bluuebunny/crossref_metadata_2025 huggingface dataset:
IFITM3 protects the heart during influenza virus infection
Authors: Kenney Adam D. , McMichael Temet M. , Imas Alexander , Chesarino Nicholas M. , Zhang Lizhi , Dorn Lisa E. , Wu Qian , Alfaour Omar , Amari Foued , Chen Min , Zani Ashley , Chemudupati Mahesh , Accornero Federica , Coppola Vincenzo , Rajaram Murugesan V.S. , Yount Jacob S.
Published: January 2019

Influenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferon-induced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.
Syntrophic co-culture amplification of production phenotype for high-throughput screening of microbial strain libraries
Authors: Saleski Tatyana E. , Kerner Alissa R. , Chung Meng Ting , Jackman Corine M. , Khasbaatar Azzaya , Kurabayashi Katsuo , Lin Xiaoxia Nina
Published: January 2019

Microbes can be engineered to synthesize a wide array of bioproducts, yet production phenotype evaluation remains a frequent bottleneck in the design-build-test cycle where strain development requires iterative rounds of library construction and testing. Here, we presentSyntrophicCo-cultureAmplification ofProduction phenotype (SnoCAP). Through a metabolic cross-feeding circuit, the production level of a target molecule is translated into highly distinguishable co-culture growth characteristics, which amplifies differences in production into highly distinguishable growth phenotypes. We demonstrate SnoCAP with the screening ofEscherichia colistrains for production of two target molecules: 2-ketoisovalerate, a precursor of the drop-in biofuel isobutanol, and L-tryptophan. The dynamic range of the screening can be tuned by employing an inhibitory analog of the target molecule. Screening based on this framework requires compartmentalization of individual producers with the sensor strain. We explore three formats of implementation with increasing throughput capability: confinement in microtiter plates (102-104assays/experiment), spatial separation on agar plates (104-105assays/experiment), and encapsulation in microdroplets (105-107assays/experiment). Using SnoCAP, we identified an efficient isobutanol production strain from a random mutagenesis library, reaching a final titer that is 5-fold higher than that of the parent strain. The framework can also be extended to screening for secondary metabolite production using a push-pull strategy. We expect that SnoCAP can be readily adapted to the screening of various microbial species, to improve production of a wide range of target molecules.

Highlights

A high-throughput screening platform based on cross-feeding auxotrophs was developed.

Compartmentalization was implemented in three formats: microplates, agar plates, and microdroplets.

Utility of the screening was demonstrated for two proof-of-concept target molecules: 2-ketoisovalerate and L-tryptophan.

The assay dynamic range was tuned by addition of an inhibitory analog.

The screening was applied to identify a strain from a chemically mutagenized library that produces 5-fold higher isobutanol titer than the parent strain.
MetFish: A Metabolomics Platform for Studying Microbial Communities in Chemically Extreme Environments
Authors: Xu Chengdong , Couvillion Sneha P. , Sontag Ryan L. , Isern Nancy G. , Maezato Yukari , Lindemann Stephen R. , Chowdhury Taniya Roy , Zhao Rui , Morton Beau R. , Moore Ronald J. , Jansson Janet K. , Bailey Vanessa L. , Mouser Paula J. , Romine Margaret F. , Fredrickson James F. , Metz Thomas O.
Published: January 2019

Metabolites have essential roles in microbial communities, including as mediators of nutrient and energy exchange, cell-to-cell communication, and antibiosis. However, detecting and quantifying metabolites and other chemicals in samples having extremes in salt or mineral content using liquid chromatography-mass spectrometry (LC-MS)-based methods remains a significant challenge. Here we report a facile method based onin situchemical derivatization followed by extraction for analysis of metabolites and other chemicals in hypersaline samples, enabling for the first time direct LC-MS-based exo-metabolomics analysis in sample matrices containing up to 2 molar total dissolved salts. The method, MetFish, is applicable to molecules containing amine, carboxylic acid, carbonyl, or hydroxyl functional groups, and can be integrated into either targeted or untargeted analysis pipelines. In targeted analyses, MetFish provided limits of quantification as low as 1 nM, broad linear dynamic ranges (up to 5-6 orders of magnitude) with excellent linearity, and low median inter-day reproducibility (e.g. 2.6%). MetFish was successfully applied in targeted and untargeted exo-metabolomics analyses of microbial consortia, quantifying amino acid dynamics in the exo-metabolome during community succession;in situin a native prairie soil, whose exo-metabolome was isolated using a hypersaline extraction; and in input and produced fluids from a hydraulically fractured well, identifying dramatic changes in the exo-metabolome over time in the well.
Evolution of asymmetric gamete signaling and suppressed recombination at the mating type locus
Authors: Hadjivasiliou Zena , Pomiankowski Andrew
Published: January 2019

