bluuebunny/crossref_metadata_2025 huggingface dataset:
fMRI replicability depends upon sufficient individual-level data
Authors: Nee Derek Evan
Published: June 2018

The replicability of findings drawn from functional magnetic resonance imaging (fMRI) data have increasingly been called into question. Concerns have been raised that historically, sample sizes have been insufficient to produce adequate power, leading to unreliable results. Recently, Turner and colleagues demonstrated that even with large sample sizes, the replicability of fMRI can be worryingly low. However, their datasets featured low amounts of data at the individual-level. Here, I demonstrate that replicability depends critically on sufficient individual-level sampling. I show that fMRI can have strong replicability even at modest sample sizes when individuals are adequately sampled, but that inadequate individual-level sampling leads to poor replicability. These data indicate that fMRI replicability cannot be judged solely on sample size, and that adequate sampling at the individual-level is a critical design consideration.
Full life-cycle models from ring-recovery data: estimating fecundity from age ratios at capture
Authors: Arnold Todd. W.
Published: June 2018

Tag-recovery data from organisms captured and marked post breeding are commonly used to estimate juvenile and adult survival. If annual fecundity could also be estimated, tagging studies such as European and North American bird-ringing schemes could provide all parameters needed for building full life-cycle projection models.

I modified existing tag-recovery models to allow estimation of annual fecundity using age composition and recapture probabilities obtained during routine banding operations of northern pintails (Anas acuta) and dark-eyed juncos (Junco hyemalis), and I conducted simulations to assess estimator performance in relation to sample size.

For pintails, population growth rate from band-recovery data (λ = 0.929, SD 0.060) was similar but less precise than count-based estimates from the Waterfowl Breeding Pair and Habitat Survey (λ 0.945, SE 0.001). Models with temporal variation in vital rates indicated that annual population growth in pintails was driven primarily by variation in fecundity. Juncos had lower survival but greater fecundity, and their estimated population growth rate (λ 1.01, SD 0.19) was consistent with count-based surveys (λ 0.986).

Simulations indicated that reliable (CV < 0.10) estimates of fecundity could be obtained with >1000 same-season live encounters. Although precision of survival estimates depended primarily on numbers of adult recoveries, estimates of population growth rate were most sensitive to total number of live encounters.

Synthesis and applications: Large-scale ring-recovery programmes could be used to estimate annual fecundity in many species of birds, but the approach requires better data curation, including accurate assessment of age, better reporting of banding totals and greater emphasis on obtaining and reporting same-season live encounters.
Integration of phased Hi-C and molecular phenotype data to study genetic and epigenetic effects on chromatin looping
Authors: Greenwald William W. , Li He , Benaglio Paola , Jakubosky David , Matsui Hiroko , Schmitt Anthony , Selvaraj Siddarth , D’Antonio Matteo , D’Antonio-Chronowska Agnieszka , Smith Erin N. , Frazer Kelly A.
Published: June 2018

While genetic variation at chromatin loops is relevant for human disease, the relationships between loop strength, genetics, gene expression, and epigenetics are unclear. Here, we quantitatively interrogate this relationship using Hi-C and molecular phenotype data across cell types and haplotypes. We find that chromatin loops consistently form across multiple cell types and quantitatively vary in strength, instead of exclusively forming within only one cell type. We show that large haplotype loop imbalance is primarily associated with imprinting and copy number variation, rather than genetically driven traits such as allele-specific expression. Finally, across cell types and haplotypes, we show that subtle changes in chromatin loop strength are associated with large differences in other molecular phenotypes, with a 2-fold change in looping corresponding to a 100-fold change in gene expression. Our study suggests that regulatory genetic variation could mediate its effects on gene expression through subtle modification of chromatin loop strength.
Emergence and rapid global dissemination of CTX-M-15-associated Klebsiella pneumoniae strain ST307
Authors: Wyres Kelly L. , Hawkey Jane , Hetland Marit A.K. , Fostervold Aasmund , Wick Ryan R. , Judd Louise M. , Hamidian Mohammad , Howden Benjamin P. , Löhr Iren H. , Holt Kathryn E.
Published: June 2018

Recent reports indicate the emergence of a new carbapenemase producing Klebsiella pneumoniae clone, ST307. Here we show that ST307 emerged in the mid-1990s (nearly 20 years prior to its first report), is already globally distributed and is intimately associated with a conserved plasmid harbouring the blaCTX-M-15 extended-spectrum beta-lactamase (ESBL) gene plus other antimicrobial resistance determinants. Our findings support the need for enhanced surveillance of this widespread ESBL clone in which carbapenem resistance is now emerging.
CRISPR delivery particles for developing therapeutic strategies in metabolic disease
Authors: Shen Yuefei , Cohen Jessica L. , Nicoloro Sarah M. , Kelly Mark , Yenilmez Batuhan , Henriques Felipe , Tsagkaraki Emmanouela , Edwards Yvonne J.K. , Hu Xiaodi , Friedline Randall H. , Kim Jason K. , Czech Michael P.
Published: June 2018

