bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of the nephrotic syndrome in bone marrow transplantation recipient, histologically showing overlapped glomerular lesions of thrombotic microangiopathy and membranous nephropathy
Authors: Masuzawa Naoko , Nishimura Ayako , Kitani Takashi , Tamagaki Keiichi , Sugitani Mio , Nagoshi Hisao , Kuroda Junya , Konishi Eiichi
Published: September 2017

Nephrotic syndrome (NS) rarely occurs in post‐hematopoietic stem cell transplantation (HSCT) recipients but represents the renal manifestation of graft‐versus‐host disease (GVHD). Membranous nephropathy (MN) accounts for almost two thirds of post‐HSCT NS and is caused by immune complex deposition. Renal thrombotic microangiopathy (TMA) without fulfillment of clinical criteria for TMA has been underreported because of reduced opportunity for histological examination. However, renal TMA has recently been reported in association with GVHD and humoral immunological reactions. Although both MN and TMA after HSCT are associated with GVHD and immunological abnormalities, these diseases are exceptionally coexistent in renal biopsy specimens. We herein describe a case of post‐HSCT NS, histologically showing overlapped lesions of TMA and MN. Renal biopsy specimen after presentation of NS revealed early stage MN and TMA with evidence of chronicity. TMA was thought to have preceded MN, and renal biopsy at the phase of pre‐nephrotic proteinuria might reveal earlier histological changes of isolated renal TMA. Detection of subclinical renal TMA earlier by spontaneous renal biopsy can help prevent progression of renal injury or overlapping of other renal pathologies. We also demonstrated Th2 predominant intraglomerular infiltration of lymphocytes by immunohistochemistry.
Ozone‐induced stomatal sluggishness changes stomatal parameters of Jarvis‐type model in white birch and deciduous oak
Authors: Hoshika Y. , Watanabe M. , Carrari E. , Paoletti E. , Koike T.
Published: September 2017

Stomatal ozone flux is closely related to ozone injury to plants. Jarvis‐type multiplicative model has been recommended for estimating stomatal ozone flux in forest trees. Ozone can change stomatal conductance by both stomatal closure and less efficient stomatal control (stomatal sluggishness). However, current Jarvis‐type models do not account for these ozone effects on stomatal conductance in forest trees.

We examined seasonal course of stomatal conductance in two common deciduous tree species native to northern Japan (white birch: Betula platyphylla var. japonica; deciduous oak: Quercus mongolica var. crispula) grown under free‐air ozone exposure. We innovatively considered stomatal sluggishness in the Jarvis‐type model using a simple parameter, s, relating to cumulative ozone uptake (defined as POD: phytotoxic ozone dose).

We found that ozone decreased stomatal conductance of white birch leaves after full expansion (−28%). However, such a reduction of stomatal conductance by ozone fell in late summer (−10%). At the same time, ozone reduced stomatal sensitivity of white birch to VPD and increased stomatal conductance under low light conditions. In contrast, in deciduous oak, ozone did not clearly change the model parameters.

The consideration of both ozone‐induced stomatal closure and stomatal sluggishness improved the model performance to estimate stomatal conductance and to explain the dose–response relationship on ozone‐induced decline of photosynthesis of white birch. Our results indicate that ozone effects on stomatal conductance (i.e. stomatal closure and stomatal sluggishness) are crucial for modelling studies to determine stomatal response in deciduous trees, especially in species sensitive to ozone.
Leveraging ideas from user innovation communities: using text‐mining and case‐based reasoning
Authors: Kim Jieun , Park Yongtae
Published: September 2017

User innovation communities, where end users voluntarily share their ideas about new products or services, have become an important source of innovation. While efforts have been made to extract and develop ideas from these sources, existing studies have largely focused on company‐led efforts to facilitate user participation, rather than on voluntary user discussions within communities themselves. As a remedy, this research proposes to directly target those voluntary ideas from user innovation communities for product/service innovation. Because quantities of textual information within these communities are rather massive, we propose a modified and integrated approach of text‐mining (TM) and case‐based reasoning (CBR). Specifically, by constructing two casebases on ideas and existing products using TM and checking for overlap between the two using CBR, the approach enables the identification of opportunities for innovation and reference products for adaptation. We demonstrate the approach through a case of mobile apps in Apple App Store, and our findings suggest that the approach can help firms and users/developers broaden the source of ideas and leverage them into new product concepts.
Volunteers' Power and Resistance in the Struggle for Shelter Animal Survival
Authors: Guenther Katja M.
Published: September 2017