The two partners required for sexual reproduction are rarely the same. This pattern extends to species which lack sexual dimorphism yet possess self-incompatible gametes determined at mating-type regions of suppressed recombination, likely precursors of sex chromosomes. Here we investigate the role of cellular signaling in the evolution of mating-types. We develop a model of ligand-receptor dynamics within cells, and identify factors that determine the capacity of cells to send and receive signals. The model specifies conditions favoring the evolution of gametes producing ligand and receptor asymmetrically and shows how these are affected by recombination. When the recombination rate can evolve, the conditions favoring asymmetric signaling also favor tight linkage of ligand and receptor loci in distinct linkage groups. These results suggest that selection for asymmetric signaling between gametes was the first step in the evolution of non-recombinant mating-type loci, paving the road for the evolution of anisogamy and sexes.
BDNF/TrkB.T1 signaling is a novel mechanism for astrocyte morphological maturation
Authors: Holt Leanne M. , Pacheco Natasha L. , Hernandez Raymundo , Hossain Muhannah , Olsen Michelle L.
Published: January 2019

Brain derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of neurons, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF’s receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1 which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1 in vivo revealed morphologically immature astrocytes with significantly reduced volume and branching, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte functions, including synaptogenic genes. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.
A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm
Authors: Britton George , Heemskerk Idse , Hodge Rachel , Qutub Amina A , Warmflash Aryeh
Published: January 2019

During development, the ectoderm is patterned by a combination of BMP and WNT signaling. Research in model organisms has provided substantial insight, however, there are currently no systems to study this patterning in humans. Further, the complexity of neural plate border specification has made it difficult to transition from discovering the genes involved to deeper mechanistic understanding. Here, we develop anin vitromodel of human ectodermal patterning, in which hESCs self-organize to form robust and quantitatively reproducible patterns corresponding to the dorsal-ventral axis of the embryo. Using this platform, we show that the duration of endogenous WNT signaling is a crucial control parameter, and that cells sense relative levels of BMP and WNT signaling in making fate decisions. These insights allowed us to develop an improved protocol for placodal differentiation. Thus, our platform is a powerful tool for studying human ectoderm patterning and for improving directed differentiation protocols.
Kin-dependent dispersal influences relatedness and genetic structuring in a lek system
Authors: Cayuela Hugo , Boualit Laurent , Laporte Martin , Prunier Jérôme G. , Preiss Françoise , Laurent Alain , Foletti Francesco , Clobert Jean , Jacob Gwenaël
Published: January 2019

Kin selection and dispersal play a critical role in the evolution of cooperative breeding systems. Limited dispersal dramatically increases relatedness in spatially structured populations (population viscosity), with the result that neighbours tend to be genealogical relatives. Yet the increase in neighbours’ performance through altruistic interaction may also result in habitat saturation and thus exacerbate local competition between kin. Our goal was to detect the footprint of kin selection and competition by examining the spatial structure of relatedness and by comparing non-effective and effective dispersal in a population of a lekking bird,Tetrao urogallus. For this purpose, we analysed capture–recapture and genetic data collected over a 6-year period on a spatially structured population ofT. urogallusin France. Our findings revealed a strong spatial structure of relatedness in males. They also indicated that the population viscosity allowed male cooperation through two non-exclusive mechanisms. First, at their first lek attendance, males aggregate in a lek composed of relatives. Second, the distance corresponding to non-effective dispersal dramatically outweighed effective dispersal distance, which suggests that dispersers incur high post-settlement costs. These two mechanisms result in strong population genetic structuring in males. In females, our findings revealed a lower level of spatial structure of relatedness and genetic structure in respect to males. Additionally, non-effective dispersal and effective dispersal distances in females were highly similar, which suggests limited post-settlement costs. These results indicate that kin-dependent dispersal decisions and costs are factors driving the evolution of cooperative courtship and have a genetic footprint in wild populations.
Diversity decoupled from sulfur isotope fractionation in a sulfate reducing microbial community
Authors: Colangelo Jesse , Pelikan Claus , Herbold Craig W. , Altshuler Ianina , Loy Alexander , Whyte Lyle G. , Wing Boswell A.
Published: January 2019

