bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mammal‐Derived Respiratory Lipocalin Allergens do not Exhibit Dendritic Cell‐Activating Capacity
Authors: Parviainen S. , Kinnunen T. , Rytkönen‐Nissinen M. , Nieminen A. , Liukko A. , Virtanen T. 
Published: January 2013

AbstractMost mammal‐derived respiratory allergens belong to the lipocalin family of proteins. Determinants of their allergenic capacity are still unknown. Innate immune cells, in particular dendritic cells, have been shown to be involved in the allergenicity of some proteins. As recognition by dendritic cells is one of the few plausible mechanisms for the allergenicity of proteins, we wanted to investigate their role in the allergenicity of lipocalin allergens. Therefore, we first incubated human monocyte‐derived dendritic cells with immunologically functional recombinant allergens mouse Mus m 1, dog Can f 1 and 2, cow Bos d 2, horse Equ c 1 and natural Bos d 2. Then, the surface marker expression and cytokine production of dendritic cells and their capacity to promote T cell proliferation and Th2 immune deviation in naïve CD4+ T cells were examined in vitro. We found that near to endotoxin‐free lipocalin allergens had no effect on the activation, allostimulatory capacity or cytokine production of dendritic cells. The dendritic cells could not induce immune deviation in naïve CD4+ T cells. In contrast, lipopolysaccharide activated the dendritic cells efficiently. However, lipocalin allergens were not able to modify the lipopolysaccharide‐induced responses. We conclude that an important group of mammal‐derived respiratory allergens, lipocalins, appear not to be able to activate dendritic cells, a major component involved in the allergenicity of some proteins. It is conceivable that this incapacity of lipocalin allergens to arouse innate immunity may be associated with their poor capacity to induce a strong T cell response, verified in several studies.
Pro‐IL‐16 is Associated withMHCClassII‐Mediated Negative Regulation of Mouse Resting B Cell Activation throughMAPKinases,NF‐κB and Skp2‐Dependent p27kipRegulation
Authors: Yang H.‐Y. , Kim J. , Kim S.‐H. , Choe C.‐H. , Jang Y.‐S. 
Published: January 2013

AbstractMHCclassIImolecules, in addition to their essential role as antigen‐presenting molecules toCD4+T cell receptor, have a signal‐transducing role related to B cell function. We identified pro‐IL‐16 as one of the proteins associated withMHCclassII‐mediated signalling in an analysis ofMHCclassII‐associated molecules using immunoprecipitation and proteomics data obtained from the 38B9 resting B cell line, and investigated the role of pro‐IL‐16 in resting B cell activation. We found that pro‐IL‐16, rather than mature form ofIL‐16, is present both in the cytoplasm and nucleus of resting B cells, and its expression is influenced byMHCclassII‐mediated signalling. In addition, overexpression of pro‐IL‐16 impaired resting B cell proliferation and this inhibitory effect was mediated through regulating nuclear factor (NF)‐κB activation. Knock‐down of pro‐IL‐16 expression using siRNAdecreased the level of cell‐cycle inhibitor p27kipand increased the level of Skp2. In addition, knock‐down of pro‐IL‐16 modulated mitogen‐activated protein kinase activation. Given thatIL‐16 acts as an immunomodulator by impairing antigen‐induced T cell activation and its precursor, pro‐IL‐16, plays a role in regulating the cell cycle in T lymphocytes and T cell lymphoma, we concluded that pro‐IL‐16 is involved in resting B cell proliferation, similar to its function in T lymphocytes.
Thinking Outside the Disciplinary Box in Coping with Dilemmas in Geoinformation Management for Public Policy
Authors: de Man W.H. Erik 
Published: January 2013

