bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing Alzheimer's disease through metabolomics and investigating anti‐Alzheimer's disease effects of natural products
Authors: Yi Lunzhao , Liu Wenbin , Wang Zhe , Ren Dabing , Peng Weijun
Published: June 2017

Alzheimer's disease (AD) is the most common cause of dementia in elderly people and is among the greatest healthcare challenges of the 21st century. However, the etiology and pathogenesis of AD remain poorly understood, and no curative treatments are available to slow down or stop the degenerative effects of AD. As a high‐throughput approach, metabolomics is gaining significant attention in AD research, because it has a powerful potential to discover novel biomarkers, unravel new therapeutic targets for AD, and identify perturbed metabolic pathways involved in AD progression. Here, we systematically review metabolomics with regard to its recent advances and applications in the identification of potential biomarkers for early AD diagnosis and pathogenesis research. In addition, we illustrate the developments in metabolomics as an effective tool for understanding the anti‐AD mechanisms of natural products. We believe that the insights from these advances can narrow the gap between metabolomics research and clinical applications of laboratory findings. Moreover, we discuss some limitations and perspectives of biomarker identification in metabolomics.
Tight junction strand formation by claudin‐10 isoforms and claudin‐10a/‐10b chimeras
Authors: Milatz Susanne , Piontek Jörg , Hempel Caroline , Meoli Luca , Grohe Christoph , Fromm Anja , Lee In‐Fah M. , El‐Athman Rukeia , Günzel Dorothee
Published: June 2017

Claudins are integral components of tight junctions (TJs) in epithelia and endothelia. When expressed in cell lines devoid of TJs, claudins are able to form TJ‐like strands at contacts between adjacent cells. According to a current model of TJ strand formation, claudin protomers assemble in an antiparallel double row within the plasma membrane of each cell (cis‐interaction) while binding to corresponding double rows from the neighboring cells (trans‐interaction). Cis‐interaction was proposed to involve two interfaces of the protomers’ first extracellular segment (extracellular loop (ECL)1). In the current study, three naturally occurring claudin‐10 isoforms and two claudin‐10 chimeras were used to investigate strand formation. All constructs were able to interact in cis (Förster/fluorescence resonance energy transfer (FRET)), to integrate into TJs of MDCK‐C7 cells (confocal laser scanning microscopy), and to form TJ‐like strands in HEK293 cells (freeze‐fracture electron microscopy). Strand formation occurred despite the fact that isoform claudin‐10a_i1 lacks both structural ECL1 elements reported to be crucial for cis‐interaction. Furthermore, results from FRET experiments on claudin‐10 chimeras indicated that identity of the first transmembrane region rather than ECL1 is decisive for claudin‐10 cis‐interaction. Therefore, in addition to the interaction interfaces suggested in the current model for TJ strand assembly, alternative interfaces must exist.
Understanding body modification: A process‐based framework
Authors: Lane David C.
Published: June 2017

This manuscript evaluates existing literature on body modification. Prior research has focused on the modification itself, either the motivation for attaining it or the meanings behind it from the perspective of the wearer. Considering these prior findings, scholars have neglected to examine how body modifications are the outcome of a complex social process. This manuscript rectifies these weaknesses by addressing the field of body modification through the framework of cultural production. This shifts the focus from the outcome of a social process, the modification, to an analysis of the processes by which modifications are produced. By examining these processes, a more coherent theoretical understanding can be developed.
Job Satisfaction in Public and Private Schools: Competition is Key
Authors: Dahler‐Larsen Peter , Foged Søren Kjær
Published: June 2017

Should the public sector become more like the private sector? This is a key question in debates about public management. However, the public/private distinction includes many elements. Two of these are ownership and competition. These aspects are not always sorted out empirically. Another challenge is that dissimilar functional areas are studied which makes it difficult to isolate effects of privatization as such. We respond to these challenges by carrying out an empirical analysis of job satisfaction among teachers who teach Danish to immigrants. The teachers work in comparable schools, carry out the same task, and are subject to the same performance management system, but some of the schools are public, some are private, and some have been subject to competitive tendering. We demonstrate that competition has a greater impact than ownership upon job satisfaction. We also show that one of the key mechanisms which translate competition into reduced job satisfaction relates to changing relations between managers and employees. Advocates and opponents of privatization alike should pay more attention to specific aspects and mechanisms related to privatization, in particular the element of competition.
Degradation, restitution and the elusive culture of rural-urban thinking
Authors: Dymitrow Mirek
Published: June 2017

