulation of NFATc1 levels. Furthermore, RANKL and p300 induce PCAF acetylation and stability, thereby enhancing the transcriptional activity of NFATc1. Down-regulation of PCAF by siRNA (small interfering RNA) decreases NFATc1 acetylation and stability, as well as RANKL-induced osteoclastogenesis. Taken together, the results of the present study demonstrate that RANKL induces HAT-mediated NFATc1 acetylation and stability, and subsequently increases the transcriptional activity of NFATc1 during osteoclast differentiation.
Glucan particles for selective delivery of siRNA to phagocytic cells in mice
Authors: Tesz Gregory J. , Aouadi Myriam , Prot Matthieu , Nicoloro Sarah M. , Boutet Emilie , Amano Shinya U. , Goller Anca , Wang Mengxi , Guo Chang-An , Salomon William E. , Virbasius Joseph V. , Baum Rebecca A. , O'Connor Mark J. , Soto Ernesto , Ostroff Gary R. , Czech Michael P.
Published: March 2011

Phagocytic macrophages and dendritic cells are desirable targets for potential RNAi (RNA interference) therapeutics because they often mediate pathogenic inflammation and autoimmune responses. We recently engineered a complex 5 component glucan-based encapsulation system for siRNA (small interfering RNA) delivery to phagocytes. In experiments designed to simplify this original formulation, we discovered that the amphipathic peptide Endo-Porter forms stable nanocomplexes with siRNA that can mediate potent gene silencing in multiple cell types. In order to restrict such gene silencing to phagocytes, a method was developed to entrap siRNA–Endo-Porter complexes in glucan shells of 2–4 μm diameter in the absence of other components. The resulting glucan particles containing fluorescently labelled siRNA were readily internalized by macrophages, but not other cell types, and released the labelled siRNA into the macrophage cytoplasm. Intraperitoneal administration of such glucan particles containing siRNA–Endo-Porter complexes to mice caused gene silencing specifically in macrophages that internalized the particles. These results from the present study indicate that specific targeting to phagocytes is mediated by the glucan, whereas Endo-Porter peptide serves both to anchor siRNA within glucan particles and to catalyse escape of siRNA from phagosomes. Thus we have developed a simplified siRNA delivery system that effectively and specifically targets phagocytes in culture or in intact mice.
Combination of Poly I:C and arsenic trioxide triggers apoptosis synergistically via activation of TLR3 and mitochondrial pathways in hepatocellular carcinoma cells
Authors: Shen Peng , Jiang Tingwang , Lu Huiqi , Han Huanxing , Luo Rongcheng
Published: March 2011

Poly I:C (polyinosinic acid:polycytidylic acid), an analogue of dsRNA (double‐stranded RNA), can lead to apoptosis in human cancer cells and has been used as an adjuvant to treat cancer patients. ATO (arsenic trioxide) is used effectively in the treatment of HCC (hepatocellular carcinoma). We sought to evaluate whether Poly I:C could enhance the potentiation of ATO in HCC. Combination of Poly I:C and ATO synergistically inhibited the growth of SMMC‐7721 cells. Treatment with Poly I:C alone or combined with ATO‐activated TLR3 (Toll‐like receptor 3) pathway, increased ROS (reactive oxygen species) generation and mitochondrial dysfunction. The combined treatment also caused caspase‐3, −8, −9 activation. Moreover, the combined therapy caused Bcl‐2 and survivin down‐regulation, Bax up‐regulation and Bid activation. In conclusion, the Poly I:C and ATO combination is potentially a novel and effective approach for the treatment of HCC.
Hepatic stellate cells stimulate HCC cell migration via laminin-5 production
Authors: Santamato Angela , Fransvea Emilia , Dituri Francesco , Caligiuri Alessandra , Quaranta Michele , Niimi Tomoaki , Pinzani Massimo , Antonaci Salvatore , Giannelli Gianluigi
Published: March 2011

