bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Common‐Pool Resource Principles to Design Local Government Fiscal Sustainability
Authors: Tang Shui‐Yan , Callahan Richard F. , Pisano Mark
Published: September 2014

This article analyzes local government fiscal sustainability as a common‐pool resource (CPR) problem. Comparing the experiences of Los Angeles County, San Bernardino City, and San Bernardino County, California, the analysis applies a framework developed from three decades ofCPRresearch to show the importance of six micro‐situational variables—communications with the full set of participants, known reputations of participants, high marginal per capita return, entry or exit capabilities, longer time horizon, and agreed‐upon sanctioning capabilities—in shaping collective action dynamics and building the trust and reciprocity among stakeholders needed to achieve fiscal sustainability. The underlying contextual conditions for these micro‐situational variables vary based on specific socioeconomic and political settings, but the findings suggest that institutions and processes can be designed based on several well‐tested principles inCPRgovernance to encourage stakeholders to look beyond their immediate self‐interests and make decisions that account for the community's long‐term fiscal sustainability.
Buddhist Manuscript Cultures in Premodern Japan
Authors: Lowe Bryan D.
Published: September 2014

Recent discoveries and scholarship on Japanese Buddhist manuscripts have illuminated new areas of research and raised previously unexplored questions in Buddhist studies and East Asian religions. This article introduces some of the recent finds and approaches to these materials. It focuses on three sets of sources: scriptorium documents from an imperial treasure house known as the Shōsōin, canonical manuscripts (issaikyō) based on texts translated or composed in China, and sacred works (shōgyō) produced and collected by Japanese monks for use in temple life. In addition to surveying these sources and the most influential secondary literature on them, this article proposes methodological alternatives to philological studies by focusing on what I call ritual, curricular, social, and material approaches.
Light modulated activity of root alkaline/neutral invertase involves the interaction with 14‐3‐3 proteins
Authors: Gao Jing , van Kleeff Paula J. M. , Oecking Claudia , Li Ka Wan , Erban Alexander , Kopka Joachim , Hincha Dirk K. , de Boer Albertus H.
Published: September 2014

Alkaline/neutral invertases (A/N‐Invs) are now recognized as essential proteins in plant life. They catalyze the irreversible breakdown of sucrose into glucose and fructose and thus supply the cells with energy as well as signaling molecules. In this study we report on a mechanism that affects the activity of the cytosolic invertase AtCINV1 (At‐A/N‐InvG or AT1G35580). We demonstrate that Ser547 at the extreme C‐terminus of the AtCINV1 protein is a substrate of calcium‐dependent kinases (CPK3 and 21) and that phosphorylation creates a high‐affinity binding site for 14‐3‐3 proteins. The invertase as such has basal activity, but we provide evidence that interaction with 14‐3‐3 proteins enhances its activity. The analysis of three quadruple 14‐3‐3 mutants generated from six T‐DNA insertion mutants of the non‐epsilon family shows both specificity as well as redundancy for this function of 14‐3‐3 proteins. The strong reduction in hexose levels in the roots of one 14‐3‐3 quadruple mutant plant is in line with the activating function of 14‐3‐3 proteins. The physiological relevance of this mechanism that affects A/N‐invertase activity is underscored by the light‐induced activation and is another example of the central role of 14‐3‐3 proteins in mediating dark/light signaling. The nature of the light‐induced signal that travels from the shoot to root and the question whether this signal is transmitted via cytosolic Ca++ changes that activate calcium‐dependent kinases, await further study.
Transmission line cochlear models: Improved accuracy and efficiency
Authors: Altoè Alessandro , Pulkki Ville , Verhulst Sarah
Published: September 2014

This paper presents an efficient method to compute the numerical solutions of transmission-line (TL) cochlear models, and its application on the model of Verhulst et al. The stability region of the model is extended by adopting a variable step numerical method to solve the system of ordinary differential equations that describes it, and by adopting an adaptive scheme to take in account variations in the system status within each numerical step. The presented method leads to improve simulations numerical accuracy and large computational savings, leading to employ TL models for more extensive simulations than currently possible.
Draft Genome Sequence of the Yeast
Pseudozyma antarctica
Type Strain JCM10317, a Producer of the Glycolipid Biosurfactants, Mannosylerythritol Lipids
Authors: Saika Azusa , Koike Hideaki , Hori Tomoyuki , Fukuoka Tokuma , Sato Shun , Habe Hiroshi , Kitamoto Dai , Morita Tomotake
Published: September 2014

The basidiomycetous yeast
Pseudozyma antarctica
is known as a producer of industrial enzymes and the extracellular glycolipids, mannosylerythritol lipids. Here, we report the draft genome sequence of the type strain JCM10317. The draft genome assembly has a size of 18.1 Mb and a G+C content of 60.9%, and it consists of 197 scaffolds.
Whole-Genome Sequences of Nine
Francisella
Isolates
Authors: Davenport K. W. , Daligault H. E. , Minogue T. D. , Bishop-Lilly K. A. , Broomall S. M. , Bruce D. C. , Chain P. S. , Coyne S. R. , Frey K. G. , Gibbons H. S. , Jaissle J. , Koroleva G. I. , Ladner J. T. , Palacios G. F. , Redden C. L. , Rosenzweig C. N. , Scholz M. B. , Teshima H. , Johnson S. L.
Published: September 2014

