bluuebunny/crossref_metadata_2025 huggingface dataset:
DIDS inhibits overexpression BAK1‐induced mitochondrial apoptosis through GSK3β/β‐catenin signaling pathway
Authors: Yang Xiayun , Tang Shusheng , Li Daowen , Yu Xiaohong , Wang Fuyun , Xiao Xilong
Published: December 2017

Bcl‐2 homologous antagonist/killer (BAK1) is a critical regulator of mitochondrial apoptosis. Although upregulation of BAK1 induces apoptosis has been established, the underlying molecular mechanism is far from clear. 4,4′‐diisothiocyanostilbene‐2,2′‐disulfonic acid (DIDS), an organic anion used as a blocker of anion exchangers and chloride channels, has been proved to rescue cell apoptosis both in vitro and in vivo. However, whether DIDS can inhibit BAK1‐induced mitochondrial apoptosis remains undefined. Thus, this study aimed to explore whether DIDS could protect BAK1‐induced apoptosis through GSK3β/β‐catenin signaling pathway. The results showed overexpression BAK1 in 293T cells induced mitochondrial apoptosis accompanied by increasing the expression levels of cleaved caspase‐9, ‐3, poly (ADP‐ribose) polymerase (PARP) and reducing the MMP. Furthermore, overexpression BAK1 decreased the expression levels of Ser9‐GSK3β and β‐catenin. In addition, lithium chloride (LiCl), an activator of Wnt/β‐catenin signaling pathway, markedly attenuated overexpression BAK1‐induced mitochondrial apoptosis by restoring the expression levels of Ser9‐GSK3β and β‐catenin. Finally, DIDS absolutely abolished overexpression BAK1‐mediated mitochondrial apoptosis through recovering the expression levels of Ser9‐GSK3β and β‐catenin. Taken together, our results reveal that DIDS blocks overexpression BAK1‐induced mitochondrial apoptosis through GSK3β/β‐catenin pathway.
The US Food and Drug Administration's tentative approval process and the global fight against HIV
Authors: Chahal Harinder Singh , Murray Jeffrey S , Shimer Martin , Capella Peter , Presto Ryan , Valdez Mary Lou , Lurie Peter G
Published: December 2017

Introduction

In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource‐constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource‐constrained settings. Although the tFDA was originally intended to support the United States’ President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in‐depth review of the relevant legal and regulatory processes.

Discussion

USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use.

Conclusions

In this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource‐constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example.
Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy
Authors: Sharma Shaunik , Puttachary Sreekanth , Thippeswamy Thimmasettappa
Published: December 2017

Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease‐modifying agents. For translational studies, SE targets are appropriate for screening anticonvulsive drugs prior to their advancement as therapeutic agents, while targets of epileptogenesis are relevant for identification and development of therapeutic agents that can either prevent or modify the disease or its onset. The acute seizure models do not reveal antiepileptogenic properties of anticonvulsive drugs. This review highlights the important components of epileptogenesis and the long‐term impact of intervening one of these components, nitric oxide (NO), in rat and mouse kainate models of TLE. NO is a putative pleotropic gaseous neurotransmitter and an important contributor of nitro‐oxidative stress that coexists with neuroinflammation and epileptogenesis. The long‐term impact of inhibiting the glial source of NO during early epileptogenesis in the rat model of TLE is reviewed. The importance of sex as a biological variable in disease modification strategies in epilepsy is also briefly discussed.
JCB to Infinity and Beyond: A Personal Recollection and Recommendation
Authors: Simonton Dean Keith
Published: December 2017

The author starts by narrating his personal experiences with the Journal of Creative Behavior. Although the author began publishing his creativity research in 1975, he did not submit his first manuscript until 1981, 14 years after JCB's founding—a manuscript that was finally published in 1983 without ever being formally accepted! The author then turns to the events leading up to his assumption of the journal's editorship in 1993, describing the editorial endeavor that lasted until 1999. He concludes by discussing the aftermath, including the tremendous growth in publication opportunities for creativity research. That proliferation then inspires the recommendation that JCB continue to be considered a principal vehicle for all creativity researchers.
Looking Forward: The Potential of Creativity for Social Justice and Equity (and Other Exciting Outcomes)
Authors: Kaufman James C.
Published: December 2017

This brief essay argues for the importance for more work on how creativity predicts positive outcomes, with a particular emphasis on expanding our definitions of these positive outcomes. The way that creativity may lead to increased equity and social justice is used as an example of these type of potential research questions.
Creative Thinking Processes: The Past and the Future
Authors: Mumford Michael D. , McIntosh Tristan
Published: December 2017

