bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of calcium clock‐mediated pacemaking by inositol‐1,4,5‐trisphosphate receptors in mouse sinoatrial nodal cells
Authors: Kapoor Nidhi , Tran Andrew , Kang Jeanney , Zhang Rui , Philipson Kenneth D. , Goldhaber Joshua I. 
Published: April 2015

Key points
Inositol‐1,4,5‐trisphosphate receptors (IP3Rs) modulate pacemaking in embryonic heart, but their role in adult sinoatrial node (SAN) pacemaking is uncertain.
We found that stimulation of IP3Rs accelerates spontaneous pacing rate in isolated mouse SAN cells, whereas inhibition of IP3Rs slows pacing.
In atrial‐specific sodium‐calcium exchanger (NCX) knockout (KO) SAN cells, where the Ca2+ clock is uncoupled from the membrane clock, IP3R agonists and antagonists modulate the rate of spontaneous Ca2+ waves, suggesting that IP3R‐mediated Ca2+ release modulates the Ca2+ clock.
IP3R modulation also regulates Ca2+ spark parameters, a reflection of ryanodine receptor open probability, consistent with the effect of IP3 signalling on Ca2+ clock frequency.
Modulation of Ca2+ clock frequency by IP3 signalling in NCX KO SAN cells demonstrates that the effect is independent of NCX.
These findings support development of IP3 signalling modulators for regulation of heart rate, particularly in heart failure where IP3Rs are upregulated.
AbstractCardiac pacemaking initiated by the sinus node is attributable to the interplay of several membrane currents. These include the depolarizing ‘funny current’ (If) and the sodium‐calcium exchanger current (INCX). The latter is activated by ryanodine receptor (RyR)‐mediated calcium (Ca2+) release from the sarcoplasmic reticulum (SR). Another SR Ca2+ release channel, the inositol‐1,4,5‐triphosphate receptor (IP3R), has been implicated in the generation of spontaneous Ca2+ release in atrial and ventricular cardiomyocytes. Whether IP3R‐mediated Ca2+ release also influences SAN automaticity is controversial, in part due to the confounding influence of periodic Ca2+ flux through the sarcolemma accompanying each beat. We took advantage of atrial‐specific sodium–calcium exchanger (NCX) knockout (KO) SAN cells to study the influence of IP3 signalling on cardiac pacemaking in a system where periodic intracellular Ca2+ cycling persists despite the absence of depolarization or Ca2+ flux across the sarcolemma. We recorded confocal line scans of spontaneous Ca2+ release in WT and NCX KO SAN cells in the presence or absence of an IP3R blocker (2‐aminoethoxydiphenyl borate, 2‐APB), or during block of IP3 production by the phospholipase C inhibitor U73122. 2‐APB and U73122 decreased the frequency of spontaneous Ca2+ transients and waves in WT and NCX KO cells, respectively. Alternatively, increased IP3 production induced by phenylephrine increased Ca2+ transient and wave frequency. We conclude that IP3R‐mediated SR Ca2+ flux is crucial for initiating and modulating the RyR‐mediated Ca2+ cycling that regulates SAN pacemaking. Our results in NCX KO SAN cells also demonstrate that RyRs, but not NCX, are required for IP3 to modulate Ca2+ clock frequency.
Magnesium Hydride Slurry: A Better Answer to Hydrogen
Storage
Authors: McClaine Andrew W. , Brown Kenneth , Bowen David D. G. 
Published: April 2015

Abstract
By storing hydrogen in an oil-based slurry with powdered magnesium hydride, inexpensive and safe hydrogen storage can be realized. This paper describes the characteristics and benefits of cycling hydrogen in and out of magnesium hydride slurry. An application of magnesium hydride slurry in a baseload wind power system is discussed. It concludes that a 150 MW baseload wind power system can produce an internal rate of return (IRR) of 10% with an electric price of $0.088/kWh. The costs and performance characteristics of this power plant are described.
Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
Authors: Bruno Vincent M. , Shetty Amol C. , Yano Junko , Fidel Paul L. , Noverr Mairi C. , Peters Brian M. 
Published: April 2015