Primarily a zoonotic disease,
Francisella tularensis
is a fastidious intracellular pathogen and is listed as a CDC category A pathogen with notably high pathogenicity. Here we present the scaffolded genome assemblies of nine
Francisella
strains: eight
F. tularensis
and one
F. philomiragia
.
Therapist-guided, Internet-based cognitive–behavioural therapy for body dysmorphic disorder (BDD-NET): a feasibility study
Authors: Enander Jesper , Ivanov Volen Z , Andersson Erik , Mataix-Cols David , Ljótsson Brjánn , Rück Christian
Published: September 2014

Objectives

Cognitive–behavioural therapy (CBT) is an effective treatment for body dysmorphic disorder (BDD). However, most sufferers do not have access to this treatment. One way to increase access to CBT is to administer treatment remotely via the Internet. This study piloted a novel therapist-supported, Internet-based CBT program for BDD (BDD-NET).

Design

Uncontrolled clinical trial.

Participants

Patients (N=23) were recruited through self-referral and assessed face to face at a clinic specialising in obsessive–compulsive and related disorders. Suitable patients were offered secure access to BDD-NET.

Intervention

BDD-NET is a 12-week treatment program based on current psychological models of BDD that includes psychoeducation, functional analysis, cognitive restructuring, exposure and response prevention, and relapse prevention modules. A dedicated therapist provides active guidance and feedback throughout the entire process.

Main outcome measure

The clinician-administered Yale-Brown Obsessive Compulsive Scale for BDD (BDD-YBOCS). Symptom severity was assessed pretreatment, post-treatment and at the 3-month follow-up.

Results

BDD-NET was deemed highly acceptable by patients and led to significant improvements on the BDD-YBOCS (p=<0.001) with a large within-group effect size (Cohen's d=2.01, 95% CI 1.05 to 2.97). At post-treatment, 82% of the patients were classified as responders (defined as≥30% improvement on the BDD-YBOCS). These gains were maintained at the 3-month follow-up. Secondary outcome measures of depression, global functioning and quality of life also showed significant improvements with moderate to large effect sizes. On average, therapists spent 10 min per patient per week providing support.

Conclusions

The results suggest that BDD-NET has the potential to greatly increase access to CBT, at least for low-risk individuals with moderately severe BDD symptoms and reasonably good insight. A randomised controlled trial of BDD-NET is warranted.

Trial registration number

Clinicaltrials.gov registration IDNCT01850433.
Overdetection in breast cancer screening: development and preliminary evaluation of a decision aid
Authors: Hersch Jolyn , Jansen Jesse , Barratt Alexandra , Irwig Les , Houssami Nehmat , Jacklyn Gemma , Thornton Hazel , Dhillon Haryana , McCaffery Kirsten
Published: September 2014

Objective

To develop, pilot and refine a decision aid (ahead of a randomised trial evaluation) for women around age 50 facing their initial decision about whether to undergo mammography screening.

Design

Two-stage mixed-method pilot study including qualitative interviews (n=15) and a randomised comparison using a quantitative survey (n=34).

Setting

New South Wales, Australia.

Participants

Women aged 43–59 years with no personal history of breast cancer.

Interventions

The decision aid provides evidence-based information about important outcomes of mammography screening over 20 years (breast cancer mortality reduction, overdetection and false positives) compared with no screening. The information is presented in a short booklet for women, combining text and visual formats. A control version produced for the purposes of comparison omits the overdetection-related content.

Outcomes

Comprehension of key decision aid content and acceptability of the materials.

Results

Most women considered the decision aid clear and helpful and would recommend it to others. Nonetheless, the piloting process raised important issues that we tried to address in iterative revisions. Some participants found it hard to understand overdetection and why it is of concern, while there was often confusion about the distinction between overdetection and false positives. In a screening context, encountering balanced information rather than persuasion appears to be contrary to people's expectations, but women appreciated the opportunity to become better informed.

Conclusions

The concept of overdetection is complex and new to the public. This study highlights some key challenges for communicating about this issue. It is important to clarify that overdetection differs from false positives in terms of its more serious consequences (overtreatment and associated harms). Screening decision aids also must clearly explain their purpose of facilitating informed choice. A staged approach to development and piloting of decision aids is recommended to further improve understanding of overdetection and support informed decision-making about screening.
Managing end of life medications at home—accounts of bereaved family carers: a qualitative interview study
Authors: Payne Sheila , Turner Mary , Seamark David , Thomas Carol , Brearley Sarah , Wang Xu , Blake Susan , Milligan Christine
Published: September 2014

Objective

To explore how bereaved family members recall managing end of life medications when delivering care to a patient dying at home in England.

Design

Qualitative study.

Setting

Domestic homes in two contrasting areas in England.

Participants

59 bereaved family carers who have delivered care to a patient who spent a minimum of 2 weeks at home prior to their death from cancer or other non-malignant condition. Cases were excluded if the place of death was: a hospice, nursing home or National Health Service (NHS) hospital.