This article presents an analysis of how volunteers use different forms of capital to resist the practices and discourses of the organization for which they volunteer. Volunteers at a large public animal shelter do not share the shelter's institutionally held belief that shelter death is an inevitable result of homelessness among companion animals; to reduce shelter death, they craft challenges to the shelter practice of putting dogs down and work to construct shelter death as an avoidable and problematic outcome. Their repertoire of resistance includes educational, health‐based, relational, moral, reputational, and legal strategies. The findings illuminate that volunteers’ social location outside of the shelter provides them with capital to engage in resistance within the shelter.
Genotyping of the ABCG2 gene using Matrix‐Associated Laser Desorption/Ionisation, Time‐of‐Flight Mass Spectrometry
Authors: Tanaka M. , Kamada I. , Takahashi J. , Kimura T. , Tani Y.
Published: September 2017

Objectives

The aim of this study was to evaluate the applicability of genotyping of the ABCG2 gene using MALDI‐TOF MS and to estimate the allele frequency in the Japanese population.

Background

Jr (a−) phenotype has a prevalence of approximately 0·05% among Japanese blood donors; DNA‐based genotyping was conducted to investigate the molecular basis of the Jr (a−) phenotype along with serological typing. To detect all SNPs of the ABCG2 gene, a high‐throughput SNP genotyping platform is needed.

Methods

Overall, 1004 Jr (a−) blood samples were collected from blood donors in Japan and pre‐genotyped. To detect the SNPs of the ABCG2 gene using MALDI‐TOF MS, polymerase chain reaction and unextend primer were designed. In total, 205 Jr (a−) samples were genotyped using MALDI‐TOF MS analysis.

Results

The SNPs of 1004 Jr (a−) samples were identified using the HRM analysis and DNA sequencing, and 799 of 1004 (80%) Jr (a−) samples had the homozygous for c.376 T. The designed primers for MALDI‐TOF MS perfectly detected the SNPs of the ABCG2 gene. A total of 205 Jr (a−) samples were genotyped using MALDI‐TOF MS. Calling failures occurred in only two samples with the mutations c.736CT to c.376C and c.421C to c.421CA. The concordance rate between the pre‐genotyped and MALDI‐TOF MS‐based genotyping results was very high (99·02%) for all ABCG2 alleles.

Conclusions

Jr (a‐) Japanese donors had almost the homozygous for c.376 T. However, detections of more than 20 SNPs of the ABCG2 gene for the JR blood group genotyping are needed. MALDI‐TOF MS‐based genotyping was highly concordant with the pre‐genotyped results for all ABCG2 alleles.
The Effect of In-service Training of Computer Science Teachers on Scratch Programming Language Skills Using an Electronic Learning Platform on Programming Skills and the Attitudes towards Teaching Programming
Authors: Alkaria Ahmed , Alhassan Riyadh
Published: September 2017

This study was conducted to examine the effect of in-service training of computer science teachers in Scratch language using an electronic learning platform on acquiring programming skills and attitudes towards teaching programming. The sample of this study consisted of 40 middle school computer science teachers. They were assigned into two groups; 20 teachers were in the control group and 20 teachers in the experimental group. The study tools consist of an achievement test in Scratch programming language and a measure of attitudes toward programming instruction. After the experimental treatment at the end of the second semester, the teachers were examined and the results showed that there were statistically significant differences between the achievement test mean scores in favor of the experimental group that trained using an electronic training platform. The results also showed a positive effect on attitudes toward teaching programming for the experimental group.
Assessing the mechanical properties of anisotropic soft tissues using guided wave elastography: Inverse method and numerical experiments
Authors: Li Guo-Yang , Cao Yanping
Published: September 2017

Determining the mechanical properties of soft biological tissues can be of great importance. For example, the microstructures of many soft tissues, such as those of the human Achilles tendon, have been identified as typical anisotropic materials. This paper proposes an inverse approach that uses guided wave elastography to determine the anisotropic elastic and hyperelastic parameters of thin-walled transversely isotropic biological soft tissues. This approach was developed from the theoretical solutions for the dispersion relations of guided waves, which were derived based on a constitutive model suitable for describing the deformation behavior of such tissues. The properties of these solutions were investigated; in particular, sensitivity to data errors was addressed by introducing the concept of the condition number. To further validate the proposed inverse approach, the guided wave elastography of thin-walled transversely isotropic soft tissues was investigated using numerical experiments. The results indicated that the four constitutive parameters (other than the tensile modulus along the direction of the fibers, EL) could be determined with a good level of accuracy using this method.
Russia heightens defenses against climate change
Authors: Davydova Angelina
Published: September 2017

