bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of plasma membrane H
+
-ATPase in guard cells promotes light-induced stomatal opening and enhances plant growth
Authors: Wang Yin , Noguchi Ko , Ono Natsuko , Inoue Shin-ichiro , Terashima Ichiro , Kinoshita Toshinori
Published: December 2013

Significance

Stomata are microscopic pores surrounded by two guard cells and play an important role in the uptake of CO
2
for photosynthesis. Recent researches revealed that light-induced stomatal opening is mediated by at least three key components: blue light receptor phototropin, plasma membrane H
+
-ATPase, and plasma membrane inward-rectifying K
+
channels. Here, we showed that only increasing the amount of H
+
-ATPase in guard cells had a significant effect on light-induced stomatal opening. Transgenic
Arabidopsis
plants by overexpressing H
+
-ATPase in guard cells exhibited enhanced photosynthesis activity and plant growth. Our results demonstrate that stomatal aperture is a limiting factor in photosynthesis and plant growth, and that overexpression of the H
+
-ATPase in guard cells is useful for promotion of plant growth.
Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes
Authors: Yang Chen-Ying , Vogt Tobias K. , Favre Stéphanie , Scarpellino Leonardo , Huang Hsin-Ying , Tacchini-Cottier Fabienne , Luther Sanjiv A.
Published: December 2013

Significance

Lymph node swelling is a hallmark of adaptive immunity. Fibroblastic reticular cells form a fairly rigid scaffold throughout lymph nodes. They not only support organ structure and compartmentalization, but also guide lymphocyte trafficking. We describe how this rigid fibroblast network reacts to acute organ swelling. Rather than being disrupted or destroyed, the fibroblast network rapidly expands by proliferation and finally covers a much larger volume to accommodate many more lymphocytes. We identified naive lymphocyte trapping by innate triggers as an early fibroblast growth signal, with activated lymphocytes playing a role only in the later growth phase.
Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration
Authors: Singh Sarvjeet , Canseco Diana C. , Manda Shilpa M. , Shelton John M. , Chirumamilla Rajendra R. , Goetsch Sean C. , Ye Qiu , Gerard Robert D. , Schneider Jay W. , Richardson James A. , Rothermel Beverly A. , Mammen Pradeep P. A.
Published: December 2013

Significance

Mammalian skeletal muscle is a dynamic and plastic tissue, capable of responding to physiological demands and pathophysiological stresses. This response relies on the muscle’s ability to activate myogenic progenitor cells (MPCs) resulting in myogenesis. In this study, we demonstrate that cytoglobin, a stress-responsive hemoprotein abundantly expressed in MPCs, is capable of modulating MPCs’ viability and proliferative/differentiative capacity. Collectively, our data demonstrate that cytoglobin serves an important role in muscle regeneration. Thus, an enhanced understanding of cytoglobin’s role in myogenesis may enable the development of therapeutic approaches for treating patients with muscle injuries and other neuromuscular disorders.
Democratic decisions establish stable authorities that overcome the paradox of second-order punishment
Authors: Hilbe Christian , Traulsen Arne , Röhl Torsten , Milinski Manfred
Published: December 2013

Significance

Humans usually punish free riders but refuse to sanction those who cooperate but do not punish. However, such second-order punishment is essential to maintain cooperation. The central authorities established in modern societies punish both free riders and tax evaders. This is a paradox: would individuals who do not engage in second-order punishment strive for an authority that does? We address this puzzle with a mathematical model and an economic experiment. When individuals can choose between authorities by migrating between different communities, we find a costly bias against second-order punishment. When subjects use a majority vote instead, they vote for an authority with second-order punishment. These findings also suggest that other pressing social dilemmas could be solved by democratic voting.
Heteromerization of PIP aquaporins affects their intrinsic permeability
Authors: Yaneff Agustín , Sigaut Lorena , Marquez Mercedes , Alleva Karina , Pietrasanta Lía Isabel , Amodeo Gabriela
Published: December 2013

Significance

Aquaporins are known for their capacity to increase transcellular water exchange. In plants, a highly conserved group known as plasma membrane intrinsic proteins (PIP) affects the adjustment of not only membrane water permeability but also overall plant hydraulic conductivity. An experimental design combined with a mathematical modeling approach allowed us to explore the interplay of channel gating, membrane translocation, and channel stoichiometric arrangement of a pair of PIP1 and PIP2 aquaporins. We dissect the individual contribution of each PIP, showing that (
i
) PIP1 has a high water transport capacity when coexpressed with PIP2, (
ii
) PIP2 water permeability is enhanced if it physically interacts with PIP1, and (
iii
) the PIP1–PIP2 interaction results in the formation of heterotetramers with random stoichiometric arrangement.
Effects of genotypic and phenotypic variation on establishment are important for conservation, invasion, and infection biology
Authors: Forsman Anders
Published: December 2013

Significance

This paper provides a synthesis of results from experimental studies on plants and animals, and shows that there is strong evidence that genotypic and heritable phenotypic diversity improves establishment success and population persistence. An increased focus on among-individual variation may improve the success of conservation programs aiming to revitalize declining populations and species. Recognizing the role of diversity may also improve our ability to identify and ultimately prevent potential harmful invading species from spreading outside of their native ranges, and aid the development of means for improved protection against epizootics and epidemics.
Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin
Authors: Kwon Oh-Joon , Zhang Li , Ittmann Michael M. , Xin Li
Published: December 2013