Activated HSCs (hepatic stellate cells) are the main source of extracellular matrix proteins present in cirrhotic liver on which HCC (hepatocellular carcinoma) commonly develops. HCC cells behave differently according to differences in the surrounding microenvironment. In the present study, we have investigated a mechanism whereby HSCs modulate the migratory activity of HCC cells. We used primary cultures of human HSCs to investigate their effect on Hep3B, Alexander, HLE and HLF HCC cells. The expression of Ln-5 (laminin-5) was documented at transcript and protein levels both in vitro and in vivo. HCC cells strongly adhere, migrate and spread in the presence of HSC-conditioned medium and of co-culture. HSCs produce and secrete Ln-5 in the CM (conditioned medium). The electrophoretic pattern of secreted Ln-5 is consistent with that of a migratory substrate, showing the presence of the γ2x fragment. Blocking antibodies against Ln-5 inhibit HCC migration in the presence of HSC-CM. HCC cells migrate very poorly in the presence of Ln-5 immunodepleted HSC-CM. HCC migration in the presence of HSCs is dependent on the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathway, but not the PI3K (phosphoinositide 3-kinase)/Akt pathway. HSC-CM, as well as Ln-5, activates the MEK/ERK but not the PI3K/Akt pathway. In human HCC tissues, Ln-5 is mainly distributed along α-SMA (smooth muscle actin)-positive cells, whereas in peritumoural tissues, Ln-5 is absent. HSCs stimulate HCC migration via the production and secretion of Ln-5.
An Accretion-Disc Model for the Algol-Type Eclipsing Binary System AV Del
Authors: Ghoreyshi S. M. R. , Ghanbari J. , Salehi F.
Published: March 2011

This study inspects the light and radial-velocity curves of the eclipsing binary AV Del. In comparison with other studies already done, the study shows that the absolute elements, fundamental orbital and physical parameters of the system can be determined using the Wilson-Devinney code. Using these parameters, the configuration of the system is presented. Then, an accretion disc model for the system is introduced by using the shellspec code. The results indicate that AV Del is a semi-detached system in which an optically thick accretion disc is surrounding the primary star. The outer radius of the disc is 8.0 R⊙, corresponding to a distance of 1.1 R⊙ from the surface of the secondary. Also, the temperature of the disc is calculated to be T = 5700 K.
Growth, geometry, and mechanics of a blooming lily
Authors: Liang Haiyi , Mahadevan L.
Published: March 2011

Despite the common use of the blooming metaphor, its floral inspiration remains poorly understood. Here we study the physical process of blooming in the asiatic lily
Lilium casablanca
. Our observations show that the edges of the petals wrinkle as the flower opens, suggesting that differential growth drives the deployment of these laminar shell-like structures. We use a combination of surgical manipulations and quantitative measurements to confirm this hypothesis and provide a simple theory for this change in the shape of a doubly curved thin elastic shell subject to differential growth across its planform. Our experiments and theory overturn previous hypotheses that suggest that blooming is driven by differential growth of the inner layer of the petals and in the midrib by providing a qualitatively different paradigm that highlights the role of edge growth. This functional morphology suggests new biomimetic designs for deployable structures using boundary or edge actuation rather than the usual bulk or surface actuation.
Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines
Authors: Flatz Lukas , Roychoudhuri Rahul , Honda Mitsuo , Filali-Mouhim Abdelali , Goulet Jean-Philippe , Kettaf Nadia , Lin Min , Roederer Mario , Haddad Elias K. , Sékaly Rafick P. , Nabel Gary J.
Published: March 2011