Results

Participants identified a number of important concerns about managing end of life medication for the dying person at home. Although some support with medications is provided by general practitioners and nurses in the community, family carers take primary responsibility for drug administration and storage. They reported anxiety about giving correct and timely dosages, and concerns about keeping the patient comfortable without overdosing them or risking shortening their lives. In particular, they reported that certain analgesic medications, especially opioids, were considered to have a symbolic significance increasing analgesia requirements, and the use of a syringe driver was associated with deterioration and approaching death. Key barriers to managing end of life medications at home included: complex regimes; unwanted responsibility in deciding when to use ‘as needed’ medication; disagreements with professional staff, and anxiety about medication errors, especially if perceived to have implications for survival.

Conclusions

Family carers require more information about end of life drugs and their effects, support and training in managing medication for a dying person.
Intelligent Architecture for Comparative Analysis of Public Companies Using Semantics and XBRL Data
Authors: Radzimski Mateusz , Sanchez-Cervantes Jose Luis , Garcia-Crespo Angel , Temiño-Aguirre Ignacio
Published: September 2014

"The new source of power is not money in the hands of a few, but information in the hands of many." The aforementioned quote from John Naisbitt seems to be even more relevant in the world of finance at this very moment. Many financial decisions come from watching the information stream, selecting relevant data, analyzing it and acting accordingly. With the increasing global competition, the need for swift data analysis, high accuracy and quality becomes a must. XBRL (Extensible Business Reporting Language)XBRL: http://www.xbrl.org/ standard was proposed to improve efficiency of data exchange in the financial domain. However; it is still struggling with interoperability problems, not to mention comparability of data or multisource data integration. This paper presents the FLORA intelligent platform: an approach for dealing with current financial information shortcomings and achieving more effective way of processing financial data based on the Linked Data principles. The article also explains the process of data extraction and semantic modeling which are the cornerstones of efficient financial data analysis. As a result, the FLORA architecture facilitates effective, data-driven, financial analyses and Web-scale integration between financial applications and platforms.
A lubrication fracture model in a poro-elastic medium
Authors: Girault V. , Wheeler M. F. , Ganis B. , Mear M. E.
Published: September 2014

We present a non-planar fracture model in a poro-elastic medium. The medium in which the fracture is embedded is governed by the standard Biot equations of linear poro-elasticity and the flow of the fluid within the fracture is governed by the lubrication equation. We establish existence and uniqueness of the linearized coupled system under weak assumptions on the data. Two discretizations of the problem are formulated: one with a continuous Galerkin method and one with a mixed method for the flow in the reservoir and in the fracture. We perform the numerical analysis of the former and we provide an algorithm and numerical experiments for the latter.
Surface energies arising in microscopic modeling of martensitic transformations
Authors: Kitavtsev Georgy , Luckhaus Stephan , Rüland Angkana
Published: September 2014

In this paper we construct and analyze a two-well Hamiltonian on a 2D atomic lattice. The two wells of the Hamiltonian are prescribed by two rank-one connected martensitic twins, respectively. By constraining the deformed configurations to special 1D atomic chains with position-dependent elongation vectors for the vertical direction, we show that the structure of ground states under appropriate boundary conditions is close to the macroscopically expected twinned configurations with additional boundary layers localized near the twinning interfaces. In addition, we proceed to a continuum limit, show asymptotic piecewise rigidity of minimizing sequences and rigorously derive the corresponding limiting form of the surface energy.
New KEMIRA Method for Determining Criteria Priority and Weights in Solving MCDM Problem
Authors: Krylovas Aleksandras , Zavadskas Edmundas Kazimieras , Kosareva Natalja , Dadelo Stanislav
Published: September 2014

This study presents a new KEmeny Median Indicator Ranks Accordance (KEMIRA) method for determining criteria priority and selection criteria weights in the case of two separate groups of criteria for solving multiple criteria decision making (MCDM) problem. Kemeny median method is proposed to generalize experts' opinion. Medians are calculated applying three different measure functions. Criteria weights are calculated and alternatives ranking accomplished by solving optimization problem — minimization of ranks discrepancy function calculated for two groups of criteria. A numerical example for solving specific task of elite selection from security personnel is given to illustrate the proposed method.
Automatically Terminated Particle Swarm Optimization with Principal Component Analysis
Authors: Ong Bun Theang , Fukushima Masao
Published: September 2014

A hybrid Particle Swarm Optimization (PSO) that features an automatic termination and better search efficiency than classical PSO is presented. The proposed method is combined with the so-called "Gene Matrix" to provide the search with a self-check in order to determine a proper termination instant. Its convergence speed and reliability are also increased by the implementation of the Principal Component Analysis (PCA) technique and the hybridization with a local search method. The proposed algorithm is denominated as "Automatically Terminated Particle Swarm Optimization with Principal Component Analysis" (AT-PSO-PCA). The computational experiments demonstrate the effectiveness of the automatic termination criteria and show that AT-PSO-PCA enhances the convergence speed, accuracy and reliability of the PSO paradigm. Furthermore, comparisons with state-of-the-art evolutionary algorithms (EA) yield competitive results even under the automatically detected termination instant.
THEORETICAL AND NUMERICAL INVESTIGATIONS OF FREQUENCY ANALYSIS OF TWO CIRCULAR CYLINDERS OSCILLATING IN A INCOMPRESSIBLE VISCOUS FLUID
Authors: EL BAROUDI ADIL , RAZAFIMAHERY FULGENCE
Published: September 2014