Significance

Inflammation promotes the initiation of various malignancies by inducing genetic and epigenetic changes. Here we show that bacterial infection-induced prostatitis results in microenvironmental changes that enhance the differentiation of prostate basal cells into luminal cells, a cellular process that rarely occurs under normal physiological conditions. Previously, we showed in a mouse model that disease initiation for prostate cancer with a basal cell origin requires and is limited by basal-to-luminal differentiation and that prostatic inflammation induced by bacterial infection accelerates disease initiation by enhancing basal-to-luminal differentiation. Collectively, our results show that inflammation-induced microenvironmental changes alter the prostate epithelial lineage differentiation program, and we propose this alteration as a distinct and complementary process through which inflammation promotes tumor initiation.
Optical control of trimeric P2X receptors and acid-sensing ion channels
Authors: Browne Liam E. , Nunes João P. M. , Sim Joan A. , Chudasama Vijay , Bragg Laricia , Caddick Stephen , Alan North R.
Published: December 2013

Significance

P2X receptors are trimeric proteins in which an extracellular transmitter (ATP) binds to open a transmembrane ion permeation pathway. We have designed a thiol-reactive, light-sensitive azobenzene molecule that can attach between cysteines introduced by mutagenesis into different channel subunits. Such chemically modified channels can be opened within milliseconds by irradiation at 440 nm, and closed by light at 360 nm, in the absence of any extracellular ligand. A similar result was obtained for heterotrimeric P2X2/3 receptors and for structurally unrelated (but trimeric) acid-sensing ion channels. The work extends our understanding of the molecular mechanism of gating and provides a tool to investigate the role of P2X receptors and acid-sensing ion channels in intact cells and tissues.
Evidence of Lévy walk foraging patterns in human hunter–gatherers
Authors: Raichlen David A. , Wood Brian M. , Gordon Adam D. , Mabulla Audax Z. P. , Marlowe Frank W. , Pontzer Herman
Published: December 2013

Significance

Lévy walks are a random walk search strategy used by a wide variety of organisms when searching for heterogeneously distributed food. This type of search involves mostly short move steps (defined as the distance traveled before pausing or changing direction) combined with rarer longer move steps. Here, we show that the Hadza, hunter–gatherers from northern Tanzania, perform Lévy walks when foraging for a wide variety of food items, suggesting that Lévy walks are an important movement pattern for the most cognitively complex foragers on Earth. Our results suggest that scale-invariant, superdiffusive movement profiles are a fundamental feature of human landscape use, regardless of the physical or cultural environment, and may have played an important role in the evolution of human mobility.
Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility
Authors: Wang Zhongyuan , Wu Yanping , Wang Haifeng , Zhang Yangqing , Mei Lin , Fang Xuexun , Zhang Xudong , Zhang Fang , Chen Hongbo , Liu Ying , Jiang Yuyang , Sun Shengnan , Zheng Yi , Li Na , Huang Laiqiang
Published: December 2013

Significance

How receptor for hyaluronan-mediated motility (RHAMM) expression is regulated, how statins exert anticancer effects, and what roles mevalonate and Hippo pathways play in tumors are important issues in cancer biology. We find that the two pathways converge onto Yes-associated protein (YAP)/TEAD to control RHAMM transcription leading to ERK activation and cancer metastasis, which is inhibited by simvastatin. YAP/TEAD binds RHAMM promoter at specific sites to activate RHAMM transcription, and mevalonate/simvastatin affects RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic distribution. These in vitro and in vivo findings identify a mechanism regulating RHAMM expression and cancer metastasis wherein RHAMM is a downstream effector of mevalonate/Hippo pathways, and a YAP/TEAD-transcription and simvastatin-inhibition target, revealing interesting interplay of the pathways and potential targets for cancer therapeutic agents.
Identification of cancer initiating cells in
K-Ras
driven lung adenocarcinoma
Authors: Mainardi Sara , Mijimolle Nieves , Francoz Sarah , Vicente-Dueñas Carolina , Sánchez-García Isidro , Barbacid Mariano
Published: December 2013

Significance

K-RAS
oncogene-driven lung adenocarcinomas is one of the most malignant human tumors for which there are no efficacious therapeutic strategies. Here, we have used a mouse tumor model that closely recapitulates this human disease to illustrate that adult lung cells are uniquely sensitive to transformation by this oncogene. Monitoring lung cells at the single-cell level revealed that they respond differently to
K-Ras
oncogenic signals. Whereas
K-Ras
–expressing Clara cells required an inflammatory response to yield hyperplasias and adenomas, alveolar type II cells or their committed precursors led to the generation of malignant adenocarcinoma regardless of their surrounding microenvironment.
Protein kinase LKB1 regulates polarized dendrite formation of adult hippocampal newborn neurons
Authors: Huang Wei , She Liang , Chang Xing-ya , Yang Rong-rong , Wang Liang , Ji Hong-bin , Jiao Jian-wei , Poo Mu-ming
Published: December 2013