CD8 T cells play a key role in mediating protective immunity against selected pathogens after vaccination. Understanding the mechanism of this protection is dependent upon definition of the heterogeneity and complexity of cellular immune responses generated by different vaccines. Here, we identify previously unrecognized subsets of CD8 T cells based upon analysis of gene-expression patterns within single cells and show that they are differentially induced by different vaccines. Three prime-boost vector combinations encoding HIV
Env
stimulated antigen-specific CD8 T-cell populations of similar magnitude, phenotype, and functionality. Remarkably, however, analysis of single-cell gene-expression profiles enabled discrimination of a majority of central memory (CM) and effector memory (EM) CD8 T cells elicited by the three vaccines. Subsets of T cells could be defined based on their expression of
Eomes
,
Cxcr3
, and
Ccr7
, or
Klrk1
,
Klrg1
, and
Ccr5
in CM and EM cells, respectively. Of CM cells elicited by DNA prime-recombinant adenoviral (rAd) boost vectors, 67% were
Eomes
−

Ccr7
+
Cxcr3

−
, in contrast to only 7% and 2% stimulated by rAd5-rAd5 or rAd-LCMV, respectively. Of EM cells elicited by DNA-rAd, 74% were
Klrk1
−

Klrg1
−
Ccr5
−

compared with only 26% and 20% for rAd5-rAd5 or rAd5-LCMV. Definition by single-cell gene profiling of specific CM and EM CD8 T-cell subsets that are differentially induced by different gene-based vaccines will facilitate the design and evaluation of vaccines, as well as enable our understanding of mechanisms of protective immunity.
Stearoyl-acyl carrier protein desaturases are associated with floral isolation in sexually deceptive orchids
Authors: Schlüter Philipp M. , Xu Shuqing , Gagliardini Valeria , Whittle Edward , Shanklin John , Grossniklaus Ueli , Schiestl Florian P.
Published: March 2011

The orchids
Ophrys sphegodes
and
O. exaltata
are reproductively isolated from each other by the attraction of two different, highly specific pollinator species. For pollinator attraction, flowers chemically mimic the pollinators’ sex pheromones, the key components of which are alkenes with different double-bond positions. This study identifies genes likely involved in alkene biosynthesis, encoding stearoyl-acyl carrier protein (ACP) desaturase (SAD) homologs. The expression of two isoforms,
SAD1
and
SAD2
, is flower-specific and broadly parallels alkene production during flower development.
SAD2
shows a significant association with alkene production, and in vitro assays show that
O. sphegodes
SAD2 has activity both as an 18:0-ACP Δ
9
and a 16:0-ACP Δ
4
desaturase. Downstream metabolism of the SAD2 reaction products would give rise to alkenes with double-bonds at position 9 or position 12, matching double-bond positions observed in alkenes in the odor bouquet of
O. sphegodes
.
SAD1
and
SAD2
show evidence of purifying selection before, and positive or relaxed purifying selection after gene duplication. By contributing to the production of species-specific alkene bouquets, SAD2 is suggested to contribute to differential pollinator attraction and reproductive isolation among these species. Taken together, these data are consistent with the hypothesis that
SAD2
is a florally expressed barrier gene of large phenotypic effect and, possibly, a genic target of pollinator-mediated selection.
Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis
Authors: Karalay Özlem , Doberauer Kathrin , Vadodaria Krishna C. , Knobloch Marlen , Berti Lucia , Miquelajauregui Amaya , Schwark Manuela , Jagasia Ravi , Taketo Makoto M. , Tarabykin Victor , Lie D. Chichung , Jessberger Sebastian
Published: March 2011

Neural stem cells (NSCs) generate new granule cells throughout life in the mammalian hippocampus. Canonical Wnt signaling regulates the differentiation of NSCs towards the neuronal lineage. Here we identified the prospero-related homeodomain transcription factor Prox1 as a target of β-catenin–TCF/LEF signaling in vitro and in vivo. Prox1 overexpression enhanced neuronal differentiation whereas shRNA-mediated knockdown of Prox1 impaired the generation of neurons in vitro and within the hippocampal niche. In contrast, Prox1 was not required for survival of adult-generated granule cells after they had matured, suggesting a role for Prox1 in initial granule cell differentiation but not in the maintenance of mature granule cells. The data presented here characterize a molecular pathway from Wnt signaling to a transcriptional target leading to granule cell differentiation within the adult brain and identify a stage-specific function for Prox1 in the process of adult neurogenesis.
AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress
Authors: Williams Tyisha , Courchet Julien , Viollet Benoit , Brenman Jay E. , Polleux Franck
Published: March 2011