The extent of fractionation of sulfur isotopes by sulfate reducing microbes is dictated by genomic and environmental factors. A greater understanding of species-specific fractionations may better inform interpretation of sulfur isotopes preserved in the rock record. To examine whether gene diversity influences net isotopic fractionationin situ, we assessed environmental chemistry, sulfate reduction rates, diversity of putative sulfur metabolizing organisms by 16SrRNAand dissimilatory sulfite reductase (dsrB) gene amplicon sequencing, and net fractionation of sulfur isotopes along a sediment transect of a hypersaline Arctic spring.In situsulfate reduction rates yielded minimum cell-specific sulfate reduction rates <0.3 x 10−15moles cell−1day−1. Neither 16SrRNAnordsrBdiversity indices correlated with relatively constant (38 to 45‰) net isotope fractionation (ε34Ssulfide−sulfate). Measured ε34S values could be reproduced in a mechanistic fractionation model if 1-2% of the microbial community (10-60% of Deltaproteobacteria) were engaged in sulfate respiration, indicating heterogeneous respiratory activity within sulfate-metabolizing populations. This model indicated enzymatic kinetic diversity of Apr was more likely to correlate with sulfur fractionation than DsrB. We propose that, above a threshold alpha diversity value, the influence of the specific composition of the microbial community responsible for generating an isotope signal is overprinted by the control exerted by environmental variables on microbial physiology.

Subject categories

Integrated genomics and post-genomics approaches in microbial ecology

Microbial ecology and functional diversity of natural habitats
Prefrontal-posterior coupling mediates emotion transitions and their influence on executive function
Authors: Hao Yu , Yao Lin , Smith Derek. M. , Sorel Edward , Anderson Adam K. , Schumacher Eric H. , Evans Gary W.
Published: January 2019

Although emotions often result from dynamic experiences with self-regulation unfolding over time, most research has focused on responses to affective stimuli from a rather static perspective. We studied and analyzed emotion transitions, attempting to reveal brain functions related to affect dynamics. EEG responses were examined during exposure to stable versus changing emotion-eliciting images (static vs dynamic conditions) plus their impact on executive function (EF) assessed with the flanker task. During dynamic conditions, reduced prefrontal to posterior EEG coherence in the beta frequency band and greater left frontal activity occurred compared to the static conditions. Among individuals suffering higher chronic stress, subsequent EF was hindered after dynamic conditions. Furthermore, the adverse effects of emotion transitions on EF for more chronically stressed individuals were mediated by prefrontal-posterior coherence in low beta frequency band during emotional image sequences. Emotion appears to influence EF through changes in large-scale synchronization. Individuals high in chronic stress are vulnerable to these effects.
Short Tandem Repeats Information in TCGA is Statistically Biased by Amplification
Authors: Jain Siddharth , Mazaheri Bijan , Raviv Netanel , Bruck Jehoshua
Published: January 2019

The current paradigm in data science is based on the belief that given sufficient amounts of data, classifiers are likely to uncover the distinction between true and false hypotheses. In particular, the abundance of genomic data creates opportunities for discovering disease risk associations and help in screening and treatment. However, working with large amounts of data is statistically beneficial only if the data is statistically unbiased. Here we demonstrate that amplification methods of DNA samples in TCGA have a substantial effect on short tandem repeat (STR) information. In particular, we design a classifier that uses the STR information and can distinguish between samples that have an analyte code D and an analyte code W. This artificial bias might be detrimental to data driven approaches, and might undermine the conclusions based on past and future genome wide studies.
Aphids can acquire the nitrogen delivered to plants by arbuscular mycorrhizal fungi
Authors: Wilkinson Thomas D. J. , Ferrari Julia , Hartley Sue E. , Hodge Angela
Published: January 2019

Above‐ and below‐ground organisms can interact by altering the quality of shared host plants. Arbuscular mycorrhizal fungi (AMF) influence plant nutrient uptake, including nitrogen (N) acquisition. Under low N and phosphorus conditions, AMF delivery of N from organic sources not immediately available to the plant can have large impacts on plant N status, a limiting nutrient in the aphid diet.

