bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incomplete transfer of accessory loci influencing SbMATE expression underlies genetic background effects for aluminum tolerance in sorghum
Authors: Melo Janaina O. , Lana Ubiraci G. P. , Piñeros Miguel A. , Alves Vera M. C. , Guimarães Claudia T. , Liu Jiping , Zheng Yi , Zhong Silin , Fei Zhangjun , Maron Lyza G. , Schaffert Robert E. , Kochian Leon V. , Magalhaes Jurandir V. 
Published: September 2012

SummaryImpaired root development caused by aluminum (Al) toxicity is a major cause of grain yield reduction in crops cultivated on acid soils, which are widespread worldwide. In sorghum, the major Al‐tolerance locus, AltSB, is due to the function of SbMATE, which is an Al‐activated root citrate transporter. Here we performed a molecular and physiological characterization of various AltSB donors and near‐isogenic lines harboring various AltSB alleles. We observed a partial transfer of Al tolerance from the parents to the near‐isogenic lines that was consistent across donor alleles, emphasizing the occurrence of strong genetic background effects related to AltSB. This reduction in tolerance was variable, with a 20% reduction being observed when highly Al‐tolerant lines were the AltSB donors, and a reduction as great as 70% when other AltSB alleles were introgressed. This reduction in Al tolerance was closely correlated with a reduction in SbMATE expression in near‐isogenic lines, suggesting incomplete transfer of loci acting in trans on SbMATE. Nevertheless, AltSB alleles from the highly Al‐tolerant sources SC283 and SC566 were found to retain high SbMATE expression, presumably via elements present within or near the AltSB locus, resulting in significant transfer of the Al‐tolerance phenotype to the derived near‐isogenic lines. Allelic effects could not be explained by coding region polymorphisms, although occasional mutations may affect Al tolerance. Finally, we report on the extensive occurrence of alternative splicing for SbMATE, which may be an important component regulating SbMATE expression in sorghum by means of the nonsense‐mediated RNA decay pathway.
Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus
Authors: Dougherty Kelly A. , Islam Tasnim , Johnston Daniel 
Published: September 2012

Key points
The dorsal (DHC) and ventral (VHC) regions of the rodent hippocampus are anatomically, behaviourally, and biochemically distinct.
The intrinsic electrophysiological properties of CA1 pyramidal neurones from these regions however, have not been fully characterized.
In this study, we found that VHC neurones were intrinsically more excitable than DHC neurones.
The difference in intrinsic excitability stems from a higher input resistance (Rin) and more depolarized resting membrane potential observed in the soma and apical dendrite of VHC neurones.
Morphological analysis of reconstructed neurones revealed significantly more dendritic surface area for DHC than VHC neurones.
Simulations using morphologically realistic passive models indicate that morphological differences could, in principle, underlie somatic but not dendritic differences in Rin.
Abstract  The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non‐spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole‐cell current‐clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; Δ7 mV) and higher input resistance (Rin; Δ46 MΩ measured from RMP) observed in VHC neurones. These differences in RMP and Rin were also observed in dendritic whole‐cell current‐clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic Rin of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability.
Influence of the Protein Kinase C Activator Phorbol Myristate Acetate on the Intracellular Activity of Antibiotics against Hemin- and Menadione-Auxotrophic Small-Colony Variant Mutants of Staphylococcus aureus and Their Wild-Type Parental Strain in Human THP-1 Cells
Authors: Garcia Laetitia G. , Lemaire Sandrine , Kahl Barbara C. , Becker Karsten , Proctor Richard A. , Tulkens Paul M. , Van Bambeke Françoise 
Published: September 2012