Despite fierce criticisms, ‘rural’ and ‘urban’ still constitute powerful narratives around which our society is structured. The ‘formal reality’, however, frequently disregards the cultural nature of these concepts, elevating them to the role of objective spaces apt to serve as acceptable guiding perspectives. While the analytical inadequacy of rural-urban ideations is well-documented, the phenomenon of formal-cultural conflation remains much less explored. Acknowledging that ideational space of social representations can only exist through the practices of discursive interaction, this paper’s objective is to lay bare the phenomenon of rural-urban thinking when externalized through the little-known practices of ‘degradation’ and ‘restitution’ in Poland. Using conceptual methods, including discourse analysis and historical deconstruction, this paper assays the hidden architectures of formal-cultural conflation by means of a richly contextualized analysis. The findings, presented in four discursive openings, reveal embedded elements of hierarchy, loss, injustice and self-victimization, which may create a divisive culture spawned by elusive promises of development at the cost of misinterpretations of history, local disappointment and cultural segmentation. In conclusion, formal appropriation of historical concepts is likely to engender a cultural geography of discord spun around a largely insignificant division, especially when development-oriented aspects of urbanization become entwined with emotional issues.
Extension of Nonlinear Stochastic Solution to Include Sinusoidal Excitation—Illustrated by Duffing Oscillator
Authors: Chang R. J.
Published: June 2017

A new non-Gaussian linearization method is developed for extending the analysis of Gaussian white-noise excited nonlinear oscillator to incorporate sinusoidal excitation. The non-Gaussian linearization method is developed through introducing a modulated correction factor on the linearization coefficient which is obtained by Gaussian linearization. The time average of cyclostationary response of variance and noise spectrum is analyzed through the correction factor. The validity of the present non-Gaussian approach in predicting the statistical response is supported by utilizing Monte Carlo simulations. The present non-Gaussian analysis, without imposing restrictive analytical conditions, can be obtained by solving nonlinear algebraic equations. The non-Gaussian solution effectively predicts accurate sinusoidal and noise response when the nonlinear system is subjected to both sinusoidal and white-noise excitations.
Causes and Radiological Consequences of the Chernobyl and Fukushima Nuclear Accidents
Authors: Sihver L. , Yasuda N.
Published: June 2017

In this paper, the causes and the radiological consequences of the explosion of the Chernobyl reactor occurred at 1:23 a.m. (local time) on Apr. 26, 1986, and of the Fukushima Daiichi nuclear disaster following the huge Tsunami caused by the Great East Japan earthquake at 2.46 p.m. (local time) on Mar. 11, 2011 are discussed. The need for better severe accident management (SAM), and severe accident management guidelines (SAMGs), are essential in order to increase the safety of the existing and future operating nuclear power plants (NPPs). In addition to that, stress tests should, on a regular basis, be performed to assess whether the NPPs can withstand the effects of natural disasters and man-made failures and actions. The differences in safety preparations at the Chernobyl and Fukushima Daiichi will therefore be presented, as well as recommendations concerning improvements of safety culture, decontamination, and disaster planning. The need for a high-level national emergency response system in case of nuclear accidents will be discussed. The emergency response system should include fast alarms, communication between nuclear power plants, nuclear power authorities and the public people, as well as well-prepared and well-established evacuation plans and evacuation zones. The experiences of disaster planning and the development of a new improved emergency response system in Japan will also be presented together with the training and education program, which have been established to ensure that professional rescue workers, including medical staff, fire fighters, and police, as well as the normal populations including patients, have sufficient knowledge about ionizing radiation and are informed about the meaning of radiation risks and safety.
Damage Detection Through Pipe Bends
Authors: Vogelaar Bouko , Golombok Michael
Published: June 2017

Axial pipeline defects are detectable from torsional guided wave reflections through 90 deg elbows. This paper demonstrates that detection of localized damage in carbon steel pipes with a so-called standard long and very long radius elbow is possible using a single permanently installed source–receiver pair. We use dispersion imaging to determine why this is not possible in a short radius elbow pipe. Although the remote damage is detected in a standard short radius bend pipe, there is not enough signal to detect localized damage. Since pipeline bends are normally of at least standard long radius, the acoustical behavior is similar to that previously determined in straight pipes. The reflective method can thus be applied fruitfully to monitor structural health beyond industrial pipeline bends.
Cumulative Effect of an Antimicrobial Stewardship and Rapid Diagnostic Testing Bundle on Early Streamlining of Antimicrobial Therapy in Gram-Negative Bloodstream Infections
Authors: Bookstaver P. B. , Nimmich E. B. , Smith T. J. , Justo J. A. , Kohn J. , Hammer K. L. , Troficanto C. , Albrecht H. A. , Al-Hasan M. N.
Published: June 2017

The use of rapid diagnostic tests (RDTs) enhances antimicrobial stewardship program (ASP) interventions in optimization of antimicrobial therapy. This quasi-experimental cohort study evaluated the combined impact of an ASP/RDT bundle on the appropriateness of empirical antimicrobial therapy (EAT) and time to de-escalation of broad-spectrum antimicrobial agents (BSAA) in Gram-negative bloodstream infections (GNBSI). The ASP/RDT bundle consisted of system-wide GNBSI treatment guidelines, prospective stewardship monitoring, and sequential introduction of two RDTs, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and the FilmArray blood culture identification (BCID) panel. The preintervention period was January 2010 through December 2013, and the postintervention period followed from January 2014 through June 2015. The postintervention period was conducted in two phases; phase 1 followed the introduction of MALDI-TOF MS, and phase 2 followed the introduction of the FilmArray BCID panel. The interventions resulted in significantly improved appropriateness of EAT (95% versus 91%;
P
= 0.02). Significant reductions in median time to de-escalation from combination antimicrobial therapy (2.8 versus 1.5 days), antipseudomonal beta-lactams (4.0 versus 2.5 days), and carbapenems (4.0 versus 2.5 days) were observed in the postintervention compared to the preintervention period (
P
< 0.001 for all). The reduction in median time to de-escalation from combination therapy (1.0 versus 2.0 days;
P
= 0.03) and antipseudomonal beta-lactams (2.2 versus 2.7 days;
P
= 0.04) was further augmented during phase 2 compared to phase 1 of the postintervention period. Implementation of an antimicrobial stewardship program and RDT intervention bundle in a multihospital health care system is associated with improved appropriateness of EAT for GNBSI and decreased utilization of BSAA through early de-escalation.
The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection
Authors: Ames Rachel Y. , Ting Li-Min , Gendlina Inessa , Kim Kami , Macian Fernando
Published: June 2017

Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3. The molecular events that lead to the induction of this phenotype have, however, not been fully characterized. In T cells, members of the NFAT family of transcription factors not only are responsible for the expression of many activation-induced genes but also are crucial for the induction of transcriptional programs that inhibit T cell activation and maintain tolerance. Here we show that NFAT1-deficient CD4+T cells maintain higher proliferative capacity and expression of effector cytokines followingPlasmodium yoeliiinfection and are therefore more resistant toP. yoelii-induced exhaustion than their wild-type counterparts. Consequently, gene expression microarray analysis of CD4+T cells followingP. yoelii-induced exhaustion shows upregulation of effector T cell-associated genes in the absence of NFAT1 compared with wild-type exhausted T cells. Furthermore, adoptive transfer of NFAT1-deficient CD4+T cells into mice infected withP. yoeliiresults in increased production of antibodies to cognate antigen. Our results support the idea that NFAT1 is necessary to fully suppress effector responses duringPlasmodium-induced CD4+T cell exhaustion.
SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection
Authors: McIntosh Anne , Meikle Lynsey M. , Ormsby Michael J. , McCormick Beth A. , Christie John M. , Brewer James M. , Roberts Mark , Wall Daniel M.
Published: June 2017

Salmonellainvasion protein A (SipA) is a dual-function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes, SipA or otherSalmonellapathogenicity island 1 effectors had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag, which can pass through the type three secretion system, allowed visualization and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in anex vivointestinal model. This allowed visualization of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag forin vivotracking of individual effectors.
Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases
Authors: Parashar Kaustubh , Kopping Erik , Frank David , Sampath Vinaya , Thanassi David G. , Carpino Nick
Published: June 2017

The
S
uppressor of
T
CR
s
ignaling proteins (Sts-1 and Sts-2) are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic lineages, including T lymphocytes. Mice lacking Sts expression are characterized by enhanced T cell responses. Additionally, a recent study demonstrated that
Sts
−/−
mice are profoundly resistant to systemic infection by
Candida albicans
, with resistance characterized by enhanced survival, more rapid fungal clearance in key peripheral organs, and an altered inflammatory response. To investigate the role of Sts in the primary host response to infection by a bacterial pathogen, we evaluated the response of
Sts
−/−
mice to infection by a Gram-negative bacterial pathogen.
Francisella tularensis
is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia.
Francisella
infections are characterized by a delayed immune response, followed by an intense inflammatory reaction that causes widespread tissue damage and septic shock. Herein, we demonstrate that mice lacking Sts expression are significantly resistant to infection by the
l
ive
v
accine
s
train (LVS) of
F. tularensis
. Resistance is characterized by reduced lethality following high-dose intradermal infection, an altered cytokine response in the spleen, and enhanced bacterial clearance in multiple peripheral organs.
Sts
−/−
bone marrow-derived monocytes and neutrophils, infected with
F. tularensis
LVS
ex vivo
, display enhanced restriction of intracellular bacteria. These observations suggest the Sts proteins play an important regulatory role in the host response to bacterial infection, and they underscore a role for Sts in regulating functionally relevant immune response pathways.
Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays
Authors: Baarda Benjamin I. , Emerson Sarah , Proteau Philip J. , Sikora Aleksandra E.
Published: June 2017

The function and extracellular location of cell envelope proteins make them attractive candidates for developing vaccines against bacterial diseases, including challenging drug-resistant pathogens, such as
Neisseria gonorrhoeae
. A proteomics-driven reverse vaccinology approach has delivered multiple gonorrhea vaccine candidates; however, the biological functions of many of them remain to be elucidated. Herein, the functions of six gonorrhea vaccine candidates—NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344—in cell envelope homeostasis were probed using phenotype microarrays under 1,056 conditions and a Δ
bamE
mutant (Δ
ngo1780
) as a reference of perturbed outer membrane integrity. Optimal growth conditions for an
N. gonorrhoeae
phenotype microarray assay in defined liquid medium were developed, which can be useful in other applications, including rapid and thorough antimicrobial susceptibility assessment. Our studies revealed 91 conditions having uniquely positive or negative effects on one of the examined mutants. A cluster analysis of 37 and 57 commonly beneficial and detrimental compounds, respectively, revealed three separate phenotype groups: NGO2121 and NGO1985; NGO1344 and BamE; and the trio of NGO1205, NGO2111, and NGO2054, with the last protein forming an independent branch of this cluster. Similar phenotypes were associated with loss of these vaccine candidates in the highly antibiotic-resistant WHO X strain. Based on their extensive sensitivity phenomes, NGO1985 and NGO2121 appear to be the most promising vaccine candidates. This study establishes the principle that phenotype microarrays can be successfully applied to a fastidious bacterial organism, such as
N. gonorrhoeae
.