But carbon emission reductions are off the table.
Liquid phase condensation in cell physiology and disease
Authors: Shin Yongdae , Brangwynne Clifford P.
Published: September 2017

Phase separation and cellular organization

Cells are compartmentalized to allow distinct processes to occur in membrane-delimited organelles. But similar spatial restriction of cellular components in membrane-less intracellular assemblies or condensates also appears to occur—much like oil droplets in water. These compartments contribute to multiple biological processes and regulatory mechanisms. Shin and Brangwynne review the protein-protein and protein-RNA interactions that result in formation of these structures. They explain known and potential functions of such structures in a range of examples, from signaling and local control of biochemical reactants to spatial segregation. In disease, such aggregation may go awry and contribute to neurodegenerative syndromes associated with inappropriate protein aggregation.

Science
, this issue p.
eaaf4382
Titanium isotopic evidence for felsic crust and plate tectonics 3.5 billion years ago
Authors: Greber Nicolas D. , Dauphas Nicolas , Bekker Andrey , Ptáček Matouš P. , Bindeman Ilya N. , Hofmann Axel
Published: September 2017

An early call for plate tectonics

The composition of continental crust far back in Earth's history gives us insight into when plate tectonics ramped up and has influenced ocean chemistry. Greber
et al.
looked at titanium isotopes in shales, which form from eroded continental crustal sediments, to estimate the composition 3.5 billion years ago, closer to the origins of Earth. They found a silica-rich composition, which indicates that plate tectonics was happening deep in our distant past. Other changes in crustal composition might be linked to changing ocean chemistry and major events such as the oxygenation of our atmosphere.

Science
, this issue p.
1271
RNA localization feeds translation
Authors: Gáspár Imre , Ephrussi Anne
Published: September 2017

RNAs of the protein synthesis machinery relocalize to enhance the response to nutrients
The social origins of persistence
Authors: Butler Lucas P.
Published: September 2017

Infants can learn the value of persistence by observing adult behavior
A Selective Bottleneck Shapes the Evolutionary Mutant Spectra of Enterovirus A71 during Viral Dissemination in Humans
Authors: Huang Sheng-Wen , Huang Yi-Hui , Tsai Huey-Pin , Kuo Pin-Hwa , Wang Shih-Min , Liu Ching-Chuan , Wang Jen-Ren
Published: September 2017

RNA viruses accumulate mutations to rapidly adapt to environmental changes. Enterovirus A71 (EV-A71) causes various clinical manifestations with occasional severe neurological complications. However, the mechanism by which EV-A71 evolves within the human body is unclear. Utilizing deep sequencing and haplotype analyses of viruses from various tissues of an autopsy patient, we sought to define the evolutionary pathway by which enterovirus A71 evolves fitness for invading the central nervous system in humans. Broad mutant spectra with divergent mutations were observed at the initial infection sites in the respiratory and digestive systems. After viral invasion, we identified a haplotype switch and dominant haplotype, with glycine at VP1 residue 31 (VP1-31G) in viral particles disseminated into the integumentary and central nervous systems.In vitroviral growth and fitness analyses indicated that VP1-31G conferred growth and a fitness advantage in human neuronal cells, whereas VP1-31D conferred enhanced replication in human colorectal cells. A higher proportion of VP1-31G was also found among fatal cases, suggesting that it may facilitate central nervous system infection in humans. Our data provide the first glimpse of EV-A71 quasispecies from oral tissues to the central nervous system within humans, showing broad implications for the surveillance and pathogenesis of this reemerging viral pathogen.