RNA-guided engineered nucleases derived from a prokaryotic adaptive immune system known as CRISPR-Cas represent a promising platform for gene deletion and editing. As a therapeutic approach, direct delivery of Cas9 protein and guide RNA could circumvent the safety problems associated with plasmid delivery and therefore represents an attractive tool for genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fat oxidation and secretion of bioactive factors through a “browning” process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed novel CRISPR delivery particles, denoted CriPs, composed of nano-size complexes of Cas9 protein and single guide (sg)RNA, coated with an amphipathic peptide called Endo-Porter that mediates entry into cells. Efficient CRISPR-Cas9 mediated gene deletion of ectopically expressed Green fluorescent protein (GFP) by CriPs was achieved in multiple cell types including a macrophage cell line, primary macrophages and primary pre-adipocytes. Significant GFP loss was also observed in peritoneal exudate cells with minimum systemic toxicity in GFP expressing mice following intraperitoneal injection of CriPs containing sgRNA targeting Gfp. Furthermore, the disruption of the Nrip1 gene in white adipocytes by CriPs enhanced adipocyte “browning” with a marked increase of UCP1 expression. Deletion of Nrip1 by CriPs did not produce detectable off-target effects. Thus CriPs represent a novel CRISPR delivery system for Cas9 and sgRNA that is effective for ablating targeted gene products in cultured cells and in vivo, and provide a potential therapeutic strategy for metabolic disease.
A Novel AuNPs-based Glucose Oxidase Mimic with Enhanced Activity and Selectivity Constructed by Molecular Imprinting and O2-Containing Nanoemulsion Embedding
Authors: Fan Lin , Wu Haoan , Lou Doudou , Zhang Xizhi , Zhu Yefei , Gu Ning , Zhang Yu
Published: June 2018

In spite of the competitive advantages, inorganic nanoparticle mimic enzymes exhibit inherent disadvantages of limited catalytic efficiency and lacking selectivity. Here a AuNPs based mimic enzyme with significantly enhanced glucose selectivity and catalytic activity was constructed and demonstrated for the first time. Aminophenylboronic acid was employed to increase the affinity to glucose, as well as build molecular imprinted polymer shells to realize the selectivity for template molecules of glucose. Besides that, heptadecafluoro-n-octyl bromide nanoemulsion with the function of providing oxygen was introduced to gain a further improvement in catalytic activity, which successfully enhanced the catalytic efficiency (kcat/Km) up to about 270-fold. Based on the demonstrated catalytic properties, AuNPs based glucose oxidase mimics have been successfully applied in practical glucose detection of drinks and blood glucose.
Drosophila melanogasterinfected withWolbachiastrainwMelCS prefer cooler temperatures
Authors: Arnold Pieter A. , Levin Samantha C. , Stevanovic Aleksej L. , Johnson Karyn N.
Published: June 2018

Temperature plays a fundamental role in the dynamics of host-pathogen interactions.

Wolbachiais an endosymbiotic bacteria that infects about 40% of arthropod species, which can affect host behaviour and reproduction. Yet, the effect ofWolbachiaon host thermoregulatory behaviour is largely unknown, despite its use in disease vector control programs in thermally variable environments.

Here, we used a thermal gradient to test whetherDrosophila melanogasterinfected withWolbachiastrainwMelCS exhibit different temperature preferences (Tp) to uninfected flies.

We found thatWolbachia-infected flies preferred a cooler mean temperature (Tp= 25.06±0.25°C) than uninfected flies (Tp= 25.78±0.24°C).

This finding suggests thatWolbachia-infected hosts might seek out cooler microclimates to reduce exposure to and lessen the consequences of high temperatures. This finding has generated hypotheses that will be fruitful in areas of research for exploring the mechanisms by which the change inTpoccurs in this complex and significant host-pathogen-environment interaction.
Logical design of oral glucose ingestion pattern minimizing blood glucose in humans
Authors: Fujii Masashi , Murakami Yohei , Karasawa Yasuaki , Sumitomo Yohei , Fujita Suguru , Koyama Masanori , Uda Shinsuke , Kubota Hiroyuki , Inoue Hiroshi , Konishi Katsumi , Oba Shigeyuki , Ishii Shin , Kuroda Shinya
Published: June 2018

Excessive increase in blood glucose level after eating increases the risk of macroangiopathy, and a method for not increasing the postprandial blood glucose level is desired. However, a logical design method of the dietary ingestion pattern controlling the postprandial blood glucose 2 level has not yet been established. We constructed a mathematical model of blood glucose control by oral glucose ingestion in 3 healthy human subjects, used the model to predict an optimal glucose ingestion pattern, and showed that the optimal ingestion pattern minimized the peak value of blood glucose level. Subjects orally ingested 3 doses of glucose by bolus or over 2 hours, and blood glucose, insulin, C-peptide and incretins were measured for 4 hours. We constructed an ordinary differential equation model that reproduced the time course data of the blood glucose and blood hormone levels. Using the model, we predicted that intermittent ingestion 30 minutes apart was the optimal glucose ingestion patterns that minimized the peak value of blood glucose level. We confirmed with subjects that this intermittent pattern decreased the peak value of blood glucose level. This approach could be applied to design optimal dietary ingestion patterns.

In Brief

As a forward problem, we measured blood glucose and hormones in three human subjects after oral glucose ingestion and constructed a mathematical model of blood glucose control. As an inverse problem, we used the model to predict the optimal oral glucose ingestion pattern that minimized the peak value of blood glucose level, and validated the pattern with the subjects.