Mammalian brain connectivity requires the coordinated production and migration of billions of neurons and the formation of axons and dendrites. The LKB1/Par4 kinase is required for axon formation during cortical development in vivo partially through its ability to activate SAD-A/B kinases. LKB1 is a master kinase phosphorylating and activating at least 11 other serine/threonine kinases including the metabolic sensor AMP-activated protein kinase (AMPK), which defines this branch of the kinome. A recent study using a gene-trap allele of the β1 regulatory subunit of AMPK suggested that AMPK catalytic activity is required for proper brain development including neurogenesis and neuronal survival. We used a genetic loss-of-function approach producing AMPKα1/α2-null cortical neurons to demonstrate that AMPK catalytic activity is not required for cortical neurogenesis, neuronal migration, polarization, or survival. However, we found that application of metformin or AICAR, potent AMPK activators, inhibit axogenesis and axon growth in an AMPK-dependent manner. We show that inhibition of axon growth mediated by AMPK overactivation requires TSC1/2-mediated inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. Our results demonstrate that AMPK catalytic activity is not required for early neural development in vivo but its overactivation during metabolic stress impairs neuronal polarization in a mTOR-dependent manner.
Genetic basis of eye and pigment loss in the cave crustacean,
Asellus aquaticus
Authors: Protas Meredith E. , Trontelj Peter , Patel Nipam H.
Published: March 2011

Understanding the process of evolution is one of the great challenges in biology. Cave animals are one group with immense potential to address the mechanisms of evolutionary change. Amazingly, similar morphological alterations, such as enhancement of sensory systems and the loss of eyes and pigmentation, have evolved multiple times in a diverse assemblage of cave animals. Our goal is to develop an invertebrate model to study cave evolution so that, in combination with a previously established vertebrate cave system, we can address genetic questions concerning evolutionary parallelism and convergence. We chose the isopod crustacean,
Asellus aquaticus
, and generated a genome-wide linkage map for this species. Our map, composed of 117 markers, of which the majority are associated with genes known to be involved in pigmentation, eye, and appendage development, was used to identify loci of large effect responsible for several pigmentation traits and eye loss. Our study provides support for the prediction that significant morphological change can be mediated through one or a few genes. Surprisingly, we found that within population variability in eye size occurs through multiple mechanisms; eye loss has a different genetic basis than reduced eye size. Similarly, again within a population, the phenotype of albinism can be achieved by two different genetic pathways—either by a recessive genotype at one locus or doubly recessive genotypes at two other loci. Our work shows the potential of
Asellus
for studying the extremes of parallel and convergent evolution—spanning comparisons within populations to comparisons between vertebrate and arthropod systems.
Modification of deeply buried hydrophobic interfaces by ionic surfactants
Authors: Tamam Lilach , Pontoni Diego , Sapir Zvi , Yefet Shai , Sloutskin Eli , Ocko Benjamin M. , Reichert Harald , Deutsch Moshe
Published: March 2011

Hydrophobicity, the spontaneous segregation of oil and water, can be modified by surfactants. The way this modification occurs is studied at the oil–water interface for a range of alkanes and two ionic surfactants. A liquid interfacial monolayer, consisting of a mixture of alkane molecules and surfactant tails, is found. Upon cooling, it freezes atTs, well above the alkane’s bulk freezing temperature,Tb. The monolayer’s phase diagram, derived by surface tensiometry, is accounted for by a mixtures-based theory. The monolayer’s structure is measured by high-energy X-ray reflectivity above and belowTs. A solid–solid transition in the frozen monolayer, occurring approximately 3 °C belowTs, is discovered and tentatively suggested to be a rotator-to-crystal transition.
Dendritic cell chemotaxis in 3D under defined chemokine gradients reveals differential response to ligands CCL21 and CCL19
Authors: Haessler Ulrike , Pisano Marco , Wu Mingming , Swartz Melody A.
Published: March 2011

