bluuebunny/crossref_metadata_2025_split huggingface dataset:
Food Allergen–Induced Mast Cell Degranulation is Dependent on PI3K‐Mediated Reactive Oxygen Species Production and Upregulation of Store‐Operated Calcium Channel Subunits
Authors: Yang B. , Yang C. , Wang P. , Li J. , Huang H. , Ji Q. , Liu J. , Liu Z. 
Published: May 2013

AbstractThe importance of Ca2+ influx via store‐operated calcium channels (SOCs) leading to mast cell degranulation is well known in allergic disease. However, the underlying mechanisms are not fully understood. With food‐allergic rat model, the morphology of degranulated mast cell was analysed by toluidine blue stain and electron microscope. Ca2+ influx via SOCs was checked by Ca2+ imaging confocal microscope. Furthermore, the mRNA and protein expression of SOCs subunits were investigated using qPCR and Western blot. We found that ovalbumin (OVA) challenge significantly increased the levels of Th2 cytokines and OVA‐specific IgE in allergic animals. Parallel to mast cell activation, the levels of histamine in serum and supernatant of rat peritoneal lavage solution were remarkably increased after OVA treatment. Moreover, the Ca2+ entry through SOCs evoked by thapsigargin was increased in OVA‐challenged group. The mRNA and protein expressions of SOC subunits, stromal interaction molecule 1 (STIM1) and Orail (calcium‐release‐activated calcium channel protein 1), were dramatically elevated under food‐allergic condition. Administration of Ebselen, a scavenger of reactive oxygen species (ROS), significantly attenuated OVA sensitization‐induced intracellular Ca2+ rise and upregulation of SOCs subunit expressions. Intriguingly, pretreatment with PI3K‐specific inhibitor (Wortmannin) partially abolished the production of ROS and subsequent elevation of SOCs activity and their subunit expressions. Taken together, these results imply that enhancement of SOC‐mediated Ca2+ influx induces mast cell activation, contributing to the pathogenesis of OVA‐stimulated food allergy. PI3K‐dependent ROS generation involves in modulating the activity of SOCs by increasing the expressions of their subunit.
Inhibitors of BTK and ITK: State of the New Drugs for Cancer, Autoimmunity and Inflammatory Diseases
Authors: Vargas L. , Hamasy A. , Nore B. F. , E. Smith C. I. 
Published: May 2013

AbstractBTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss‐of‐function mutations causing X‐linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein–Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small‐molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug‐induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI‐32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non‐Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.
Psychometric properties of the Norwegian version of the Childhood Trauma Questionnaire in high‐risk groups
Authors: Dovran Anders , Winje Dagfinn , Øverland Simon N. , Breivik Kyrre , Arefjord Kjersti , Dalsbø Anita S. , Jentoft Mette B. , Hansen Anita L. , Waage Leif 
Published: May 2013

The Childhood Trauma Questionnaire ‐ Short Form (CTQ‐SF) is widely used to measure childhood abuse of all types. In the present study, we examined the psychometric properties of the Norwegian version of the instrument. The participants constituted four subsamples (n = 517): substance abusers (n = 126), psychiatric patients (n = 210), prisoners (n = 109) and adolescents in out‐of‐home placements (n = 72). Confirmatory factor analysis revealed a reasonable fit of the data to the original five‐factor structure of the CTQ‐SF. Measurement invariance was found across gender and the four subsamples. It was concluded that the Norwegian version of the CTQ‐SF has acceptable psychometric properties, with good reliability and satisfactory accuracy, to assess different dimensions of childhood trauma.
Influence of wastewater treatment on sludge production and processing
Authors: Barber William Pablo Freese 
Published: May 2013