ABSTRACT

In a previous study (L. G. Garcia et al., Antimicrob. Agents Chemother. 56:3700–3711, 2012), we evaluated the intracellular fate of
menD
and
hemB
mutants (corresponding to menadione- and hemin-dependent small-colony variants, respectively) of the parental COL methicillin-resistant
Staphylococcus aureus
strain and the pharmacodynamic profile of the intracellular activity of a series of antibiotics in human THP-1 monocytes. We have now examined the phagocytosis and intracellular persistence of the same strains in THP-1 cells activated by phorbol 12-myristate 13-acetate (PMA) and measured the intracellular activity of gentamicin, moxifloxacin, and oritavancin in these cells. Postphagocytosis intracellular counts and intracellular survival were lower in PMA-activated cells, probably due to their higher killing capacities. Gentamicin and moxifloxacin showed a 5- to 7-fold higher potency (lower static concentrations) against the parental strain, its
hemB
mutant, and the genetically complemented strain in PMA-activated cells and against the
menD
strain in both activated and nonactivated cells. This effect was inhibited when cells were incubated with
N
-acetylcysteine (a scavenger of oxidant species). In parallel, we observed that the MICs of these drugs were markedly reduced if bacteria had been preexposed to H
2
O
2
. In contrast, the intracellular potency of oritavancin was not different in activated and nonactivated cells and was not decreased by the addition of
N
-acetylcysteine, regardless of the phenotype of the strains. The oritavancin MIC was also unaffected by preincubation of the bacteria with H
2
O
2
. Thus, activation of THP-1 cells by PMA may increase the intracellular potency of certain antibiotics (probably due to synergy with reactive oxygen species), but this effect cannot be generalized to all antibiotics.
Efficacy of Ceftaroline Fosamil in a Staphylococcal Murine Pneumonia Model
Authors: Bhalodi Amira A. , Crandon Jared L. , Biek Donald , Nicolau David P. 
Published: September 2012

ABSTRACT

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant
Staphylococcus aureus
(MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against
S. aureus
in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen
S. aureus
(2 methicillin-susceptible
Staphylococcus aureus
[MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum
f
T>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log
10
kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log
10
CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the
f
T>MICs required for stasis and a 1-log
10
kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum
f
T>MIC targets required in this lung infection model were similar to those observed with ceftaroline against
S. aureus
in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.
Susceptibility to Progressive Cryptococcus neoformans Pulmonary Infection Is Regulated by Loci on Mouse Chromosomes 1 and 9
Authors: Carroll Scott F. , Lafferty Erin I. , Flaczyk Adam , Fujiwara T. Mary , Homer Robert , Morgan Kenneth , Loredo-Osti J C. , Qureshi Salman T. 
Published: September 2012

ABSTRACTGenetic factors that regulate the pathogenesis of pneumonia caused by the fungusCryptococcus neoformansare poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection withC. neoformansATCC 24067. The aim of the present study was to characterize the inflammatory response of C3H/HeN mice followingC. neoformanspulmonary infection and to identify genetic loci that regulate host defense. Following cryptococcal infection, C3H/HeN mice demonstrated a Th2 immune response with heightened airway and tissue eosinophilia, goblet cell metaplasia, and significantly higher lung interleukin-5 (IL-5) and IL-13 protein expression relative to CBA/J mice. Conversely, CBA/J mice exhibited greater airway and tissue neutrophilia that was associated with significantly higher pulmonary expression of gamma interferon, CXCL10, and IL-17 proteins than C3H/HeN mice. Using the fungal burden at 4 weeks postinfection as a phenotype, genome-wide quantitative trait locus (QTL) analysis among 435 segregating (C3H/HeN × CBA/J)F2 (C3HCBAF2) hybrids identified two significant QTLs on chromosomes 1 (Cnes4) and 9 (Cnes5) that control susceptibility to cryptococcal pneumonia in an additive manner. Susceptible C3H/HeN mice carry a resistance allele atCnes4and a susceptibility allele atCnes5. These studies reveal additional genetic complexity of the host response toC. neoformansthat is associated with divergent patterns of pulmonary inflammation.
Cyclic Di-GMP Stimulates Biofilm Formation and Inhibits Virulence of Francisella novicida
Authors: Zogaj Xhavit , Wyatt Geoff C. , Klose Karl E. 
Published: September 2012