For more than one hundred years, students of creativity, including seminal efforts published in theJournal of Creative Behavior, have sought to identify the key processes people must execute to produce creative problem solutions. In recent years, we have seen a consensual model of key creative thinking processes being accepted by the field. In the present effort, we review the evidence bearing on the eight core processes proposed in this consensual model. Subsequently, directions for future research on creative thinking processes are discussed.
Land use dynamics derived from colluvial deposits and bogs in the Black Forest, Germany
Authors: Henkner Jessica , Ahlrichs Jan , Fischer Elske , Fuchs Markus , Knopf Thomas , Rösch Manfred , Scholten Thomas , Kühn Peter
Published: December 2017

The Black Forest is considered to be a rather unfavorable area, having a short vegetation period, low mean annual temperatures, high precipitation, and a pronounced relief. These conditions do not favor agricultural land use and thus it is widely accepted that people only began using the land intensively during the Middle Ages. In this integrated study 17 soil profiles, two peat bogs and a database of archaeological finds were used to reconstruct past land use impacts on the environment. AMS–14C datings of charcoals, luminescence datings of colluvial deposits, archaeological finds and pollen records indicate land use already during the Neolithic. This pre‐medieval land use might be related to seasonal settlements dominated by pastoralism and the use of wood or bedrock to build settlements and infrastructure or as energy supply. There is new evidence of human activity dating back to the Bronze and Iron Age, which is a discrepancy to the absence of archaeological finds in the direct vicinity of the studied sites. With the beginning of the Middle Ages land use practices changed, most likely with the expansion and intensification of agricultural land use, which coincides with the increasing use of natural resources in the Black Forest. Hence, the main phases of colluvial deposition date to the Middle Ages and Modern Times. Increased contents of As, Cr, Cu, Pb, or Zn in medieval colluvial deposits might indicate smelting or mining, even though there are no known archeological sites pointing to such activities nearby. Whereas the pattern of colluvial deposition in the southeastern Black Forest points to distinct, but local land use in pre‐medieval times and to intensified and widespread land use since the Middle Ages, thick and multi‐layered colluvial deposits indicate intensive land use in the neighboring Baar region since the Neolithic. The different land use patterns of these two regions originate from the rather favorable conditions for agriculture in terms of soils, climate, and topography in the Baar region compared to the unfavorable conditions in the Black Forest.
Tree age affects physicochemical, functional quality and storability of Amrapali mango (Mangifera indica L.) fruits
Authors: Meena Nirmal Kumar , Asrey Ram
Published: December 2017

BACKGROUND

The effect of tree age on physicochemical quality attributes and storage behaviour of Amrapali mango fruit was evaluated. Physiologically mature fruits were harvested from 6‐, 18‐ and 30‐year‐old trees and kept for ripening under ambient conditions (temperature 35 ± 3 °C, relative humidity 60 ± 5%). Observations were recorded at 3‐day intervals.

RESULTS

Highest total soluble solids and total sugars were found in the fruit sourced from 18‐year‐old trees. At the end of storage, least titratable acidity (0.17%) and higher carotenoids (10.86 mg 100 g−1) were found in 30‐year‐old tree fruits during the last day of storage. Highest total phenols (TP) (251.33 μg gallic acid g−1), antioxidant capacity (AC) (5.63 μmol Trolox g−1) and ascorbic acid (AA) (31.13 mg 100 g−1) were reported in fruits from younger trees of 6 years old. Maximum respiratory and ethylene evolution peak was observed in fruits obtained from oldest trees, whereas least activities of pectin methyl esterase (0.31 μmol min−1 g−1 fresh weight) and polygalacturonase (53.67 μg galacturonic acid g−1 h−1) were observed in 6‐year‐old tree fruits at the end of the 9‐day storage period.

CONCLUSION

Higher total soluble solids and total sugars were found in fruit harvested from middle‐age‐group (18‐year‐old) trees during the entire storage period of 9 days. Most of the functional parameters, such as TP, AC and AA, were observed to be higher in fruits from younger (6‐year‐old) trees. The obtained results revealed that produce from middle‐age‐group (18‐year‐old) Amrapali mango orchards suit consumers' and processors' requirements. © 2017 Society of Chemical Industry
Interactive effects of dietary phosphorus and iron on Daphnia life history
Authors: Lind Patrick R. , Jeyasingh Punidan D.
Published: December 2017

Food quality of freshwater consumers is often defined as the relative supply of carbon (C) to phosphorus (P) in diet. The growth rate hypothesis makes mechanistic links between P supply, ribosome biogenesis, and growth, with subsequent impacts on other life history traits such as age at maturity and clutch size. However, we know surprisingly little about the role and importance of other elements in impacting life histories of freshwater zooplankton. Because there is much evidence indicating a pivotal role for iron (Fe) in oogenesis, we hypothesized that dietary Fe content will invoke distinct effects on consumer life history compared to P. We tested this hypothesis in four species of Daphnia, by characterizing the relative impact of P and Fe on life history traits, and also measuring changes in Fe kinetics in response to dietary P and Fe. We found that while P had the largest influence on growth rate, Fe was particularly important in impacting reproductive traits. Radiotracer (Fe55) analyses revealed differences in the acquisition and retention rates of Fe between two species of Daphnia. Finally, we found that P‐ and Fe‐supply driven differences in growth and reproduction had significant effects on population growth. These results indicate that Fe can constrain production of freshwater zooplankton. Understanding the interaction between the supply of P in relation to trace elements should provide a clearer picture on how stoichiometric constraints are realized in lakes.
The DNABII family of proteins is comprised of the only nucleoid associated proteins required for nontypeable Haemophilus influenzae biofilm structure
Authors: Devaraj Aishwarya , Buzzo John , Rocco Christopher J. , Bakaletz Lauren O. , Goodman Steven D.
Published: December 2017