Dendritic cell (DC) homing to the lymphatics and positioning within the lymph node is important for adaptive immunity, and is regulated by gradients of CCL19 and CCL21, ligands for CCR7. Despite the importance of DC chemotaxis, it is not well understood how DCs interpret gradients of these chemokines in a complex 3D microenvironment. Here, we use a microfluidic device that allows rapid establishment of stable gradients in 3D matrices to show that DC chemotaxis in 3D can respond to CCR7 ligand gradients as small as 0.4%, which helps explain how DCs sense lymphatic vessels in an environment where broadcast distance for chemokine diffusion is hindered by convective flows into the vessel. Interestingly, DCs displayed similar sensitivities to both chemokines at small gradients (≤ 60 nM/mm), but migrated more efficiently towards higher gradients of CCL21, which unlike CCL19 binds strongly to matrix proteoglycans and signals without the need for internalization. Furthermore, cells preferentially migrated towards CCL21 when exposed to equal and opposite gradients of CCL21 and CCL19 simultaneously, even when matrix-binding of CCL21 was prevented. Although these ligands have similar binding affinity to CCR7, our results demonstrate that, in a 3D environment, CCL21 is a more potent directional cue for DC migration than CCL19. These findings provide new quantitative insight into DC chemotaxis in a physiological 3D environment and suggest how CCL19 and CCL21 may signal differently to fine-tune DC homing and positioning within the lymphatic system. These results also have broad relevance to other systems of cell chemotaxis, which remain poorly understood in the 3D context.
Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance
Authors: Kobayashi Naoki , Ueki Kohjiro , Okazaki Yukiko , Iwane Aya , Kubota Naoto , Ohsugi Mitsuru , Awazawa Motoharu , Kobayashi Masatoshi , Sasako Takayoshi , Kaneko Kazuma , Suzuki Miho , Nishikawa Yoshitaka , Hara Kazuo , Yoshimura Kotaro , Koshima Isao , Goyama Susumu , Murakami Koji , Sasaki Junko , Nagai Ryozo , Kurokawa Mineo , Sasaki Takehiko , Kadowaki Takashi
Published: March 2011

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (

Pik3cg
−/−

), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese

Pik3cg
−/−

mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.
Potential social interactions are important to social attention
Authors: Laidlaw Kaitlin E. W. , Foulsham Tom , Kuhn Gustav , Kingstone Alan
Published: March 2011

Social attention, or how spatial attention is allocated to biologically relevant stimuli, has typically been studied using simplistic paradigms that do not provide any opportunity for social interaction. To study social attention in a complex setting that affords social interaction, we measured participants’ looking behavior as they were sitting in a waiting room, either in the presence of a confederate posing as another research participant, or in the presence of a videotape of the same confederate. Thus, the potential for social interaction existed only when the confederate was physically present. Although participants frequently looked at the videotaped confederate, they seldom turned toward or looked at the live confederate. Ratings of participants’ social skills correlated with head turns to the live, but not videotaped, confederate. Our results demonstrate the importance of studying social attention within a social context, and suggest that the mere opportunity for social interaction can alter social attention.
Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling
Authors: Chen Shih-Yu , Huang Pei-Hsin , Cheng Hwai-Jong
Published: March 2011

Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and well-characterized
Caenorhabditis elegans
motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in
C. elegans
motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function
rac
genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in
C. elegans
motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.
Updated chronology for the Miocene hominoid radiation in Western Eurasia
Authors: Casanovas-Vilar Isaac , Alba David M. , Garcés Miguel , Robles Josep M. , Moyà-Solà Salvador
Published: March 2011