Highlights

Modeling blood glucose concentrations predicts an intermittent ingestion pattern is optimal

Human validation shows ingestion at 30-minute intervals limits peak blood glucose

We provide a strategy to design optimal dietary ingestion patterns
TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3
Authors: Drubay Vincent , Skrypek Nicolas , Cordiez Lucie , Vasseur Romain , Schulz Céline , Boukrout Nihad , Duchêne Bélinda , Coppin Lucie , Seuningen Isabelle Van , Jonckheere Nicolas
Published: June 2018

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the western countries because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cell also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatment for PDAC.

TGF-β possesses both tumor-suppressive and oncogenic activities in pancreatic cancer. TGF-β signalling pathway plays complex role during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as tumor suppressor pathway. TGF-β binds to its receptor TGF-βRII and activates different pathways: canonical pathway involving the Smad proteins and alternative pathways such as MAPKs. Smad4 is mutated in 50-80% of PDAC. Mutations of TGF-βRII also occurs (5-10%). In order to decipher the role of TGF-β in carcinogenesis and chemoresistance, we decided to characterize the knocking down of TGF-βRII that is the first actor of TGF-β signalling. We developed pancreatic cancer cell lines stably invalidated for TGF-βRII and studied the impact on biological properties of pancreatic cancer cells both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to. TGF-βRII silencing also leads to S727 STAT3 and S-63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype.

In the future, the better understanding TGF-β signaling pathways and underlying cellular mechanisms in chemoresistance to gemcitabine may bring new therapeutic tools to clinicians.
Nucleoporin 133 deficiency leads to glomerular damage in zebrafish
Authors: Cosentino Chiara Cianciolo , Berto Alessandro , Hari Michelle , Loffing Johannes , Neuhauss Stephan C. F. , Doye Valérie
Published: June 2018

Although structural nuclear pore proteins (nucleoporins) are seemingly required in every cell type to assemble a functional nuclear transport machinery, mutations or deregulation of a subset of them have been associated with specific human hereditary diseases. In particular, previous genetic studies of patients with nephrotic syndrome identified mutations inNup107that impaired the expression or the localization of its direct partner at nuclear pores, Nup133. In the present study, we characterized the zebrafishnup133orthologous gene and its expression pattern during larval development. Morpholino-mediated gene knockdown revealed that Nup133 depletion in zebrafish larvae leads to the formation of kidney cysts, a phenotype that can be rescued by co-injection of wild type mRNA. Analysis of different markers for tubular and glomerular development shows that the overall kidney development is not affected bynup133knockdown. On the other hand, we demonstrate thatnup133is essential for the organization and functional integrity of the pronephric glomerular filtration barrier, as its downregulation results in proteinuria and moderate foot process effacement, mimicking some of the abnormalities typically featured by patients with nephrotic syndrome. These data indicate thatnup133is a new gene required for proper glomerular structure and function in zebrafish.
Inter-trial effects in visual pop-out search: Factorial comparison of Bayesian updating models
Authors: Allenmark Fredrik , Müller Hermann J. , Shi Zhuanghua
Published: June 2018

Many previous studies on visual search have reported inter-trial effects, that is, observers respond faster when some target property, such as a defining feature or dimension, or the response associated with the target repeats versus changes across consecutive trial episodes. However, what processes drive these inter-trial effects is still controversial. Here, we investigated this question using a combination of Bayesian modeling of belief updating and evidence accumulation modeling in perceptual decision-making. In three visual singleton (‘pop-out’) search experiments, we explored how the probability of the response-critical states of the search display (e.g., target presence/absence) and the repetition/switch of the target-defining dimension (color/ orientation) affect reaction time distributions. The results replicated the mean reaction time (RT) inter-trial and dimension repetition/switch effects that have been reported in previous studies. Going beyond this, to uncover the underlying mechanisms, we used the Drift-Diffusion Model (DDM) and the Linear Approach to Threshold with Ergodic Rate (LATER) model to explain the RT distributions in terms of decision bias (starting point) and information processing speed (evidence accumulation rate). We further investigated how these different aspects of the decision-making process are affected by different properties of stimulus history, giving rise to dissociable inter-trial effects. We approached this question by (i) combining each perceptual decision making model (DDM or LATER) with different updating models, each specifying a plausible rule for updating of either the starting point or the rate, based on stimulus history, and (ii) comparing every possible combination of trial-wise updating mechanism and perceptual decision model in a factorial model comparison. Consistently across experiments, we found that the (recent) history of the response-critical property influences the initial decision bias, while repetition/switch of the target-defining dimension affects the accumulation rate, likely reflecting an implicit ‘top-down’ modulation process. This provides strong evidence of a disassociation between response- and dimension-based inter-trial effects.
Functional properties of CD8+ T cells under lymphopenic conditions
Authors: Silaeva Yu. Yu. , Kalinina A. A. , Khromykh L. M. , Kazansky D. B.
Published: June 2018