Biofilms play a central role in the pathobiology of otitis media (OM), bronchitis, sinusitis, conjunctivitis, and pneumonia caused by nontypeable Haemophilus influenzae (NTHI). Our previous studies show that extracellular DNA (eDNA) and DNABII proteins are essential components of biofilms formed by NTHI. The DNABII protein family includes integration host factor (IHF) and the histone‐like protein HU and plays a central role in NTHI biofilm structural integrity. We demonstrated that immunological targeting of these proteins during NTHI‐induced experimental OM in a chinchilla model caused rapid clearance of biofilms from the middle ear. Given the essential role of DNABII proteins in maintaining the structure of an NTHI biofilm, we investigated whether any of the other nucleoid associated proteins (NAPs) expressed by NTHI might play a similar role, thereby serving as additional target(s) for intervention. We demonstrated that although several NAPs including H‐NS, CbpA, HfQ and Dps are present within the biofilm extracellular matrix, only the DNABII family of proteins is critical for the structural integrity of the biofilms formed by NTHI. We have also demonstrated that IHF and HU are located at distinct regions within the extracellular matrix of NTHI biofilms formed in vitro, indicative of independent functions of these two proteins.
An inverse problem for an integro‐differential operator on a star‐shaped graph
Authors: Bondarenko Natalia P.
Published: December 2017

A partial inverse problem for an integro‐differential Sturm‐Liouville operator on a star‐shaped graph is studied. We suppose that the convolution kernels are known on all the edges of the graph except one and recover the kernel on the remaining edge from a part of the spectrum. We prove the uniqueness theorem for this problem and develop a constructive algorithm for its solution, based on the reduction of the inverse problem on the graph to the inverse problem on the interval by using the Riesz basis property of the special system of functions.
Boundedness in a parabolic‐elliptic chemotaxis system with nonlinear diffusion and sensitivity and logistic source
Authors: Viglialoro Giuseppe , Woolley Thomas E.
Published: December 2017

In this paper, we study the zero‐flux chemotaxis‐system

urn:x-wiley:mma:media:mma4707:mma4707-math-0001
where Ω is a bounded and smooth domain of
, n≥1, and where
, k,μ>0 and α≤1. For any v≥0, the chemotactic sensitivity function is assumed to behave as the prototype χ(v)=χ0/(1+av)2, with a≥0 and χ0>0. We prove that for any nonnegative and sufficiently regular initial data u(x,0), the corresponding initial‐boundary value problem admits a unique global bounded classical solution if α<1; indeed, for α=1, the same conclusion is obtained provided μ is large enough. Finally, we illustrate the range of dynamics present within the chemotaxis system in 1, 2, and 3 dimensions by means of numerical simulations.
Some remarks on the deterministic particle swarm optimization algorithm
Authors: Wang Jinxun , Xu Qiwen , Li Qin
Published: December 2017

In this paper, we give a simple proof for the convergence of the deterministic particle swarm optimization algorithm under the weak chaotic assumption and remark that the weak chaotic assumption does not relax the stagnation assumption in essence. Under the spectral radius assumption, we propose a convergence criterion for the deterministic particle swarm optimization algorithm in terms of the personal best and neighborhood best position of the particle that incorporates the stagnation assumption or the weak chaotic assumption as a special case.
Complete magnetic field dependence of SABRE‐derived polarization
Authors: Kiryutin Alexey S. , Yurkovskaya Alexandra V. , Zimmermann Herbert , Vieth Hans‐Martin , Ivanov Konstantin L.
Published: December 2017

Signal amplification by reversible exchange (SABRE) is a promising hyperpolarization technique, which makes use of spin‐order transfer from parahydrogen (the H2 molecule in its singlet spin state) to a to‐be‐polarized substrate in a transient organometallic complex, termed the SABRE complex. In this work, we present an experimental method for measuring the magnetic field dependence of the SABRE effect over an ultrawide field range, namely, from 10 nT to 10 T. This approach gives a way to determine the complete magnetic field dependence of SABRE‐derived polarization. Here, we focus on SABRE polarization of spin‐1/2 hetero‐nuclei, such as 13C and 15N and measure their polarization in the entire accessible field range; experimental studies are supported by calculations of polarization. Features of the field dependence of polarization can be attributed to level anticrossings in the spin system of the SABRE complex. Features at magnetic fields of the order of 100 nT–1 μT correspond to “strong coupling” of protons and hetero‐nuclei, whereas features found in the mT field range stem from “strong coupling” of the proton system. Our approach gives a way to measuring and analyzing the complete SABRE field dependence, to probing NMR parameters of SABRE complexes and to optimizing the polarization value.
Prospective motion correction enables highest resolution time‐of‐flight angiography at 7T
Authors: Mattern Hendrik , Sciarra Alessandro , Godenschweger Frank , Stucht Daniel , Lüsebrink Falk , Rose Georg , Speck Oliver
Published: December 2017