AbstractNotwithstanding optimistic rhetoric about integrating geospatial data from different sources and supporting good governance, much of the literature on geoinformation management is limited to a technical orientation with a positivist paradigm. Complex geoinformation management, like public policy, must go beyond these boundaries. The article calls attention to the underexposed role of dilemmas in geoinformation management and how to cope with them. It uses lessons from the development of ‘integrated surveys’ at the former International Training Centre for Aerial Survey (ITC) in TheNetherlands as an early and practical case of managing geoinformation for public policy some 40 years ago. These lessons are apparently also relevant to modern digital geoinformation management, as inSDI. Focus on public policy requires not only integration of geospatial data from different sources but also integration of geoinformation into complex decision‐making processes. This complexity probably creates dilemmas because of mutually incompatible perspectives between different actors on what is to be managed. Geoinformation management for public policy therefore requires the ability to find, over and over again, a common ground between and beyond incompatible perspectives. The article proposes a ‘transdisciplinary’ framing of geoinformation management to support the required thinking outside the box.
Using Pattern‐oriented Modeling (POM) to Cope with Uncertainty in Multi‐scale Agent‐based Models of Land Change
Authors: Magliocca Nicholas R. , Ellis Erle C. 
Published: January 2013

AbstractLocal land‐use and ‐cover changes (LUCCs) are the result of both the decisions and actions of individual land‐users, and the larger global and regional economic, political, cultural, and environmental contexts in which land‐use systems are embedded. However, the dearth of detailed empirical data and knowledge of the influences of global/regional forces on local land‐use decisions is a substantial challenge to formulating multi‐scale agent‐based models (ABMs) of land change. Pattern‐oriented modeling (POM) is a means to cope with such process and parameter uncertainty, and to design process‐based land change models despite a lack of detailed process knowledge or empirical data.POMwas applied to a simplified agent‐based model ofLUCCto design and test model relationships linking global market influence to agents’ land‐use decisions within an example test site. Results demonstrated that evaluating alternative model parameterizations based on their ability to simultaneously reproduce target patterns led to more realistic land‐use outcomes. This framework is promising as an agent‐based virtual laboratory to test hypotheses of how and under what conditions driving forces of land change differ from a generalized model representation depending on the particular land‐use system and location.
Does Indeterminacy Matter?
Authors: Buford Christopher T. 
Published: January 2013

AbstractDerek Parfit has offered numerous arguments in an attempt to establish that identity is not what matters. Jens Johannson has recently argued that Parfit's various arguments for the claim that identity is not what matters fail to establish what Parfit takes such arguments to establish. Johannson contends that this is due in part to the invalidity of one of Parfit's key arguments, and the fact that Parfit ignores a position that is compatible with the conclusions of his successful arguments and the claim that identity is in fact what matters, namely, that I survive fission as either one of the fission products or the other, but it is indeterminate which one I survive as. I aim to establish here that both of Johannson's assertions are problematic. As a corollary of this task, I hope to shed some light on the relationship between indeterminacy and fission‐based arguments for the claim that identity is not what matters.
The Aquilegia FRUITFULL‐like genes play key roles in leaf morphogenesis and inflorescence development
Authors: Pabón‐Mora Natalia , Sharma Bharti , Holappa Lynn D. , Kramer Elena M. , Litt Amy 
Published: January 2013

SummaryThe APETALA1/FRUITFULL (AP1/FUL) MADS box transcription factors are best known for the role of AP1 in Arabidopsis sepal and petal identity, the canonical A function of the ABC model of flower development. However, this gene lineage underwent multiple duplication events during angiosperm evolution, providing different taxa with unique gene complements. One such duplication correlates with the origin of the core eudicots, and produced the euAP1 and euFUL clades. Together, euAP1 and euFUL genes function in proper floral meristem identity and repression of axillary meristem growth. Independently, euAP1 genes function in floral meristem and sepal identity, whereas euFUL genes control phase transition, cauline leaf growth and fruit development. To investigate the impact of the core eudicot duplication on the functional diversification of this gene lineage, we studied the role of pre‐duplication FUL‐like genes in columbine (Aquilegia coerulea). Our results show that AqcFL1 genes are broadly expressed in vegetative and reproductive meristems, leaves and flowers. Virus‐induced gene silencing of the loci results in plants with increased branching, shorter inflorescences with fewer flowers, and dramatic changes in leaf shape and complexity. However, aqcfl1 plants have normal flowers and fruits. Our results show that, in contrast to characterized AP1/FUL genes, the AqcFL1 loci are either genetically redundant or have been decoupled from the floral genetic program, and play a major role in leaf morphogenesis. We analyze the results in the context of the core eudicot duplication, and discuss the implications of our findings in terms of the genetic regulation of leaf morphogenesis in Aquilegia and other flowering plants.
Gating of long‐term depression by Ca2+/calmodulin‐dependent protein kinase II through enhanced cGMP signalling in cerebellar Purkinje cells
Authors: Kawaguchi Shin‐ya , Hirano Tomoo 
Published: January 2013

