bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Tumor Volume Change Predicts Long-term Survival and Histological Response to Preoperative Chemotherapy in Locally Advanced Esophageal Cancer
Authors: Makino Tomoki , Yamasaki Makoto , Tanaka Koji , Masuike Yasunori , Tatsumi Mitsuaki , Motoori Masaaki , Kimura Yutaka , Hatazawa Jun , Mori Masaki , Doki Yuichiro
Published: May 2018

Objective:

Here, we assess the ability of metabolic tumor volume (MTV) as measured by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) to evaluate neoadjuvant chemotherapy response for patients with locally advanced esophageal cancer (EC).

Background:

Optimal methods to evaluate treatment response for EC patients have not yet been established. Although previous studies have reported the value of standardized uptake value (SUV), the accuracy of predicting histological response or long-term survival in EC is limited.

Methods:

In all, 102 EC patients without distant metastasis who underwent 18F-FDG PET/CT both before and after the preoperative chemotherapy series were analyzed.

Results:

The median primary tumor MTV values before and after preoperative chemotherapy were 22.55 (range 0.4–183.1) and 2.75 (0–52.9), respectively, and the median MVT reduction rate was 86.5%. We found the most significant difference in survival between PET responders and nonresponders with a cut-off value of 60% MTV reduction, using a 10% stepwise cut-off analysis [2-year progression-free survival (PFS): 79.2 vs 44.4%; hazard ratio (HR) 3.397; P < 0.0001). With this cut-off value, histological response (P = 0.0091), tumor location (P = 0.0102), pT (P = 0.0011), and pN (P = 0.0110) were significantly associated with PET response. Univariate analysis of PFS indicated a correlation between PFS and tumor size, cT, decrease of primary lesion by CT, SUVmax reduction rate, MTV reduction rate, pT, pN, and pM. Multivariate analysis further identified pM (HR 3.063; P = 0.0279) and MTV reduction rate (HR 2.471; P = 0.0263) to be independent prognostic predictors, but not decrease of primary lesion by CT or SUVmax reduction rate.

Conclusion:

MTV change is clinically useful in predicting both long-term survival and histological response to preoperative chemotherapy in EC patients, after determining the optimal cut-off value based on survival analysis.
Co-expression patterns define epigenetic regulators associated with neurological dysfunction
Authors: Boukas Leandros , Havrilla James M. , Quinlan Aaron R. , Bjornsson Hans T. , Hansen Kasper D.
Published: May 2018

Coding variants in genes encoding for epigenetic regulators are an emerging cause of neurological dysfunction and cancer. However, a systematic effort to identify disease candidates within the human epigenetic machinery (EM) has not been performed, and it is unclear whether features exist that distinguish between variation-intolerant and variation-tolerant EM genes, and between EM genes associated with neurological dysfunction versus cancer. Here, we rigorously define a set of 295 human genes with a direct role in epigenetic regulation (writers, erasers, remodelers, readers). Systematic exploration of these genes reveals that while individual enzymatic functions are always mutually exclusive, readers often also exhibit enzymatic activity as well (dual function EM genes). We find that the majority of EM genes are very intolerant to loss-of-function variation, even when compared to the dosage sensitive group of transcription factors. Using this strategy, we identify 103 novel EM disease candidates. We show that the intolerance to loss-of-function variation is driven by the protein domains encoding the epigenetic function, strongly suggesting that disease is caused by a perturbed chromatin state. Unexpectedly, we also describe a large subset of EM genes that are co-expressed within multiple tissues. This subset is almost exclusively populated by extremely variation-intolerant EM genes, and shows enrichment for dual function EM genes. It is also highly enriched for genes associated with neurological dysfunction, even when accounting for dosage sensitivity, but not for cancer-associated EM genes. These findings prioritize novel disease candidate EM genes, and suggest that the co-expression itself may play a functional role in normal neurological homeostasis.
Evaluation of Methods for Cell Nuclear Structure Analysis from Microscopy Data
Authors: Kalinin Alexandr A. , Athey Brian D. , Dinov Ivo D.
Published: May 2018

Changes in cell nuclear architecture are regulated by complex biological mechanisms that associated with the altered functional properties of a cell. Quantitative analyses of structural alterations of nuclei and their compartments are important for understanding such mechanisms. In this work we present a comparison of approaches for nuclear structure classification, evaluated on 2D per-channel representations from a 3D microscopy imaging dataset by maximum intensity projection. Specifically, we compare direct classification of pixel data from either raw intensity images or binary masks that contain only information about morphology of the object, but not intensity. We evaluate a number of widely used classification algorithms using 2 different cross-validation schemes to assess batch effects. We compare obtained results with the previously reported baselines and discuss novel findings.
Shared genetic contribution to type 1 and type 2 diabetes risk
Authors: Aylward Anthony , Chiou Joshua , Okino Mei-Lin , Kadakia Nikita , Gaulton Kyle J
Published: May 2018