ABSTRACTFrancisella tularensisis a Gram-negative bacterium that is highly virulent in humans, causing the disease tularemia.F. novicidais closely related toF. tularensisand exhibits high virulence in mice, but it is avirulent in healthy humans. AnF. novicida-specific gene cluster (FTN0451 to FTN0456) encodes two proteins with diguanylate cyclase (DGC) and phosphodiesterase (PDE) domains that modulate the synthesis and degradation of cyclic di-GMP (cdGMP). No DGC- or PDE-encoding protein genes are present in theF. tularensisgenome.F. novicidastrains lacking either the two DGC/PDE genes (cdgAandcdgB) or the entire gene cluster (strain KKF457) are defective for biofilm formation. In addition, expression of CdgB or a heterologous DGC in strain KKF457 stimulatedF. novicidabiofilms, even in a strain lacking the biofilm regulator QseB. Genetic evidence suggests that CdgA is predominantly a PDE, while CdgB is predominantly a DGC. TheF. novicida qseBstrain showed reducedcdgAandcdgBtranscript levels, demonstrating anF. novicidabiofilm signaling cascade that controls cdGMP levels. Interestingly, KKF457 with elevated cdGMP levels exhibited a decrease in intramacrophage replication and virulence in mice, as well as increased growth yields and biofilm formationin vitro. Microarray analyses revealed that cdGMP stimulated the transcription of a chitinase (ChiB) known to contribute to biofilm formation. Our results indicate that elevated cdGMP inF. novicidastimulates biofilm formation and inhibits virulence. We suggest that differences in human virulence betweenF. novicidaandF. tularensismay be due in part to the absence of cdGMP signaling inF. tularensis.
Involvement of Signal Regulatory Protein α, a Negative Regulator of Toll-Like Receptor Signaling, in Impairing the MyD88-Independent Pathway and Intracellular Killing of Burkholderia pseudomallei-Infected Mouse Macrophages
Authors: Baral Pankaj , Utaisincharoen Pongsak 
Published: September 2012

ABSTRACT

The facultative intracellular Gram-negative bacterium
Burkholderia pseudomallei
is the causative agent of melioidosis and is known for its ability to evade the Toll-like receptor (TLR)-mediated innate immune response. Previously it has been demonstrated that this bacterium was able to suppress the MyD88-independent pathway and can survive macrophage intracellular killing. However, the underlying mechanisms responsible for the suppression of this pathway are not fully understood. In the present study, we showed that both living and heat-killed
B. pseudomallei
bacteria restrict the TLR signaling response, particularly macrophage inducible nitric oxide synthase (iNOS) expression, by preventing downregulation of constitutively expressed signal regulatory protein α (SIRPα) molecule, a known negative regulator of TLR signaling. In contrast, a lipopolysaccharide (LPS) mutant of
B. pseudomallei
, a less virulent strain, was able to downregulate SIRPα expression in mouse macrophages. However, depletion of constitutively expressed SIRPα was able to induce the gene expression downstream of TLR signaling pathways (particularly the MyD88-independent pathway), such as that of the iNOS gene, leading to enhanced macrophage intracellular killing of
B. pseudomallei
. Induction of gene expression was consistent with the enhanced degradation pattern of IκBα with SIRPα depletion. Additionally, the downregulation of SIRPα expression with upregulation of iNOS was observed when the macrophages were pretreated with gamma interferon (IFN-γ) prior to the infection, suggesting that the enhanced intracellular killing of bacteria by IFN-γ is associated with the decreased SIRPα expression. Altogether our findings demonstrate that
B. pseudomallei
evades macrophage intracellular killing by preventing the downregulation of SIRPα that results in the inhibition of gene expression downstream of the MyD88-independent pathway.
Nocardia farcinica Activates Human Dendritic Cells and Induces Secretion of Interleukin-23 (IL-23) Rather than IL-12p70
Authors: Eisenblätter Martin , Buchal Ariane , Gayum Hermine , Jasny Edith , Renner Viveros Pablo , Ulrichs Timo , Schneider Thomas , Schumann Ralf R. , Zweigner Janine , Ignatius Ralf 
Published: September 2012