A peripheral pool of T lymphocytes consists of several functionally distinct populations of CD8+ T cells. One of the major surface markers that allow to define different populations of T cells are CD44 and CD62L. Expression profile of these markers depends on the functional status of T lymphocyte. Naive CD8+ T cells express CD62L and do not express CD44 (CD62LhiCD44lo), clones of T cells activated during the primary immune response lose CD62L and express CD44 (CD62LloCD44hi). Central memory CD8+ T cells express both CD44 and CD62L (CD44hiCD62Lhi). However expression of activation markers not always correlate with an antigen experience of T cell. It is known, that in lymphopenic conditions peripheral T cells undergo homeostatic proliferation and acquire the memory like surface phenotype CD44hiCD62Lhi, but data about functional activity of these cells remain controversial. We studied relationship between surface expression of the markers CD44 and CD62L and functional properties of CD8+ T cells under lymphopenic conditions. We proved that surface expression of CD44 in not the only condition for T lymphocyte to acquire the functional properties of memory T-cells. It means that identification of CD8 + T-memory cells based solely on an expression profile of surface markers is not completely correct and requires confirmation by functional tests. Moreover, results of our research may become of practical importance for blood transfusion and bone marrow transplantation.
Options for calibrating CERES-maize genotype specific parameters under data-scarce environments
Authors: Adnan A.A , Diels J. , Jibrin J.M. , Kamara A.Y. , Craufurd P. , Mohammed I. B. , Tonnang Z.E.H.
Published: June 2018

Most crop simulation models require the use of Genotype Specific Parameters (GSPs) which provide the Genotype component of G×E×M interactions. Estimation of GSPs is the most difficult aspect of most modelling exercises because it requires expensive and time-consuming field experiments. GSPs could also be estimated using multi-year and multi locational data from breeder evaluation experiments. This research was set up with the following objectives: i) to determine GSPs of 10 newly released maize varieties for the Nigerian Savannas using data from both calibration experiments and by using existing data from breeder varietal evaluation trials; ii) to compare the accuracy of the GSPs generated using experimental and breeder data; and iii) to evaluate CERES-Maize model to simulate grain and tissue nitrogen contents. For experimental evaluation, 8 different experiments were conducted during the rainy and dry seasons of 2016 across the Nigerian Savanna. Breeder evaluation data was also collected for 2 years and 7 locations. The calibrated GSPs were evaluated using data from a 4 year experiment conducted under varying nitrogen rates (0, 60 and 120kg N ha−1). For the model calibration using experimental data, calculated model efficiency (EF) values ranged between 0.86-0.92 and coefficient of determination (d-index) between 0.92-0.98. Calibration of time-series data produced nRMSE below 7% while all prediction deviations were below 10% of the mean. For breeder experiments, EF (0.52-0.81) and d-index (0.46-0.83) ranges were lower. Prediction deviations were below 17% of the means for all measured variables. Model evaluation using both experimental and breeder trials resulted in good agreement (low RMSE, high EF and d-index values) between observed and simulated grain yields, and tissue and grain nitrogen contents. We conclude that higher calibration accuracy of CERES-Maize model is achieved from detailed experiments. If unavailable, data from breeder experimental trials collected from many locations and planting dates can be used with lower but acceptable accuracy.
β-Blocker inhibits myocardial infarction-induced brown adipose tissue D2 activation and maintains a low thyroid hormone state in rats
Authors: Seara Fernando A. C. , Araujo Iracema G. , Império Güínever E. , Marassi Michelle P. , Silva Alba C. M. , Mecawi André S. , Reis Luis C. , Olivares Emerson L.
Published: June 2018

Considering the recognized role of thyroid hormones on the cardiovascular system during health and disease, we hypothesized that type 2 deiodinase (D2) activity, the main activation pathway of thyroxine (T4)-to-triiodothyronine (T3), could be an important site to modulate thyroid hormone status, which would then constitute a possible target for β-adrenergic blocking agents in a myocardial infarction (MI) model induced by left coronary occlusion in rats. Despite a sustained and dramatic fall in serum T4 concentrations (60-70%), the serum T3 concentration fell only transiently in the first week post-infarction (53%) and returned to control levels at 8 and 12 weeks after surgery compared to Sham group (P<0.05). Brown adipose tissue (BAT) D2 activity (fmoles T4/min.mg ptn) was dramatically increased by approximately 77% in the 8th week and approximately 100% in the 12th week in the MI group compared to that of the Sham group (P<0.05). Beta-blocker treatment (propranolol given in the drinking water, 0.5 g/L) maintained a low T3 state in MI animals, dampening both BAT D2 activity (44% reduction) and serum T3 (66% reduction in serum T3) compared to that of the non-treated MI group 12 weeks after surgery (P<0.05). Propranolol improved cardiac function (assessed by echocardiogram) in MI group compared to MI-non treated one by 40 and 57 % 1 and 12 weeks after treatment respectively (P<0.05). Our data suggest that the beta-adrenergic pathway may contribute to BAT D2 hyperactivity and T3 normalization after MI in rats. Propranolol treatment maintains low T3 state and improves cardiac function additionally.
Yeast Ded1 promotes 48S translation pre-initiation complex assembly in an mRNA-specific and eIF4F-dependent manner
Authors: Gupta Neha , Lorsch Jon R. , Hinnebusch Alan G.
Published: June 2018