IMPORTANCEEV-A71 continues to be a worldwide burden to public health. Although EV-A71 is the major etiological agent of hand, foot, and mouth disease, it can also cause neurological pulmonary edema, encephalitis, and even death, especially in children. Understanding selection processes enabling dissemination and accurately estimating EV-A71 diversity during invasion in humans are critical for applications in viral pathogenesis and vaccine studies. Here, we define a selection bottleneck appearing in respiratory and digestive tissues. Glycine substitution at VP1 residue 31 helps viruses break through the bottleneck and invade the central nervous system. This substitution is also advantageous for replication in neuronal cellsin vitro. Considering that fatal cases contain enhanced glycine substitution at VP1-31, we suggest that the increased prevalence of VP1-31G may alter viral tropism and aid central nervous system invasion. Our findings provide new insights into a dynamic mutant spectral switch active during acute viral infection with emerging viral pathogens.
The Conserved Spore Coat Protein SpoVM Is Largely Dispensable in Clostridium difficile Spore Formation
Authors: Ribis John W. , Ravichandran Priyanka , Putnam Emily E. , Pishdadian Keyan , Shen Aimee
Published: September 2017

The spore-forming obligate anaerobe
Clostridium difficile
is the leading cause of antibiotic-associated diarrheal disease in the United States. When
C. difficile
spores are ingested by susceptible individuals, they germinate within the gut and transform into vegetative, toxin-secreting cells. During infection,
C. difficile
must also induce spore formation to survive exit from the host. Since spore formation is essential for transmission, understanding the basic mechanisms underlying sporulation in
C. difficile
could inform the development of therapeutic strategies targeting spores. In this study, we determine the requirement of the
C. difficile
homolog of SpoVM, a protein that is essential for spore formation in
Bacillus subtilis
due to its regulation of coat and cortex formation. We observed that SpoVM plays a minor role in
C. difficile
spore formation, in contrast with
B. subtilis
, indicating that this protein would not be a good target for inhibiting spore formation.
Low dietary protein and high carbohydrate infant formula affects the microbial ecology of the large intestine in neonatal rats
Authors: Fan Wenguang , Ren Haiwei , Cao Yingying , Wang Yonggang , Huo Guicheng
Published: September 2017

The aim of this study was to investigate the effects of a low dietary protein and high carbohydrate infant formula on the large intestine of neonatal rats. A total of 24 neonatal Sprague–Dawley rats (14-days-old) were randomly assigned to the low protein, high carbohydrate infant formula-fed group (I group) and a human breast milk-fed group (H group). After 7 days, we selected 6 rats at random from each group to study. No significantly different microbial colonization patterns were observed in the 2 groups at the phylum level. At the family level, Enterobacteriaceae and Bacteroidaceae were the dominant bacteria in I and H rats. While Bacteroides was the most abundant bacteria at the genus level, no significant difference was observed between the 2 groups. Methanoic acid, acetate, and butyrate increased in concentration in the I group compared with the H group. Protease activities, ammonia, and indole in the large intestine were lower in I rats than H rats. A significant increase in the expression of GADPH and decrease in the expression of aquaporin 8, aminopeptidase A, cathepsin F precursor, and ubiquitin carboxyl-terminal hydrolase FAF-Y were observed in I rats compared with H rats. These results suggest that a low protein diet could modulate the microbial ecology in the large intestine of neonatal rats.
THE EFFECTS OF COMPETITION ON EFFICIENCY: THE VIETNAMESE BANKING INDUSTRY EXPERIENCE
Authors: NGUYEN THANH PHAM THIEN , NGHIEM SON HONG
Published: September 2017

Given considerable changes in the Vietnamese banking environment brought about by significant reforms towards liberalization during the last two decades, this study investigates the evolution of competition and efficiency, compares the competition and efficiency of state-owned banks to joint-stock banks, and then tests the “quiet life” hypothesis in this industry over the period 2000–2014. This study employs the efficiency-adjusted Lerner index (i.e., market power) to capture competition, and the cost efficiency estimated by a Fourier-flexible function stochastic frontier analysis (SFA) to capture bank efficiency. This study firstly finds a slight improvement of competition and cost efficiency in the Vietnamese banking sector over the analysis period. Secondly, there are no significant differences in competition and cost efficiency level between state-owned and joint-stock banks. Thirdly, a positive causality running from competition to cost efficiency is documented, providing evidence of supporting the “quiet life” hypothesis. Finally, positive efficiency effects of the banks’ capital ratio and size are found, while insignificant impacts of the growth of GDP per capita and 2007 global financial crisis were observed. The results are strongly robust to a variety of tests. The findings suggest pro-competition, pro-capitalization and pro-size expansion policies in the Vietnamese banking sector if targeting at improving the cost efficiency of Vietnamese banks.
Kinks and branes in models with hyperbolic interactions
Authors: Bazeia D. , Lima Elisama E. M. , Losano L.
Published: September 2017