AbstractThe challenge of stricter wastewater standards is resulting in configuration changes to wastewater treatment. As facilities upgrade, the type of sludge produced is changing, with growing quantities of secondary and chemical sludge at the expense of primary sludge. It is already understood that secondary sludge is harder to treat than its primary equivalent; therefore, increasing the quantity of this type of sludge will have detrimental impacts downstream. As legislation tightens further, extended aeration times may be required during processing to remove more nutrients. Work has shown that extended aeration further exacerbates the treatability of secondary sludge. This paper explains how tightening wastewater legislation fundamentally alters the nature of the sludge produced, and how these alterations impact further processing, especially with respect to sludge production and type; sludge energy content; performance of anaerobic digestion and dewatering, and potential for thermal energy recovery.
Voluntary locomotion linked with cerebral activation is mediated by vasopressin V1a receptors in free‐moving mice
Authors: Masuki Shizue , Sumiyoshi Eri , Koshimizu Taka‐aki , Qian Jinze , Higuchi Keiichi , Tsujimoto Gozoh , Nose Hiroshi 
Published: May 2013

Key points
Arterial blood pressure rises at the onset of voluntary locomotion, which is probably advantageous for increasing blood flow to contracting muscles without delay.
We previously reported in free‐moving mice that the feedback control of arterial blood pressure through peripheral baroreceptors, which was dominant at rest, was suppressed during activation of the cerebral cortex; however, no neurotransmitter for the mechanisms has been identified.
Central suppression of the feedback control of arterial blood pressure at the onset of voluntary locomotion was abolished in vasopressin V1a receptor‐deficient mice and by local infusion of a V1a receptor antagonist into the brainstem area, termed the nucleus tractus solitarii, of control mice.
Thus, central vasopressin might play an important role as a neurotransmitter in the pressor response at the onset of voluntary locomotion.
Abstract  We previously reported that cerebral activation suppressed baroreflex control of heart rate (HR) at the onset of voluntary locomotion. In the present study, we examined whether vasopressin V1a receptors in the brain were involved in these responses by using free‐moving V1a receptor knockout (KO, n= 8), wild‐type mice locally infused with a V1a receptor antagonist into the nucleus tractus solitarii (BLK, n= 8) and control mice (CNT, n= 8). Baroreflex sensitivity (ΔHR/ΔMAP) was determined from HR response (ΔHR) to a spontaneous change in mean arterial pressure (ΔMAP) every 4 s during the total resting period, which was ∼8.7 h, of the 12 h measuring period in the three groups. ΔHR/ΔMAP was determined during the periods when the cross‐correlation function (R(t)) between ΔHR and ΔMAP was significant (P < 0.05). Cerebral activity was determined from the power density ratio of θ to δ wave band (θ/δ) on the electroencephalogram every 4 s. Spontaneous changes in θ/δ were significantly correlated with R(t) during 62 ± 3% of the total resting period in CNT (P < 0.05), but only 38 ± 4% in KO and 47 ± 2% in BLK (vs. CNT, both P < 0.001). When R(t) and ΔHR/ΔMAP were divided into six bins according to the level of θ/δ, both were positively correlated with θ/δ in CNT (both P < 0.001), while neither was correlated in KO or BLK (all P > 0.05). Moreover, the probability that mice started to move after an increase in θ/δ was 24 ± 4% in KO and 24 ± 6% in BLK, markedly lower than 61 ± 5% in CNT (both P < 0.001), with no suppression of the baroreflex control of HR. Thus, central V1a receptors might play an important role in suppressing baroreflex control of HR during cerebral activation at the onset of voluntary locomotion.
Paired‐pulse facilitation at recurrent Purkinje neuron synapses is independent of calbindin and parvalbumin during high‐frequency activation
Authors: Bornschein Grit , Arendt Oliver , Hallermann Stefan , Brachtendorf Simone , Eilers Jens , Schmidt Hartmut 
Published: May 2013