DEAD-box RNA helicase Dedl is thought to resolve secondary structures in mRNA 5′-untranslated regions (5′-UTRs) that impede 48S preinitiation complex (PIC) formation at the initiation codon. We reconstituted Ded1 acceleration of 48S PIC assembly on native mRNAs in a pure system, and recapitulated increased Ded1-dependence of mRNAs that are Ded1-hyperdependent in vivo. Stem-loop (SL) structures in 5′-UTRs of native and synthetic mRNAs increased the Ded1 requirement to overcome their intrinsically low rates of 48S PIC recruitment. Ded1 acceleration of 48S assembly was greater in the presence of eIF4F, and domains mediating one or more Ded1 interactions with eIF4G or helicase eIF4A were required for efficient recruitment of all mRNAs; however, the relative importance of particular Ded1 and eIF4G domains were distinct for each mRNA. Our results account for the Ded1 hyper-dependence of mRNAs with structure-prone 5′-UTRs, and implicate an eIF4E·eIF4G·eIF4A·Ded1 complex in accelerating 48S PIC assembly on native mRNAs.
Ensemble Feature Selection and Meta-Analysis of Cancer miRNA Biomarkers
Authors: Alejandro Lopez-Rincon , Marlet Martinez-Archundia , Gustavo Ulises Martinez-Ruiz , Alberto Tonda
Published: June 2018

The role of microRNAs (miRNAs) in cellular processes captured the attention of many researchers, since their dysregulation is shown to affect the cancer disease landscape by sustaining proliferative signaling, evading program cell death, and inhibiting growth suppressors. Thus, miRNAs have been considered important diagnostic and prognostic biomarkers for several types of tumors. Machine learning algorithms have proven to be able to exploit the information contained in thousands of miRNAs to accurately predict and classify cancer types. Nevertheless, extracting the most relevant miRNA expressions is fundamental to allow human experts to validate and make sense of the results obtained by automatic algorithms. We propose a novel feature selection approach, able to identify the most important miRNAs for tumor classification, based on consensus on feature relevance from high-accuracy classifiers of different typologies. The proposed methodology is tested on a real-world dataset featuring 8,129 patients, 29 different types of tumors, and 1,046 miRNAs per patient, taken from The Cancer Genome Atlas (TCGA) database. A new miRNA signature is suggested, containing the 100 most important oncogenic miRNAs identified by the presented approach. Such a signature is proved to be sufficient to identify all 29 types of cancer considered in the study, with results nearly identical to those obtained using all 1,046 features in the original dataset. Subsequently, a meta-analysis of the medical literature is performed to find references to the most important biomarkers extracted by the methodology. Besides known oncomarkers, 15 new miRNAs previously not ranked as important biomarkers for diagnosis and prognosis in cancer pathologies are uncovered. Such miRNAs, considered relevant by the machine learning algorithms, but still relatively unexplored by specialized literature, could provide further insights in the biology of cancer.
Nitrogen regulator GlnR directly controls transcription ofprpDBCoperon involved in methylcitrate cycle inMycobacterium smegmatis
Authors: Liu Xin-Xin , Liu Wei-Bing , Shen Meng-Jia , Ye Bang-Ce
Published: June 2018

Mycobacterium tuberculosisutilizes the fatty acids of the host as the carbon source. While the metabolism of odd chain fatty acids produces propionyl-CoA. Methylcitrate cycle is essential for Mycobacteria to utilize the propionyl-CoA to persist and grow on these fatty acids. InM. smegmatis, methylcitrate synthase, methylcitrate dehydratase, and methylisocitrate lyase involved in methylcitrate cycle were respectively encoded byprpC,prpD,and prpBin operonprpDBC. In this study, we found that the nitrogen regulator GlnR directly binds to the promoter region ofprpDBCoperon and inhibits its transcription. The typical binding sequence of GlnR was identified by bioinformatics analysis and electrophoretic mobility shift assay. The GlnR-binding motif was seperated by 164 bp with the binding site of PrpR which was a pathway-specific transcriptional activator of methylcitrate cycle. Moreover, the affinity constant of GlnR was much stronger than that of PrpR toprpDBC. The deletion ofglnRresulted in poor growth in propionate or cholesterol medium comparing with wild-type strain. The ΔglnRmutant strain also showed a higher survival in macrophages. These results illustrated that the nitrogen regulator GlnR regulated methylcitrate cycle through directly repressing the transcription ofprpDBCoperon. The finding reveals an unprecedented link between nitrogen metabolism and methylcitrate pathway, and provides a potential application for controlling populations of pathogenic mycobacteria.

Author Summary

Nutrients are crucial for the survival and pathogenicity ofMycobacterium tuberculosis. The success of this pathogen survival in macrophage due to its ability to assimilate fatty acids and cholesterol from host. The cholesterol and fatty acids are catabolized via β-oxidation to generate propionyl-CoA, which is then mainly metabolized via the methylcitrate cycle. The assimilation of propionyl-CoA needs to be tightly regulated to prevent its accumulation and alleviate toxicity in cell. Here, we identified a new regulator GlnR (the nitrogen transcriptional regulator) that repressed the transcription ofprpoperon involved in methylcitrate cycle inM. smegmatis. In this study, we found a typical GlnR binding box inprpoperon, and the affinity is much stronger than that of PrpR which is known as a pathway-specific transcriptional activator of methylcitrate cycle. In addition, deletion ofglnRobviously affect the growth of mutant in propionate or cholesterol medium, and show a better viability in macrophage. The findings not only provide the insights into the regulatory mechanism underlying crosstalk of nitrogen metabolism and carbon metabolism, but also reveal a potential application for controlling populations of pathogenic mycobacteria.
β-lactam Antibiotics Stimulate the Pathogenicity of Methicillin-resistant Staphylococcus aureus Via SarA-controlled Tandem Lipoprotein Expression
Authors: Shang Weilong , Rao Yifan , Zheng Ying , Yang Yi , Hu Qiwen , Hu Zhen , Yuan Jizhen , Peng Huagang , Xiong Kun , Tan Li , Li Shu , Zhu Junmin , Li Ming , Hu Xiaomei , Mao Xuhu , Rao Xiancai
Published: June 2018