Key points
Long‐term depression (LTD) at parallel fibre synapses on a cerebellar Purkinje cell has been regarded as a cellular basis for motor learning.
Although Ca2+/calmodulin‐dependent protein kinase II (CaMKII) has been implicated in the LTD induction and motor learning, the underlying molecular mechanism remains unclear.
By combined application of simulation and experiments, we have attempted to explore the potential signalling pathway underlying the CaMKII involvement in LTD. Our data show that CaMKII supports the LTD‐inducing signalling pathway consisting of other protein kinases such as protein kinase C and mitogen‐activated protein kinase.
The gating of the LTD‐inducing pathway by CaMKII is mediated by negative regulation of phosphodiesterase 1, and the resultant facilitation of the cGMP/protein kinase G (PKG) pathway. As a result, protein phosphatase 2A activity was suppressed, supporting the LTD induction.
In addition, nitric oxide‐mediated cGMP/PKG activation compensated for the lack of CaMKII activation in LTD induction.
This study provides a comprehensive understanding of elaborate intracellular signalling mechanisms for LTD regulation.
Abstract  Long‐term depression (LTD) at parallel fibre synapses on a cerebellar Purkinje cell has been regarded as a cellular basis for motor learning. Although Ca2+/calmodulin‐dependent protein kinase II (CaMKII) has been implicated in the LTD induction as an important Ca2+‐sensing molecule, the underlying signalling mechanism remains unclear. Here, we attempted to explore the potential signalling pathway underlying the CaMKII involvement in LTD using a systems biology approach, combined with validation by electrophysiological and FRET imaging experiments on a rat cultured Purkinje cell. Model simulation predicted the following cascade as a candidate mechanism for the CaMKII contribution to LTD: CaMKII negatively regulates phosphodiesterase 1 (PDE1), subsequently facilitates the cGMP/protein kinase G (PKG) signalling pathway and down‐regulates protein phosphatase 2A (PP‐2A), thus supporting the LTD‐inducing positive feedback loop consisting of mutual activation of protein kinase C (PKC) and mitogen‐activated protein kinase (MAPK). This model suggestion was corroborated by whole‐cell patch clamp recording experiments. In addition, FRET measurement of intracellular cGMP concentration revealed that CaMKII activation causes sustained increase of cGMP, supporting the signalling mechanism of LTD induction by CaMKII. Furthermore, we found that activation of the cGMP/PKG pathway by nitric oxide (NO) can support LTD induction without activation of CaMKII. Thus, this study clarified interaction between NO and Ca2+/CaMKII, two important factors required for LTD.
Genetically encoded pH‐indicators reveal activity‐dependent cytosolic acidification of Drosophila motor nerve termini in vivo
Authors: Rossano Adam J. , Chouhan Amit K. , Macleod Gregory T. 
Published: January 2013