The role of shared genetic risk in the etiology of type 1 diabetes (T1D) and type 2 diabetes (T2D) and the mechanisms of these effects is unknown. In this study, we generated T1D association data of 15k samples imputed into the HRC reference panel which we compared to T2D association data of 159k samples imputed into 1000 Genomes. The effects of genetic variants on T1D and T2D risk at known loci and genome-wide were positively correlated, which we replicated using data from the UK Biobank and clinically-defined diabetes in the WTCCC. Increased risk of T1D and T2D was correlated with higher fasting insulin and fasting glucose level and decreased birth weight, among T1D- and T2D-specifc correlations, and T1D and T2D associated variants were enriched in regulatory elements for pancreatic, insulin resistance (adipose, CD19+ B cell), and developmental (CD184+ endoderm) cell types. We fine-mapped causal variants at known T1D and T2D loci and found evidence for co-localization at five signals, four of which had same direction of effect, including CENPW and GLIS3. Shared risk variants at GLIS3 and other signals were associated with measures of islet function, while CENPW was associated with early growth, and we identified shared risk variants at GLIS3 in islet accessible chromatin with allelic effects on islet regulatory activity. Our findings support shared genetic risk involving variants affecting islet function as well as insulin resistance, growth and development in the etiology of T1D and T2D.
Combining landscape genomics and ecological modelling to investigate local adaptation of indigenous Ugandan cattle to East Coast fever
Authors: Vajana Elia , Barbato Mario , Colli Licia , Milanesi Marco , Rochat Estelle , Fabrizi Enrico , Mukasa Christopher , Del Corvo Marcello , Masembe Charles , Muwanika Vincent , Kabi Fredrick , Sonstegard Tad Stewart , Jay Huson Heather , Negrini Riccardo , Joost Stéphane , Ajmone-Marsan Paolo ,   on behalf of The NextGen Consortium^
Published: May 2018

East Coast fever (ECF) is a fatal sickness affecting cattle populations of eastern, central, and southern Africa. The disease is transmitted by the tickRhipicephalus appendiculatus, and caused by the protozoanTheileria parva parva, which invades host lymphocytes and promotes their clonal expansion. Importantly, indigenous cattle show tolerance to infection in ECF-endemically stable areas. Here, the putative genetic bases underlying ECF-tolerance were investigated using molecular data and epidemiological information from 823 indigenous cattle from Uganda. Vector distribution and host infection risk were estimated over the study area and subsequently tested as triggers of local adaptation by means of landscape genomics analysis. We identified 41 and seven candidate adaptive loci for tick resistance and infection tolerance, respectively. Among the genes associated with the candidate adaptive loci arePRKG1andSLA2.PRKG1was already described as associated with tick resistance in indigenous South African cattle, due to its role into inflammatory response.SLA2 is part of the regulatory pathways involved into lymphocytes’ proliferation. Additionally, local ancestry analysis suggested the zebuine origin of the genomic region candidate for tick resistance.

Author summary

The tick-borne parasiteTheileria parva parvainfects cattle populations of eastern, central and southern Africa, by causing a highly fatal pathology called “East Coast fever”. The disease is especially severe for the exotic breeds imported to Africa, as well as outside the endemic areas of East Africa. In these regions, indigenous cattle populations can survive to infection, and this tolerance might result from unique adaptations evolved to fight the disease. We investigated this hypothesis by using a method named “landscape genomics”, with which we compared the genetic characteristics of indigenous Ugandan cattle coming from areas at different infection risk, and located genomic sites potentially attributable to tolerance. In particular, the method pinpointed two genes, one (PRKG1) involved into inflammatory response and potentially affecting East Coast fever vector attachment, the other (SLA2) involved into lymphocytes proliferation, a process activated byT. parva parvainfection. Our findings can orientate future research on the genetic basis of East Coast fever-tolerance, and derive from a general method that can be applied to investigate adaptation in analogous host-vector-parasite systems. Characterization of the genetic factors underlying East Coast-fever-tolerance represents an essential step towards enhancing sustainability and productivity of local agroecosystems.
HiCAGE : an R package for large-scale annotation and visualization of 3C-based genomic data
Authors: Workman Michael J. , Silva Tiago C. , Coetzee Simon G. , Hazelett Dennis J.
Published: May 2018

Chromatin interactions measured by the 3C-based family of next generation technologies are becoming increasingly important for measuring the physical basis for regulatory interactions between different classes of functional domains in the genome. Software is needed to streamline analyses of these data and integrate them with custom genome annotations, RNA-seq, and gene ontologies. We introduce a new R package compatible with Bioconductor—Hi-C Annotation and Graphics Ensemble (HiCAGE)—to perform these tasks with minimum effort. In addition, the package contains a shiny/R web app interface to provide ready access to its functions.