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections worldwide. MRSA resists nearly all β-lactam antibiotics that have a bactericidal activity and a signal inducer effect. However, studies have yet to clarify whether the inducer effect of empirically used β-lactams stimulates MRSA pathogenicity in vivo. Here, we showed that a new cluster of tandem lipoprotein genes (tlpps) was upregulated in MRSA in response to the subinhibitory concentrations of β-lactam induction. The increased Tlpps significantly altered immune responses by macrophages with high IL-6 and TNFα levels. The deletion of the tlpps mutant (N315Δtlpps) significantly decreased the proinflammatory cytokine levels in vitro and in vivo. The bacterial loads of N315Δtlpps in the mouse kidney were also reduced compared with those of the wild type N315. The β-lactam-treated MRSA exacerbated cutaneous infections with increased lesion size, extended illness, and flake-like abscess-formation compared with those of the nontreatment. The β-lactam antibiotics that promoted the MRSA pathogenicity were SarA dependent, and the increasing expression of tlpps after β-lactam treatment was directly controlled by the global regulator SarA. Overall, our findings suggested that β-lactams should be used carefully because it might lead to a worse outcome of MRSA infection than inaction in the treatment.

Author summary

β-lactams are widely used in practice to treat infectious diseases, however, β-lactams worsening the outcome of a certain disease is poorly understood. In this study, we have identified a new cluster of tandem lipoprotein genes (tlpps) that is upregulated in the major clinically prevalent MRSA clones in response to the subinhibitory concentrations of β-lactams induction. The major highlight in this work is that β-lactams induce SarA expression, and then SarA directly binds to the tlpp cluster promoter region and upregulates the tlpp expression in MRSA. Moreover, the β-lactam stimulated Tlpps are important virulence factors that enhance MRSA pathogenicity. The deletion of the tlpps mutant significantly decreases the proinflammatory cytokine levels in vitro and in vivo. The β-lactam induced Tlpps enhance the host inflammatory responses by triggering the expression of IL-6 and TNFα, thereby promoting bacterial colonization and abscess formation. These data elucidate that β-lactams can worsen the outcome of MRSA infection through the induction of tlpps that are controlled by the global regulator SarA.
Pan-cancer systematic identification of lncRNAs associated with cancer prognosis
Authors: Ung Matthew H. , Schaafsma Evelien , Mattox Daniel E. , Wang George L. , Cheng Chao
Published: June 2018

The “dark matter” of the genome harbors several non-coding RNA species including IncRNAs, which have been implicated in neoplasias but remain understudied. RNA-seq has provided deep insights into the nature of lncRNAs in cancer but current RNA-seq data are rarely accompanied by longitudinal patient survival information. In contrast, a plethora of microarray studies have collected these clinical metadata that can be leveraged to identify novel associations between gene expression and clinical phenotypes. In this study, we developed an analysis framework that computationally integrates RNA-seq and microarray data to systematically screen 9,463 lncRNAs for association with mortality risk across 20 cancer types. In total, we identified a comprehensive list of associations between lncRNAs and patient survival and demonstrate that these prognostic lncRNAs are under selective pressure and may be functional. Our results provide valuable insights that facilitate further exploration of lncRNAs and their potential as cancer biomarkers and drug targets.
Isolation and Purification of Active Antimicrobial Peptides from Hermetia illucens L., and Its Effects on CNE2 Cells
Authors: Tian Zhong , Feng Qun , Sun Hongxia , Liao Ye , Du Lianfeng , Yang Rui , Li Xiaofei , Yang Yufeng , Xia Qiang
Published: June 2018

Active antimicrobial peptide HI-3 was isolated and purified from the 5th instar larvae of Hermetia illucens L., and its effects on proliferation, apoptosis and migration of nasopharyngeal carcinoma (CNE2) cells were investigated. The expressions of telomerase reverse transcriptase (hTERT) in CNE2 cells were also studied in vitro to elucidate the mechanism involved in the action of HI-3 on CNE2 cells. Results showed that three fractions (HI-1, HI-2, HI-3) were isolated from the hemolymph of H. illucens larvae. After purified by RP-HPLC, only HI-3 showed the inhibitory activities to four strains of bacteria. It was also showed that HI-3 could effectively inhibit the proliferation of CNE2 cells in a dose- and time-dependent manner. Apoptosis of CNE2 cells was observed in the treatment with 160 μg/ml HI-3, and the early apoptosis rate up to 27.59 ± 1.14%. However, no significantly inhibitory effects and apoptosis were found on human umbilical vein endothelial cells (HUV-C). Moreover, HI-3 could significantly reduce the migration ability of CNE2 cells when compared with that of the control. On the other hand, the levels of mRNA and protein of hTERT in the HI-3 treatment were all significantly lower than that of the control. Results indicated that HI-3 could inhibit the proliferation of CNE2 cells and induce the apoptosis of CNE2 cells by down-regulating the telomerase activity in CNE2 cells, while no obvious effect was occurred on HUV-C. It inferred that HI-3 is a potential anti-tumor drug with low toxicity to normal cells.