This study investigated the effect of AMF colonisation upon aphid number and determined the consequences of AMF directly accessing an organic nutrient patch that the plant cannot. We hypothesised that AMF colonisation of plants will increase plant and aphid N status, plant performance and aphid number, but only when the AMF had direct access to the added organic patch.

Barley plants hosting the grain aphid Sitobion avenae were colonised by the AMF, Funneliformis mosseae, or no AMF. A two‐compartment microcosm was used to separate the plant roots from a 15N‐labelled organic patch in a second compartment. AMF‐colonised plants, but without access to the second compartment, were used to examine the effect of AMF colonisation on aphid number. In a separate treatment, and to determine whether AMF access to a plant inaccessible N source modified the effect of AMF colonisation on aphid number, AMF hyphae were permitted access to the second compartment containing an organic patch. As a control for AMF accessing a larger substrate volume, AMF were allowed access to a second compartment without an organic patch.

When the AMF accessed the organic patch, more N from the patch was delivered to the plant resulting in a higher grain N concentration although plant growth was depressed. More N from the patch was also delivered to the aphids, but the N status of the aphid remained unchanged. Regardless of the level of access to the organic patch, AMF colonisation did not affect aphid number.

Our data show that by accessing N sources not readily available to plants, AMF can indirectly deliver N to above‐ground organisms, a finding which has major implications for N‐transfer between higher trophic levels.

A plain language summary is available for this article.
Nutrient starvation impairs the trophic plasticity of reef‐building corals under ocean warming
Authors: Ezzat Leïla , Maguer Jean‐François , Grover Renaud , Rottier Cécile , Tremblay Pascale , Ferrier‐Pagès Christine
Published: January 2019

Global warming of the world's oceans is driving reef‐building corals towards their upper thermal limit, inducing bleaching, nutrient starvation and mortality. In addition, corals are predicted to experience large fluctuations in seawater nutrient concentrations, following water column stratification or eutrophication problems, which can further alter their nutritional capacities and ultimately their resilience to global change.

We investigated the effect of thermal stress and dissolved inorganic nutrient (DINUT) availability on the auto‐ and heterotrophic nutritional capacities of corals. In particular, we assessed the effect of nitrogen enrichment or DINUT depletion (both in nitrogen and in phosphorus) on the assimilation of heterotrophic nutrients and on the heat‐stress tolerance of the reef‐building coralStylophora pistillata.

Here, we show that DINUT depletion enhanced coral bleaching under thermal stress and more importantly, significantly impaired rates of heterotrophic nutrient assimilation, inducing coral starvation. In contrast, corals grown under nitrogen enrichment maintained high rates of heterotrophic nutrient assimilation and avoided bleaching, although nutrient uptake rates were lowered. We therefore observed a positive coupling between auto‐ and heterotrophy within the coral–dinoflagellate symbiosis, indicating that heterotrophic processes require a minimum of autotrophically acquired nutrients to be functional.

These findings show that the trophic plasticity of corals directly depends on the availability of dissolved inorganic nutrients in seawater. The lack of a shift towards greater heterotrophy under DINUT depletion may lead to substantial modifications of the role that feeding plays in the response of reef‐building corals to climate change.

Aplain language summaryis available for this article.
Active buoyancy adjustment increases dispersal potential in benthic marine animals
Authors: Hamel Jean‐François , Sun Jiamin , Gianasi Bruno L. , Montgomery Emaline M. , Kenchington Ellen L. , Burel Benoit , Rowe Sherrylynn , Winger Paul D. , Mercier Annie
Published: January 2019

While the study of dispersal and connectivity in the ocean typically centres on pelagic species and planktonic larval stages of benthic species, the present work explores an overlooked locomotor means in post‐settlement benthic stages that redefines their dispersal potential.

Members of the echinoderm class Holothuroidea colonize a diversity of marine environments world‐wide, where they play key ecological and economical roles, making their conservation a priority. Holothuroids are commonly called sea cucumbers or sea slugs to reflect their slow movements and are assumed to disperse chiefly through pelagic larvae.

The present study documents and explores their unexpected ability to actively modify their buoyancy, leading them to tumble or float at speeds orders of magnitudes faster than through benthic crawling. Two focal species representing different taxonomic orders, geographic distributions and reproductive strategies were studied over several years.