ABSTRACT

Treatment of vulvovaginal candidiasis (VVC), caused most frequently by
Candida albicans
, represents a significant unmet clinical need.
C. albicans
, as both a commensal and a pathogenic organism, has a complex and poorly understood interaction with the vaginal environment. Understanding the complex nature of this relationship is necessary for the development of desperately needed therapies to treat symptomatic infection. Using transcriptome sequencing (RNA-seq), we characterized the early murine vaginal and fungal transcriptomes of the organism during VVC. Network analysis of host genes that were differentially expressed between infected and naive mice predicted the activation or repression of several signaling pathways that have not been previously associated with VVC, including NLRP3 inflammasome activation. Intravaginal challenge of Nlrp3
−/−
mice with
C. albicans
demonstrated severely reduced levels of polymorphonuclear leukocytes (PMNs), alarmins, and inflammatory cytokines, including interleukin-1β (IL-1β) (the hallmarks of VVC immunopathogenesis) in vaginal lavage fluid. Intravaginal administration of wild-type (WT) mice with glyburide, a potent inhibitor of the NLRP3 inflammasome, reduced PMN infiltration and IL-1β to levels comparable to those observed in Nlrp3
−/−
mice. Furthermore, RNA-seq analysis of
C. albicans
genes indicated robust expression of hypha-associated secreted aspartyl proteinases 4, 5, and 6 (SAP4–6), which are known inflammasome activators. Despite colonization similar to that of the WT strain, Δ
SAP4–6
triple and Δ
SAP5
single mutants induced significantly less PMN influx and IL-1β during intravaginal challenge. Our findings demonstrate a novel role for the inflammasome in the immunopathogenesis of VVC and implicate the hypha-associated SAPs as major
C. albicans
virulence determinants during vulvovaginal candidiasis.

IMPORTANCE
Vaginitis, most commonly caused by the fungus
Candida albicans
, results in significant quality-of-life issues for all women of reproductive age. Recent efforts have suggested that vaginitis results from an immunopathological response governed by host innate immunity, although an explanatory mechanism has remained undefined. Using comprehensive genomic, immunological, and pharmacological approaches, we have elucidated the NLRP3 inflammasome as a crucial molecular mechanism contributing to host immunopathology. We have also demonstrated that
C. albicans
hypha-associated secreted aspartyl proteinases (SAP4–6 and SAP5, more specifically) contribute to disease immunopathology. Ultimately, this study enhances our understanding of the complex interplay between host and fungus at the vaginal mucosa and provides proof-of-principle evidence for therapeutic targeting of inflammasomes for symptomatic vulvovaginal candidiasis.
Methicillin-Resistant Staphylococcus aureus Adaptation to Human Keratinocytes
Authors: Soong Grace , Paulino Franklin , Wachtel Sarah , Parker Dane , Wickersham Matthew , Zhang Dongni , Brown Armand , Lauren Christine , Dowd Margaret , West Emily , Horst Basil , Planet Paul , Prince Alice 
Published: April 2015

ABSTRACT

Skin is the most common site of
Staphylococcus aureus
infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that
S. aureus
is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of
S. aureus
isolated from chronically infected patients with atopic dermatitis, we noted 22% had an
agr
mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient,
agr
mutants of methicillin-resistant
S. aureus
(MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58%
agr
or RNAIII mutants (
P
< 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing
agr
-dependent toxins. Our results illustrate the dynamic interplay between
S. aureus
and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms.

IMPORTANCE
Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant
Staphylococcus aureus
(MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that
S. aureus
mutants, by exploiting autophagy, can persist within human keratinocytes.
Results of Florida's Amyotrophic Lateral Sclerosis Surveillance Project, 2009–2011
Authors: Freer Cecilia , Hylton Tara , Jordan Heather M , Kaye Wendy E , Singh Sabrina , Huang Youjie 
Published: April 2015

ObjectiveStudies to determine the incidence and prevalence of amyotrophic lateral sclerosis (ALS) in defined geographic areas in the USA are needed. The Florida Department of Health received funding from the federal Agency for Toxic Substances and Disease Registry to implement a state-wide ALS Surveillance Project. The objectives of the project were to describe the demographic characteristics of ALS cases and to calculate the incidence and prevalence of ALS in Florida.Setting/participantsAll neurologists were asked to submit case reports for persons with ALS diagnosed and/or under their care during 1 January 2009 through 31 December 2011. A medical record verification form and an electromyogram (EMG) report were requested for a sample of cases and reviewed by an independent consulting neurologist to confirm ALS diagnosis. Death data were used to aid with case report collection.Primary and secondary outcome measuresDemographics, relevant history and clinical characteristics, El Escorial classifications, time from symptom onset to diagnosis, crude annual incidence rates and 2009 period prevalence are presented.ResultsThe 1450 reported ALS cases were more likely to be older, male, white and non-Hispanic. Slightly more than 4% of cases were reported as also having dementia, and 4.8% were reported to have an immediate family member diagnosed with ALS. Incidence rates ranged from 1.7 to 1.9 per 100 000 person-years during the project period and the 2009 period prevalence was 4.0 per 100 000 persons.ConclusionsProject findings are generally consistent with findings of population-based studies in Europe, as well as geographically limited studies in the USA. Our findings add to the growing body of epidemiological literature about ALS in the USA. Future epidemiological studies in the USA should focus on identifying cases from minority groups and those that may have limited access to healthcare, and should consider conducting capture–recapture analysis to assess case ascertainment.
Emergence agitation during recovery from intracranial surgery under general anaesthesia: a protocol and statistical analysis plan for a prospective multicentre cohort study
Authors: Yan Li-Mei , Chen Han , Yu Rong-Guo , Wang Zhu-Heng , Zhou Guan-Hua , Wang Yong-Jin , Zhang Xia , Xu Ming , Chen Lu , Zhou Jian-Xin 
Published: April 2015