A potential flow is presented in this paper for the analysis of the fluid-structure interaction systems including, but not limited to, the idealized human head. The model considers a cerebro-spinal fluid (CSF) medium interacting with two solid domain. The fluid field is governed by the linearized Navier–Stokes equation. A potential technique is used to obtain a general solution for a problem. The method consists in solving analytically partial differential equations obtained from the linearized Navier–Stokes equation. From the solution, modal shapes and stokes cells are shown. In the analysis, the elastic skull model and the rigid skull model are presented. A finite element analysis is also used to check the validity of the present method. The results from the proposed method are in good agreement with numerical solutions. The effects of the fluid thickness is also investigated.
Traces of singular values of Hauptmoduln
Authors: Beneish Lea , Larson Hannah
Published: September 2014

In an important paper, Zagier proved that certain half-integral weight modular forms are generating functions for traces of polynomials in the j-function. It turns out that Zagier's work makes it possible to algorithmically compute Hilbert class polynomials using a canonical family of modular forms of weight [Formula: see text]. We generalize these results and consider Hauptmoduln for levels 1, 2, 3, 5, 7, and 13. We show that traces of singular values of polynomials in Hauptmoduln are again described by coefficients of half-integral weight modular forms. This realization makes it possible to algorithmically compute class polynomials.
Synthesis and Applications of One-Dimensional Porous Nanowire Arrays: A Review
Authors: Ma Guanshui , Wang Xiaoguang
Published: September 2014

In recent years, particular attention has been drawn to one-dimensional (1D) porous nanowires due to their high surface-to-volume ratios as well as the as-revealed excellent performance in varieties of applications. This review begins with a wide introduction to the as-reported various preparation methods for the typical 1D porous nanowires mainly consisting of template-free method (i.e., chemical etching, chemical vapor deposition, hydrothermal, electrospinning, gas-solid reaction, etc.) and template-assisted method (i.e., using hard template and soft template, respectively). Based on the classification of design and preparation strategies, the as-evolved various nonmetallic and metallic 1D nanoporous materials with varied microstructural features have been highlighted, followed by the corresponding description and discussion on their typical applications in catalysis, sensors, rechargeable batteries, solar cells, super-capacitors, water treatment, random lasers and so forth.
Chapter 21 A review of sedimentation since the Last Glacial Maximum on the continental shelf of eastern China
Authors: Yang Shouye , Wang Zhongbo , Dou Yanguang , Shi Xuefa
Published: September 2014

The contiguous continental shelf of the Bohai, Yellow and East China seas has a total area of about 0.75×10
6
km
2
and a width of over 600 km. The basement is tectonically stable and the accumulated thickness of Quaternary sediment is up to 500 m. During the post-glacial period, the epicontinental shelf received a large influx of fluvial sediments with complex fluvial–marine interactions. The river-dominated shelf sedimentation is characterized by two types of terrigenous sediment source-to-sink transport processes represented by the two mega-rivers, Changjiang (Yangtze River) and Huanghe (Yellow River), and the small mountainous rivers in Taiwan Island, in total contributing about 10% of the world's total river sediment load. Mud patches and belts, and tidal sand ridges were well developed on the shelf during the post-glacial period. These muds are generally interpreted as eddy sedimentation formed after the highest post-glacial transgression, while the tidal sand ridges with several formation stages developed under variable oceanic regimes. The changes in monsoon climate-induced river flux, sea level and oceanic circulation primarily controlled the stratigraphic framework and sedimentary facies on the shelf during the late Quaternary. Nevertheless, many aspects of sedimentary processes and river–sea interactions at different spatial and temporal scales require more investigation.
Chapter 5 The southern Brazilian shelf
Authors: Nagai Renata H. , Sousa Silvia H. M. , Mahiques Michel M.
Published: September 2014

The southern Brazilian shelf (extending from 34°S to 22°S) is discussed with special emphasis on its Holocene sedimentary evolution. The onset of the Rio de la Plata plume influence on the inner shelf during the Late Holocene and the reworking of seafloor sediments by the Brazil Current in the outer shelf and upper slope are key elements. High-resolution sedimentary records have revealed palaeoceanographic changes in the Brazilian shelf, highlighting the importance of this sector of the Brazilian shelf to the comprehension of the palaeoclimate of South America, especially regarding oscillations of wind regime and humidity. These records also reveal that the recent sedimentary and oceanographic contrasts north and south of São Sebastião Island (24°S) have been present in the Brazilian shelf at least since the Early Holocene.
Chapter 6 The Argentine continental shelf: morphology, sediments, processes and evolution since the Last Glacial Maximum
Authors: Violante R. A. , Paterlini C. M. , Marcolini S. I. , Costa I. P. , Cavallotto J. L. , Laprida C. , Dragani W. , García Chapori N. , Watanabe S. , Totah V. , Rovere E. I. , Osterrieth M. L.
Published: September 2014