Active buoyancy adjustment (ABA) was achieved through a rapid increase in water‐to‐flesh ratio by up to 740%, leading to bloating, and simultaneously detachment from the substrate. It occurred as early as 6 months post settlement in juveniles and was recorded in wild adult populations. In experimental trials, ABA was triggered by high conspecific density, decreasing salinity and increasing water turbidity. Based on field video footage, ABA‐assisted movements generated speeds of up to 90 km/day.

These findings imply that displacement during planktonic larval stages may not supersede the locomotor capacity of benthic stages, challenging the notion of sedentarity. Combining the present results and anecdotal reports, ABA emerges as a generalized means of dispersal among benthic animals, with critical implications for world‐wide management and conservation of commercially and ecologically significant species.
Foreign impact on geography in China through translation over the past 100 years
Authors: Sun Jun , Wu Youde , Pan Yujun , Lei Xiangyang
Published: January 2019

Through a study of the publication data about translations in the field of geography in China from 1900 to 2017, this paper discusses translation as an inherent factor implying foreign geography's impact on modernising and promoting geography in China. The progress of geographical translation in China has been circuitous and arduous, and can be classified into four distinct yet interconnected phases according to the four‐fold aspects of growth, dominant origin, main field of the translations, and proportion of translations among the selected published works. Although translation has been so ubiquitous in Chinese geography that it seems the impact of foreign geography is inescapable, “impact” cannot be equal to translation. With that in mind, indicators including the number and proportion of translations, the import and absorption of translations, the intertwined variation of translations from various countries in different fields and phases, and the social and political contexts in China are considered. The discussion demonstrates that the role of translation in the growth of geography in China changed situationally, and translation implied not only a “foreign impact” but also a “domestic remodelling” of the discipline. Although the status of geography in China is very different from what it used to be, this conclusion suggests that “importing” quality work is necessary for the further promotion of Chinese geography.
Cefuroxime plasma and tissue concentrations in patients undergoing elective cardiac surgery: Continuous vs bolus application. A pilot study
Authors: Skhirtladze‐Dworschak Keso , Hutschala Doris , Reining Georg , Dittrich Peter , Bartunek Anna , Dworschak Martin , Tschernko Edda M.
Published: January 2019

Aims

Surgical site infections contribute to morbidity and mortality after surgery. The authors hypothesized that higher antibiotic tissue concentrations can be reached for a prolonged time span by continuous administration of prophylactic cefuroxime compared to bolus administration.

Methods

Twelve patients undergoing elective cardiac surgery were investigated. Group A received 1.5 g cefuroxime as bolus infusions before surgery, and 12 and 24 hours thereafter. In group B, a continuous infusion of 3.0 g cefuroxime was started after a bolus of 1.5 g. Cefuroxim levels were determined in blood and tissue (microdialysis). T‐test, Wilcoxon signed rank test and χ2 test were used for statistical analysis.

Results

The area under the curve (AUC) of plasma cefuroxime concentrations was greater in group B (399 [333–518]) as compared to group A (257 [177–297] h mg L−1, [median and interquartile range], P = .026). Furthermore, a significantly longer percentage of time > minimal inhibitory concentrations of 2 mg L−1 (100% vs 50%), 4 mg L−1 (100% vs 42%), 8 mg L−1 (100% vs 17%) and 16 mg L−1 (83% vs 8%) was found for free plasma cefuroxime in group B. In group B, area under the curve in subcutaneous tissue (78 [61–113] h mg L−1) and median peak concentration (33 [26–38] mg L−1) were markedly higher compared to group A (P = 0.041 and P = .026, respectively).

Conclusions

Higher cefuroxime concentrations were measured in plasma and subcutaneously over a prolonged period of time when cefuroxime was administered continuously. The clinical implication of this finding still has to be elucidated.
Sildenafil, a phosphodiesterase type 5 inhibitor, augments sphincter bursting and bladder afferent activity to enhance storage function and voiding efficiency in mice
Authors: Ito Hiroki , Chakrabarty Basu , Drake Marcus J. , Fry Christopher H. , Kanai Anthony J. , Pickering Anthony E.
Published: January 2019

Objectives

To investigate the influence of low‐dose sildenafil, a phosphodiesterase type 5 inhibitor (PDE5‐I), on the function of the mouse lower urinary tract (LUT).