In this work, we investigate several models described by a single real scalar field with nonpolynomial interactions, constructed to support topological solutions. We do this using the deformation procedure to introduce a function which allows to construct two distinct families of hyperbolic potentials, controlled by three distinct parameters, in the standard formalism. In this way, the procedure allows us to get analytical solutions, and then investigate the energy density, linear stability and zero mode. We move on and introduce a nonstandard formalism to obtain compact solutions, analytically. We also investigate these hyperbolic models in the braneworld context, considering both the standard and nonstandard possibilities. The results show how to construct distinct braneworld models which are implemented via the first-order formalism and are stable against fluctuation of the metric tensor.
An approach of traffic signal control based on NLRSQP algorithm
Authors: Zou Yuan-Yang , Hu Yu
Published: September 2017

This paper presents a linear program model with linear complementarity constraints (LPLCC) to solve traffic signal optimization problem. The objective function of the model is to obtain the minimization of total queue length with weight factors at the end of each cycle. Then, a combination algorithm based on the nonlinear least regression and sequence quadratic program (NLRSQP) is proposed, by which the local optimal solution can be obtained. Furthermore, four numerical experiments are proposed to study how to set the initial solution of the algorithm that can get a better local optimal solution more quickly. In particular, the results of numerical experiments show that: The model is effective for different arrival rates and weight factors; and the lower bound of the initial solution is, the better optimal solution can be obtained.
Recent progresses about statistical declaration and probable error for surface drag force of chemically reactive squeezing flow with temperature dependent thermal conductivity
Authors: Alsaedi A. , Khan M. Ijaz , Hayat T.
Published: September 2017

This communication addresses unsteady squeezing flow of second grade liquid. NonFourier heat flux model is implemented to discuss heat transfer features subject to heat generation/absorption. Homogeneous–heterogeneous reactions are addressed. Firstly, the problems are nondimensionalized by suitable variables and then solutions for strong nonlinear systems are presented. Convergence region is particularly determined for obtained solutions. Statistical declaration and probable error for drag force are computed. Velocity is found to decay for larger estimation of fluid parameter while thermal and concentration fields are enhanced for higher heat generation and squeezing parameters.
What Shapes Consumer Choice and Financial Products? A Review
Authors: Agarwal Sumit , Chomsisengphet Souphala , Lim Cheryl
Published: September 2017

Central to the field of consumer finance is that consumers make financial decisions that do not always coincide with the financial decisions ideally depicted in optimal economic models. In this review, we discuss developments in the field of household finance, focusing on how consumers make suboptimal financial decisions across different types of settings and factors that affect their decisions. Rather than conducting a comprehensive survey, we focus specifically on consumer choice in the context of research on credit card borrowing, housing and mortgage debts, investment and savings decisions, and spending and consumption. We also discuss financial product design and marketing, as well as the regulatory landscape of lenders of consumer financial products. We present five future research directions and considerations for researchers and policymakers.
The Relationship Between the Human Genome and Microbiome Comes into View
Authors: Goodrich Julia K. , Davenport Emily R. , Clark Andrew G. , Ley Ruth E.
Published: September 2017

The body's microbiome, composed of microbial cells that number in the trillions, is involved in human health and disease in ways that are just starting to emerge. The microbiome is assembled at birth, develops with its host, and is greatly influenced by environmental factors such as diet and other exposures. Recently, a role for human genetic variation has emerged as also influential in accounting for interpersonal differences in microbiomes. Thus, human genes may influence health directly or by promoting a beneficial microbiome. Studies of the heritability of gut microbiotas reveal a subset of microbes whose abundances are partly genetically determined by the host. However, the use of genome-wide association studies (GWASs) to identify human genetic variants associated with microbiome phenotypes has proven challenging. Studies to date are small by GWAS standards, and cross-study comparisons are hampered by differences in analytical approaches. Nevertheless, associations between microbes or microbial genes and human genes have emerged that are consistent between human populations. Most notably, higher levels of beneficial gut bacteria called Bifidobacteria are associated with the human lactase nonpersister genotype, which typically confers lactose intolerance, in several different human populations. It is time for the microbiome to be incorporated into studies that quantify interactions among genotype, environment, and the microbiome in order to predict human disease susceptibility.
Noncoding RNAs in Polycomb and Trithorax Regulation: A Quantitative Perspective
Authors: Ringrose Leonie
Published: September 2017