IMPORTANCE
Innovative approaches are required to develop vaccines against prevalent and neglected sexually transmitted infections, such as gonorrhea. Herein, we have utilized phenotype microarrays in the first such investigation into
Neisseria gonorrhoeae
to probe the function of proteome-derived vaccine candidates in cell envelope homeostasis. Information gained from this screening can feed the vaccine candidate decision tree by providing insights into the roles these proteins play in membrane permeability, integrity, and overall
N. gonorrhoeae
physiology. The optimized screening protocol can be applied in investigations into the function of other hypothetical proteins of
N. gonorrhoeae
discovered in the expanding number of whole-genome sequences, in addition to revealing phenotypic differences between clinical and laboratory strains.
The DNA Repair Repertoire of Mycobacterium smegmatis FenA Includes the Incision of DNA 5′ Flaps and the Removal of 5′ Adenylylated Products of Aborted Nick Ligation
Authors: Uson Maria Loressa , Ghosh Shreya , Shuman Stewart
Published: June 2017

We characterize
Mycobacterium smegmatis
FenA as a manganese-dependent 5′-flap endonuclease homologous to the 5′-exonuclease of DNA polymerase I. FenA incises a nicked 5′ flap between the first and second nucleotides of the duplex segment to yield a 1-nucleotide gapped DNA, which is then further resected in dinucleotide steps. Initial FenA cleavage at a Y-flap or nick occurs between the first and second nucleotides of the duplex. However, when the template 3′ single strand is eliminated to create a 5′-tailed duplex, FenA incision shifts to between the second and third nucleotides. A double-flap substrate with a mobile junction (mimicking limited strand displacement synthesis during gap repair) is preferentially incised as the 1-nucleotide 3′-flap isomer, with the scissile phosphodiester shifted by one nucleotide versus a static double flap. FenA efficiently removes the 5′ App(dN) terminus of an aborted nick ligation reaction intermediate, thereby highlighting FenA as an agent of repair of such lesions, which are formed under a variety of circumstances by bacterial NAD
+
-dependent DNA ligases and especially by mycobacterial DNA ligases D and C.

IMPORTANCE
Structure-specific DNA endonucleases are implicated in bacterial DNA replication, repair, and recombination, yet there is scant knowledge of the roster and catalytic repertoire of such nucleases in
Mycobacteria
. This study identifies
M. smegmatis
FenA as a stand-alone endonuclease homologous to the 5′-exonuclease domain of mycobacterial DNA polymerase 1. FenA incises 5′ flaps, 5′ nicks, and 5′ App(dN) intermediates of aborted nick ligation. The isolated N-terminal domain of
M. smegmatis
Pol1 is also shown to be a flap endonuclease.
Are fire safe cigarettes actually fire safe? Evidence from changes in US state laws
Authors: Bonander Carl , Jakobsson Niklas , Nilson Finn
Published: June 2017

Objective

To estimate the effects of fire safe cigarette laws on fire mortality and cigarette-related fires in the USA.

Methods

We examined the gradual implementation of the laws to identify their average effects, using difference-in-differences analysis to account for common year effects, time-invariant state effects, state-specific trends and observable time-varying state-level covariates.

Results

We found no statistically significant effects on all-cause fire mortality, residential fire mortality or cigarette-caused fire rates. The estimates for cigarette-caused fire deaths were significant under some specifications, but were not robust to the inclusion of state-specific trends or comparisons to effects on other cause-determined fires.

Conclusions

Given the mixed state of our results, we conclude that previous claims regarding the effects of fire safe cigarette laws may be premature.
Self-Stabilizing Weak Leader Election in Anonymous Trees Using Constant Memory per Edge
Authors: Datta Ajoy K. , Devismes Stephane , Larmore Lawrence L. , Villain Vincent
Published: June 2017

We propose a deterministic silent self-stabilizing algorithm for the weak leader election problem in anonymous trees. Our algorithm is designed in the message passing model, and requires only O(1) bits of memory per edge. It does not necessitate the a priori knowledge of any global parameter on the network. Finally, its stabilization time is at most [Formula: see text] time units, where 𝒟 is the diameter of the network, X is an upper bound on the time to execute some recurrent code by processes, and Imax is the maximal number of messages initially in a link.
Towards a dS/MERA correspondence
Authors: Kunkolienkar Raj Sinai , Banerjee Kinjal
Published: June 2017