Availability and Implementation

The software is implemented in R and is freely available under GPLv3. HiCAGE runs in R (version 3.4) and is freely available through github (https://github.com/mworkman13/HiCAGE) or on the web (https://junkdnalab.shinyapps.io/hicage).
Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice
Authors: Herber Candice B. , Krause William C. , Wang Liping , Bayrer James R. , Li Alfred , Schmitz Matthew , Fields Aaron , Ford Breanna , Reid Michelle S. , Nomura Daniel K. , Nissenson Robert A. , Correa Stephanie M. , Ingraham Holly A.
Published: May 2018

Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in female rodents. Here, we ablate estrogen receptor alpha (ERα) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα in the arcuate nucleus increases bone mass in both intact and estrogen-depleted females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα activity in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly identified female brain-to-bone pathway exists as a homeostatic regulator to divert calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for the treatment of age-related bone disease.
Genome Sequence of Indian Peacock Reveals the Peculiar Case of a Glittering Bird
Authors: Jaiswal Shubham K. , Gupta Ankit , Saxena Rituja , Vishnu Prasoodanan P. K. , Sharma Ashok K. , Mittal Parul , Roy Ankita , Shafer Aaron B.A. , Vijay Nagarjun , Sharma Vineet K.
Published: May 2018

The unique ornamental features and extreme sexual traits of Peacock have always intrigued the scientists. However, the genomic evidence to explain its phenotype are yet unknown. Thus, we report the first genome sequence and comparative analysis of peacock with the available high-quality genomes of chicken, turkey, duck, flycatcher and zebra finch. The candidate genes involved in early developmental pathways including TGF-β, BMP, and Wnt signaling pathway, which are also involved in feather patterning, bone morphogenesis, and skeletal muscle development, showed signs of adaptive evolution and provided useful clues on the phenotype of peacock. The innate and adaptive immune components such as complement system and T-cell response also showed signs of adaptive evolution in peacock suggesting their possible role in building a robust immune system which is consistent with the between species predictions of Hamilton-Zuk hypothesis. This study provides novel genomic and evolutionary insights into the molecular understanding towards the phenotypic evolution of Indian peacock.
Spatial variation in exploited metapopulations obscures risk of collapse
Authors: Okamoto Daniel K , Hessing-Lewis Margot , Samhouri Jameal F , Shelton Andrew O , Stier Adrian , Levin Philip S , Salomon Anne K
Published: May 2018

Unanticipated declines among exploited species have commonly occurred despite harvests that appeared sustainable prior to collapse. This is particularly true in the oceans where spatial scales of management are often mismatched with spatially complex metapopulations. We explore causes, consequences and potential solutions for spatial mismatches in harvested metapopulations in three ways. First, we generate novel theory illustrating when and how harvesting metapopulations increases spatial variability and in turn masks local scale volatility. Second, we illustrate why spatial variability in harvested metapopulations leads to negative consequences using an empirical example of a Pacific herring metapopulation. Finally, we construct a numerical management strategy evaluation model to identify and highlight potential solutions for mismatches in spatial scale and spatial variability. Our results highlight that spatial complexity can promote stability at large scales, however ignoring spatial complexity produces cryptic and negative consequences for people and animals that interact with resources at small scales. Harvesting metapopulations magnifies spatial variability, which creates discrepancies between regional and local trends while increasing risk of local population collapses. Such effects asymmetrically impact locally constrained fishers and predators, which are more exposed to risks of localized collapses. Importantly, we show that dynamically optimizing harvest can minimize local risk without sacrificing yield. Thus, multiple nested scales of management may be necessary to avoid cryptic collapses in metapopulations and the ensuing ecological, social and economic consequences.
Mobile-CRISPRi: Enabling Genetic Analysis of Diverse Bacteria
Authors: Peters Jason M. , Koo Byoung-Mo , Patino Ramiro , Heussler Gary E. , Hearne Cameron C. , Inclan Yuki F. , Hawkins John S. , Lu Candy H. S. , Harden M. Michael , Osadnik Hendrik , Peters Joseph E. , Engel Joanne N. , Dutton Rachel J. , Grossman Alan D. , Gross Carol A. , Rosenberg Oren S.
Published: May 2018

Introductory paragraph

The vast majority of bacteria, including human pathogens and microbiome species, lack genetic tools needed to systematically associate genes with phenotypes. This is the major impediment to understanding the fundamental contributions of genes and gene networks to bacterial physiology and human health. CRISPRi, a versatile method of blocking gene expression using a catalytically inactive Cas9 protein (dCas9) and programmable single guide RNAs (sgRNAs), has emerged as a powerful genetic tool to dissect the functions of essential and non-essential genes in species ranging from bacteria to human. However, the difficulty of establishing effective CRISPRi systems in non-model bacteria is a major barrier to its widespread use to dissect bacterial gene function. Here, we establish “Mobile-CRISPRi”, a suite of CRISPRi systems that combine modularity, stable genomic integration and ease of transfer to diverse bacteria by conjugation. Focusing predominantly on human pathogens associated with antibiotic resistance, we demonstrate the efficacy of Mobile-CRISPRi in Proteobacteria and Firmicutes at the individual gene scale by examining drug-gene synergies and at the library scale by systematically phenotyping conditionally essential genes involved in amino acid biosynthesis. Mobile-CRISPRi enables genetic dissection of non-model bacteria, facilitating analyses of microbiome function, antibiotic resistances and sensitivities, and comprehensive screens for host-microbe interactions.
A role for differential gene regulation in the rapid diversification of melanic plumage coloration in the dark-eyed junco (Junco hyemalis)
Authors: Abolins-Abols Mikus , Kornobis Etienne , Ribeca Paolo , Wakamatsu Kazumasa , Peterson Mark P. , Ketterson Ellen D. , Milá Borja
Published: May 2018