Significance

Dendrites are highly polarized structures that are important for synaptic input and signal integration. However, the molecular and cellular mechanism underlying the polarized dendrite development in vivo remains largely unknown. This report shows that LKB1, a serine-threonine protein kinase known to be involved in axon formation in embryonic cortical pyramidal neurons, is essential for the polarized initiation and oriented extension of the primary dendrite in adult-born hippocampal granule cells, and provides further evidence that this morphogenic effect of LKB1 is mediated via regulation of polarized distribution of Golgi apparatus. These findings not only add a unique function to the growing list of LKB1 cellular actions, but also provide new clues to the subcellular mechanism of LKB1’s action.
Kondo conductance across the smallest spin 1/2 radical molecule
Authors: Requist Ryan , Modesti Silvio , Baruselli Pier Paolo , Smogunov Alexander , Fabrizio Michele , Tosatti Erio
Published: December 2013

Significance

Molecular electronics, with molecules functioning as the basic building blocks of circuits, is considered by some to be one of the contenders for next-generation electronics. Radical molecules are interesting because a quantum phenomenon, the Kondo effect, involving the radical’s unpaired electron and its spin, has the potential to enhance and control conductance. Examples of molecular Kondo are known experimentally in geometries including mechanical break junctions and scanning tunneling spectroscopy (STS), but so far it has not been possible to make accurate theoretical predictions. Here we predict the Kondo effect expected for the simplest molecular radical, nitric oxide, on a gold surface. Subsequently we verify that experimentally by STS. Both agreements and discrepancies offer a quantitative lesson of considerable future use.
Comparison of explicit and incidental learning strategies in memory-impaired patients
Authors: Smith Christine N. , Urgolites Zhisen J. , Hopkins Ramona O. , Squire Larry R.
Published: December 2013

Significance

Declarative memory for rapidly learned, novel associations is thought to depend on structures in the medial temporal lobe (MTL). A recent study suggested that rapidly learned associations can nevertheless be supported by structures outside the MTL when a promising, incidental encoding procedure termed “fast mapping” (FM) is used. In two experiments with memory-impaired patients, we found that the FM procedure yielded the same deficits in learning and memory that have been obtained with the use of other more traditional paradigms. We suggest that the effects of the FM procedure are not robust and, if replicable, depend on yet-unknown aspects of how the test is given.
The N terminus of SKAP55 enables T cell adhesion to TCR and integrin ligands via distinct mechanisms
Authors: Ophir Michael J. , Liu Beiyun C. , Bunnell Stephen C.
Published: December 2013

The T cell receptor (TCR) triggers the assembly of “SLP-76 microclusters,” which mediate signals required for T cell activation. In addition to regulating integrin activation, we show that Src kinase–associated phosphoprotein of 55 kD (SKAP55) is required for microcluster persistence and movement, junctional stabilization, and integrin-independent adhesion via the TCR. These functions require the dimerization of SKAP55 and its interaction with the adaptor adhesion and degranulation-promoting adaptor protein (ADAP). A “tandem dimer” containing two ADAP-binding SKAP55 Src homology 3 (SH3) domains stabilized SLP-76 microclusters and promoted T cell adhesion via the TCR, but could not support adhesion to integrin ligands. Finally, the SKAP55 dimerization motif (DM) enabled the coimmunoprecipitation of the Rap1-dependent integrin regulator Rap1-GTP–interacting adaptor molecule (RIAM), the recruitment of talin into TCR-induced adhesive junctions, and “inside-out” signaling to β1 integrins. Our data indicate that SKAP55 dimers stabilize SLP-76 microclusters, couple SLP-76 to the force-generating systems responsible for microcluster movement, and enable adhesion via the TCR by mechanisms independent of RIAM, talin, and β1 integrins.
Phase transitions and size scaling of membrane-less organelles
Authors: Brangwynne Clifford P.
Published: December 2013

The coordinated growth of cells and their organelles is a fundamental and poorly understood problem, with implications for processes ranging from embryonic development to oncogenesis. Recent experiments have shed light on the cell size–dependent assembly of membrane-less cytoplasmic and nucleoplasmic structures, including ribonucleoprotein (RNP) granules and other intracellular bodies. Many of these structures behave as condensed liquid-like phases of the cytoplasm/nucleoplasm. The phase transitions that appear to govern their assembly exhibit an intrinsic dependence on cell size, and may explain the size scaling reported for a number of structures. This size scaling could, in turn, play a role in cell growth and size control.
The noodle defense
Authors: Swanson Joel A.
Published: December 2013

Macrophages ingest and kill microbes by phagocytosis and delivery to lysosomes. In this issue, Prashar et al. (2013, J. Cell Biol. http://dx.doi.org/10.1083/jcb.201304095) demonstrate that the elongated morphology of filamentous bacteria does not prevent ingestion by macrophages or the fusion of lysosomes, but creates a chimeric, unclosed phagolysosomal compartment whose leakiness blunts the toxicity of lysosomal enzymes, thereby increasing bacterial survival.
Bone resorption is regulated by cell-autonomous negative feedback loop of Stat5–Dusp axis in the osteoclast
Authors: Hirose Jun , Masuda Hironari , Tokuyama Naoto , Omata Yasunori , Matsumoto Takumi , Yasui Tetsuro , Kadono Yuho , Hennighausen Lothar , Tanaka Sakae
Published: December 2013