IntroductionEmergence agitation after intracranial surgery is an important clinical issue during anaesthesia recovery. The aim of this multicentre cohort study is to investigate the incidence of emergence agitation, identify the risk factors and determine clinical outcomes in adult patients after intracranial surgery under general anaesthesia. Additionally, we will deliberately clarify the relationship between postoperative pneumocephalus and agitation.Methods and analysisThe present study is a prospective multicentre cohort study. Five intensive care units (ICUs) in China will participate in the study. Consecutive adult patients admitted to the ICUs after intracranial surgery will be enrolled. Sedation-Agitation Scale (SAS) or Richmond Agitation-Sedation Scale (RASS) will be used to evaluate the patients 12 h after the enrolment. Agitation is defined as an SAS score of 5–7, or an RASS score of +2 to +4. According to the maximal SAS and RASS score, patients will be divided into two cohorts: the agitation group and the non-agitation group. Factors potentially related to emergence agitation will be collected at study entry, during anaesthesia and operation, during postoperative care. Univariate analyses between the agitation and the non-agitation groups will be performed. The stepwise backward logistic regression will be carried out to identify the independent predictors of agitation. Patients will be followed up for 72 h after the operation. Accidental self-extubation of the endotracheal tube and removal of other catheters will be documented. The use of sedatives and analgesics will be collected.Ethics and disseminationEthics approval has been obtained from each of five participating hospitals. Study findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberNCT02318199.
Ohmage
Authors: Tangmunarunkit H. , Hsieh C. K. , Longstaff B. , Nolen S. , Jenkins J. , Ketcham C. , Selsky J. , Alquaddoomi F. , George D. , Kang J. , Khalapyan Z. , Ooms J. , Ramanathan N. , Estrin D. 
Published: April 2015

Participatory sensing (PS) is a distributed data collection and analysis approach where individuals, acting alone or in groups, use their personal mobile devices to systematically explore interesting aspects of their lives and communities [Burke et al. 2006]. These mobile devices can be used to capture diverse spatiotemporal data through both intermittent self-report and continuous recording from on-board sensors and applications.
Ohmage (http://ohmage.org) is a modular and extensible open-source, mobile to Web PS platform that records, stores, analyzes, and visualizes data from both prompted self-report and continuous data streams. These data streams are authorable and can dynamically be deployed in diverse settings. Feedback from hundreds of behavioral and technology researchers, focus group participants, and end users has been integrated into ohmage through an iterative participatory design process. Ohmage has been used as an enabling platform in more than 20 independent projects in many disciplines. We summarize the PS requirements, challenges and key design objectives learned through our design process, and ohmage system architecture to achieve those objectives. The flexibility, modularity, and extensibility of ohmage in supporting diverse deployment settings are presented through three distinct case studies in education, health, and clinical research.
Bounds for the Quantifier Depth in Finite-Variable Logics
Authors: Berkholz Christoph , Krebs Andreas , Verbitsky Oleg 
Published: April 2015

Given two structures
G
and
H
distinguishable in FO

k

(first-order logic with
k
variables), let A

k

(
G
,
H
) denote the minimum alternation depth of a FO

k

formula distinguishing
G
from
H
. Let A

k

(
n
) be the maximum value of A

k

(
G
,
H
) over
n
-element structures. We prove the strictness of the quantifier alternation hierarchy of FO
2
in a strong quantitative form, namely A
2
(
n
) >
n
/8 − 2, which is tight up to a constant factor. For each
k
⩾ 2, it holds that A

k

(
n
) > log

k
+ 1

n
− 2 even over colored trees, which is also tight up to a constant factor if
k
⩾ 3. For
k
⩾ 3, the last lower bound holds also over uncolored trees, whereas the alternation hierarchy of FO
2
collapses even over all uncolored graphs. We also show examples of colored graphs
G
and
H
on
n
vertices that can be distinguished in FO
2
much more succinctly if the alternation number is increased just by one: Whereas in Σ

i

it is possible to distinguish
G
from
H
with bounded quantifier depth, in Π

i

this requires quantifier depth Ω(
n
2
). The quadratic lower bound is best possible here because, if
G
and
H
can be distinguished in FO

k

with
i
quantifier alternations, this can be done with quantifier depth
n

2
k
− 2

+ 1 and the same number of alternations.
Quantification of Nonenhancing Tumor Burden in Gliomas Using Effective T2 Maps Derived from Dual-Echo Turbo Spin-Echo MRI
Authors: Ellingson Benjamin M. , Lai Albert , Nguyen Huytram N. , Nghiemphu Phioanh L. , Pope Whitney B. , Cloughesy Timothy F. 
Published: April 2015