Key points
Endogenous Ca2+ binding proteins such as calbinding‐D28k (CB) and parvalbumin (PV) are considered important regulators of short‐term synaptic plasticity.
Cerebellar Purkinje neurons express large amounts of CB and PV and are laterally connected by inhibitory synapses that show paired‐pulse facilitation (PPF) during high‐frequency activation.
We report quantal synaptic release parameters of these synapses in wild‐type and in CB and PV knock‐out mice; evidence is provided that these synapses operate at nanodomain influx‐release coupling.
We find that PPF is independent of CB and PV, using a combination of paired electrophysiological recordings, synaptic Ca2+ imaging and numerical computer simulations.
Our results suggest that PPF during high‐frequency activation results from slow Ca2+ unbinding from the sensor for transmitter release, which is reminiscent of the ‘active Ca2+’ mechanism of PPF suggested by Katz and Miledi in 1968.
Abstract  Paired‐pulse facilitation (PPF) is a dynamic enhancement of transmitter release considered crucial in CNS information processing. The mechanisms of PPF remain controversial and may differ between synapses. Endogenous Ca2+ buffers such as parvalbumin (PV) and calbindin‐D28k (CB) are regarded as important modulators of PPF, with PV acting as an anti‐facilitating buffer while saturation of CB can promote PPF. We analysed transmitter release and PPF at intracortical, recurrent Purkinje neuron (PN) to PN synapses, which show PPF during high‐frequency activation (200 Hz) and strongly express both PV and CB. We quantified presynaptic Ca2+ dynamics and quantal release parameters in wild‐type (WT), and CB and PV deficient mice. Lack of CB resulted in increased volume averaged presynaptic Ca2+ amplitudes and in increased release probability, while loss of PV had no significant effect on these parameters. Unexpectedly, none of the buffers significantly influenced PPF, indicating that neither CB saturation nor residual free Ca2+ ([Ca2+]res) was the main determinant of PPF. Experimentally constrained, numerical simulations of Ca2+‐dependent release were used to estimate the contributions of [Ca2+]res, CB, PV, calmodulin (CaM), immobile buffer fractions and Ca2+ remaining bound to the release sensor after the first of two action potentials (‘active Ca2+’) to PPF. This analysis indicates that PPF at PN–PN synapses does not result from either buffer saturation or [Ca2+]res but rather from slow Ca2+ unbinding from the release sensor.
Caspofungin MICs Correlate with Treatment Outcomes among Patients with Candida glabrata Invasive Candidiasis and Prior Echinocandin Exposure
Authors: Shields Ryan K. , Nguyen M. Hong , Press Ellen G. , Updike Cassaundra L. , Clancy Cornelius J. 
Published: May 2013

ABSTRACT

Mutations in
Candida glabrata FKS
genes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identify
C. glabrata
FKS
mutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile-site
C. glabrata
isolates harbored
FKS1
(
n
= 3) or
FKS2
(
n
= 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (
P
= 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 μg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifying
FKS
mutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD-antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (
P
= 0.002) or infection with an
FKS
mutant (
P
= 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (
P
≤ 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (
P
< 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifying
C. glabrata
FKS
mutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes for
C. glabrata
invasive candidiasis.
Antimicrobial Activity of Nanoemulsion in Combination with Cetylpyridinium Chloride in Multidrug-Resistant Acinetobacter baumannii
Authors: Hwang Yoon Y. , Ramalingam Karthikeyan , Bienek Diane R. , Lee Valerie , You Tao , Alvarez Rene 
Published: May 2013