Signal transducer and activator of transcription 5 (Stat5) is essential for cytokine-regulated processes such as proliferation, differentiation, and survival in hematopoietic cells. To investigate the role of Stat5 in osteoclasts, we generated mice with an osteoclast-specific conditional deletion of Stat5 (Stat5 conditional knockout [cKO] mice) and analyzed their bone phenotype. Stat5 cKO mice exhibited osteoporosis caused by an increased bone-resorbing activity of osteoclasts. The activity of mitogen-activated protein kinases (MAPKs), in particular extracellular signal–related kinase, was increased in Stat5 cKO osteoclasts, whereas the expression of the MAPK phosphatases dual specificity phosphatase 1 (Dusp1) and Dusp2 was significantly decreased. Interleukin-3 (IL-3) stimulated the phosphorylation and nuclear translocation of Stat5 in osteoclasts, and Stat5 expression was up-regulated in response to receptor activator of nuclear factor κB ligand (RANKL). The results suggest that Stat5 negatively regulates the bone-resorbing function of osteoclasts by promoting Dusp1 and Dusp2 expression, and IL-3 promotes Stat5 activation in osteoclasts.
IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo
Authors: Starbeck-Miller Gabriel R. , Xue Hai-Hui , Harty John T.
Published: December 2013

TCR ligation and co-stimulation induce cellular division; however, optimal accumulation of effector CD8 T cells requires direct inflammatory signaling by signal 3 cytokines, such as IL-12 or type I IFNs. Although in vitro studies suggest that IL-12/type I IFN may enhance T cell survival or early proliferation, the mechanisms underlying optimal accumulation of CD8 T cells in vivo are unknown. In particular, it is unclear if disparate signal 3 cytokines optimize effector CD8 T cell accumulation by the same mechanism and how these inflammatory cytokines, which are transiently produced early after infection, affect T cell accumulation many days later at the peak of the immune response. Here, we show that transient exposure of CD8 T cells to IL-12 or type I IFN does not promote survival or confer an early proliferative advantage in vivo, but rather sustains surface expression of CD25, the high-affinity IL-2 receptor. This prolongs division of CD8 T cells in response to basal IL-2, through activation of the PI3K pathway and expression of FoxM1, a positive regulator of cell cycle progression genes. Thus, signal 3 cytokines use a common pathway to optimize effector CD8 T cell accumulation through a temporally orchestrated sequence of cytokine signals that sustain division rather than survival.
Initiation of MLL-rearranged AML is dependent on C/EBPα
Authors: Ohlsson Ewa , Hasemann Marie Sigurd , Willer Anton , Lauridsen Felicia Kathrine Bratt , Rapin Nicolas , Jendholm Johan , Porse Bo Torben
Published: December 2013

MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL–induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion–driven transformation and find that it sharply demarcates tumor initiation and maintenance.
Automated Alerts Coupled with Antimicrobial Stewardship Intervention Lead to Decreases in Length of Stay in Patients with Gram-Negative Bacteremia
Authors: Pogue Jason M. , Mynatt Ryan P. , Marchaim Dror , Zhao Jing J. , Barr Viktorija O. , Moshos Judy , Sunkara Bharath , Chopra Teena , Chidurala Sowmya , Kaye Keith S.
Published: December 2013

Objective.

To assess the impact of active alerting of positive blood culture data coupled with stewardship intervention on time to appropriate therapy, length of stay, and mortality in patients with gram-negative bacteremia.

Design.

Quasi-experimental retrospective cohort study in patients with gram-negative bacteremia at the Detroit Medical Center from 2009 to 2011.

Setting.

Three hospitals (1 community, 2 academic) with active antimicrobial stewardship programs within the Detroit Medical Center.

Patients.

All patients with monomicrobial gram-negative bacteremia during the study period.

Intervention.

Active alerting of positive blood culture data coupled with stewardship intervention (2010-2011) compared with patients who received no formalized stewardship intervention (2009).

Results.

Active alerting and intervention led to a decreased time to appropriate therapy (8 [interquartile range (IQR), 2-24] vs 14 [IQR, 2-35] hours; P = .014) in patients with gram-negative bacteremia. After controlling for differences between groups, being in the intervention arm was associated with an independent reduction in length of stay (odds ratio [OR], 0.73 [95% confidence interval (CI), 0.62-0.86]), correlating to a median attributable decrease in length of stay of 2.2 days. Additionally, multivariate modeling of patients who were not on appropriate antimicrobial therapy at the time of initial culture positivity showed that patients in the intervention group had a significant reduction in both length of stay (OR, 0.76 [95% CI, 0.66-0.86]) and infection-related mortality (OR, 0.24 [95% CI, 0.08-0.76]).

Conclusions.

Active alerting coupled with stewardship intervention in patients with gram-negative bacteremia positively impacted time to appropriate therapy, length of stay, and mortality and should be a target of antimicrobial stewardship programs.
Chlorhexidine Bathing in a Tertiary Care Neonatal Intensive Care Unit: Impact on Central Line–Associated Bloodstream Infections
Authors: Quach Caroline , Milstone Aaron M. , Perpête Chantal , Bonenfant Mario , Moore Dorothy L. , Perreault Therese
Published: December 2013

Background.