Key points
Changes in pH occur within neurons during nerve activity and in response to hypoxic insult.
Many aspects of neurophysiology are potentially influenced by intracellular pH changes.
At the fruit fly larval neuromuscular junction, fluorescent genetically encoded pH‐indicators (GEpHIs) revealed significant cytosolic acidification of presynaptic termini during nerve activity.
GEpHIs revealed that presynaptic pH changes occur in live intact larvae, indicating for the first time that such pH changes are not an artifact of experimental conditions.
The pH changes in presynaptic termini are substantial and are likely to influence synaptic function.
Abstract  All biochemical processes, including those underlying synaptic function and plasticity, are pH sensitive. Cytosolic pH (pHcyto) shifts are known to accompany nerve activity in situ, but technological limitations have prevented characterization of such shifts in vivo. Genetically encoded pH‐indicators (GEpHIs) allow for tissue‐specific in vivo measurement of pH. We expressed three different GEpHIs in the cytosol of Drosophila larval motor neurons and observed substantial presynaptic acidification in nerve termini during nerve stimulation in situ. SuperEcliptic pHluorin was the most useful GEpHI for studying pHcyto shifts in this model system. We determined the resting pH of the nerve terminal cytosol to be 7.30 ± 0.02, and observed a decrease of 0.16 ± 0.01 pH units when the axon was stimulated at 40 Hz for 4 s. Realkalinization occurred upon cessation of stimulation with a time course of 20.54 ± 1.05 s (τ). The chemical pH‐indicator 2′,7′‐bis‐(2‐carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein corroborated these changes in pHcyto. Bicarbonate‐derived buffering did not contribute to buffering of acid loads from short (≤4 s) trains of action potentials but did buffer slow (∼60 s) acid loads. The magnitude of cytosolic acid transients correlated with cytosolic Ca2+ increase upon stimulation, and partial inhibition of the plasma membrane Ca2+‐ATPase, a Ca2+/H+ exchanger, attenuated pHcyto shifts. Repeated stimulus trains mimicking motor patterns generated greater cytosolic acidification (∼0.30 pH units). Imaging through the cuticle of intact larvae revealed spontaneous pHcyto shifts in presynaptic termini in vivo, similar to those seen in situ during fictive locomotion, indicating that presynaptic pHcyto shifts cannot be dismissed as artifacts of ex vivo preparations.
Rectal Swabs Are Suitable for Quantifying the Carriage Load of KPC-Producing Carbapenem-Resistant Enterobacteriaceae
Authors: Lerner A. , Romano J. , Chmelnitsky I. , Navon-Venezia S. , Edgar R. , Carmeli Y. 
Published: January 2013

ABSTRACT

It is more convenient and practical to collect rectal swabs than stool specimens to study carriage of colon pathogens. In this study, we examined the ability to use rectal swabs rather than stool specimens to quantify
Klebsiella pneumoniae
carbapenemase (KPC)-producing carbapenem-resistant
Enterobacteriaceae
(CRE). We used a quantitative real-time PCR (qPCR) assay to determine the concentration of the
bla
KPC
gene relative to the concentration of 16S rRNA genes and a quantitative culture-based method to quantify CRE relative to total aerobic bacteria. Our results demonstrated that rectal swabs are suitable for quantifying the concentration of KPC-producing CRE and that qPCR showed higher correlation between rectal swabs and stool specimens than the culture-based method.
Preliminary Pharmacokinetic Study of Repeated Doses of Rifampin and Rifapentine in Guinea Pigs
Authors: Dutta Noton K. , Alsultan Abdullah , Peloquin Charles A. , Karakousis Petros C. 
Published: January 2013

ABSTRACT
Substitution of rifapentine (RFP) for rifampin (RIF) in the standard antituberculous regimen reduces the time required to cure chronic tuberculosis (TB) infection in mice, but not in guinea pigs. In order to gain insight into these discrepant findings, we conducted a steady-state pharmacokinetic (PK) study in healthy guinea pigs to study the metabolism and autoinduction of RIF and RFP. Both RFP and RIF 25-desacetyl metabolites (desRFP and desRIF, respectively), were detected at low concentrations in the serum of guinea pigs. The metabolite concentrations in guinea pigs are much lower than those seen in humans at steady state.
Discovery of a Novel Class of Boron-Based Antibacterials with Activity against Gram-Negative Bacteria
Authors: Hernandez Vincent , Crépin Thibaut , Palencia Andrés , Cusack Stephen , Akama Tsutomu , Baker Stephen J. , Bu Wei , Feng Lisa , Freund Yvonne R. , Liu Liang , Meewan Maliwan , Mohan Manisha , Mao Weimin , Rock Fernando L. , Sexton Holly , Sheoran Anita , Zhang Yanchen , Zhang Yong-Kang , Zhou Yasheen , Nieman James A. , Anugula Mahipal Reddy , Keramane El Mehdi , Savariraj Kingsley , Reddy D. Shekhar , Sharma Rashmi , Subedi Rajendra , Singh Rajeshwar , O'Leary Ann , Simon Nerissa L. , De Marsh Peter L. , Mushtaq Shazad , Warner Marina , Livermore David M. , Alley M. R. K. , Plattner Jacob J. 
Published: January 2013

ABSTRACTGram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms inEscherichia coliandPseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, includingEnterobacteriaceaebearing NDM-1 and KPC carbapenemases, as well asP. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious againstE. coliandP. aeruginosain murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
Arrested Protein Synthesis Increases Persister-Like Cell Formation
Authors: Kwan Brian W. , Valenta John A. , Benedik Michael J. , Wood Thomas K. 
Published: January 2013