Color plays a prominent role in reproductive isolation, therefore understanding the proximal basis of pigmentation can provide insight into speciation. Subspecies of the dark-eyed junco (Junco hyemalis) have evolved marked differences in plumage coloration since the Last Glacial Maximum, yet whether color differences are caused by mutations in coding regions of expressed genes or are instead the result of regulatory differences remains unknown. To address this question, we studied the pigment composition and the genetic basis of coloration in two divergent subspecies, the slate-colored and Oregon juncos. We used HPLC and light microscopy to investigate pigment composition and deposition in feathers from four body areas. We then used RNAseq to compare the relative roles of differential gene expression in developing feathers and sequence divergence in transcribed loci under common garden conditions. Junco feathers differed in eumelanin and pheomelanin content and distribution. Within subspecies, in lighter feathers melanin synthesis genes were downregulated (including PMEL, TYR, TYRP1, OCA2, MLANA), ASIP was upregulated. Feathers from different body regions also showed differential expression of HOX and Wnt genes. Feathers from the same body regions that differed in color between the two subspecies showed differential expression of ASIP and three other genes (MFSD12, KCNJ13, HAND2) associated with pigmentation in other taxa. Sequence variation in the expressed genes was not related to color differences. Our findings support the hypothesis that differential regulation of a few genes can account for marked differences in coloration, a mechanism that may underlie the rapid diversification of juncos.
Quantifying heterogeneity of stochastic gene expression
Authors: Iida Keita , Obata Nobuaki , Kimura Yoshitaka
Published: May 2018

The heterogeneity of stochastic gene expression, which refers to the temporal fluctuation of the gene product and its cell-to-cell variation, has attracted considerable interest from biologists, physicists, and mathematicians. The dynamics of protein production and degradation have been modeled as random processes with transition probabilities. However, there is a gap between theory and phenomena, particularly in terms of analytical formulation and parameter estimation. In this study, we propose a theoretical framework in which we present a basic model of a gene regulatory system, derive a steady-state solution, and provide a Bayesian approach for estimating the model parameters from single-cell experimental data. The proposed framework is demonstrated to be applicable for various scales of single-cell experiments at both the mRNA and protein levels, and it is useful for comparing kinetic parameters across species, genomes, and cell strains.
Automated Tracking of Biopolymer Growth and Network Deformation with TSOAX
Authors: Xu Ting , Langouras Christos , Koudehi Maral Adeli , Vos Bart E. , Wang Ning , Koenderink Gijsje H. , Huang Xiaolei , Vavylonis Dimitrios
Published: May 2018

Studies of how individual semi-flexible biopolymers and their network assemblies change over time reveal dynamical and mechanical properties important to the understanding of their function in tissues and living cells. Automatic tracking of biopolymer networks from fluorescence microscopy time-lapse sequences facilitates such quantitative studies. We present an open source software tool that combines a global and local correspondence algorithm to track biopolymer networks in 2D and 3D, using stretching open active contours. We demonstrate its application in fully automated tracking of elongating and intersecting actin filaments, detection of loop formation and constriction of tilted contractile rings in live cells, and tracking of network deformation under shear deformation.
Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells
Authors: Freimer Jacob W. , Hu TJ , Blelloch Robert
Published: May 2018

Translation and mRNA degradation are intimately connected, yet the mechanisms that regulate them are not fully understood. Here we studied the link between translation and mRNA stability in embryonic stem cells (ESCs). Transcripts showed a wide range of stabilities, which correlated with their translation levels. The protein DHH1 links translation to mRNA stability in yeast; however loss of the mammalian homolog, DDX6, in ESCs did not disrupt the correlation across transcripts. Instead, the loss of DDX6 led to upregulated translation of microRNA targets, without concurrent changes in mRNA stability. TheDdx6knockout cells were phenotypically and molecularly similar to cells lacking all microRNAs (Dgcr8knockout ESCs). These data show that the loss of DDX6 can separate the two canonical functions of microRNAs: translational repression and transcript destabilization. Furthermore, these data uncover a central role for translational repression independent of transcript destabilization in defining the downstream consequences of microRNA loss.
CSB-dependent CDK9 degradation and RNA Polymerase II phosphorylation during Transcription Coupled Repair
Authors: Donnio Lise-Marie , Lagarou Anna , Sueur Gabrielle , Mari Pierre-Olivier , Giglia-Mari Giuseppina
Published: May 2018