The question of how noncoding RNAs are involved in Polycomb group (PcG) and Trithorax group (TrxG) regulation has been on an extraordinary journey over the last three decades. Favored models have risen and fallen, and healthy debates have swept back and forth. The field has recently reached a critical mass of compelling data that throws light on several previously unresolved issues. The time is ripe for a fruitful combination of these findings with two other long-running avenues of research, namely the biochemical properties of the PcG/TrxG system and the application of theoretical mathematical models toward an understanding of the system's regulatory properties. I propose that integrating our current knowledge of noncoding RNA into a quantitative biochemical and theoretical framework for PcG and TrxG regulation has the potential to reconcile several apparently conflicting models and identifies fascinating questions for future research.
Getting Nervous: An Evolutionary Overhaul for Communication
Authors: Varoqueaux Frederique , Fasshauer Dirk
Published: September 2017

The evolution of a nervous system as a control system of the body's functions is a key innovation of animals. Its fundamental units are neurons, highly specialized cells dedicated to fast cell–cell communication. Neurons pass signals to other neurons, muscle cells, or gland cells at specialized junctions, the synapses, where transmitters are released from vesicles in a Ca2+-dependent fashion to activate receptors in the membrane of the target cell. Reconstructing the origins of neuronal communication out of a more simple process remains a central challenge in biology. Recent genomic comparisons have revealed that all animals, including the nerveless poriferans and placozoans, share a basic set of genes for neuronal communication. This suggests that the first animal, the Urmetazoan, was already endowed with neurosecretory cells that probably started to connect into neuronal networks soon afterward. Here, we discuss scenarios for this pivotal transition in animal evolution.
Big Lessons from Little Yeast: Budding and Fission Yeast Centrosome Structure, Duplication, and Function
Authors: Cavanaugh Ann M. , Jaspersen Sue L.
Published: September 2017

Centrosomes are a functionally conserved feature of eukaryotic cells that play an important role in cell division. The conserved γ-tubulin complex organizes spindle and astral microtubules, which, in turn, separate replicated chromosomes accurately into daughter cells. Like DNA, centrosomes are duplicated once each cell cycle. Although in some cell types it is possible for cell division to occur in the absence of centrosomes, these divisions typically result in defects in chromosome number and stability. In single-celled organisms such as fungi, centrosomes [known as spindle pole bodies (SPBs)] are essential for cell division. SPBs also must be inserted into the membrane because fungi undergo a closed mitosis in which the nuclear envelope (NE) remains intact. This poorly understood process involves events similar or identical to those needed for de novo nuclear pore complex assembly. Here, we review how analysis of fungal SPBs has advanced our understanding of centrosomes and NE events.
Computational Phylogenetics
Authors: Bowern Claire
Published: September 2017

Although there have long been links between research in historical linguistics and research in biological evolution, the last few years have witnessed growth in historical linguistic research that treats languages as evolutionary systems that can be investigated using tools from computational phylogenetics. In this review, I explore some of the advantages and disadvantages of using computational tools for historical linguistics. I describe the theory that underlies treating languages as evolutionary systems (in general terms), present the results of classifying languages lexically, and review some of the implications of this research.
Words in Edgewise
Authors: Horn Laurence R.
Published: September 2017

Well before I turned pro linguist, words were my life. In my career I have been not just a word consumer (or word processor) but a periodic donor, a supplier of lexical utensils for the semanticist's arsenal. My proposed coinages have experienced varying degrees of success and ignominy within several overlapping areas of the field—the “Border Wars” between semantics and pragmatics, the nature of negation and polarity, and the exploration of lexical pragmatics, where context and speakers’ intentions and beliefs inform the lexicon in domains from word formation to the etymological urban legend. The coinages on display here are intended to trace my half-century journey through the vibrant (if motley) landscape of meaning and to show how the pursuit of linguistic byways can not only inform but delight. The article concludes with a chronology of landmark events and people that have shaped my thoughts about words and meanings.
Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer
Authors: Angus Steven P. , Zawistowski Jon S. , Johnson Gary L.
Published: September 2017

Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change—often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell–like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.
Improving Student Outcomes in Higher Education: The Science of Targeted Intervention
Authors: Harackiewicz Judith M. , Priniski Stacy J.
Published: September 2017