Purpose

Higher magnetic field strengths enable time‐of‐flight (TOF) angiography with higher resolution to depict small‐vessel pathologies. However, this potential is limited by the subject's ability to remain motionless. Even small‐scale, involuntary motion can degrade vessel depiction, thus limiting the effective resolution. The aim of this study was to overcome this resolution limit by deploying prospectively motion‐corrected (PMC) TOF.

Methods

An optical, marker‐based, in‐bore tracking system was used to update the imaging volume prospectively according to the subject's head motion. PMC TOF was evaluated in 12 healthy, cooperative subjects at isotropic resolution of up to 150 μm. Image quality was assessed qualitatively through reader rating and quantitatively with the average edge‐strength metric.

Results

PMC significantly increased the average edge strength and qualitatively improved the vessel depiction in nine out of 11 cases. Image quality was never degraded by motion correction. PMC also enabled acquisition of the highest resolution human brain in vivo TOF angiography to date.

Conclusion

With PMC enabled, high‐resolution TOF is able to visualize brain vasculature beyond the effective resolution limit. Magn Reson Med 80:248–258, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Cardiac gating using scattering of an 8‐channel parallel transmit coil at 7T
Authors: Jaeschke Sven H.F. , Robson Matthew D. , Hess Aaron T.
Published: December 2017

Purpose

To establish a cardiac signal from scattering matrix or scattering coefficient measurements made on a 7T 8‐channel parallel transmit (pTx) system, and to evaluate its use for cardiac gating.

Methods

Measurements of the scattering matrix and scattering coefficients were acquired using a monitoring pulse sequence and during a standard cine acquisition, respectively. Postprocessing used an independent component analysis and gating feature identification. The effect of the phase of the excitation radiofrequency (RF) field (
shim) on the cardiac signal was simulated for multiple
shim configurations, and cine images were reconstructed from both the scattering coefficients and electrocardiogram (ECG).

Results

The cardiac motion signal was successfully identified in all subjects with a mean signal‐to‐noise ratio of 33.1 and 5.7 using the scattering matrix and scattering coefficient measurements, respectively. The dominant gating feature in the cardiac signal was a peak aligned with end‐systole that occurred on average at 311 and 391 ms after the ECG trigger, with a mean standard deviation of 13.4 and 18.1 ms relative to ECG when using the scattering matrix and scattering coefficients measurements, respectively. The scattering coefficients showed a dependence on
shim with some shim configurations not showing any cardiac signal. Cine images were successfully reconstructed using the scattering coefficients with minimal differences compared to those using ECG.

Conclusion

We have shown that the scattering of a pTx RF coil can be used to estimate a cardiac signal, and that scattering matrix and coefficients can be used to cardiac gate MRI acquisitions with the scattering matrix providing a superior cardiac signal. Magn Reson Med 80:633–640, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
The dimension splitting and improved complex variable element‐free Galerkin method for 3‐dimensional transient heat conduction problems
Authors: Cheng H. , Peng M.J. , Cheng Y.M.
Published: December 2017

In this paper, by combining the dimension splitting method and the improved complex variable element‐free Galerkin method, the dimension splitting and improved complex variable element‐free Galerkin (DS‐ICVEFG) method is presented for 3‐dimensional (3D) transient heat conduction problems. Using the dimension splitting method, a 3D transient heat conduction problem is translated into a series of 2‐dimensional ones, which can be solved with the improved complex variable element‐free Galerkin (ICVEFG) method. In the ICVEFG method for each 2‐dimensional problem, the improved complex variable moving least‐square approximation is used to obtain the shape functions, and the penalty method is used to apply the essential boundary conditions. Finite difference method is used in the 1‐dimensional direction, and the Galerkin weak form of 3D transient heat conduction problem is used to obtain the final discretized equations. Then, the DS‐ICVEFG method for 3D transient heat conduction problems is presented. Four numerical examples are given to show that the new method has higher computational precision and efficiency.
Obesity and healthcare resource utilization: comparative results from the UK and the USA
Authors: Nørtoft E. , Chubb B. , Borglykke A.
Published: December 2017

Objectives

To estimate the differences between individuals with and without obesity on healthcare resource utilization using two large electronic medical record databases.