The Argentine continental shelf is one of the largest and smoothest siliciclastic shelves in the world. Although it is largely emplaced in a passive continental margin, the southernmost regions are related to transcurrent and active margins respectively associated with the Malvinas Plateau and Scotia Arc. Sea-level fluctuations, sediment dynamics and climatic/oceanographic processes were the most important conditioning factors in the modelling of the shelf, with a minor influence from isostatic and tectonic factors that are more relevant in the southernmost regions. The shelf is shaped by diverse geomorphic features, among which the most significant are four sets of terraces genetically associated to sea-level stillstands during the post-glacial transgression; the final one occurred at around 11 ka and is associated with the Younger Dryas event. The Last Glacial Maximum (LGM) sedimentary sequence is composed of, on average, 5–15 m-thick terrigenous, siliciclastic, relict–palimpsest sands mainly sourced from the Andean region, with minor amounts of bioclast and gravels, resulting from the reworking of pre-transgressive coastal environments.
Alcohol impairs skeletal muscle protein synthesis and mTOR signaling in a time-dependent manner following electrically stimulated muscle contraction
Authors: Steiner Jennifer L. , Lang Charles H.
Published: September 2014

Alcohol (EtOH) decreases protein synthesis and mammalian target of rapamycin (mTOR)-mediated signaling and blunts the anabolic response to growth factors in skeletal muscle. The purpose of the current investigation was to determine whether acute EtOH intoxication antagonizes the contraction-induced increase in protein synthesis and mTOR signaling in skeletal muscle. Fasted male mice were injected intraperitoneally with 3 g/kg EtOH or saline (control), and the right hindlimb was electrically stimulated (10 sets of 6 contractions). The gastrocnemius muscle complex was collected 30 min, 4 h, or 12 h after stimulation. EtOH decreased in vivo basal protein synthesis (PS) in the nonstimulated muscle compared with time-matched Controls at 30 min, 4 h, and 12 h. In Control, but not EtOH, PS was decreased 15% after 30 min. In contrast, PS was increased in Control 4 h poststimulation but remained unchanged in EtOH. Last, stimulation increased PS 10% in Control and EtOH at 12 h, even though the absolute rate remained reduced by EtOH. The stimulation-induced increase in the phosphorylation of S6K1 Thr421/Ser424(20–52%), S6K1 Thr389(45–57%), and its substrate rpS6 Ser240/244(37–72%) was blunted by EtOH at 30 min, 4 h, and 12 h. Phosphorylation of 4E-BP1 Ser65was also attenuated by EtOH (61%) at 4 h. Conversely, phosphorylation of extracellular signal-regulated kinase Thr202/Tyr204was increased by stimulation in Control and EtOH mice at 30 min but only in Control at 4 h. Our data indicate that acute EtOH intoxication suppresses muscle protein synthesis for at least 12 h and greatly impairs contraction-induced changes in synthesis and mTOR signaling.
A single bout of high-intensity aerobic exercise facilitates response to paired associative stimulation and promotes sequence-specific implicit motor learning
Authors: Mang Cameron S. , Snow Nicholas J. , Campbell Kristin L. , Ross Colin J. D. , Boyd Lara A.
Published: September 2014

The objectives of the present study were to evaluate the impact of a single bout of high-intensity aerobic exercise on 1) long-term potentiation (LTP)-like neuroplasticity via response to paired associative stimulation (PAS) and 2) the temporal and spatial components of sequence-specific implicit motor learning. Additionally, relationships between exercise-induced increases in systemic brain-derived neurotrophic factor (BDNF) and response to PAS and motor learning were evaluated. Sixteen young healthy participants completed six experimental sessions, including the following: 1) rest followed by PAS; 2) aerobic exercise followed by PAS; 3) rest followed by practice of a continuous tracking (CT) task and 4) a no-exercise 24-h retention test; and 5) aerobic exercise followed by CT task practice and 6) a no-exercise 24-h retention test. The CT task included an embedded repeated sequence allowing for evaluation of sequence-specific implicit learning. Slope of motor-evoked potential recruitment curves generated with transcranial magnetic stimulation showed larger increases when PAS was preceded by aerobic exercise (59.8% increase) compared with rest (14.2% increase, P = 0.02). Time lag of CT task performance on the repeated sequence improved under the aerobic exercise condition from early (−100.8 ms) to late practice (−75.2 ms, P < 0.001) and was maintained at retention (−79.2 ms, P = 0.004) but did not change under the rest condition ( P > 0.16). Systemic BDNF increased on average by 3.4-fold following aerobic exercise ( P = 0.003), but the changes did not relate to neurophysiological or behavioral measures ( P > 0.42). These results indicate that a single bout of high-intensity aerobic exercise can prime LTP-like neuroplasticity and promote sequence-specific implicit motor learning.
Multiplexed Quantitative Analysis of CD3, CD8, and CD20 Predicts Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Brown Jason R. , Wimberly Hallie , Lannin Donald R. , Nixon Christian , Rimm David L. , Bossuyt Veerle
Published: September 2014

Purpose: Although tumor-infiltrating lymphocytes (TIL) have been associated with response to neoadjuvant therapy, measurement typically is subjective, semiquantitative, and unable to differentiate among subpopulations. Here, we describe a quantitative objective method for analyzing lymphocyte subpopulations and assessing their predictive value.