AUTHOR SUMMARY

DNA lesions block cellular processes such as transcription, inducing apoptosis, tissue failures and premature ageing. To counteract the deleterious effects of DNA damage, cells are equipped with various DNA repair pathways. Transcription Coupled Repair specifically removes helix-distorting DNA adducts in a coordinated multi-step process. This process has been extensively studied, however once the repair reaction is accomplished, little is known about how transcription restarts. In this study, we show that, after UV irradiation, the CDK9/CyclinT1 kinase unit is specifically released from the HEXIM1 complex and that this released fraction is degraded in the absence of CSB. We determine that UV-irradiation induces a specific Ser2 phosphorylation of the RNA polymerase II and that this phosphorylation is CSB dependent. Surprisingly CDK9 is not responsible for this phosphorylation but instead plays a non-enzymatic role in transcription restart after DNA repair.
Site-specific PEGylation crosslinking of L-asparaginase subunits to improve its therapeutic efficiency
Authors: Ramirez-Paz Josell , Saxena Manoj , Delinois Louis J. , Joaquín-Ovalle Freisa M. , Lin Shiru , Chen Zhongfang , Rojas-Nieves Virginia A. , Griebenow Kai
Published: May 2018

L-Asparaginase is an enzyme successfully being used in the treatment of acute lymphoblastic leukemia, acute myeloid leukemia, and non-Hodgkin’s lymphoma. However, some disadvantages still limit its full application potential, e.g., allergic reactions, pancreatitis, and blood clotting impairment. Therefore, much effort has been directed at improving its performance. A popular strategy is to randomly conjugate L-asparaginase with mono-methoxy polyethylene glycol, which became a commercial FDA approved formulation widely used in recent years. To improve this formulation by PEGylation, herein we performed cysteine-directed site-specific conjugation of the four L-asparaginase subunits to prevent dissociation-induced loss of activity. The conjugation sites were selected at surface-exposed positions on the protein to avoid affecting the catalytic activity. Three conjugates were obtained using different linear PEGs of 1000, 2000, and 5000 g/mol, with physical properties ranging from a semi-solid gel to a fully soluble state. The soluble-conjugate exhibited higher catalytic activity than the non-conjugated mutant, and the same activity than the native enzyme. Site-specific crosslinking of the L-asparaginase subunits produced a higher molecular weight conjugate compared to the native tetrameric enzyme. This strategy might improve L-asparaginase efficiency for leukemia treatment by reducing glomerular filtration due to the increase in hydrodynamic size thus extending half-live, while at the same time retaining full catalytic activity.
The recognition and expectations of ex-inpatients of mental health services: A web-based questionnaire survey in Japan
Authors: Shiina Akihiro , Ojio Yasutaka , Sato Aiko , Sugiyama Naoya , Iyo Masaomi , Fujii Chiyo
Published: May 2018

Concern about mental health issues and the treatment of mentally disordered offenders attracts a lot of public attention. This study aimed to gather the experiences and opinions of people who have experienced admission to a psychiatric ward in order to understand their reaction to, and understanding of, the legislation behind the involuntary admission of psychiatric patients. A web-based questionnaire survey was conducted with a total of 379 participants, using a cross-sectional, exploratory design. The data were analyzed using a chi-square test, Fisher’s exact test, and a logistic regression analysis. According to the results, many patients were satisfied with their psychiatric admission, however, few participants said that they had been given adequate explanation for their involuntary treatment. Most participants expected qualified aids after discharge, although the prospect of a regular visit from an official was not entirely supported by the participants. Patient satisfaction was relevant to the discussion of their needs after discharge and in developing a crisis plan during admission. These findings suggests that psychiatric patients accept inpatient treatment as long as they receive an adequate explanation. More qualified care such as relapse prevention would be expected to lead to better satisfaction. In order for them to welcome regular visits from an official, patients may need more information and discussion.
Spinal astrocyte-neuron lactate shuttle contributes to the PACAP/PAC1 receptor-induced nociceptive behaviors
Authors: Kambe Yuki , Yokai Masafumi , Takasaki Ichiro , Kurihara Takashi , Miyata Atsuro
Published: May 2018

Previously, we showed that spinal pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor signaling triggers long-lasting pain behaviors through astroglial activation. Since astrocyte-neuron lactate shuttle (ANLS) could be essential for long-term synaptic facilitation, we aimed to elucidate a possible involvement of spinal ANLS in the development of the PACAP/PAC1 receptor-induced pain behaviors. A single intrathecal administration of PACAP induced short-term spontaneous aversive behaviors, followed by long-lasting mechanical allodynia. These pain behaviors were inhibited by DAB, an inhibitor of glycogenolysis, and this inhibition was reversed by simultaneous L-lactate application. In the cultured spinal astrocytes, the PACAP-evoked glycogenolysis and lactate secretion were inhibited by a protein kinase C (PKC) inhibitor, and the PKC inhibitor attenuated the PACAP-induced pain behaviors. Finally, an inhibitor for the monocarboxylate transporters blocked the lactate secretion from the spinal astrocytes and inhibited the PACAP-induced pain behaviors. These results suggested that PAC1 receptor-PKC-ANLS signaling is involved in the PACAP-induced pain behaviors.
Activation of the mTOR/ Akt pathway in thymic epithelial cells derived from thymomas
Authors: Maury Jean-Michel , du Vignaux Claire Merveilleux , Drevet Gabrielle , Zarza Virginie , Chalabreysse Lara , Tronc François , Girard Nicolas , Leroux Caroline
Published: May 2018