Many theoretically based interventions have been developed over the past two decades to improve educational outcomes in higher education. Based in social-psychological and motivation theories, well-crafted interventions have proven remarkably effective because they target specific educational problems and the processes that underlie them. In this review, we evaluate the current state of the literature on targeted interventions in higher education with an eye to emerging theoretical and conceptual questions about intervention science. We review three types of interventions, which focus on the value students perceive in academic tasks, their framing of academic challenges, and their personal values, respectively. We consider interventions that (a) target academic outcomes (e.g., grades, major or career plans, course taking, retention) in higher education, as well as the pipeline to college, and (b) have been evaluated in at least two studies. Finally, we discuss implications for intervention science moving forward.
Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension
Authors: Suzuki Toshio , Carrier Erica J. , Talati Megha H. , Rathinasabapathy Anandharajan , Chen Xinping , Nishimura Rintaro , Tada Yuji , Tatsumi Koichiro , West James
Published: September 2017

Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sortm4(ACTB-tdTomato,EGFP)Luo/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.
A new paradigm of sodium regulation in inflammation and hypertension
Authors: Kirabo Annet
Published: September 2017

Dysregulation of sodium (Na+) balance is a major cause of hypertensive cardiovascular disease. The current dogma is that interstitial Na+readily equilibrates with plasma and that renal excretion and reabsorption is sufficient to regulate extracellular fluid volume and control blood pressure. These ideas have been recently challenged by the discovery that Na+accumulates in tissues without commensurate volume retention and activates immune cells, leading to hypertension and autoimmune disease. However, objections have been raised to this new paradigm, with some investigators concerned about where and how salt is stored in tissues. Further concerns also include how Na+is mobilized from tissue stores and how it interacts with various organ systems to cause hypertension and end-organ damage. This review assesses these two paradigms of Na+regulation in the context of inflammation-mediated hypertension and cardiovascular disease pathogenesis. Also highlighted are future perspectives and important gaps in our understanding of how Na+is linked to inflammation and hypertension. Understanding mechanisms of salt and body fluid regulation is the sine qua non of research efforts to identify therapeutic targets for hypertension and cardiovascular disease.
Junctional Adhesion Molecules (JAMs): Cell Adhesion Receptors With Pleiotropic Functions in Cell Physiology and Development
Authors: Ebnet Klaus
Published: September 2017

Junctional adhesion molecules (JAM)-A, -B and -C are cell-cell adhesion molecules of the immunoglobulin superfamily which are expressed by a variety of tissues, both during development and in the adult organism. Through their extracellular domains, they interact with other adhesion receptors on opposing cells. Through their cytoplasmic domains, they interact with PDZ domain-containing scaffolding and signaling proteins. In combination, these two properties regulate the assembly of signaling complexes at specific sites of cell-cell adhesion. The multitude of molecular interactions has enabled JAMs to adopt distinct cellular functions such as the regulation of cell-cell contact formation, cell migration, or mitotic spindle orientation. Not surprisingly, JAMs regulate diverse processes such as epithelial and endothelial barrier formation, hemostasis, angiogenesis, hematopoiesis, germ cell development, and the development of the central and peripheral nervous system. This review summarizes the recent progress in the understanding of JAMs, including their characteristic structural features, their molecular interactions, their cellular functions, and their contribution to a multitude of processes during vertebrate development and homeostasis.
Towards Precision Medicine for Hypertension: A Review of Genomic, Epigenomic, and Microbiomic Effects on Blood Pressure in Experimental Rat Models and Humans
Authors: Padmanabhan Sandosh , Joe Bina
Published: September 2017

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the “structural backbone,” this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex “triad” of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach.
Differential Pressure Shunt for Simultaneous Diversion of Ventricular Fluid and Extracerebral Fluid
Authors: Craig Daniel , Winston Ken R. , Folzenlogen Zach , Beauchamp Kathryn A.
Published: September 2017