Methods

Data from the UK Clinical Practice Research Datalink and US General Electric Centricity database of adults (≥18 years) with registration date before 01/01/2010. Differences between individuals with and without obesity on 5‐year rates of Primary Care Physician (PCP) contacts, prescriptions and hospitalizations were analysed.

Results

The study contained 1,878,017 UK and 4,414,883 US individuals. Compared with body mass index (BMI) (18.5–24.9 kg m−2), significant (p < 0.0001) increases in healthcare usage were observed with increasing BMI. Individuals with BMI 30–34.9 kg m−2 had higher PCP contact rate (rate ratios [RR] 1.27 and 1.28 for UK and USA, respectively), higher prescription rate (RR 1.61 and 1.51) and higher hospitalization rate (RR 1.10 and 1.13) than individuals with BMI 18.5–24.9 kg m−2. Individuals with BMI >40 kg m−2 also had higher PCP contact rate (RR 1.56 and 1.64), prescription rate (RR 2.48 and 2.14) and hospitalization rate (RR 1.27 and 1.30) than individuals with BMI 18.5–24.9 kg m−2.

Conclusions

The utilization of healthcare resources is significantly higher in individuals with obesity. A similar trend was observed in both the UK and US cohorts.
Response in a child with a BRAF V600E mutated desmoplastic infantile astrocytoma upon retreatment with vemurafenib
Authors: van Tilburg Cornelis M. , Selt Florian , Sahm Felix , Bächli Heidi , Pfister Stefan M. , Witt Olaf , Milde Till
Published: December 2017

Infants with low‐grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re‐)treatment regimens are briefly discussed.
Diagnostic value of cell bound and circulating neutrophil antibody detection in pediatric neutropenia
Authors: Porretti Laura , Farruggia Piero , Colombo Federico Simone , Cattaneo Alessandra , Ghilardi Roberta , Mirra Nadia , Notarangelo Lucia Dora , Martire Baldassarre , Trombetta Elena , Milani Silvano , Vener Claudia , Rebulla Paolo
Published: December 2017

Background

Chronic benign neutropenia of infancy includes primary autoimmune neutropenia (pAIN) and chronic idiopathic neutropenia (CIN). A diagnosis of CIN is supported by the absence of free and/or cell‐bound neutrophil autoantibodies, which can be detected by flow cytometry with the indirect‐granulocyte immunofluorescence test (I‐GIFT) and direct‐granulocyte immunofluorescence test (D‐GIFT), respectively. Conclusive evidence is lacking on the diagnostic value of the D‐GIFT, whose performance requires specific laboratory expertise, may be logistically difficult, and hampered by very low neutrophil count in patient samples. This study investigated whether the evaluation of D‐GIFT improves the diagnostic accuracy of pediatric neutropenia.

Procedure

I‐GIFT and D‐GIFT were performed in 174 pAIN, 162 CIN, 81 secondary AIN, 51 postinfection neutropenic, and 65 nonautoimmune neutropenic children referred to this laboratory during 2002–2014.

Results

Using 90% specific median fluorescence intensity cut‐off values calculated by receiver operating characteristic curves, D‐GIFT was positive in 49% of CIN patients, who showed similar clinical features as those with pAIN. In 44 (27%) of 162 CIN patients, I‐GIFT was repeated two to three times in a year, resulting positive in 12 and two patients at second and third screening, respectively. Interestingly, 10 of the latter 14 patients showed a positive D‐GIFT at the first serological screening. False positive D‐GIFT was shown by 12% and 22% of nonneutropenic and nonautoimmune neutropenic patients, respectively.

Conclusions

D‐GIFT evaluation improves the diagnostic accuracy of pediatric neutropenia, but improvement of cell‐bound antibody detection is needed to decrease false positive results.
Parents’ pain medication underdosing is associated with more emergency department visits in sickle cell disease
Authors: Morrison Andrea K. , Myrvik Matthew P. , Brousseau David C. , Drendel Amy L. , Scott J. Paul , Visotcky Alexis , Panepinto Julie A.
Published: December 2017

Objective

To determine the association between health literacy, medication knowledge, and pain treatment skills with emergency department (ED) use of parents of children with sickle cell disease (SCD).

Methods

Parents of children 1‐ to 12‐years‐old with SCD were enrolled. Health literacy was assessed using the Newest Vital Sign. Parents completed a structured interview assessing knowledge of the dosage and frequency of home pain medications and an applied skills task requiring them to dose a prescribed pain medication. Underdosage was defined by too small a dose (dosage error) or too infrequent a dose (frequency error). The association between medication knowledge and applied skills with ED visits for pain over the past year was evaluated using Poisson regression adjusting for genotype.