Materials and Methods

Adult male mice were decerebrated and arterially perfused with a carbogenated Ringer's solution to establish the decerebrate arterially perfused mouse (DAPM). To allow distinction between central neural and peripheral actions of sildenafil, experiments were conducted in both the DAPM and in a ‘pithed’ DAPM, which has no functional brainstem or spinal cord. The action of systemic and intrathecal sildenafil on micturition was assessed in urethane‐anaesthetised mice.

Results

In the DAPM, systemic perfusion of sildenafil (30 pm) decreased the voiding threshold pressure [to a mean (sem) 84.7 (3.8)% of control] and increased bladder compliance [to a mean (sem) 140.2 (8.3)% of control, an effect replicated in the pithed DAPM]. Sildenafil was without effect on most voiding variables but significantly increased the number of bursts of the external urethral sphincter (EUS) per void in DAPM [to a mean (sem) 130.1 (6.9)% of control at 30 pm] and in urethane‐anaesthetised mice [to a mean (sem) 117.5 (5.8)% of control at 14 ng/kg]. Sildenafil (10 and 30 pm) increased pelvic afferent activity during both bladder filling and the isovolumetric phase [to a mean (sem) 205.4 (30.2)% of control at 30 pm]. Intrathecal application of sildenafil (5 μL of either 150 pm or 1.5 nm) did not alter cystometry and EUS‐electromyography variables in urethane‐anaesthetised mice.

Conclusions

Low‐dose sildenafil increases bladder compliance, increases pelvic nerve afferent activity, and augments the bursting activity of the EUS. We propose that the novel actions on afferent traffic and sphincter control may contribute to its beneficial actions to restore storage and voiding efficiency in LUT dysfunction.
Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway
Authors: Qi Jianguo , Huang Jing , Zhou Xiaomin , Luo Wen , Xie Jiaxin , Niu Linqiang , Yan Zhijie , Luo Yang , Men Yuhui , Chen Yanan , Zhang Yahong , Wang Jianhong
Published: January 2019

A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC50 in the range of 0.19–0.51 μM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose‐dependent manner. Western blot analysis showed that compound 12 induced up‐regulation of p21 and affected the expression of cell cycle‐related proteins. The binding mode was also probed by molecular docking.
Constitutional mosaicism in RASA1‐related capillary malformation‐arteriovenous malformation
Authors: Gordo Gema , Rodriguez‐Laguna Lara , Agra Noelia , Mendez Pilar , Feito Marta , Lapunzina Pablo , Lopez‐Gutierrez Juan C. , Martinez‐Glez Victor
Published: January 2019

Capillary malformation‐arteriovenous malformation (CM‐AVM) is caused by germline RASA1 and EPHB4 alterations. RASA1 intralesional second hits have also been reported. Here we report RASA1 constitutional mosaicism, defined here as the presence of a mosaic variant in all cell types of an individual, in two patients with CM‐AVM. High‐throughput sequencing was used to search for RASA1 pathogenic variants in blood samples from two unrelated patients with CM‐AVM. An affected tissue sample from one of the patients was also analyzed. Both patients showed different nonsense RASA1 variants in mosaic, ranging from 7% to 21.5%, in blood samples and in the corresponding affected tissue sample from one of the patients. In conclusion, we report for the first time the presence of RASA1 constitutional mosaicism in CM‐AVM. Constitutional mosaicism has implications for accurate molecular diagnosis and recurrence risk and helps to explain the great phenotypic variability in CM‐AVM.
Bone response to porous tantalum implants in a gap‐healing model
Authors: Fraser David , Mendonca Gustavo , Sartori Elisa , Funkenbusch Paul , Ercoli Carlo , Meirelles Luiz
Published: January 2019

Objectives

The objective of this study was to determine the relative osteogenic behavior of titanium implants with or without a porous tantalum modification when placed with a gap between the implant and existing bone.

Materials and Methods

A gap‐healing model in the rabbit tibia was used for placement of titanium implants. Forty‐eight rabbits received 96 implants, with 48 of the implants containing a porous tantalum middle section and the remaining 48 implants were composed of solid titanium. After 4, 8, and 12 weeks of healing, biomechanical stability was measured with removal torque testing, implant‐adherent cells were isolated for analysis of osteogenic gene expression, and histomorphometric analysis was performed on sections of the implants and surrounding bone.

Results

Increased osteogenic activity at 4 weeks was demonstrated by upregulation of key osteogenic genes at implants containing porous tantalum which was accompanied by greater bone–implant contact at 4, 8, and 12 weeks and significantly greater removal torque at 8 and 12 weeks.