The pathogenesis of thymic epithelial tumors remains poorly elucidated. The PI3K/Akt/mTOR pathway plays a key role in various cancers; interestingly, several phase I/II study reported a positive effect of mTOR inhibitors in disease control in thymoma patients. A major limit for deciphering cellular and molecular events leading to the transformation of thymic epithelial cells or for testing drug candidates is the lack of reliable in vitro cell system

We analyzed protein expression and activation of key players of the Akt/mTOR pathway namely Akt, mTOR, and P70S6K in thirteen A, B and AB thymomas as well as in normal thymuses. While only Akt and the phospho-Akt were expressed in normal thymuses, both Akt and mTOR were activated, with B2 thymomas expressing higher level of activated phospho-Akt than A or AB subtypes. Phospho-P70S6K was expressed in all thymic tumors whatever their subtypes, and absent in normal thymus. Interestingly, in primary thymic epithelial cells maintained for short period of time after their derivation from seven AB and B thymomas, we report the activation of Akt; mTOR and P70S6. Finally, we analyzed the effect of mTOR inhibitor on thymoma derived epithelial cells and showed that rapamycin (100 nM/ ml) significantly reduced cell proliferation.

Our results suggest that the activation of the Akt/ mTOR pathway might participate to the cell proliferation associated with tumor growth. Ultimately, our data enhance the potential role of thymic epithelial cells derived from tissue specimens forin vitroexploration of molecular abnormalities specific to rare thymic tumors.
PLK1 plays dual roles in centralspindlin regulation during cytokinesis
Authors: Adriaans Ingrid E. , Basant Angika , Ponsioen Bas , Glotzer Michael , Lens Susanne M. A.
Published: May 2018

Cytokinesis starts in anaphase with the formation of an actomyosin-based contractile ring at the equatorial cortex, which is governed by the local activation of the small GTPase RhoA. Here we delineated the contributions of PLK1 and Aurora B to RhoA activation and cytokinesis initiation in human cells. Knock-down of PRC1, which disrupts the spindle midzone, revealed the existence of two pathways that can initiate cleavage furrow ingression. One pathway depends on a well-organized spindle midzone and PLK1, while the other depends on Aurora B activity and centralspindlin oligomerization at the equatorial cortex and can operate independently of PLK1. We further show that PLK1 inhibition sequesters centralspindlin onto the spindle midzone making it unavailable for Aurora B-dependent oligomerization at the equatorial cortex. We propose that PLK1 activity promotes the release of centralspindlin from the spindle midzone through inhibition of PRC1, allowing centralspindlin to function as a regulator of spindle midzone formation and as an activator of RhoA at the equatorial cortex.
Regional integration and entrepreneurship: evidence from European Union
Authors: Tarabar Danko
Published: May 2018

Purpose

The purpose of this paper is to empirically uncover the relationship between economic integration and levels of entrepreneurial activity across 24 EU countries between 2004 and 2012. The deepening of EU integration corresponds to increases in the size and competitiveness of domestic markets as member states reorient economic activity toward the larger, competitive single market. Spillovers of both economic and political dimensions of integration in the common market on micro firm and self-employment are considered. The paper contributes to the understanding of the hypothesized relationship between globalization and the rise of entrepreneurial economy.

Design/methodology/approach

The paper uses fixed effects linear regression models to estimate the marginal effects of economic integration on entrepreneurial activity. Several dependent variables and controls for social, economics, and institutional context are used to confirm the robustness of the results.

Findings

The paper finds that increased economic activity of member countries within the EU common market, as well as institutional compliance and integration in the European Monetary Union and Schengen Agreement are positively and significantly associated with the rise of entrepreneurship. Notably, it is found that a standard deviation increase in economic and political integration is associated with, respectively, 16 and 7.2 percent increase in micro firm density. Some preliminary evidence on the quality of the arising entrepreneurial activity are also given.

Originality/value

The paper takes stock of existing descriptive and theoretical literature on global economic integration and entrepreneurship to uncover, for the first time, the empirical relationship between entrepreneurship and levels of economic and political integration within the EU bloc.
Effect of distance to edge and edge interaction on seedling regeneration and biotic damage in tropical rainforest fragments: A long‐term experiment
Authors: Benítez‐Malvido Julieta , Lázaro Amparo , Ferraz Isolde D. K.
Published: May 2018

In forest fragments, edge effects can influence forest regeneration, but little is known about how edge effects influence seedling performance and the interaction between seedlings and their natural enemies over time.