Extant apes (Primates: Hominoidea) are the relics of a group that was much more diverse in the past. They originated in Africa around the Oligocene/Miocene boundary, but by the beginning of the Middle Miocene they expanded their range into Eurasia, where they experienced a far-reaching evolutionary radiation. A Eurasian origin of the great ape and human clade (Hominidae) has been favored by several authors, but the assessment of this hypothesis has been hampered by the lack of accurate datings for many Western Eurasian hominoids. Here we provide an updated chronology that incorporates recently discovered Iberian taxa and further reevaluates the age of many previously known sites on the basis of local biostratigraphic scales and magnetostratigraphic data. Our results show that identifiable Eurasian kenyapithecins (GriphopithecusandKenyapithecus) are much younger than previously thought (ca. 14 Ma instead of 16 Ma), which casts serious doubts on the attribution of the hominoid tooth from Engelswies (16.3–16.5 Ma) to cf.Griphopithecus. This evidence is further consistent with an alternative scenario, according to which the Eurasian pongines and African hominines might have independently evolved in their respective continents from similar kenyapithecin ancestors, resulting from an early Middle Miocene intercontinental range extension followed by vicariance. This hypothesis, which would imply an independent origin of orthogrady in pongines and hominines, deserves further testing by accurately inferring the phylogenetic position of European dryopithecins, which might be stem pongines rather than stem hominines.
An evolutionary process that assembles phenotypes through space rather than through time
Authors: Shine Richard , Brown Gregory P. , Phillips Benjamin L.
Published: March 2011

In classical evolutionary theory, traits evolve because they facilitate organismal survival and/or reproduction. We discuss a different type of evolutionary mechanism that relies upon differential dispersal. Traits that enhance rates of dispersal inevitably accumulate at expanding range edges, and assortative mating between fast-dispersing individuals at the invasion front results in an evolutionary increase in dispersal rates in successive generations. This cumulative process (which we dub “spatial sorting”) generates novel phenotypes that are adept at rapid dispersal, irrespective of how the underlying genes affect an organism's survival or its reproductive success. Although the concept is not original with us, its revolutionary implications for evolutionary theory have been overlooked. A range of biological phenomena (e.g., acceleration of invasion fronts, insular flightlessness, preadaptation) may have evolved via spatial sorting as well as (or rather than) by natural selection, and this evolutionary mechanism warrants further study.
Time-dependent corticosteroid modulation of prefrontal working memory processing
Authors: Henckens Marloes J. A. G. , van Wingen Guido A. , Joëls Marian , Fernández Guillén
Published: March 2011

Corticosteroids are potent modulators of human higher cognitive function. They are released in response to stress, and are thought to be involved in the modulation of cognitive function by inducing distinct rapid nongenomic, and slow genomic changes, affecting neural plasticity throughout the brain. However, their exact effects on the neural correlates of higher-order cognitive function as performed by the prefrontal cortex at the human brain system level remain to be elucidated. Here, we targeted these time-dependent effects of corticosteroids on prefrontal cortex processing in humans using a working memory (WM) paradigm during functional MRI scanning. Implementing a randomized, double-blind, placebo-controlled design, 72 young, healthy men received 10 mg hydrocortisone either 30 min (rapid corticosteroid effects) or 240 min (slow corticosteroid effects), or placebo before a numerical n-back task with differential load (0- to 3-back). Corticosteroids’ slow effects appeared to improve working memory performance and increased neuronal activity during WM performance in the dorsolateral prefrontal cortex depending on WM load, whereas no effects of corticosteroids’ rapid actions were observed. Thereby, the slow actions of corticosteroids seem to facilitate adequate higher-order cognitive functioning, which may support recovery in the aftermath of stress exposure.
Ordered assembly of murine leukemia virus capsid protein on lipid nanotubes directs specific binding by the restriction factor, Fv1
Authors: Hilditch Laura , Matadeen Rishi , Goldstone David C. , Rosenthal Peter B. , Taylor Ian A. , Stoye Jonathan P.
Published: March 2011