Recent advances have suggested that spacetime itself emerges from the entanglement of the quantum degrees of freedom living on the boundary. In the case of the anti-de Sitter (AdS) spacetimes, a particular class of tensor networks has been shown to realize the same via Multi-Scale Entanglement Renormalization Ansatz (MERA). In this paper, we suggest a prescription for the dS/MERA correspondence and recover a discrete version of dS Penrose diagram by using the MERA on conformal theories identified with the future/past boundaries ([Formula: see text]) of the dS spacetime. In this case, as anticipated, time appears as the emergent direction. We comment on the possible interpretation that the dS cosmological horizon entropy involves entanglement with degrees of freedom across the cosmological horizon as well as the implications of our construction for cosmology.
IMPACT OF MOTIVATION AND PERSONALITY CHARACTERISTICS ON BUMIPUTERAS’ ENTREPRENEURIAL PERSISTENCE IN MALAYSIA
Authors: SABIU IBRAHIM TIJJANI , ABDULLAH ABDUL AZIZ , AMIN AZIZ
Published: June 2017

The Malaysian government has been providing support to boost Bumiputra entrepreneurship development; however, the growth achieved by the Bumiputras is not on the same pace with the economic advancement. The Bumiputra entrepreneurs struggle with challenges that caused their failure in the early years of their operations. Hence, this study examines the impact of motivation and personality characteristics on Bumiputeras’ entrepreneurial persistence. The findings indicate that Bumiputras are energized by the need of achievement motivation in striving to overcome challenges and remain competitive with other races in the business environment. Equally, they indicate that Bumiputras exhibit a positive outlook to life and are open to new and innovative ways to thrive in business as compared to the previous generation.
Stability and Hopf Bifurcation for a Delayed Computer Virus Model with Antidote in Vulnerable System
Authors: Zhang Zizhen , Wang Yougang , Ferrara Massimiliano
Published: June 2017

A delayed computer virus model with antidote in vulnerable system is investigated. Local stability of the endemic equilibrium and existence of Hopf bifurcation are discussed by analyzing the associated characteristic equation. Further, direction of the Hopf bifurcation and stability of the bifurcating periodic solutions are investigated by using the normal form theory and the center manifold theorem. Finally, numerical simulations are presented to show consistency with the obtained results.
Infection Exposure PromotesETV6-RUNX1Precursor B-cell Leukemia via Impaired H3K4 Demethylases
Authors: Rodríguez-Hernández Guillermo , Hauer Julia , Martín-Lorenzo Alberto , Schäfer Daniel , Bartenhagen Christoph , García-Ramírez Idoia , Auer Franziska , González-Herrero Inés , Ruiz-Roca Lucia , Gombert Michael , Okpanyi Vera , Fischer Ute , Chen Cai , Dugas Martin , Bhatia Sanil , Linka René Martin , Garcia-Suquia Marta , Rascón-Trincado María Victoria , Garcia-Sanchez Angel , Blanco Oscar , García-Cenador Maria Begoña , García-Criado Francisco Javier , Cobaleda César , Alonso-López Diego , De Las Rivas Javier , Müschen Markus , Vicente-Dueñas Carolina , Sánchez-García Isidro , Borkhardt Arndt
Published: June 2017

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365–77. ©2017 AACR.
Dose-Finding Methods: Moving Away from the 3 + 3 to Include Richer Outcomes
Authors: Paoletti Xavier , Drubay Damien , Collette Laurence
Published: June 2017

The most commonly used method for dose finding, the 3 + 3, has poor performance. New adaptive designs are more efficient. Nevertheless, they have reached a maximum performance level, and further improvement requires either larger sample sizes or outcomes measures richer than the simplistic severe toxicity measured at cycle 1. Clin Cancer Res; 23(15); 3977–9. ©2017 AACR.

See related article by Yan et al., p. 3994
Efficacy of Liposomal Cytarabine in the Treatment of Leptomeningeal Metastasis of Breast Cancer
Authors: Laakmann Elena , Witzel Isabell , Müller Volkmar
Published: June 2017

Background: Breast cancer is one of the most frequent causes of leptomeningeal metastasis (LM) among solid tumors in adults. The prognosis of patients with LM is poor. A treatment option is the intrathecal administration of liposomal cytarabine. Case Reports: The first case represents a 53-year-old woman with LM of breast cancer. A neurological response was achieved shortly after the start of the multimodal treatment including intrathecal liposomal cytarabine. The response duration reached 79 days. The second case represents a 48-year-old woman with LM of breast cancer treated with intrathecal liposomal cytarabine as a part of a multimodal treatment approach. A neurological response was achieved in the first 2 weeks of treatment and is still lasting after 18 months. Conclusion: These cases suggest that a rapid response to a prompt start of treatment with intrathecal liposomal cytarabine in patients with LM of breast cancer is feasible. In 1 case an extremely long progression-free survival (18+ months) was achieved. The cases support the efficacy of liposomal cytarabine in the management of LM in breast cancer patients as a part of a multimodal treatment approach and underline the need for further investigations in this specific cohort.
Hodgkin Lymphoma Mimicking Osteomyelitis
Authors: Majeed Aneela , Chan Onyee , Okolo Onyemaechi , Shponka Volodymyr , Georgescu Anca , Persky Daniel
Published: June 2017