ABSTRACTStudying the interaction of dendritic cells (DCs) with bacteria controlled by T-cell-mediated immune responses may reveal novel adjuvants for the induction of cellular immunity. Murine studies and the observation that nocardias infect predominantly immunosuppressed patients have suggested that these bacteria may possess an adjuvant potential. Moreover, adjuvants on the basis of the nocardial cell wall have been applied in clinical studies. Since the handling of adjuvants by DCs may determine the type of immune responses induced by a vaccine, the present study aimed at investigating the interaction of immature human monocyte-derived DCs with live or inactivatedNocardia farcinicain vitroand determining the cellular phenotypic changes as well as alterations in characteristic functions, such as phagocytosis, induction of T-cell proliferation, and cytokine secretion. Human DCs ingestedN. farcinicaand eradicated the bacterium intracellularly. DCs exposed to inactivatedN. farcinicawere activated, i.e., they developed a mature phenotype, downregulated their phagocytic capacity, and stimulated allogeneic T cells in mixed leukocyte reactions. Soluble factors were not involved in this process. To elucidate the potential adjuvant effect ofN. farcinicaon the induction of T-cell-mediated immune responses, we characterized the cytokines produced by nocardia-exposed DCs and detected substantial amounts of tumor necrosis factor alpha (TNF-α) and interleukin-12 p40 (IL-12p40). However, nocardia-treated DCs secreted only small amounts of IL-12p70, which were significantly smaller than the amounts of IL-23. Thus,N. farcinicaactivates DCs, but adjuvants based on this bacterium may have only a limited capacity to induce Th1 immune responses.
A new workflow for carbonate reservoir modelling based on MPS: shoal bodies in outcrop analogues (Triassic, SW Germany)
Authors: Jung Andre , Aigner Thomas , Palermo Denis , Nardon Sergio , Pontiggia Marco 
Published: September 2012

Abstract
This study presents a workflow for 3D modelling of carbonate reservoirs using multiple-point statistics (MPS) in the framework of a pre-existing model. It consists of the following steps: (1) applying a hierarchical classification scheme for carbonate geobodies; (2) based on this classification, retrieval of relevant data from Carbdb, a novel software to manage a database of analogue studies; (3) construction of training images based on the retrieved data from Carbdb; and (4) using the training images when building a 3D reservoir model with MPS. MPS makes use of training images to capture depositional patterns, which will then be reproduced during the stochastic simulations. Carbdb provides a library of quantitative data such as dimensions, geometries and the distribution pattern of geobody analogues necessary for building training images. The MPS workflow was applied to carbonate shoal bodies from a reservoir analogue, the Muschelkalk in SW Germany. Present-day shoal bodies from the Arabian Gulf were retrieved from Carbdb as possible modern analogues to generate training images. The realizations of this MPS approach are compared with a previously established 3D geocellular model that was built deterministically by interactive facies modelling. The MPS simulations produced geologically more realistic facies distributions with higher facies heterogeneity, similar to the depositional patterns observed in modern analogues.
Metabolic Associations of Reduced Proliferation and Oxidative Stress in Advanced Breast Cancer
Authors: Jerby Livnat , Wolf Lior , Denkert Carsten , Stein Gideon Y. , Hilvo Mika , Oresic Matej , Geiger Tamar , Ruppin Eytan 
Published: September 2012

AbstractAberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent “go or grow” dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)+ versus ER− tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer. Cancer Res; 72(22); 5712–20. ©2012 AACR.
Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes
Authors: Husted Steen , James Stefan , Becker Richard C. , Horrow Jay , Katus Hugo , Storey Robert F. , Cannon Christopher P. , Heras Magda , Lopes Renato D. , Morais Joao , Mahaffey Kenneth W. , Bach Richard G. , Wojdyla Daniel , Wallentin Lars ,   for the PLATO study group
Published: September 2012

Background—
Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (≥75 years of age) with acute coronary syndrome compared with those <75 years of age.

Methods and Results—

The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ≥75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction
P
=0.56), myocardial infarction (
P
=0.33), cardiovascular death (
P
=0.47), definite stent thrombosis (
P
=0.81), or all-cause mortality (
P
=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ≥75 years (hazard ratio, 1.02; 95% confidence interval, 0.82–1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94–1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction.

Conclusions—
The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00391872.