Results

One hundred parent/child pairs were included; 50% of parents had low health literacy. Low health literacy was associated with more underdose frequency errors (38% vs. 19%, P = 0.02) on the skills task. On medication knowledge, underdose dosage errors (adjusted incidence rate ratio [aIRR] 2.0, 95% confidence interval [CI] 1.3–3.0) and underdose frequency errors (aIRR, 1.7, 95% CI 1.2–2.6) were associated with a higher rate of ED visits for pain. On the skills task, underdose dosage errors (aIRR 1.6, 95% CI 1.1‐2‐.4) and underdose frequency errors were associated with more ED visits (aIRR 1.5, 95% CI 1.1–2.1).

Conclusions

For medication knowledge and skills tasks, children of parents who underdosed pain medication had a higher rate of ED visits for pain. Health literate strategies to improve parents’ medication skills may improve pain treatment at home and decrease healthcare utilization.
Modeling of a C‐end rule peptide adsorbed onto gold nanoparticles
Authors: Triguero Jordi , Flores‐Ortega Alejandra , Zanuy David , Alemán Carlos
Published: December 2017

The RPAR peptide, a prototype C‐end Rule (CendR) sequence that binds to neuropilin‐1 (NRP‐1), has potential therapeutic uses as internalization trigger in anticancer nanodevices. Recently, the functionalization of gold nanoparticles with CendR peptides has been proved to be a successful strategy to target the NRP‐1 receptor in prostate cancer cells. In this work, we investigate the influence of two gold surface facets, (100) and (111), on the conformational preferences of RPAR using molecular dynamics simulations. Both clustering and conformational analyses revealed that the peptide backbone becomes very rigid upon adsorption onto gold, which is a very fast and favored process, the only flexibility being attributed to the side chains of the two Arg residues. Thus, the different components of RPAR tend to adopt an elongated shape, which is characterized by the pseudo‐extended conformation of both the backbone and the Arg side chains. This conformation is very different from the already known bioactive conformation, indicating that RPAR is drastically affected by the substrate. Interestingly, the preferred conformations of the peptide adsorbed onto gold facets are not stabilized by salt bridges and/or specific intramolecular hydrogen bonds, which represent an important difference with respect to the conformations found in other environments (e.g. the peptide in solution and interacting with NRP‐1 receptor). However, the conformational changes induced by the substrate are not detrimental for the use of gold nanoparticles as appropriate vehicles for the transport and targeted delivery of the RPAR. Thus, once their high affinity for the NRP‐1 receptor induces the targeted delivery of the elongated peptide molecules from the gold nanoparticles, the lack of intramolecular interactions facilitates their evolution towards the bioactive conformation, increasing the therapeutic efficacy of the peptide.
A multi‐modality tracking, navigation and calibration for a flexible robotic drill system for total hip arthroplasty
Authors: Ahmad Fuad Ahmad Nazmi Bin , Deep Kamal , Yao Wei
Published: December 2017

Background

This paper presents a novel multi‐modality tracking and navigation system that provides a unique capability to guild a flexible drill tip inside the bone with accurate curved tunnelling.

Methods

As the flexible drill tip cannot be tracked optically inside the bone, this research focuses on developing a hybrid tracking and navigation system for tracking a flexible drill tip by using both optical and kinematic tracking. The tracking information is used to guide the THA (total hip arthroplasty) procedure, providing a real‐time virtual model of the flexible drill.

Results

The flexible and steerable drill tip system is then tested on total hip arthroplasty followed by evaluation of the positioning and orientation of femoral stem placement by femoral milling.

Conclusions

Based on this study, we conclude that the tracking and navigation system is able to guide the flexible drill to mill inside femoral canal.
Regioselective Synthesis of 2‐(Trifluoromethyl)‐3‐ethoxycarbonyl‐4‐(2‐oxo‐2‐arylethyl)‐4H‐chromene Derivatives by [3, 3] Sigmatropic Rearrangement
Authors: Kuchukulla Ratnakar Reddy , Desagoni Madhu , Narra Srikanth Reddy , Goutham Santhosh Kumar , Banda Narsaiah
Published: December 2017

A new and an efficient method has been developed to synthesize ethyl 4‐(2‐oxo‐2‐arylethyl)‐2‐(trifluoromethyl)‐4H‐chromene‐3‐carboxylate derivatives 3 from 2H‐chromene 1 and aryl acetylene 2 through [3, 3] sigmatropic rearrangement in presence of catalytic amount of BF3.OEt2 (10 mol %).
Synthesis, Biological Evaluation and Molecular Docking of Novel Curcumin Derivatives as Bcl‐2 Inhibitors Targeting Human Breast Cancer MCF‐7 Cells
Authors: Bhuvaneswari Kaliyan , Sivaguru Paramasivam , Lalitha Appaswami
Published: December 2017