Abstract
Purpose: Evaluation of nonenhancing tumor (NET) burden is an important yet challenging part of brain tumor response assessment. This study focuses on using dual-echo turbo spin-echo MRI as a means of quickly estimating tissue T2, which can be used to objectively define NET burden.
Experimental Design: A series of experiments were performed to establish the use of T2 maps for defining NET burden. First, variation in T2 was determined using the American College of Radiology (ACR) water phantoms in 16 scanners evaluated over 3 years. Next, the sensitivity and specificity of T2 maps for delineating NET from other tissues were examined. Then, T2-defined NET was used to predict survival in separate subsets of patients with glioblastoma treated with radiotherapy, concurrent radiation, and chemotherapy, or bevacizumab at recurrence.
Results: Variability in T2 in the ACR phantom was 3% to 5%. In training data, ROC analysis suggested that 125 ms &lt; T2 &lt; 250 ms could delineate NET with a sensitivity of &gt;90% and specificity of &gt;65%. Using this criterion, NET burden after completion of radiotherapy alone, or concurrent radiotherapy, and chemotherapy was shown to be predictive of survival (Cox, P &lt; 0.05), and the change in NET volume before and after bevacizumab therapy in recurrent glioblastoma was also a predictive of survival (P &lt; 0.05).
Conclusions: T2 maps using dual-echo data are feasible, stable, and can be used to objectively define NET burden for use in brain tumor characterization, prognosis, and response assessment. The use of effective T2 maps for defining NET burden should be validated in a randomized, clinical trial. Clin Cancer Res; 21(19); 4373–83. ©2015 AACR.
CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
Authors: Svensson Susanne , Abrahamsson Annelie , Rodriguez Gabriela Vazquez , Olsson Anna-Karin , Jensen Lasse , Cao Yihai , Dabrosin Charlotta 
Published: April 2015

Abstract
Purpose: Novel therapeutic targets of estrogen receptor (ER)–positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models.
Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish.
Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment.
Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. Clin Cancer Res; 21(16); 3794–805. ©2015 AACR.
Accelerating the Delivery of Patient-Centered, High-Quality Cancer Care
Authors: Abrahams Edward , Foti Margaret , Kean Marcia A. 
Published: April 2015

Abstract
Significant progress has been made in the past 50 years across the field of oncology, and, as a result, the number of cancer survivors in the United States is more than 14.5 million. In fact, the number of cancer survivors continues to grow on an annual basis, which is due in part to improved treatments that help people with cancer live longer, and improvements in early detection that allow doctors to find cancer earlier when the disease is easier to treat. However, in spite of this progress, innovation in cancer research and care is at risk as the rise in health care spending is leading to significant pressure to contain costs. As the oncology community seeks to ensure that innovation in cancer research and care continues, it is imperative that stakeholders focus their attention on the value that the research and care continuum provides. Over the past several years, the Turning the Tide Against Cancer initiative has worked with the cancer community to accelerate the delivery of patient-centered, high-quality cancer research and care, while addressing value and cost. This article highlights policy recommendations that resulted from the convening of an expert working group comprising leaders from across the oncology field. Of the recommendations, the co-conveners have identified several issue areas that merit particular focus in 2015: Support FDA's efforts to modernize its framework for bringing new medicines to patients, through facilitating and implementing innovative approaches to drug development and regulatory review.Ensure that cancer clinical pathways or similar decision-support tools are transparent; developed through a physician-driven process that includes patient input; and meet minimum standards for clinical appropriateness, timeliness, and patient centeredness.Support oncology decision-support tools that are timely, clinically appropriate, and patient centered.Build on existing efforts to convene a multistakeholder committee and develop a report on ways to define and measure value in oncology care, taking into account many of the complex dynamics associated with measuring value, including the interests and needs of patients, as well as the importance of committed and ongoing support for innovative research.These policy options are intended to further the national dialogue and represent meaningful and actionable steps toward supporting cancer research and care that is innovative, efficient, and focused on the patient. Clin Cancer Res; 21(10); 2263–7. ©2015 AACR.