Experimental Design: We developed a quantitative immunofluorescence assay to measure stromal expression of CD3, CD8, and CD20 on one slide. We validated this assay by comparison with flow cytometry on tonsil specimens and assessed predictive value in breast cancer on a neoadjuvant cohort (n = 95). Then, each marker was tested for prediction of pathologic complete response (pCR) compared with pathologist estimation of the percentage of lymphocyte infiltrate.

Results: The lymphocyte percentage and CD3, CD8, and CD20 proportions were similar between flow cytometry and quantitative immunofluorescence on tonsil specimens. Pathologist TIL count predicted pCR [P = 0.043; OR, 4.77; 95% confidence interval (CI), 1.05–21.6] despite fair interobserver reproducibility (κ = 0.393). Stromal AQUA (automated quantitative analysis) scores for CD3 (P = 0.023; OR, 2.51; 95% CI, 1.13–5.57), CD8 (P = 0.029; OR, 2.00; 95% CI, 1.08–3.72), and CD20 (P = 0.005; OR, 1.80; 95% CI, 1.19–2.72) predicted pCR in univariate analysis. CD20 AQUA score predicted pCR (P = 0.019; OR, 5.37; 95% CI, 1.32–21.8) independently of age, size, nuclear grade, nodal status, ER, PR, HER2, and Ki-67, whereas CD3, CD8, and pathologist estimation did not.

Conclusions: We have developed and validated an objective, quantitative assay measuring TILs in breast cancer. Although this work provides analytic validity, future larger studies will be required to prove clinical utility. Clin Cancer Res; 20(23); 5995–6005. ©2014 AACR.
Blockade of mTOR Signaling via Rapamycin Combined with Immunotherapy Augments Antiglioma Cytotoxic and Memory T-Cell Functions
Authors: Mineharu Yohei , Kamran Neha , Lowenstein Pedro R. , Castro Maria G.
Published: September 2014

The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8+ T cells. Rats treated with rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV–treated GL26 tumor–bearing mice, associated with an increase in the frequency of tumor-specific and IFNγ+ CD8+ T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8+ T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8+ T cells within the tumor and IFNγ release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM. Mol Cancer Ther; 13(12); 3024–36. ©2014 AACR.
Rational Design of K173A Substitution Enhances Thermostability Coupled with Catalytic Activity of Enterobacter sp. Bn12 Lipase
Authors: Farrokh Parisa , Yakhchali Bagher , Karkhane Ali Asghar
Published: September 2014

ELBn12 is a lipase isolated from Enterobacter sp. Bn12 with potential application in biotechnology. Homology modeling and rational design were applied to improve thermal stability of the lipase. K173A substitution introduced an AXXXA motif on the lipase model and it may have role in dimerization and thermostability of the protein. Site-directed mutagenesis was performed to construct the lipase variant. The mutated lipase was expressed in Escherichia coli pLysS and partially purified. Thermostability of the mutated lipase after 1 h of incubation at 70°C was twice that of wild-type lipase under the same conditions. Catalytic activity of the variant was about 1.5-fold towards tricaprylin at 60°C and pH 8.0; moreover, the lipase variant preserved its stability within the pH range of 7.0-11.0. Substitution of superficial hydrophilic Lys with hydrophobic Ala residue increased stability of the mutated lipase in the presence of nonionic surfactants, but this substitution caused lower stability towards polar solvents. Analysis of circular dichroism spectroscopy showed that the K173A mutation altered the secondary structure of the lipase into a more helical one. In conclusion, results of this study demonstrate the positive role of generation of a stabilizing protein motif through rational protein engineering that improves the enzyme characteristics.
Comparative Study of Four Growth Models Applied to Weight and Height Growth Data in a Cohort of US Children from Birth to 9 Years
Authors: Regnault Nolwenn , Gillman Matthew W. , Kleinman Ken , Rifas-Shiman Sheryl , Botton Jérémie
Published: September 2014

Background/Aims: The objective of our study was to compare the fit of four growth models for weight and height in contemporary US children between birth and 9 years. Methods: In Project Viva, we collected weight and height growth data between birth and 9 years. We compared the Jenss model, the adapted Jenss model that adds a quadratic term, and the Reed 1st and 2nd order models. We used the log likelihood ratio test to compare nested models and the Akaike (AIC)/Bayesian information criterion (BIC) to compare nonnested models. Results: For weight and height, the adapted Jenss model had a better fit than the Jenss model (for weight: p < 0.0001), and the Reed 2nd order model had a better fit than the Reed 1st order model (for weight: p < 0.0001). Compared with the Reed 2nd order model, the adapted Jenss model had a better fit for both weight (adapted Jenss vs. Reed 2nd order, AIC: 66,974 vs. 82,791, BIC: 67,066 vs. 82,883) and height (adapted Jenss vs. Reed 2nd order, AIC: 87,108 vs. 87,612, BIC: 87,196 vs. 87,700). Conclusions: In this pre-birth study of children aged 0-9 years, for both weight and height the adapted Jenss model presented the best fit of all four tested models.
Economic Evaluation of Pharmacogenomics: A Value-Based Approach to Pragmatic Decision Making in the Face of Complexity
Authors: Snyder Susan R. , Mitropoulou Christina , Patrinos George P. , Williams Marc S.
Published: September 2014