An efficient one‐pot multicomponent double Michael addition strategy was developed for the synthesis of novel curcumin derivatives using 1,4‐diazabicyclo [2.2.2] octane (DABCO) as the catalyst. Selected compounds (E)‐4,4′′,5′‐trihydroxy‐6′‐(3‐(4‐hydroxy‐3‐methoxyphenyl)acryloyl)‐3,3′′‐dimethoxy‐3′,4′‐dihydro‐[1, 1′:3′, 1′′‐terphenyl]‐2′,2′(1′H)‐dicarbonitrile (4 k) and (E)‐ethyl 2′‐cyano‐4′′,5′‐dihydroxy‐6′‐(3‐(4‐hydroxy‐3‐methoxyphenyl)acryloyl)‐3′′‐methoxy‐4‐methyl‐1′,2′,3′,4′‐tetrahydro‐[1, 1′:3′, 1′′‐terphenyl]‐2′‐carboxylate (6 j) were evaluated for their in‐vitro anticancer activities against human breast cancer cells (MCF‐7) and human normal breast cells (HBL 100) and found to show effective cytotoxicity on MCF‐7 cells and less cytotoxicity on HBL 100 cells than simple curcumin. In addition, molecular docking studies helped to rationalize anti‐apoptotic Bcl‐2 binding of all the synthesized compounds and revealed that the docking of compounds 4 k and 6 j with Bcl‐2 was more potent compared to curcumin.
How firms navigate cooperation and competition in nascent ecosystems
Authors: Hannah Douglas P. , Eisenhardt Kathleen M.
Published: December 2017

Research Summary

Despite a wealth of research on competitive and cooperative strategy, gaps remain with respect to how firms successfully navigate cooperation and competition over time. This is especially true in ecosystems, in which firms depend on one another to collectively provide components and create value for consumers. Through an in‐depth multiple case study of five firms in the U.S. residential solar industry from 2007 to 2014, we induct a theoretical framework that explains how firms navigate nascent ecosystems over time. We identify three strategies, each with a distinct balance of cooperation and competition, as well as unique advantages, disadvantages, and required capabilities. Overall, we contribute to research on ecosystem strategy, crystallize the pivotal role of bottlenecks, and shed light on the dynamic interplay of cooperation and competition.

Managerial Summary

Competition and cooperation are fundamental to strategy, and often closely intertwined. But how firms navigate and balance cooperation and competition over time, especially in ecosystems where firms depend on one another to deliver value to consumers, is unclear. In this article, we conduct an in‐depth multiple‐case study of five firms in the U.S. residential solar industry to examine how firms can successfully navigate nascent ecosystems over time. We identify three distinct strategies, each with a distinct balance of cooperation and competition, and examine the unique advantages, disadvantages, and required capabilities of each. In doing so, we also contribute novel insights into the evolution of ecosystems and bottlenecks.
Correction to: If You Detonate Dynamite, You Should Know Your Fish
Authors: Doll Dietrich
Published: December 2017

In the original article, the last paragraph erroneously states that author’s upcoming study was going to be published in Diseases of the Colon and Rectum.
Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?
Authors: Becker Robert E. , Kapogiannis Dimitrios , Greig Nigel H.
Published: December 2017

Introduction

Neurodegenerative disorders have been a graveyard for hundreds of well‐intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links.

Methods

We searched the literature since 1995 using MEDLINE and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (Tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/AD pathologies and neuronal self‐induced cell death (apoptosis), we are studying brain extracellular vesicles in plasma and (‐)‐phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD.

Results

Neuronal cell death and a diverse and significant pathological cascade follow TBIs. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to Tg mice provides an indication of an AD drug candidate's potential for preventing apoptosis and resulting progression toward dementia in AD. This weight drop supplementation to Tg mouse models, the experimental drug (‐)‐phenserine, and plasma‐derived extracellular vesicles enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination, show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (‐)‐Phenserine both countered many subacute post‐TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies.

Discussion

These findings may provide support for expanding preclinical Tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD.
Normal forms for perturbations of systems possessing a Diophantine invariant torus
Authors: MASSETTI JESSICA ELISA
Published: December 2017

We give a new proof of Moser’s 1967 normal-form theorem for real analytic perturbations of vector fields possessing a reducible Diophantine invariant quasi-periodic torus. The proposed approach, based on an inverse function theorem in analytic class, is flexible and can be adapted to several contexts. This allows us to prove in a unified framework the persistence, up to finitely many parameters, of Diophantine quasi-periodic normally hyperbolic reducible invariant tori for vector fields originating from dissipative generalizations of Hamiltonian mechanics. As a byproduct, generalizations of Herman’s twist theorem and Rüssmann’s translated curve theorem are proved.
Continued fraction algorithm for Sturmian colorings of trees
Authors: KIM DONG HAN , LIM SEONHEE
Published: December 2017

Factor complexity $b_{n}(\unicode[STIX]{x1D719})$ for a vertex coloring $\unicode[STIX]{x1D719}$ of a regular tree is the number of classes of $n$-balls up to color-preserving automorphisms. Sturmian colorings are colorings of minimal unbounded factor complexity $b_{n}(\unicode[STIX]{x1D719})=n+2$. In this article, we prove an induction algorithm for Sturmian colorings using colored balls in a way analogous to the continued fraction algorithm for Sturmian words. Furthermore, we characterize Sturmian colorings in terms of the data appearing in the induction algorithm.
Exploring global and local patterns in the correlation of geographic distances and morphosyntactic variation in Swiss German
Authors: Jeszenszky Péter , Stoeckle Philipp , Glaser Elvira , Weibel Robert
Published: December 2017