The restriction factor Fv1 confers resistance to murine leukemia virus (MLV), blocking progression of the viral life cycle after reverse transcription, but before integration into the host chromosome. It is known that the specificity of restriction is determined by both the restriction factor and the viral capsid (CA), but a direct interaction between Fv1 and MLV CA has not yet been demonstrated. With the development of a previously unexplored method for in vitro polymerization of MLV CA, it has now been possible to display a binding interaction between Fv1 and MLV CA. C-terminally His-tagged CA molecules were assembled on Ni-chelating lipid nanotubes, and analysis by electron microscopy revealed the formation of a regular lattice. Comparison of binding data with existing restriction data confirmed the specificity of the binding interaction, with multiple positions of both Fv1 and CA shown to influence binding specificity.
Vibron and phonon hybridization in dielectric nanostructures
Authors: Preston Thomas C. , Signorell Ruth
Published: March 2011

Plasmon hybridization theory has been an invaluable tool in advancing our understanding of the optical properties of metallic nanostructures. Through the prism of molecular orbital theory, it allows one to interpret complex structures as “plasmonic molecules” and easily predict and engineer their electromagnetic response. However, this formalism is limited to conducting particles. Here, we present a hybridization scheme for the external and internal vibrations of dielectric nanostructures that provides a straightforward understanding of the infrared signatures of these particles through analogy to existing hybridization models of both molecular orbitals and plasmons extending the range of applications far beyond metallic nanostructures. This method not only provides a qualitative understanding, but also allows for the quantitative prediction of vibrational spectra of complex nanoobjects from well-known spectra of their primitive building blocks. The examples of nanoshells illustrate how spectral features can be understood in terms of symmetry, number of nodal planes, and scale parameters.
Towards a quantitative understanding of the late Neoproterozoic carbon cycle
Authors: Bjerrum Christian J. , Canfield Donald E.
Published: March 2011

The cycles of carbon and oxygen at the Earth surface are intimately linked, where the burial of organic carbon into sediments represents a source of oxygen to the surface environment. This coupling is typically quantified through the isotope records of organic and inorganic carbon. Yet, the late Neoproterozoic Eon, the time when animals first evolved, experienced wild isotope fluctuations which do not conform to our normal understanding of the carbon cycle and carbon-oxygen coupling. We interpret these fluctuations with a new carbon cycle model and demonstrate that all of the main features of the carbonate and organic carbon isotope record can be explained by the release of methane hydrates from an anoxic dissolved organic carbon-rich ocean into an atmosphere containing oxygen levels considerably less than today.
Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection
Authors: Batorsky Rebecca , Kearney Mary F. , Palmer Sarah E. , Maldarelli Frank , Rouzine Igor M. , Coffin John M.
Published: March 2011

HIV adaptation to a host in chronic infection is simulated by means of a Monte-Carlo algorithm that includes the evolutionary factors of mutation, positive selection with varying strength among sites, random genetic drift, linkage, and recombination. By comparing two sensitive measures of linkage disequilibrium (LD) and the number of diverse sites measured in simulation to patient data from one-time samples of
pol
gene obtained by single-genome sequencing from representative untreated patients, we estimate the effective recombination rate and the average selection coefficient to be on the order of 1% per genome per generation (10
−5
per base per generation) and 0.5%, respectively. The adaptation rate is twofold higher and fourfold lower than predicted in the absence of recombination and in the limit of very frequent recombination, respectively. The level of LD and the number of diverse sites observed in data also range between the values predicted in simulation for these two limiting cases. These results demonstrate the critical importance of finite population size, linkage, and recombination in HIV evolution.