Evidence of the value of pharmacogenomic testing is needed to inform policymakers and clinicians for decision making related to adoption and coverage, and to facilitate prioritization for research and development. Pharmacogenomics has an important role in creating a more efficient healthcare system, and this article addresses how economic evaluation can strategically target evidence gaps for public health priorities with examples from pharmacogenomic medicine. This article begins with a review of the need for and use of economic evaluations in value-based decision making for pharmacogenomic testing. Three important gaps are described with examples demonstrating how they can be addressed: (1) projected impact of hypothetical new technology, (2) pre-implementation assessment of a specific technology, and (3) post-implementation assessment from relevant analytical stakeholder perspectives. Additional needs, challenges and approaches specific to pharmacogenomic economic evaluation in the developing world are also identified. These pragmatic approaches can provide much needed evidence to support real-world value-based decision making for pharmacogenomic-based screening and treatment strategies.
Pregnancy in Multiple Sclerosis
Authors: Hellwig Kerstin
Published: September 2014

Background: The incidence of multiple sclerosis (MS) is increasing, particularly in young women (20−40 years). In line, experience in the management of pregnancies and use of disease-modifying therapy (DMT) in women with MS is accumulating. Summary: Fertility is generally not affected in MS. If assisted reproduction techniques (ART) are required, unsuccessful procedures are associated with an increased relapse risk, particularly in the first few months post-ART. During pregnancy, the risk of relapse declines continuously, especially in the third trimester, then increases early postpartum (3 months) and returns to pre-pregnancy levels at 4−6 months. The progression of MS disability is probably not influenced by pregnancy. Obstetrical outcomes show no increased risk for miscarriage/malformations, and the course of pregnancy is similar to that of women without MS, but with a tendency towards assisted delivery/cesarean section and reduced birth weights. Safety data regarding DMT in pregnancy and breastfeeding are limited. Exclusive breastfeeding may be beneficial and, hence, should not be discouraged in favour of resuming DMT except in cases of highly-active disease. Key Messages: The course of pregnancy in women with MS is broadly similar to that in women without MS; risk-to-benefit assessments are warranted when considering halting DMT before pregnancy and resuming DMT postpartum.
Phase II Study of Preoperative Concurrent Chemoradiotherapy with S-1 plus Bevacizumab for Locally Advanced Resectable Rectal Adenocarcinoma
Authors: Sadahiro Sotaro , Suzuki Toshiyuki , Tanaka Akira , Okada Kazutake , Saito Gota , Kamijo Akemi , Akiba Takeshi , Kawada Shuichi
Published: September 2014

Objective: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of preoperative chemoradiotherapy (CRT) with concurrent S-1, bevacizumab, and radiation in patients with locally advanced rectal cancer (LARC). Methods: Fifty-two patients with LARC were enrolled. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, S-1 was administered orally twice a day on days 1-14 and 22-35, and bevacizumab was administered on days 1, 15, and 29. Surgical resection was scheduled 8 weeks (6-10 weeks) after completing the CRT. Results: All 52 patients underwent R0 radical surgery. Sphincter preservation was possible in 38 (73.1%) patients. A pathologic complete response was obtained in 10 (19.2%) patients, a pathologic downstaging was achieved in 37 (71.2%) patients, and the tumor shrinkage rate was 77.1%. The only grade 3 adverse events were leukopenia and rash in 1 (1.9%) patient. The rate of postoperative complications was 28.8%. Anastomotic leakage occurred in 9 (23.7%) of the 38 patients who underwent sphincter-preserving surgery. Perineal wound dehiscence developed in 2 (14.3%) of the 14 patients who received an abdominoperineal resection. Conclusions: Adding bevacizumab to S-1 clearly increased the incidence of wound-related complications, with no distinct enhancement of tumor response. i 2014 S. Karger AG, Basel
Dietary Fatty Acids and Risk of Coronary Heart Disease in Men
Authors: Virtanen Jyrki K. , Mursu Jaakko , Tuomainen Tomi-Pekka , Voutilainen Sari
Published: September 2014

Objective—

The epidemiological evidence of the role of dietary saturated fatty acids (SFA) in the development of coronary heart disease (CHD) is inconsistent. We investigated the associations of dietary fatty acids with the risk of CHD and carotid atherosclerosis in men with high SFA intake and high rates of CHD.

Approach and Results—

In total, 1981 men from the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42 to 60 years and free of CHD at baseline in 1984 to 1989, were investigated. Food consumption was assessed with 4-day food recording. Multivariate nutrient-density models were used to analyze isocaloric replacement of nutrients. CHD events were ascertained from national registries. Carotid atherosclerosis was assessed by ultrasonography of the common carotid artery intima-media thickness in 1015 men. During the average follow-up of 21.4 years, 183 fatal and 382 nonfatal CHD events occurred. SFA or trans fat intakes were not associated with CHD risk. In contrast, monounsaturated fat intake was associated with increased risk and polyunsaturated fat intake with decreased risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. The associations with carotid atherosclerosis were broadly similar, whereas the associations with nonfatal CHD were weaker.