Using data from a Swiss German dialect syntax survey, this study aims to explore, in a spatially differentiated manner, the correlation between dialectal variation and geographic distances. A linguistic distance was expressed by a measure aggregated from 60 survey questions. To operationalize the possibility of language contact, Euclidean distance, as well as travel times in 2000, 1950 and 1850 between survey sites were used. Going beyond previous work by others, we also explore the covariation of geographic and linguistic distances at the local level, focusing on spatial subsets and individual survey sites, thus being able to paint a more differentiated picture. With the diverse physical landscape of Switzerland making an impact on potential language contact, we find that travel times are a better predictor than Euclidean distance for the syntactic variation in Swiss German dialects. However, on the local scale the difference is not always significant, depending on prevalent topography.
Culture Process and the Interpretation of Radiocarbon Data
Authors: Freeman Jacob , Byers David A , Robinson Erick , Kelly Robert L
Published: December 2017

Over the last decade, archaeologists have turned to large radiocarbon (14C) data sets to infer prehistoric population size and change. An outstanding question concerns just how direct of an estimate 14C dates are for human populations. In this paper we propose that 14C dates are a better estimate of energy consumption, rather than an unmediated, proportional estimate of population size. We use a parametric model to describe the relationship between population size, economic complexity and energy consumption in human societies, and then parametrize the model using data from modern contexts. Our results suggest that energy consumption scales sub-linearly with population size, which means that the analysis of a large 14C time-series has the potential to misestimate rates of population change and absolute population size. Energy consumption is also an exponential function of economic complexity. Thus, the 14C record could change semi-independent of population as complexity grows or declines. Scaling models are an important tool for stimulating future research to tease apart the different effects of population and social complexity on energy consumption, and explain variation in the forms of 14C date time-series in different regions.
Identification of quantitative trait loci underlying seed shape in soybean across multiple environments
Authors: Teng W. L. , Sui M. N. , Li W. , Wu D. P. , Zhao X. , Li H. Y. , Han Y. P. , Li W. B.
Published: December 2017

Seed shape (SS) affects the yield and appearance of soybean seeds significantly. However, little detailed information has been reported about the quantitative trait loci (QTL) affecting SS, especially SS components such as seed length (SL), seed width (SW) and seed thickness (ST), and their mutual ratios of length-to-weight (SLW), length-to-thickness (SLT) and weight-to-thickness (SWT). The aim of the present study was to identify QTL underlying SS components using 129 recombinant inbred lines derived from a cross between Dongnong46 and L-100. Phenotypic data were collected from this population after it was grown across nine environments. A total of 213 simple sequence repeat markers were used to construct the genetic linkage map, which covered approximately 3623·39 cM, with an average distance of 17·01 cM between markers. Five QTL were identified as being associated with SL, five with SW, three with ST, four with SLW, two with SLT and three with SWT. These QTL could explain 1·46–22·16% of the phenotypic variation in SS component traits. Three QTL were identified in more than six tested environments three for SL, two for SW, one for ST, two for SLW and one for SLT. These QTL have great potential value for marker-assistant selection of SS in soybean seeds.
Travellers Lost and Redirected: Jesuit Networks and the Limits of European Exploration in Asia
Authors: Vermote Frederik
Published: December 2017

This article analyses two databases with information on traveling Jesuit missionaries to calculate the human cost of connecting Europe and China between 1500 and 1800. After combining analysis of these statistics with travel accounts, the article argues that when missionaries did not arrive at their intended destination, it was more often the case that they had been redirected than that they had died en route. Particular groups and individual Jesuits were redirected as a result of political fissures within the global Jesuit network. Since Jesuit missionaries held allegiances to competing state patrons based on their national background, their travel patterns were altered significantly either by choice or by force.
MEXICO’S FOREIGN TRADE IN A TURBULENT ERA (1821-1870): A RECONSTRUCTION
Authors: Kuntz-Ficker Sandra , Tena-Junguito Antonio
Published: December 2017

In 1821 Mexico achieved its independence from Spain. What happened in the following 50 years has become a field of dispute for economic historians. The lack of reliable quantitative information in many fields of economic activity has led to contrasting interpretations, none of which has been accepted as definitive. The aim of this paper is to reconstruct the yearly values of Mexico’s foreign trade in that period, with the purpose of providing elements to start filling this significant gap in Mexico’s historiography. It relies on official trade statistics and consular reports from Mexico’s main trading partners. It provides new series of imports and (commodity and specie) exports, and a provisional view of the balance of trade for most of the 1821-1870 period.