In central Amazonia, we recorded survival and growth (in height and leaf number) and damage by insect herbivores and leaf‐fungal pathogens ofChrysophyllum pomiferum(Sapotaceae) seedlings that were exposed to different numbers of edges and to different distances from the forest edge. Grown seedlings were transplanted into one‐square‐metre plots within 1‐ha blocks located in the centre (no edge), the edge (one edge), and the corner (two edges), and at different distances from the edge towards the interior (i.e., 20, 40, 60, 80, and 100 m) of two rectangular fragments (10‐ and 100‐ha in size). Plots were visited once every 2 months for 1 year (1992–1993) and thereafter every 2 years for almost 8 years (1993–2001).

Overall, results showed that seedling survival, height, leaf number, and biotic damage varied over time with the presence of nearby edges and with the distance from the edge. Survival was lower in fragment edges and corners than in centres. Increase in height was similar for all positions within the 100‐ha fragment, whereas in the 10‐ha fragment seedling height had a greater increase at the edge and corner than in the centre. Furthermore, survival increased with distance from the edge as did leaf number, whereas height showed a lower increase closer to the edge than farther away.

Regarding biotic damage, for both fragments herbivory was greater at the centres and decreased with edge proximity over time, whereas leaf‐fungal damage was greater at the corners than in the edges and increased significantly over time. Biotic damage was correlated with seedling size. Small seedlings were more susceptible to fungal attack, whereas larger seedlings were so to herbivores.

Synthesis. This study demonstrated that despite stochastic environmental factors seedling survival, growth, and biotic damage by herbivores and fungal pathogens varied with the level of edge exposure and proximity, which may threaten forest regeneration in the long term.
The effect of traditional production methods on microbial, physico‐chemical and sensory properties of ‘Slovenská bryndza’ Protected Geographical Indication cheese
Authors: Semjon Boris , Reitznerová Anna , Poláková Zuzana , Výrostková Jana , Maľová Jana , Koréneková Beáta , Dudriková Eva , Lovayová Viera
Published: May 2018

Bryndza is a natural, white, mature and spreadable kind of cheese, and since 2008, it has been manufactured in specified mountainous areas of the Slovak Republic with Protected Geographical Indication. The aim of this work was to provide useful information about the microbial, physico‐chemical and sensory characteristics of bryndza, taking into consideration the variabilities related to the traditional methods of production technology of three bryndza cheese varieties. Statistically significant differences were observed in bryndza cheese production methods in chemical parameters of NaCl and malondialdehyde content (P < 0.05) and in the microbial presence of Enterococcus spp. (P < 0.001) and Staphylococcus spp. (P < 0.01).
Antidiabetic medication de‐escalation following bariatric surgery
Authors: Vouri Scott M. , Chen Jiajing , Sparkman Jayme , Salles Arghavan , Micek Scott T.
Published: May 2018

Highlights

There is a de‐escalation of antidiabetes medications prescribed following bariatric surgery.

Antidiabetes medication utilization following bariatric surgery does not appear to be consistent with clinical practice guidelines.
Immune‐related Adverse Events in Cancer Patients
Authors: Pallin Daniel J. , Baugh Christopher W. , Postow Michael A. , Caterino Jeffrey M. , Erickson Timothy B. , Lyman Gary H.
Published: May 2018

The U.S. Food and Drug Administration has approved immune checkpoint inhibitors and chimeric antigen receptor T cells (CAR‐T cells) as immunotherapy strategies for cancer. These therapies cause a wide variety of adverse events, which mimic other disease states and may emerge months after completion of treatment. This is important because ascertaining a past medical history of cancer treatment within the past year becomes necessary for many presentations. This narrative review summarizes the biology, pathophysiology, and adverse events associated with checkpoint inhibitors and CAR‐T cells and provides a rational approach to management. Proper treatment begins with heightened awareness, rapid diagnosis, and discussion with the patient's oncologist. Treatment of these adverse effects requires only corticosteroids, infliximab, tocilizumab, or fluids or vasopressors when clinically indicated.
Distress intolerance moderation of motivated attention to cannabis and negative stimuli after induced stress among cannabis users: an ERP study
Authors: Macatee Richard J. , Okey Sarah A. , Albanese Brian J. , Schmidt Norman B. , Cougle Jesse R.
Published: May 2018