Summary Statement

An active antimicrobial peptide HI-3 was isolated and purified.

Inhibitory proliferation of CNE2 cells, but no effect on normal cells.

A potential antitumoral drug.
CDeep3M - Plug-and-Play cloud based deep learning for image segmentation of light, electron and X-ray microscopy
Authors: Haberl Matthias G , Churas Christopher , Tindall Lucas , Boassa Daniela , Phan Sebastien , Bushong Eric A , Madany Matthew , Akay Raffi , Deerinck Thomas J , Peltier Steven T , Ellisman Mark H
Published: June 2018

As biological imaging datasets increase in size, deep neural networks are considered vital tools for efficient image segmentation. While a number of different network architectures have been developed for segmenting even the most challenging biological images, community access is still limited by the difficulty of setting up complex computational environments and processing pipelines, and the availability of compute resources. Here, we address these bottlenecks, providing a ready-to-use image segmentation solution for any lab, with a pre-configured, publicly available, cloud-based deep convolutional neural network on Amazon Web Services (AWS). We provide simple instructions for training and applying CDeep3M for segmentation of large and complex 2D and 3D microscopy datasets of diverse biomedical imaging modalities.
Hair Follicle Epidermal Stem Cells Define a Niche for Tactile Sensation
Authors: Cheng Chun-Chun , Tsutsui Ko , Taguchi Toru , Sanzen Noriko , Nakagawa Asako , Kakiguchi Kisa , Yonemura Shigenobu , Tanegashima Chiharu , Keeley Sean D. , Kiyonari Hiroshi , Furuta Yasuhide , Tomono Yasuko , Watt Fiona M. , Fujiwara Hironobu
Published: June 2018

The heterogeneity and compartmentalization of stem cells is a common principle in many epithelia, and is known to function in epithelial maintenance, but its other physiological roles remain elusive. Here we show transcriptional and anatomical contributions of compartmentalized epidermal stem cells (EpSCs) in tactile sensory unit formation in the hair follicle (HF). EpSCs in the follicle upper-bulge, where mechanosensory lanceolate complexes (LCs) innervate, express a unique set of extracellular matrix (ECM) and neurogenesis-related genes. These EpSCs deposit an ECM protein EGFL6 into the collar matrix, a novel ECM that tightly ensheathes LCs. EGFL6 is required for the proper patterning, touch responses, and αv integrin-enrichment of LCs. By maintaining a quiescent original EpSC niche, the old bulge, EpSCs provide anatomically stable HF-LC interfaces, irrespective of the stage of follicle regeneration cycle. Thus, compartmentalized EpSCs provide a niche linking the HF and the nervous system throughout the hair cycle.
catena-Poly[[aqua(iminodiacetato-κ3
O,N,O′)nickel(II)]-μ-4,4′-dipyridylamine-κ2
N:N′]
Authors: Meyers Abigail E. , LaDuca Robert L.
Published: June 2018

In the title compound, [Ni(C4H5NO4)(C10H9N3)(H2O)]
n
, the NiII cations are octahedrally coordinated by an N atom donor and two O donor atoms belonging to a tridentate iminodiacetate (ida) ligand in a fac fashion, an O atom donor from an aqua ligand, and cis-disposed pyridyl N donor atoms from two 4,4′-dipyridylamine (dpa) ligands. The dpa ligands are disordered over two sets of sites in a 0.594 (7):0.406 (7) ratio. Through the bridging dpa ligands, [Ni(ida)(dpa)(H2O)]
n
zigzag coordination polymer chains are formed that are oriented along the b-axis direction. These chain motifs are anchored into the three-dimensional supramolecular crystal structure of the title compound by means of O—H...O and N—H...O hydrogen-bonding pathways.
Naphthalene-2,6-diyl bis(4-methylbenzenesulfonate)
Authors: Piontek Aleksandra , Siodłak Dawid , Zarychta Bartosz
Published: June 2018

The complete molecule of the title compound, C24H20O6S2, is generated by a crystallographic inversion centre at the middle of the naphthalene ring system. The dihedral angle between the naphthalene ring system and the pendant benzene ring is 10.23 (6)° and the C—S—O—C torsion angle is −172.05 (10)°. In the crystal, weak C—H...O interactions link the molecules into (10-1) sheets.
Economic impact of data localization in five selected African countries
Authors: Badran Mona Farid
Published: June 2018

Purpose

The purpose of this study is to quantify the impact of laws and regulations that govern the cross-border flow of data on the economies of five selected African countries, namely, Egypt, Morocco, South Africa, Kenya and Mauritius. Moreover, this study addresses the state of cloud computing in Africa. Finally, policy recommendations are provided in this respect.

Design/methodology/approach

To reach accurate finding the Global Trade Analysis Project (GTAP) data was used, and then the computable general equilibrium (CGE) was computed to estimate the total cost on the economy. Using the three data regulations linkages indexes (DRLs), the increased administrative cost effect was analyzed on five to six major economic sectors in the target countries. This was followed by estimating the loss in sector-wide total factor productivity (TFP) (for the five to six shortlisted sectors). Using this data, the computable general equilibrium model (CGE) was computed, in order to estimate the economy-wide impact. Based on these findings, a set of recommendations were offered to the policy maker, reflecting the obtained results and conclusions and their implications on drafting data-related policies.