ABSTRACT

Acinetobacter baumannii
has emerged as a serious problematic pathogen due to the ever-increasing presence of antibiotic resistance, demonstrating a need for novel, broad-spectrum antimicrobial therapeutic options. Antimicrobial nanoemulsions are emulsified mixtures of detergent, oil, and water (droplet size, 100 to 800 nm) which have broad antimicrobial activity against bacteria, enveloped viruses, and fungi. Here, we screened the antimicrobial activities of five nanoemulsion preparations against four
Acinetobacter baumannii
isolates to identify the most suitable preparation for further evaluation. Among them, N5, which contains 10% (vol/vol) Triton X-100, 25% (vol/vol) soybean oil, and 1% (wt/vol) cetylpyridinium chloride (CPC), showed the best efficacy against
A. baumannii
in both its planktonic and biofilm forms and was selected for further study. Our data demonstrate that, while the killing of planktonic forms of
A. baumannii
was due to the 1% CPC component of our nanoemulsions, the breakdown of biofilms was achieved via the emulsified oil and detergent fractions. Furthermore, we documented the effect of ethanol and NaCl in combination with N5 on planktonic
A. baumannii
. In killing curves of N5 combined with other agents (ethanol or NaCl), a synergistic effect of a ≥2-log decrease in CFU/ml was observed. The antibiofilm activity of N5 was confirmed via a cell proliferation test and scanning electron microscopy. The effects of exposure to severe environmental conditions, which simulates the field conditions in Iraq and Afghanistan, were evaluated, and this exposure did not affect the overall antimicrobial activity of N5. These studies lay a solid foundation for the utilization of nanoemulsions against the antibiotic-resistant forms of
A. baumannii
.
Enhancing the Protective Immune Response against Botulism
Authors: Przedpelski Amanda , Tepp William H. , Kroken Abby R. , Fu Zhuji , Kim Jung-Ja P. , Johnson Eric A. , Barbieri Joseph T. 
Published: May 2013

ABSTRACT
The need for a vaccine against botulism has increased since the discontinuation of the pentavalent (ABCDE) botulinum toxoid vaccine by the Centers for Disease Control and Prevention. The botulinum toxins (BoNTs) are the primary virulence factors and vaccine components against botulism. BoNTs comprise three domains which are involved in catalysis (LC), translocation (HCT), and host receptor binding (HCR). Recombinant HCR subunits have been used to develop the next generation of BoNT vaccines. Using structural studies and the known entry properties of BoNT/A, an HCR subunit vaccine against BoNT/A that contained the point mutation W1266A within the ganglioside binding pocket was designed. HCR/A(W1266A) did not enter primary neurons, and the crystal structure of HCR/A(W1266A) was virtually identical to that of wild-type HCR/A. Using a mouse model, experiments were performed using a high-dose vaccine and a low-dose vaccine. At a high vaccine dose, HCR/A and HCR/A(W1266A) elicited a protective immune response to BoNT/A challenge. At the low-dose vaccination, HCR/A(W1266A) was a more protective vaccine than HCR/A. α-HCR IgG titers correlated with protection from BoNT challenge, although titers to block HCR/A entry were greater in serum in HCR/A-vaccinated mice than in HCR/A(W1266A)-vaccinated mice. This study shows that removal of receptor binding capacity enhances potency of the subunit HCR vaccine. Vaccines that lack receptor binding capacity have the added property of limited off-target toxicity.
APRICOD
Authors: Zhao Zhen Wei , Ooi Wei Tsang 
Published: May 2013

Content discovery is a major source of latency in peer-to-peer (P2P) media streaming systems, especially in the presence of noncontinuous user access, such as random seek in Video-on-Demand (VoD) streaming and teleportation in a Networked Virtual Environment (NVE). After the aforementioned user interactions, streaming systems often need to initiate the content discovery process to identify where to retrieve the requested media objects. Short content lookup latency is demanded to ensure smooth user experience. Existing content discovery systems based on either a Distributed Hash Table (DHT) or gossip mechanism cannot cope with noncontinuous access efficiently due to their long lookup latency.
In this work, we propose an access-pattern-driven distributed caching middleware named APRICOD, which caters for fast and scalable content discovery in peer-to-peer media streaming systems, especially when user interactions are present. APRICOD exploits correlations among media objects accessed by users, and adapts to shift in the user access pattern automatically. We first present a general APRICOD design that can be used with any existing content discovery system. We then present an implementation of APRICOD on top of Pastry, which we use to evaluate APRICOD. Our evaluation in a 1024-node system, using a Second Life trace with 5,735 users and a VoD trace with 54 users, shows that APRICOD can effectively resolve all continuous access queries with a single hop deterministically with node failure as an exception, and resolve noncontinuous access queries with a single hop with high probability.
Innate Signaling Promotes Formation of Regulatory Nitric Oxide–Producing Dendritic Cells Limiting T-Cell Expansion in Experimental Autoimmune Myocarditis
Authors: Kania Gabriela , Siegert Stefanie , Behnke Silvia , Prados-Rosales Rafael , Casadevall Arturo , Lüscher Thomas F. , Luther Sanjiv A. , Kopf Manfred , Eriksson Urs , Blyszczuk Przemyslaw 
Published: May 2013