Conclusions—

Our results suggest that SFA intake is not an independent risk factor for CHD, even in a population with higher ranges of SFA intake. In contrast, polyunsaturated fat intake was associated with lower risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. Further investigation on the effect of monounsaturated fat on the CHD risk is warranted.
Paul’s Argument against Gentile Circumcision in Romans 2:17-29
Authors: Thiessen Matthew
Published: September 2014

The majority of interpreters conclude that in Rom 2:17-29 Paul addresses an ethnic Jew. In contrast, Runar M. Thorsteinsson has argued recently that Paul addresses a gentile, specifically a gentile who has judaized and now thinks of himself as a Jew. This article provides further support for Thorsteinsson’s argument, contending that Paul, contrary to virtually all translations, does not redefine Jewishness in 2:28-29. Additionally, in vv. 21-27 Paul insists that, despite being circumcised, the gentile judaizer fails to keep the very law in which he boasts.
Engaging or Shaming? An Analysis of UN’s Naming and Shaming of Child Abusers in Armed Conflict
Authors: Nyamutata C.
Published: September 2014

The impact of armed conflict on children has been recognized for some time as a major humanitarian problem. In 1999, the United Nations (UN) Security Council began taking up the abuse of children during armed conflict as a regular thematic issue. As part of the protective framework, the UN adopted a “strategy” of “naming and shaming” government forces and rebel groups recruiting, killing, maiming, raping or other sexual abusing of children during conflict. The philosophical justification of the public exposures is premised on the supposed stigmatic and deterrent effect on named and shamed offenders. However, little analysis has gone into the impact of this UN policy. This paper has the modest aim of assessing the UN’s naming and shaming practice since inception of the policy in 2002. The efficacy of shaming sanctions is contestable. The recent UN annual statistics on the exposed parties do not seem to evince a convincing causal link between of naming and shaming and adherence to international humanitarian law and international human rights law, particularly among armed non-State groups (ANSAs) so far. Naming and shaming represents an antagonistic modus operandi. This paper argues that humanitarian engagement with ANSAs offers a non-confrontational and corrective approach and thus greater promise for compliance and protection of children during armed conflict than naming and shaming.
Guaranteeing the Broadest Protection to Minors in the Aftermath of Disasters: Re-Framing the International Discussion in Terms of Child Abduction, Sale, and Trafficking
Authors: Scarpa Silvia
Published: September 2014

The Article aims at demonstrating that a more effective and comprehensive protection of minors in the aftermath of disasters can be guaranteed by, first of all, re-framing the discussion of the relevant actors in this field on the various practices and processes, including sexual and labour exploitation, early and forced marriages, the involvement of children in armed conflicts, and illegal adoptions, that can be grouped under the heading of three umbrella terms, namely, the abduction, sale, and trafficking of children. These terms are, in part, already used by relevant actors in the field of disaster relief work; however, their interpretation and boundaries are not always properly clarified. Therefore, the Article discusses the definitions of these three terms and recommends that all the relevant actors follow such framework and conform to the definitions provided, so as to guarantee a greater consistency and clarity in the debate over child protection in the aftermath of disasters.
A generic review of the lysianassoid family Uristidae and descriptions of new taxa from Australian waters (Crustacea, Amphipoda, Uristidae)
Authors: LOWRY J. K. , KILGALLEN N. M.
Published: September 2014

In this paper we review the genera of the family Uristidae and report for the first time from Australian waters: the new genus and species Des griffini; the genus Euonyx with two new species; Koroga megalops; the genus Parschisturella with three new species; and Stephonyx arabiensis plus one new species. We provide keys to species in the genera Abyssorchomene, Euonyx, and Parschisturella. Ten genera and 24 species of uristid lysianassoids are now known from Australian waters.
Can We Constrain CMIP5 Rainfall Projections in the Tropical Pacific Based on Surface Warming Patterns?*
Authors: Grose Michael R. , Bhend Jonas , Narsey Sugata , Gupta Alex Sen , Brown Josephine R.
Published: September 2014

Climate warming has large implications for rainfall patterns, and identifying the most plausible pattern of rainfall change over the next century among various model projections would be valuable for future planning. The spatial pattern of projected sea surface temperature change has a key influence on rainfall changes in the tropical Pacific Ocean. Here it is shown that simple indices of the size of the equatorial peak in the spatial pattern of warming and to a lesser extent the hemispheric asymmetry in warming are useful for classifying the surface temperature change in different models from phase 5 of the Coupled Model Intercomparison Project (CMIP5). Models with a more pronounced equatorial warming show a fairly distinct rainfall response compared to those with more uniform warming, including a greater “warmer-get-wetter” or dynamical response, whereby rainfall increases follow the surface warming anomaly. Models with a more uniform warming pattern project a smaller rainfall increase at the equator and a rainfall increase in the southern tropical Pacific, a pattern that is distinct from the multimodel mean of CMIP5. Thus, the magnitude of enhanced equatorial warming and to some extent the hemispheric asymmetry in warming provides a useful framework for constraining rainfall projections. While there is not a simple emergent constraint for enhanced equatorial warming in models in terms of past trends or bias in the current climate, further understanding of the various feedbacks involved in these features could lead to a useful constraint of rainfall for the Pacific region.