Hodgkin lymphoma with symptomatic osseous involvement can have a similar presentation to osteomyelitis. Common findings in symptoms, laboratory workup, and imaging can make it very difficult to distinguish between the two diseases. Excisional biopsy should be pursued if fine-needle biopsy is equivocal and suspicion of lymphoma is high. We report a case of a 40-year-old man who presented with a history of marine animal sting on his neck and later developed erythema in the area, chest pain, constitutional symptoms, adenopathy, and imaging classic for sternal osteomyelitis. Fortunately, initial biopsy prompted the possibility of lymphoma, and further workup was initiated, which confirmed Hodgkin lymphoma. This case is a good reminder that malignancies and infections can share many common features, and keeping a broad differential diagnosis can be lifesaving. Proper staging and risk stratification of Hodgkin lymphoma help determine the optimal treatment.
Urinary Liver-Type Fatty Acid-Binding Protein Level as a Predictive Biomarker of Acute Kidney Injury in Patients with Acute Decompensated Heart Failure
Authors: Hishikari Keiichi , Hikita Hiroyuki , Nakamura Shun , Nakagama Shun , Mizusawa Masahumi , Yamamoto Tasuku , Doi Junichi , Hayashi Yosuke , Utsugi Yuya , Araki Makoto , Sudo Yuta , Kimura Shigeki , Takahashi Atsushi , Ashikaga Takashi , Isobe Mitsuaki
Published: June 2017

Background: There are no biological markers to predict the onset of acute kidney injury (AKI) in patients with acute decompensated heart failure (ADHF). Liver-type fatty acid-binding protein (L-FABP) levels are markedly upregulated in the proximal tubules after renal ischemia. We investigated whether urinary L-FABP is a suitable marker to predict AKI in ADHF patients. Methods: We examined 281 consecutive patients with ADHF. Serum creatinine (Cr) and L-FABP levels were measured at admission and 24 and 48 h after admission. Results: AKI developed in 104 patients (37%). Urinary L-FABP levels at admission were significantly higher in patients with AKI than in those without (33.0 vs. 5.2 μg/g Cr; p < 0.001). Multivariate analysis showed that baseline urinary L-FABP level was an independent predictor of AKI in ADHF patients (odds ratio 1.08, 95% confidence interval 1.05-1.12; p < 0.001). Receiver operating characteristic analysis showed that baseline urinary L-FABP level exhibited 94.2% sensitivity and 87.0% specificity at a cutoff value of 12.5 μg/g Cr. Conclusions: Urinary L-FABP level is useful for predicting the onset of AKI in patients with ADHF. The results of our study could help clinicians diagnose AKI in ADHF patients earlier, leading to possible improvements in the treatment of this group of patients.
Interaction of Soluble CXC Ligand 16 and Cardiac Injury Markers in Hemodialysis Patients
Authors: Liu Wenjin , Wang Lulu , Wei Yongyue , Li Xiurong , Gao Chaoqing , Zhou Jianmei , Wang Liang , Sun Zhuxing , Chu Hong , Bai Youwei , Yang Junwei
Published: June 2017

Background: Recent data suggest that there is a pathogenic role for CXC ligand 16 (CXCL16) in cardiovascular diseases. Little is known about circulating CXCL16 in patients with kidney dysfunction. We explored the relationships of plasma CXCL16 with cardiac injury markers in a group of dialysis patients. Methods: Plasma CXCL16 and C-reactive protein (CRP) were measured in 366 patients who were on maintenance hemodialysis. Cardiac injury was evaluated via measurements of the circulating B-type natriuretic peptide (BNP), N-terminal prohormone of brain natriuretic peptide (NT proBNP), Troponin I (TnI), and Troponin T (TnT). Sixty healthy subjects who were frequency matched with the patients on the basis of age and gender were recruited as healthy controls. Results: The mean age of the patients was 52.5 ± 12.1 years and 56.3% were male. Circulating CXCL16 was significantly higher in the patients than in the controls (patients vs. controls: 477.3 (367.0-647.1) pg/mL vs. 229.5 (203.8-254.5) pg/mL; p < 0.001). The log-transformed (log-) CXCL16 level was correlated with all 4 cardiac markers (log-BNP, log-NTproBNP, log-TnI, and log-TnT) with high levels of significance (all p < 0.001), even after extensive controls for the covariates. In contrast, CRP was correlated only with BNP (marginally) and NT proBNP and was not correlated with troponins. Conclusion: We showed, for the first time, highly significant relationships of circulating CXCL16 level with cardiac injury markers in dialysis patients. Our data suggest that circulating CXCL16 is possibly involved in the pathological process of cardiovascular damage in dialysis patients and may serve as a therapeutic target for cardiac protection in these patients.
Nubis et Nuclei: A Study on Noise and Precision
Authors: Ergenzinger Kerstin
Published: June 2017