ABSTRACT

Biofilms are associated with a wide variety of bacterial infections and pose a serious problem in clinical medicine due to their inherent resilience to antibiotic treatment. Within biofilms, persister cells comprise a small bacterial subpopulation that exhibits multidrug tolerance to antibiotics without undergoing genetic change. The low frequency of persister cell formation makes it difficult to isolate and study persisters, and bacterial persistence is often attributed to a quiescent metabolic state induced by toxins that are regulated through toxin-antitoxin systems. Here we mimic toxins via chemical pretreatments to induce high levels of persistence (10 to 100%) from an initial population of 0.01%. Pretreatment of
Escherichia coli
with (i) rifampin, which halts transcription, (ii) tetracycline, which halts translation, and (iii) carbonyl cyanide
m
-chlorophenylhydrazone, which halts ATP synthesis, all increased persistence dramatically. Using these compounds, we demonstrate that bacterial persistence results from halted protein synthesis and from environmental cues.
High Prevalence of Fluoroquinolone-Resistant Group B Streptococci among Clinical Isolates in China and Predominance of Sequence Type 19 with Serotype III
Authors: Wang Hui , Zhao Chunjiang , He Wenqiang , Zhang Feifei , Zhang Liyan , Cao Bin , Sun Ziyong , Xu Yingchun , Yang Qing , Mei Yaning , Hu Bijie , Chu Yunzhuo , Liao Kang , Yu Yunsong , Hu Zhidong , Ni Yuxing 
Published: January 2013

ABSTRACT

A total of 146 group B streptococcus isolates from 8 cities across China belonged to four serotypes. Serotype Ia was more common in children. A high prevalence of resistance was observed for levofloxacin (37.7%), erythromycin (71.2%), clindamycin, (53.4%), and tetracycline (81.5%). The levofloxacin and clindamycin resistances among the 4 serotypes differed significantly. Eighty percent of fluoroquinolone-resistant isolates belonged to the sequence type 19 (ST19)/serotype III clone, with GyrA-ParC-ParE triple substitutions. This clone carried the
erm
(B),
mef
(E), and
tet
(M) genes.
Protein-Free Efavirenz Concentrations in Cerebrospinal Fluid and Blood Plasma Are Equivalent: Applying the Law of Mass Action To Predict Protein-Free Drug Concentration
Authors: Avery L. B. , Sacktor N. , McArthur J. C. , Hendrix C. W. 
Published: January 2013

ABSTRACT

Efavirenz (EFV) is one of the most commonly prescribed antiretroviral drugs (ARVs) for the treatment of HIV. Highly protein-bound drugs, like EFV, have limited central nervous system (CNS) penetration when measured using total drug concentration gradients between blood plasma (BP) and cerebrospinal fluid (CSF). However, the more relevant pharmacologically active protein-free drug concentrations are rarely assessed directly in clinical studies. Using paired BP and CSF samples obtained from 13 subjects on an EFV-containing regimen, both the protein-free and total concentrations of EFV were determined. Despite a median (interquartile range [IQR]) total EFV BP/CSF concentration ratio of 134 (116 to 198), the protein-free EFV BP/CSF concentration ratio was 1.20 (0.97 to 2.12). EFV median (IQR) protein binding was 99.78% (99.74 to 99.80%) in BP and 76.19% (74.47 to 77.15%) in CSF. In addition, using the law of mass action and an
in vitro
-derived EFV-human serum albumin dissociation constant, we have demonstrated that the predicted median (IQR) protein-free concentration in BP, 4.59 ng/ml (4.02 to 9.44 ng/ml), compared well to that observed in BP, 4.77 ng/ml (3.68 to 6.75 ng/ml). Similar results were also observed in CSF and seminal plasma. This method provides a useful predictive tool for estimating protein binding in varied anatomic compartments. Our results of equivalent protein-free EFV concentrations in BP and CSF do not support prior concerns of the CNS as a pharmacological sanctuary from EFV. As CSF penetration of ARVs may increase our understanding of HIV-associated neurological dysfunction and antiretroviral effect, assessment of protein-free CSF concentrations of other highly protein-bound ARVs is warranted.