Despite implementation of recommended best practices, our central line-associated bloodstream infection (CLABSI) rates remained high. Our objective was to describe the impact of chlorhexidine gluconate (CHG) bathing on CLABSI rates in neonates.

Methods.

Infants with a central venous catheter (CVC) admitted to the neonatal intensive care unit from April 2009 to March 2013 were included. Neonates with a birth weight of 1,000 g or less, aged less than 28 days, and those with a birth weight greater than 1,000 g were bathed with mild soap until March 31, 2012 (baseline), and with a 2% CHG-impregnated cloth starting on April 1, 2012 (intervention). Infants with a birth weight of 1,000 g or less, aged 28 days or more, were bathed with mild soap during the entire period. Neonatal intensive care unit nurses reported adverse events. Adjusted incidence rate ratios (aIRRs), using Poisson regression, were calculated to compare CLABSIs/1,000 CVC-days during the baseline and intervention periods.

Results.

Overall, 790 neonates with CVCs were included in the study. CLABSI rates decreased during the intervention period for CHG-bathed neonates (6.00 vs 1.92/1,000 CVC-days; aIRR, 0.33 [95% confidence interval (CI), 0.15-0.73]) but remained unchanged for neonates with a birth rate of 1,000 g or less and aged less than 28 days who were not eligible for CHG bathing (8.57 vs 8.62/1,000 CVC-days; aIRR, 0.86 [95% CI, 0.17-4.44]). Overall, 195 infants with a birth weight greater than 1,000 g and 24 infants with a birth weight of 1,000 g or less, aged 28 days or more, were bathed with CHG. There was no reported adverse event.

Conclusions.

We observed a decrease in CLABSI rates in CHG-bathed neonates in the absence of observed adverse events. CHG bathing should be considered if CLABSI rates remain high, despite the implementation of other recommended measures.
The curious time lags of PG 1244+026: discovery of the iron K reverberation lag
Authors: Kara E. , Cackett E. M. , Fabian A. C. , Reynolds C. , Uttley P.
Published: December 2013

High-frequency iron K reverberation lags, where the red wing of the line responds before the line centroid, are a robust signature of relativistic reflection off the inner accretion disc. In this Letter, we report the discovery of the Fe K lag in PG 1244+026 from ∼120 ks of data (one orbit of the XMM–Newton telescope). The amplitude of the lag with respect to the continuum is 1000 s at a frequency of ∼10−4 Hz. We also find a possible frequency dependence of the line: as we probe higher frequencies (i.e. shorter time-scales from a smaller emitting region) the Fe K lag peaks at the red wing of the line, while at lower frequencies (from a larger emitting region) we see the dominant reflection lag from the rest-frame line centroid. The mean energy spectrum shows a strong soft excess, though interestingly, there is no indication of a soft lag. Given that this source has radio emission and it has little reported correlated variability between the soft excess and the hard band, we explore one possible explanation in which the soft excess in this source is dominated by the steep power-law-like emission from a jet, and that a corona (or base of the jet) irradiates the inner accretion disc, creating the blurred reflection features evident in the spectrum and the lag. General relativistic ray-tracing models fit the Fe K lag well, with the best fit giving a compact X-ray source at a height of 5rg and a black hole mass of 1.3 × 107 M⊙.
Base-displaced intercalation of the 2-amino-3-methylimidazo[4,5-f]quinolone N2-dG adduct in the NarI DNA recognition sequence
Authors: Stavros Kallie M. , Hawkins Edward K. , Rizzo Carmelo J. , Stone Michael P.
Published: December 2013

2-Amino-3-methylimidazo[4,5-f]quinolone (IQ), a heterocyclic amine found in cooked meats, undergoes bioactivation to a nitrenium ion, which alkylates guanines at both the C8-dG and N2-dG positions. The conformation of a site-specific N2-dG-IQ adduct in an oligodeoxynucleotide duplex containing the iterated CG repeat restriction site of the NarI endonuclease has been determined. The IQ moiety intercalates, with the IQ H4a and CH3 protons facing the minor groove, and the IQ H7a, H8a and H9a protons facing the major groove. The adducted dG maintains the anti-conformation about the glycosyl bond. The complementary dC is extruded into the major groove. The duplex maintains its thermal stability, which is attributed to stacking between the IQ moiety and the 5′- and 3′-neighboring base pairs. This conformation is compared to that of the C8-dG-IQ adduct in the same sequence, which also formed a ‘base-displaced intercalated’ conformation. However, the C8-dG-IQ adopted the syn conformation placing the Watson−Crick edge of the modified dG into the major groove. In addition, the C8-dG-IQ adduct was oriented with the IQ CH3 group and H4a and H5a facing the major groove. These differences may lead to differential processing during DNA repair and replication.
Cellular trafficking determines the exon skipping activity of Pip6a-PMO in mdx skeletal and cardiac muscle cells
Authors: Lehto Taavi , Castillo Alvarez Alejandra , Gauck Sarah , Gait Michael J. , Coursindel Thibault , Wood Matthew J. A. , Lebleu Bernard , Boisguerin Prisca
Published: December 2013