This study sets out to explore the perception of noise, as well as the relation toward meaning or information that it might contain, in arts, science and daily life. It is realized as an installation based on a suspended cloud of nitinol drums that create a sonic environment evolving in time and space. Digital random noise drives the instruments. Roaming freely and listening, visitors become part of an ecology of noise. As visitors explore differing regions in time and space, what appears to be noise can shift to a “meaningful” signal. This process of discovering a clear signal in a noisy background holds strong analogies to the scientific search for a nuclear resonance performed in the nuClock project.
Cartography of Tree Space
Authors: Devadoss Satyan L. , Schuh Owen
Published: June 2017

How can vibrant, contemporary art be produced that deals with vibrant, contemporary mathematics? To address this question, a collaboration began between an artist (Schuh) and a mathematician (Devadoss), revolving around recent problems in phylogenetics and the space of evolutionary trees. The result was twofold: First, a triptych of paintings was created, using acrylic, graphite, watercolor and metal leaf, that focused on different navigations within this tree space. Second, a novel set of open mathematics problems was discovered solely as a result of this investigation.
Taking the Rules of Interpretation Seriously, but Not Literally? A Theoretical Reconstruction of Orthodox Dogma
Authors: Kammerhofer Jörg
Published: June 2017

For international lawyers, the Vienna Convention rules of treaty interpretation are ‘the only game in town’; they have had the whip-hand for several decades now. Yet is this belief in the power(s) of the Vienna rules justified? Behind the claim that they are the law lies a theoretically much more interesting, yet fundamentally unsustainable second argument. It is that rules of interpretation are somehow independent of – and replace – the legal epistemic process, the ascertainment of the law’s meaning-content. These rules are seen as serving a different function, i.e. to regulate the process of the applicative construction of meaning by the organs of international law. They are doctrine’s attempt to control how treaties are construed by tribunals. However, as a matter of legal theory there are severe limits to what such rules can do. Given these limits, we will reconstruct the possible meanings and uses of the Vienna Convention rules.
A Pragmatic Argument for a Pragmatic Theory of Truth
Authors: Capps John
Published: June 2017

Even though pragmatic theories of truth are not widely held, they have advantages not found elsewhere. Here I focus on one such advantage: that a pragmatic theory of truth does not limit the range of truth-apt beliefs and thereby “block the way of inquiry.” Furthermore, I argue that this speaks for a particular formulation of the pragmatic theory of truth, one that shifts away from Peircean approaches and their emphasis on temporal independence, and toward a theory that instead emphasizes truth’s subject independence.
Pragmatism, Practice and the Politics of Critique
Authors: Livingston Alexander
Published: June 2017

Colin Koopman’s Pragmatism as Transition offers an argumentative retelling of the history of American pragmatism in terms of the tradition’s preoccupation with time. Taking time seriously offers a venue for reorienting pragmatism today as a practice of cultural critique. This article examines the political implications third wave pragmatism’s conceptualization of time, practice, and critique. I argue that Koopman’s book opens up possible lines of inquiry into historical practices of critique from William James to James Baldwin that, when followed through to their conclusion, trouble some of the book’s political conclusions. Taking time and practice seriously, as transitionalism invites pragmatists to do, demands pluralizing critique in a way that puts pressure on familiar pragmatist convictions concerning liberalism, progress, and American exceptionalism.
In Others’ Words: Quotations and Recontextualization in Putin’s Speeches
Authors: Drozdova Oksana , Robinson Paul
Published: June 2017

This article analyzes how Kremlinologists have attempted to understand ‘what Putin thinks’ by examining whom he has quoted. Kremlinologists have taken the quotations in Putin’s speeches and used them to claim that Putin is ‘ultranationalist’, ‘paleoconservative’, and even ‘fascist’. The article argues that in doing so, they have ignored the exact words of the quotations and the context in which they were used. To overcome this deficiency, the article carries out a careful examination of those words and that context, and points to much more nuanced conclusions. It shows that on occasion, Putin has used quotations to reinforce what might be considered relatively illiberal points, but more often he done so to reinforce moderately liberal rhetoric. Overall, Putin’s use of quotations would suggest that Putin positions himself as a relatively moderate conservative not as an extremist of the sort claimed by the Kremlinologists.
Tapantiomyia enigmatica, new genus and species proposed for a stilt-legged and otherwise bizarre coenosiine fly (Diptera: Muscidae) from Costa Rica
Authors: MICHELSEN VERNER
Published: June 2017

A new monotypic genus, Tapantiomyia gen. nov., is proposed for a new species of muscid fly, T. enigmatica sp. nov., found in the Tapantí National Park, Costa Rica. It is only known by a single male specimen taken in a Malaise trap in tropical cloud forest, but deserves immediate attention because of its bizarre, stilt-legged appearance in combination with several other unique apomorphies that preclude placement in any known genus of Muscidae. Tapantiomyia enigmatica is so strange that it tend to run out to Scathophagidae rather than Muscidae in keys to families of Diptera. However, the morphology of the male genitalia provides decisive evidence for a placement in Coenosiinae, a large and diverse group of predatory Muscidae. Two tribes, Limnophorini and Coenosiini, are currently recognized within Coenosiinae, but the monophyly of Limnophorini remains uncertain. Tapantiomyia is tentatively assigned to the Limnophorini.
Stethorus spp. (Coleoptera: Coccinellidae) predatory on Schizotetranychus hindustanicus (Hirst) (Acari: Tetranychidae) from South India, including a new species and a new synonymy in Indian Stethorus
Authors: POORANI J.
Published: June 2017