Findings

The obtained data indexes reveal that Mauritius is the country with the most laws and regulations governing the cross border flow of data, followed by South Africa Egypt to a lesser extent and finally Morocco and Kenya both showing an obvious lack of data regulations. The small value of the estimated elasticity of the selected countries compared to the value of the estimated elasticity in the EU-0.347 shows that the impact of data localization is less in the selected African countries than in the other set of EU countries examined in the research paper. This is because the former has smaller economies with fewer linkages to the global economy and are less reliant on sectors that are heavy users of data. Thus, the overall impact of data localization was not as profound on TFP as is the case in advanced economies. This research paper arrives at the conclusion that fighting the trend of data localization is crucial. In fact, data localization hinders the necessary and essential role of global trade in realizing economic development. Specifically, this is evident in the increase in production costs as reflected in the increase of the prices of goods, which would lead to a decline in incomes.

Originality/value

Global studies looked at the impact of data localization on the EU, as well as China, India, Korea and Vietnam, providing some data on Asia Pacific. However, no study has ever been conducted on the Middle East and Africa. This study aims to fill this gap. The approach of this study is to capture the extent of data localization mandates encoded in the laws of each of the selected five African countries showing how these mandates govern their cross-border data flow and, in turn, affect their economies. Furthermore, the policy recommendations section of this research paper makes a contribution to the existing literature.
Breaking the triple lock: further education and transformative teaching and learning
Authors: Duckworth Vicky , Smith Rob
Published: June 2018

Purpose

The purpose of this paper is to explore data from the University and College Union (UCU) Further Education in England: Transforming Lives and Communities research project and through this the paper develops a distinctive, theorised conceptualisation of transformative teaching and learning (TTL).

Design/methodology/approach

The research used an approach grounded in critical pedagogy utilising digital methods, including video interviews, to collect narratives from learners, teachers, family members and their communities from colleges across Britain.

Findings

Within a context in which there are structural pressures militating in favour of instrumentalising students in further education, TTL offers a way of theorising it as a transformative critical space that restores students’ hope and agency. The research provides evidence of how further education offers this “differential space” (Lefebvre, 1991) and subverts the prescriptive, linear spaces of compulsory education. While productivist approaches to vocational education and training support ideologies that legitimate prescribed knowledge, reproducing inequality and injustice through the practices employed (Ade-Ojo and Duckworth, 2017; Duckworth and Smith, 2017b), TTL shifts to a more holistic approach, achieving a different level of engagement with students.

Practical implications

The findings suggest that the TTL lens is a way of focusing on the dignity, needs and agency of further education students. The lens allows us also to identify how the existing structures associated with funding and marketisation can undermine the potential of TTL to activate students’ agency through education.

Originality/value

Extending on existing literature around transformative learning, and drawing on a range of theoretical frameworks, the paper formulates a new, contextually specific conceptualisation of TTL.
Inverted totalitarianism in (post) postnormal accelerated dystopia: the arrival of Brave New World and 1984 in the twenty-first century
Authors: Morgan Dennis Ray
Published: June 2018

Purpose

This paper aims to depict how the state of inverted totalitarianism is emerging in post-postnormal times and illustrate how it shares many of the same features of the totalitarianism depicted in the novels Brave New World (A. Huxley) and 1984 (G. Orwell). It also shows how a “way forward” is possible through a paradigmatic reorientation of “well-being” and “happiness”.

Design/methodology/approach

The research is based on literature within the field of futures studies, as well as relevant sources outside the futures field. It applies R Slaughter’s critical futures and F Polak’s method of social critique and reconstruction in its analysis of the state of inverted totalitarianism in post postmodern times.

Findings

It finds that the technological society and the US empire (with its attendant corporatocracy, Panopticon and PAC man values) in post-postnormal times is drifting toward a state of inverted totalitarianism, which is remarkably beginning to resemble Aldous Huxley’s Brave New World and G. Orwell’s 1984.

Research limitations/implications

The research is an essay and conceptual paper, so it is limited by its conceptual, philosophical nature and the author’s interpretation of social phenomena. It could also include the latest research on the role that the manipulation of internet algorithms plays in the state of inverted totalitarianism. It could also include more reconstructive details.

Practical implications

Sheer consciousness of the state of inverted totalitarianism and the need for social reconstruction should lead to a reevaluation of the meaning of the good society and how to realize it.

Social implications

Social critique and reconstruction are essential to the survival of any given society or civilization, as the groundwork for the emergence of wise foresight. The creative minority of a civilization must understand its predicament, the nature of its civilizational crisis, before it can even begin to understand and meet the challenge of the future.

Originality/value

The paper presents post-postnormal times as the back drop through which a state of inverted totalitarianism is emerging – a social dystopia that resembles the dystopias depicted in the novels, Brave New World and 1984. Inverted totalitarianism is shown to be an outgrowth of the technological society and the American empire (a corporatocracy and Panopticon increasingly global in nature). Freedom from this emerging totalitarianism begins with the realization of its existence and its given assumptions about the meaning of life and the pursuit of happiness. The paper also posits social critique and reconstruction (as well as critical futures) as a fundamental method to deconstruct and reconstruct the paradigm that supports inverted totalitarianism.