Cell-penetrating peptide-mediated delivery of phosphorodiamidate morpholino oligomers (PMOs) has shown great promise for exon-skipping therapy of Duchenne Muscular Dystrophy (DMD). Pip6a-PMO, a recently developed conjugate, is particularly efficient in a murine DMD model, although mechanisms responsible for its increased biological activity have not been studied. Here, we evaluate the cellular trafficking and the biological activity of Pip6a-PMO in skeletal muscle cells and primary cardiomyocytes. Our results indicate that Pip6a-PMO is taken up in the skeletal muscle cells by an energy- and caveolae-mediated endocytosis. Interestingly, its cellular distribution is different in undifferentiated and differentiated skeletal muscle cells (vesicular versus nuclear). Likewise, Pip6a-PMO mainly accumulates in cytoplasmic vesicles in primary cardiomyocytes, in which clathrin-mediated endocytosis seems to be the pre-dominant uptake pathway. These differences in cellular trafficking correspond well with the exon-skipping data, with higher activity in myotubes than in myoblasts or cardiomyocytes. These differences in cellular trafficking thus provide a possible mechanistic explanation for the variations in exon-skipping activity and restoration of dystrophin protein in heart muscle compared with skeletal muscle tissues in DMD models. Overall, Pip6a-PMO appears as the most efficient conjugate to date (low nanomolar EC50), even if limitations remain from endosomal escape.
Human Rev1 polymerase disrupts G-quadruplex DNA
Authors: Eddy Sarah , Ketkar Amit , Zafar Maroof K. , Maddukuri Leena , Choi Jeong-Yun , Eoff Robert L.
Published: December 2013

The Y-family DNA polymerase Rev1 is required for successful replication of G-quadruplex DNA (G4 DNA) in higher eukaryotes. Here we show that human Rev1 (hRev1) disrupts G4 DNA structures and prevents refolding in vitro. Nucleotidyl transfer by hRev1 is not necessary for mechanical unfolding to occur. hRev1 binds G4 DNA substrates with Kd,DNA values that are 4–15-fold lower than those of non-G4 DNA substrates. The pre-steady-state rate constant of deoxycytidine monophosphate (dCMP) insertion opposite the first tetrad-guanine by hRev1 is ∼56% as fast as that observed for non-G4 DNA substrates. Thus, hRev1 can promote fork progression by either dislodging tetrad guanines to unfold the G4 DNA, which could assist in extension by other DNA polymerases, or hRev1 can prevent refolding of G4 DNA structures. The hRev1 mechanism of action against G-quadruplexes helps explain why replication progress is impeded at G4 DNA sites in Rev1-deficient cells and illustrates another unique feature of this enzyme with important implications for genome maintenance.
Effects of Wheat Bran Extract Containing Arabinoxylan Oligosaccharides on Gastrointestinal Parameters in Healthy Preadolescent Children
Authors: François Isabelle E.J.A. , Lescroart Olivier , Veraverbeke Wim S. , Marzorati Massimo , Possemiers Sam , Hamer Henrike , Windey Karen , Welling Gjalt W. , Delcour Jan A. , Courtin Christophe M. , Verbeke Kristin , Broekaert Willem F.
Published: December 2013

Objectives:

We assessed whether wheat bran extract (WBE) containing arabinoxylan‐oligosaccharides (AXOS) elicited a prebiotic effect and modulated gastrointestinal (GI) parameters in healthy preadolescent children upon consumption in a beverage.

Methods:

This double‐blind randomized placebo‐controlled crossover trial evaluated the effects of consuming WBE at 0 (control) or 5.0 g/day for 3 weeks in 29 healthy children (8–12 years). Fecal levels of microbiota, short‐chain fatty acids, branched‐chain fatty acids, ammonia, moisture, and fecal pH were assessed at the end of each treatment and at the end of a 1‐week run‐in (RI) period. In addition, the subjects completed questionnaires scoring distress severity of 3 surveyed GI symptoms. Finally, subjects recorded defecation frequency and stool consistency.

Results:

Nominal fecal bifidobacteria levels tended to increase after 5 g/day WBE consumption (P = 0.069), whereas bifidobacteria expressed as percentage of total fecal microbiota was significantly higher upon 5 g/day WBE intake (P = 0.002). Additionally, 5 g/day WBE intake induced a significant decrease in fecal content of isobutyric acid and isovaleric acid (P < 0.01), markers of protein fermentation. WBE intake did not cause a change in distress severity of the 3 surveyed GI symptoms (flatulence, abdominal pain/cramps, and urge to vomit) (P > 0.1).