Background/Aims: The management of extracerebral collections of fluid in patients with hydrocephalus can be problematic for either their simultaneous separate management or sequential management, each of which may require multiple surgeries and the management of external drains. The object of this report is to review the experience with a shunt configuration that simultaneously diverts ventricular fluid and extracerebral fluid, whether subdural or subarachnoid in location, through different outflow resistances. Methods: The medical records, including neuroimaging of patients with hydrocephalus and clinically significant extracerebral collections of low density who were managed by implanting a differential pressure type shunt, were retrospectively reviewed. Results: Four patients, 3 children and 1 adult, met inclusion criteria. Three had the entire differential pressure shunt implanted under 1 anesthetic, and 1 had a catheter inserted into the subdural space and connected into an existing ventriculoperitoneal shunt system. The extracerebral fluid collections cleared in all 4 patients, and the CSF shunt continued to function normally. Conclusion: A single surgical procedure to implant a differential pressure shunt can simultaneously drain and obliterate an extracerebral fluid collection while managing the hydrocephalus. Compared to routines that include external drainage, differential pressure shunting requires fewer surgeries, shorter hospitalization, with expected less expense.
Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family
Authors: Vona Barbara , Maroofian Reza , Mendiratta Geetu , Croken Matthew , Peng Siwu , Ye Xiaoqian , Rezazadeh Jamileh , Bahena Paulina , Lekszas Caroline , Haaf Thomas , Edelmann Lisa , Shi Lisong
Published: September 2017

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a “blended” phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.
Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease
Authors: Albrecht Detlef , Turakhia Mintu , Ries Daniel , Marbury Thomas , Smith William , Dillon Debbie , Milner Peter , Midei Mark
Published: September 2017

Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t 1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.
Electrocardiographic Strain Pattern Is Associated With Left Ventricular Concentric Remodeling, Scar, and Mortality Over 10 Years: The Multi‐Ethnic Study of Atherosclerosis
Authors: Inoue Yuko Y. , Soliman Elsayed Z. , Yoneyama Kihei , Ambale‐Venkatesh Bharath , Wu Colin O. , Sparapani Rodney , Bluemke David A. , Lima João A.C. , Ashikaga Hiroshi
Published: September 2017

Background

Both ECG strain pattern and QRS measured left ventricular (LV) hypertrophy criteria are associated with LV hypertrophy and have been used for risk stratification. However, the independent predictive value of ECG strain in apparently healthy individuals in predicting mortality and adverse cardiovascular events is unclear.

Methods and Results

MESA (Multi‐Ethnic Study of Atherosclerosis) is a multicenter, prospective cohort of 6441 participants (mean age, 62 years; 54% women). In 2847 of these participants, cardiac magnetic resonance imaging was repeated ≈10 years later (Year‐10). At Year‐10, 1759 participants underwent cardiac magnetic resonance imaging with gadolinium to detect myocardial scar. During a median follow‐up of 11.7 years, ECG strain (n=168, 2.6%) was significantly associated with all‐cause death (adjusted hazard ratio, 1.33; 95% confidence interval, 1.01–1.77;
P
=0.045), heart failure (2.62; 1.73–3.97;
P
<0.001), myocardial infarction (1.86; 1.09–3.18;
P
=0.024), and incident cardiovascular disease (1.45; 1.06–2.00;
P
=0.022). ECG strain was also associated with an increase in LV mass (β=9.29 g;
P
<0.001) and LV mass‐to‐volume ratio (β=0.07 g/mL;
P
=0.007) and a decline in LV ejection fraction (β=−3.30%;
P
<0.001). Moreover, ECG strain either at baseline and Year‐10 was associated with LV scar (odds ratio, 4.93 and 5.22;
P
=0.002 and <0.001, respectively), whereas these associations were not observed in ECG LV hypertrophy.

Conclusions

ECG strain is independently associated with all‐cause mortality, adverse cardiovascular events, development of LV concentric remodeling and systolic dysfunction, and myocardial scar over 10 years in multiethnic participants without past cardiovascular disease. ECG strain may be an early marker of LV structural remodeling that contributes to development of adverse cardiovascular events.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov/
. Unique identifier: NCT00005487.
Two new species of the Hypnoidini Schwarz, 1906 (Coleoptera: Elateridae: Dendrometrinae) from Afghanistan
Authors: PROSVIROV ALEXANDER S.
Published: September 2017

Two new species of the tribe Hypnoidini Schwarz, 1906 are described from Afghanistan: Hypnoidus afghanus sp. nov. and Ligmargus kabakovi sp. nov. The genera Hypnoidus Dillwyn, 1829 and Ligmargus Stibick, 1976 as well as the tribe Hypnoidini are recorded for the first time in Afghanistan.