Stethorus forficatus sp. nov. and Stethorus tetranychi Kapur (Coccinellidae: Stethorini) are reported as predators of the citrus hindu mite, Schizotetranychus hindustanicus (Hirst), from the southern Indian state of Tamil Nadu. Stethorus forficatus sp. nov. is described and illustrated with diagnostic notes on S. tetranychi and S. vietnamicus Hoàng, morphologically its closest relatives. In a remarkable case of larval mimicry in Stethorus, the larva of this species mimics the larvae of S. tetranychi and S. pauperculus Weise. Stethorus curvus Hoàng, 1985 is reduced to a new junior synonym of Stethorus keralicus Kapur, 1961 (syn. nov.).
Effect of Boundary Layer Roll Vortices on the Development of an Axisymmetric Tropical Cyclone
Authors: Gao Kun , Ginis Isaac , Doyle James D. , Jin Yi
Published: June 2017

In this study, the authors numerically investigate the response of an axisymmetric tropical cyclone (TC) vortex to the vertical fluxes of momentum, heat, and moisture induced by roll vortices (rolls) in the boundary layer. To represent the vertical fluxes induced by rolls, a two-dimensional high-resolution Single-Grid Roll-Resolving Model (SRM) is embedded at multiple horizontal grid points in the mesoscale COAMPS for Tropical Cyclones (COAMPS-TC) model domain. Idealized experiments are conducted with the SRM embedded within 3 times the radius of maximum wind of an axisymmetric TC. The results indicate that the rolls induce changes in the boundary layer wind distribution and cause a moderate (approximately 15%) increase in the TC intensification rate by increasing the boundary layer convergence in the eyewall region and induce more active eyewall convection. The numerical experiments also suggest that the roll-induced tangential momentum flux is most important in contributing to the TC intensification process, and the rolls generated at different radii (within the range considered in this study) all have positive contributions. The results are not qualitatively impacted by the initial TC vortex or the setup of the vertical diffusivity in COAMPS-TC.
A Meta-Analysis of Mobile Technology Supporting Individuals With Disabilities
Authors: Cumming Therese M. , Draper Rodríguez Cathi
Published: June 2017

Mobile technology has become ubiquitous in the education and support of individuals with disabilities. While this practice is supported under the Universal Design for Learning framework, research in the area has yet to establish a solid evidence base. The majority of the studies in existence are single-subject design studies with a dearth of replication to support their results, and many do not meet the Council for Exceptional Children’s Standards for Evidence-Based Practices in Special Education guidelines. The following is a meta-analysis of studies that have been conducted in the area of using mobile technology to support individuals with disabilities. Types of mobile technology, how technology is used, and the effectiveness of its use with this population are explored. The results indicated although there is some evidence of effectiveness to support the use of mobile technology, more research in the area is needed.
Clino-suenoite, a newly approved magnesium-iron-manganese amphibole from Valmalenco, Sondrio, Italy
Authors: Oberti Roberta , Boiocchi Massimo , Hawthorne Frank C. , Ciriotti Marco E. , Revheim Olav , Bracco Roberto
Published: June 2017

Clino-suenoite, ideally □${\rm Mn}_{2}^{2 +} $Mg5Si8O22(OH)2 is a new amphibole of the magnesium-iron-manganese subgroup of the amphibole supergroup. The type specimen was found at the Lower Scerscen Glacier, Valmalenco, Sondrio, Italy, where it occurs in Mn-rich quartzite erratics containing braunite, rhodonite, spessartine, carbonates and various accessory minerals. The empirical formula derived from electron microprobe analysis and single-crystal structure refinement is: ANa0.04B(${\rm Mn}_{1.58}^{2 +} $Ca0.26Na0.16)Σ2.00C(Mg4.21${\rm Mn}_{0. 61}^{2 +} {\rm Fe}_{0.04}^{2 +} $Zn0.01Ni0.01${\rm Fe}_{0.08}^{3 +} $Al0.04)Σ5.00TSi8.00O22W[(OH1.94F0.06)]Σ=2.00. Clino-suenoite is biaxial (+), with α = 1.632(2), β = 1.644(2), γ = 1.664(2) and 2Vmeas. = 78(2)° and 2Vcalc. = 76.3°. The unit-cell parameters in the C2/m space group are a = 9.6128(11), b = 18.073(2), c = 5.3073(6) Å, β = 102.825(2)° and V = 899.1(2) Å3 with Z = 2. The strongest ten reflections in the powder X-ray diffraction pattern [d (in Å), I, (hkl)] are: 2.728, 100, (151); 2.513, 77, ($\bar 2$02); 3.079, 62, (310); 8.321, 60, (110); 3.421, 54, (131); 2.603, 42, (061); 2.175, 42, (261); 3.253, 41, (240); 2.969, 40, (221); 9.036, 40, (020).