Conclusions:

WBE is well tolerated at doses up to 5 g/day in healthy preadolescent children. In addition, the intake of 5 g/day exerts beneficial effects on gut parameters, in particular an increase in fecal bifidobacteria levels relative to total fecal microbiota, and reduction of colonic protein fermentation.
Boundary coding in the rat subiculum
Authors: Stewart Sarah , Jeewajee Ali , Wills Thomas J. , Burgess Neil , Lever Colin
Published: December 2013

The spatial mapping function of the hippocampal formation is likely derived from two sets of information: one based on the external environment and the other based on self-motion. Here, we further characterize ‘boundary vector cells’ (BVCs) in the rat subiculum, which code space relative to one type of cue in the external environment: boundaries. We find that the majority of cells with fields near the perimeter of a walled environment exhibit an additional firing field when an upright barrier is inserted into the walled environment in a manner predicted by the BVC model. We use this property of field repetition as a heuristic measure to define BVCs, and characterize their spatial and temporal properties. In further tests, we find that subicular BVCs typically treat drop edges similarly to walls, including exhibiting field repetition when additional drop-type boundaries are added to the testing environment. In other words, BVCs treat both kinds of edge as environmental boundaries, despite their dissimilar sensory properties. Finally, we also report the existence of ‘boundary-off cells’, a new class of boundary-coding cells. These cells fire everywhere except where a given BVC might fire.
Theta oscillations decrease spike synchrony in the hippocampus and entorhinal cortex
Authors: Mizuseki Kenji , Buzsaki György
Published: December 2013

Oscillations and synchrony are often used synonymously. However, oscillatory mechanisms involving both excitation and inhibition can generate non-synchronous yet coordinated firing patterns. Using simultaneous recordings from multiple layers of the entorhinal–hippocampal loop, we found that coactivation of principal cell pairs (synchrony) was lowest during exploration and rapid-eye-movement (REM) sleep, associated with theta oscillations, and highest in slow wave sleep. Individual principal neurons had a wide range of theta phase preference. Thus, while theta oscillations reduce population synchrony, they nevertheless coordinate the phase (temporal) distribution of neurons. As a result, multiple cell assemblies can nest within the period of the theta cycle.
Hippocampal theta oscillations are slower in humans than in rodents: implications for models of spatial navigation and memory
Authors: Jacobs Joshua
Published: December 2013

The theta oscillation is a neuroscience enigma. When a rat runs through an environment, large-amplitude theta oscillations (4–10 Hz) reliably appear in the hippocampus's electrical activity. The consistency of this pattern led to theta playing a central role in theories on the neural basis of mammalian spatial navigation and memory. However, in fact, hippocampal oscillations at 4–10 Hz are rare in humans and in some other species. This presents a challenge for theories proposing theta as an essential component of the mammalian brain, including models of place and grid cells. Here, I examine this issue by reviewing recent research on human hippocampal oscillations using direct brain recordings from neurosurgical patients. This work indicates that the human hippocampus does indeed exhibit rhythms that are functionally similar to theta oscillations found in rodents, but that these signals have a slower frequency of approximately 1–4 Hz. I argue that oscillatory models of navigation and memory derived from rodent data are relevant for humans, but that they should be modified to account for the slower frequency of the human theta rhythm.
Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local–global reference frames
Authors: Knierim James J. , Neunuebel Joshua P. , Deshmukh Sachin S.
Published: December 2013

The hippocampus receives its major cortical input from the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). It is commonly believed that the MEC provides spatial input to the hippocampus, whereas the LEC provides non-spatial input. We review new data which suggest that this simple dichotomy between ‘where’ versus ‘what’ needs revision. We propose a refinement of this model, which is more complex than the simple spatial–non-spatial dichotomy. MEC is proposed to be involved in path integration computations based on a global frame of reference, primarily using internally generated, self-motion cues and external input about environmental boundaries and scenes; it provides the hippocampus with a coordinate system that underlies the spatial
context
of an experience. LEC is proposed to process information about individual items and locations based on a local frame of reference, primarily using external sensory input; it provides the hippocampus with information about the
content
of an experience.
S-Carvone Suppresses Cellulase-Induced Capsidiol Production in Nicotiana tabacum by Interfering with Protein Isoprenylation
Authors: Huchelmann Alexandre , Gastaldo Clément , Veinante Mickaël , Zeng Ying , Heintz Dimitri , Tritsch Denis , Schaller Hubert , Rohmer Michel , Bach Thomas J. , Hemmerlin Andréa
Published: December 2013

S-Carvone has been described as a negative regulator of mevalonic acid (MVA) production by interfering with 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) activity, a key player in isoprenoid biosynthesis. The impact of this monoterpene on the production of capsidiol in Nicotiana tabacum, an assumed MVA-derived sesquiterpenoid phytoalexin produced in response to elicitation by cellulase, was investigated. As expected, capsidiol production, as well as early stages of elicitation such as hydrogen peroxide production or stimulation of 5-epi-aristolochene synthase activity, were repressed. Despite the lack of capsidiol synthesis, apparent HMGR activity was boosted. Feeding experiments using (1-13C)Glc followed by analysis of labeling patterns by 13C-NMR, confirmed an MVA-dependent biosynthesis; however, treatments with fosmidomycin, an inhibitor of the MVA-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) isoprenoid pathway, unexpectedly down-regulated the biosynthesis of this sesquiterpene as well. We postulated that S-carvone does not directly inhibit the production of MVA by inactivating HMGR, but possibly targets an MEP-derived isoprenoid involved in the early steps of the elicitation process. A new model is proposed in which the monoterpene blocks an MEP pathway–dependent protein geranylgeranylation necessary for the signaling cascade. The production of capsidiol was inhibited when plants were treated with some inhibitors of protein prenylation or by further monoterpenes. Moreover, S-carvone hindered isoprenylation of a prenylable GFP indicator protein expressed in N. tabacum cell lines, which can be chemically complemented with geranylgeraniol. The model was further validated using N. tabacum cell extracts or recombinant N. tabacum protein prenyltransferases expressed in Escherichia coli. Our study endorsed a reevaluation of the effect of S-carvone on plant isoprenoid metabolism.
Application of small-angle neutron scattering to the study of forces between magnetically chained monodisperse ferrofluid emulsion droplets
Authors: Jain N. , Liu C. K. , Hawkett B. S. , Warr G. G. , Hamilton W. A.
Published: December 2013