Background—

Activation of innate pattern-recognition receptors promotes CD4
+
T-cell–mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms that counterregulate exaggerated heart-specific autoimmunity are poorly understood.

Methods and Results—

Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with α-myosin heavy chain peptide and complete Freund’s adjuvant. Together with interferon-γ, heat-killed
Mycobacterium tuberculosis
, an essential component of complete Freund’s adjuvant, converted CD11b
hi
CD11c
−
monocytes into tumor necrosis factor-α– and nitric oxide synthase 2–producing dendritic cells (TipDCs). Heat-killed
M. tuberculosis
stimulated production of nitric oxide synthase 2 via Toll-like receptor 2–mediated nuclear factor-κB activation. TipDCs limited antigen-specific T-cell expansion through nitric oxide synthase 2–dependent nitric oxide production. Moreover, they promoted nitric oxide synthase 2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, nitric oxide synthase 2 production by both radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo.

Conclusions—
Innate Toll-like receptor 2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T-cell responses in experimental autoimmune myocarditis via nitric oxide. Therefore, activation of innate pattern-recognition receptors is critical not only for disease induction but also for counterregulatory mechanisms, protecting the heart from exaggerated autoimmunity.
Modeling the Vulnerability of an Urban Groundwater System due to the Combined Impacts of Climate Change and Management Scenarios
Authors: Sekhar M. , Shindekar M. , Tomer Sat K. , Goswami P. 
Published: May 2013

Abstract
Climate change impact on a groundwater-dependent small urban town has been investigated in the semiarid hard rock aquifer in southern India. A distributed groundwater model was used to simulate the groundwater levels in the study region for the projected future rainfall (2012–32) obtained from a general circulation model (GCM) to estimate the impacts of climate change and management practices on groundwater system. Management practices were based on the human-induced changes on the urban infrastructure such as reduced recharge from the lakes, reduced recharge from water and wastewater utility due to an operational and functioning underground drainage system, and additional water extracted by the water utility for domestic purposes. An assessment of impacts on the groundwater levels was carried out by calibrating a groundwater model using comprehensive data gathered during the period 2008–11 and then simulating the future groundwater level changes using rainfall from six GCMs [Institute of Numerical Mathematics Coupled Model, version 3.0 (INM-CM.3.0); L'Institut Pierre-Simon Laplace Coupled Model, version 4 (IPSL-CM4); Model for Interdisciplinary Research on Climate, version 3.2 (MIROC3.2); ECHAM and the global Hamburg Ocean Primitive Equation (ECHO-G); Hadley Centre Coupled Model, version 3 (HadCM3); and Hadley Centre Global Environment Model, version 1 (HadGEM1)] that were found to show good correlation to the historical rainfall in the study area. The model results for the present condition indicate that the annual average discharge (sum of pumping and natural groundwater outflow) was marginally or moderately higher at various locations than the recharge and further the recharge is aided from the recharge from the lakes. Model simulations showed that groundwater levels were vulnerable to the GCM rainfall and a scenario of moderate reduction in recharge from lakes. Hence, it is important to sustain the induced recharge from lakes by ensuring that sufficient runoff water flows to these lakes.