Prevalence of cannabis use is increasing, but many regular users do not develop cannabis use disorder (CUD); thus, CUD risk identification among current users is vital for targeted intervention development. Existing data suggest that high distress intolerance (DI), an individual difference reflective of the ability to tolerate negative affect, may be linked to CUD, but no studies have tested possible neurophysiological mechanisms. Increased motivated attentional processing of cannabis and negative emotional stimuli as indexed by neurophysiology [i.e. the late positive potential (LPP)], particularly during acute stress, may contribute to CUD among high DI users. Frequent cannabis users with high (n = 61) and low DI (n = 44) viewed cannabis, negative, and matched neutral images during electroencephalography (EEG) recording before and after a laboratory stressor. Cannabis cue‐elicited modulation of the 1000‐ to 3000‐milliseconds LPP was larger in high DI users at post‐stressor only, although the effect was only robust in the 1000‐ to 2000‐milliseconds window. Further, modulation magnitude in the high DI group covaried with stress‐relief craving and some CUD indices in the 400‐ to 1000‐milliseconds and 1000‐ to 3000‐milliseconds windows, respectively. No significant effects of DI on negative stimuli‐elicited LPP modulation were found, although inverse associations with some CUD indices were observed. Finally, exploratory analyses revealed some evidence for DI moderation of the relation between subjective stressor reactivity and negative stimuli‐elicited LPP modulation such that greater stressor reactivity was associated with blunted versus enhanced modulation in the high and low DI groups, respectively. Negative and cannabis stimuli‐elicited LPP modulation appear to index distinct, CUD‐relevant neural processes in high DI cannabis users.
Preventing morphine reinforcement with high‐frequency deep brain stimulation of the lateral hypothalamic area
Authors: Fattahi Mojdeh , Ashabi Ghorbangol , Karimian Seyed Morteza , Riahi Esmail
Published: May 2018

Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment‐refractory substance use disorder. Here, we investigated if high‐frequency DBS in the lateral hypothalamic area (LHA) could affect drug‐induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130 Hz, 100‐microsecond pulse duration and 150 μA) was applied during the morphine‐pairing trials (30 minutes daily for 4 days) or drug‐free postconditioning test (15 minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine‐conditioning trials blocked subsequent preference for the drug‐associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine‐induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety‐like behavior as measured by an open field test and by precluding anhedonia‐like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS‐based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.
Is there more than meets the eye? Seed bank analysis of a typical novel ecosystem, the extensive green roof
Authors: Vanstockem Jan , Ceusters Christiaan , Van Dyck Karen , Somers Ben , Hermy Martin
Published: May 2018

Questions

(a) Will seed banks develop on extensive green roofs (EGRs) – prime examples of novel ecosystems – as in (semi‐)natural systems? If so, which type of seed bank (transient or persistent) can be expected? (b) Do EGR characteristics, such as roof age and substrate depth, influence seed bank seed density and species richness? (c) Can differences in successional stages be noticed in the seed bank and vegetation on EGRs?

Location

Flanders and Brussels regions of Belgium.

Methods

We conducted a field sampling campaign in which the vegetation and seed bank of 109 EGRs were sampled. Information on roof characteristics (e.g. age, substrate depth) was also collected. Seedling emergence was monitored under standardized greenhouse conditions. Species traits were collected from several existing databases. Data analysis consisted of (generalized) linear mixed modelling.

Results

A total of 18,466 seedlings from 139 different species emerged in the seed bank analysis. Average similarity between vegetation and the seed bank was low, and the majority of species could be considered spontaneous colonizers. Most species were classified as having a transient seed bank. Life forms were shown to be significantly different between vegetation and seed bank. Older EGRs had higher seed bank species richness and seed density, both of which were also positively influenced by sampling date and the vegetation species richness. A discrepancy between seed bank and vegetation successional state, characterized by functional signatures, was present for EGRs.

Conclusions

EGRs do develop seed banks and show parallels with seed banks in other novel ecosystems. Seed bank species richness and seed density are influenced by temporal and vegetation related factors. We can also confirm EGR seed bank succession and the discrepancy between seed bank and vegetation successional state, as often observed in natural and novel systems. Furthermore, we argue that seed banks can function as biodiversity reservoirs, which can be considered in EGR vegetation restoration if a set of several conditions is fulfilled. Overall, this study explores seed bank analysis on EGR as a novel ecosystem model. It thereby provides multiple insights in processes impacting EGR plant species diversity, both on and in the soil.
Exponential Family Functional Data Analysis via a Low-Rank Model
Authors: Li Gen , Huang Jianhua Z. , Shen Haipeng
Published: May 2018

In many applications, non-Gaussian data such as binary or count are observed over a continuous domain and there exists a smooth underlying structure for describing such data. We develop a new functional data method to deal with this kind of data when the data are regularly spaced on the continuous domain. Our method, referred to as Exponential Family Functional Principal Component Analysis (EFPCA), assumes the data are generated from an exponential family distribution, and the matrix of the canonical parameters has a low-rank structure. The proposed method flexibly accommodates not only the standard one-way functional data, but also two-way (or bivariate) functional data. In addition, we introduce a new cross validation method for estimating the latent rank of a generalized data matrix. We demonstrate the efficacy of the proposed methods using a comprehensive simulation study. The proposed method is also applied to a real application of the UK mortality study, where data are binomially distributed and two-way functional across age groups and calendar years. The results offer novel insights into the underlying mortality pattern.