The optical magnetic chaining technique (MCT) developed by Leal-Calderon, Stora, Mondain-Monval, Poulin & Bibette [Phys. Rev. Lett.(1994),72, 2959–2962] allows precise measurements of force profiles between droplets in monodisperse ferrofluid emulsions. However, the method lacks anin situdetermination of droplet size and, therefore, requires a combination of separately acquired measurements of droplet chain periodicityversusan applied magnetic field from optical Bragg scattering and droplet diameter inferred from dynamic light scattering (DLS) to recover surface force–distance profiles between the colloidal particles. Compound refractive lens (CRL) focused small-angle neutron scattering (SANS) MCT should result in more consistent measurements of droplet size (form factor measurements in the absence of field) and droplet chaining period (from structure factor peaks when the magnetic field is applied), and, with access to shorter length scales, extend force measurements to closer approaches than possible by optical measurements. This article reports on CRL-SANS measurements of monodisperse ferrofluid emulsion droplets aligned in straight chains by an applied field perpendicular to the incident beam direction. Analysis of the scattering from the closely spaced droplets required algorithms that carefully treated resolution and its effect on mean scattering vector magnitudes in order to determine droplet size and chain periods to sufficient accuracy. At lower applied fields, scattering patterns indicate structural correlations transverse to the magnetic field direction owing to the formation of intermediate structures in early chain growth.
Amplicon pyrosequencing reveals spatial and temporal consistency in diazotroph assemblages of the Acropora millepora microbiome
Authors: Lema Kimberley A. , Willis Bette L. , Bourne David G.
Published: December 2013

Diazotrophic bacteria potentially play an important functional role in supplying fixed nitrogen to the coral holobiont, but the value of such a partnership depends on the stability of the association. Here we evaluate the composition of diazotroph assemblages associated with the coral Acropora millepora throughout four seasons and at two reefs, an inshore and an offshore (mid‐shelf) reef on the Great Barrier Reef, Australia. Amplicon pyrosequencing of the nifH gene revealed that diazotrophs are ubiquitous members of the bacterial community associated with A. millepora. Rhizobia (65% of the overall nifH sequences retrieved) and particularly Bradyrhizobia sp.‐affiliated sequences (> 50% of rhizobia sequences) dominated diazotrophic assemblages across all coral samples from the two sites throughout the year. In contrast to this consistency in the spatial and temporal patterns of occurrence of diazotroph assemblages, the overall coral‐associated bacterial community, assessed through amplicon sequencing of the general bacterial 16S ribosomal RNA gene, differed between inshore and mid‐shelf reef locations. Sequences associated with the Oceanospirillales family, particularly with Endozoicomonas sp., dominated bacterial communities associated with inshore corals. Although rhizobia represented a variable and generally small fraction of the overall bacterial community associated with A. millepora, consistency in the structure of these diazotrophic assemblages suggests that they have a functional role in the coral holobiont.
Ammonium induces differential expression of methane and nitrogen metabolism‐related genes in Methylocystis sp. strain SC2
Authors: Dam Bomba , Dam Somasri , Kim Yongkyu , Liesack Werner
Published: December 2013

Nitrogen source and concentration are major determinants of methanotrophic activity, but their effect on global gene expression is poorly studied. Methylocystis sp. strain SC2 produces two isozymes of particulate methane monooxygenase. These are encoded by pmoCAB1 (low‐affinity pMMO1) and pmoCAB2 (high‐affinity pMMO2). We used RNA‐Seq to identify strain SC2 genes that respond to standard (10 mM) and high (30 mM) NH4+ concentrations in the medium, compared with 10 mM NO3–. While the expression of pmoCAB1 was unaffected, pmoCAB2 was significantly downregulated (log2 fold changes of −5.0 to −6.0). Among nitrogen metabolism‐related processes, genes involved in hydroxylamine detoxification (haoAB) were highly upregulated, while those for assimilatory nitrate/nitrite reduction, high‐affinity ammonium uptake and nitrogen regulatory protein PII were downregulated. Differential expression of pmoCAB2 and haoAB was independently validated by end‐point reverse transcription polymerase chain reaction. Methane oxidation by SC2 cells exposed to 30 mM NH4+ was inhibited at ≤ 400 ppmv CH4, where pMMO2 but not pMMO1 is functional. When transferred back to standard nitrogen concentration, methane oxidation capability and pmoCAB2 expression were restored. Given that Methylocystis contributes to atmospheric methane oxidation in upland soils, differential expression of pmoCAB2 explains, at least to some extent, the strong inhibitory effect of ammonium fertilizers on this activity.