Conclusions

Implants containing porous tantalum demonstrated increased peri‐implant bone formation within this gap‐healing model as shown by significant differences in biomechanical and histomorphometric outcomes. Such implants may represent an alternative to influence bone healing in surgical sites with an existing gap.
The correlation between conventional coagulation tests and thromboelastography in each phase of liver transplantation
Authors: Yoon Ji‐Uk , Cheon Ji‐Hyun , Choi Yoon Ji , Byeon Gyeong‐Jo , Ahn Ji‐Hye , Choi Eun‐Ji , Park Ju Yeon
Published: January 2019

Introduction

Thromboelastography (TEG) is gaining increasing acceptance in liver transplantation (LT) with conventional coagulation tests (CCTs) such as prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III (ATIII), platelet count (PLT), and fibrinogen concentration. The purpose of this study was to evaluate the clinical utility of TEG in LT and investigate the correlation between TEG and CCT values during each phase of LT.

Materials and Methods

Medical records of patients who underwent deceased donor LT at a single, university hospital between October 2010 and July 2015 were retrospectively reviewed. Blood samples were obtained at each phase of LT (pre‐anhepatic, anhepatic, and neo‐hepatic phase) according to our institutional LT protocol and utilized for analysis of TEG and CCTs. The Spearman correlation coefficient between TEG and CCT values were obtained.

Results

During the pre‐anhepatic phase, the reaction time (R), PT, and aPTT did not correlate with each other, but demonstrated a negative correlation with PLT. Clot formation time (K) demonstrated a similar correlation with R and a negative correlation with fibrinogen. The maximal amplitude (MA) and α‐angle (α) were positively correlated with PLT and fibrinogen and inversely correlated with aPTT. During the anhepatic phase, MA was significantly correlated with PLT and inversely correlated with aPTT; other parameters had weak or indistinct correlation. During the neo‐hepatic phase, R and K were significantly correlated with aPTT and inversely correlated with PLT and fibrinogen. A correlation of MA and α with PLT, aPTT, and fibrinogen was also observed. Clot lysis at 30 minutes and estimated percent lysis were inversely correlated with levels of ATIII and fibrinogen.

Conclusions

Conventional coagulation tests and TEG show particularly poor comparability during the anhepatic period of liver transplantation. TEG can be most reliable in the anhepatic phase, during which dynamic hemostatic changes occur.
Volume of motor area predicts motor impulsivity
Authors: Ai Hui , Xin Yuanyuan , Luo Yue-jia , Gu Ruolei , Xu Pengfei
Published: January 2019

Impulsivity is a personality trait associated with many maladaptive behaviors. Trait impulsivity is typically divided into three different dimensions, including attentional impulsiveness, motor impulsiveness, and non‐planning impulsiveness. In the present study, we examined the neuroanatomical basis of the multidimensional impulsivity trait. Eighty‐four healthy participants were studied with structural magnetic resonance imaging. Multiple regression analyses revealed that the score of motor impulsiveness was negatively correlated with gray matter volumes of the right supplementary motor area and paracentral lobule. A machine‐learning‐based prediction analysis indicated that decreased gray matter volumes of the supplementary motor area and paracentral lobule strongly predicted the decrease in motor impulsiveness control. Our findings provide insights into the predictive role of motor brain structures in motor impulsivity and inhibition control.
Melanoma types by in vivo reflectance confocal microscopy correlated with protein and molecular genetic alterations: A pilot study
Authors: Beretti Francesca , Bertoni Laura , Farnetani Francesca , Pellegrini Cristina , Gorelli Greta , Cesinaro Anna Maria , Reggiani Bonetti Luca , Di Nardo Lucia , Kaleci Shaniko , Chester Johanna , Longo Caterina , Massi Daniela , Fargnoli Maria C. , Pellacani Giovanni
Published: January 2019

Cutaneous melanoma (CM) is one of the most prevalent skin cancers, which lacks both a prognostic marker and a specific and lasting treatment, due to the complexity of the disease and heterogeneity of patients. Reflectance confocal microscopy (RCM) in vivo analysis is a versatile approach offering immediate morphological information, enabling the identification of four primary cutaneous RCM CM types. Whether RCM CM types are associated with a specific protein and molecular genetic profiles at the tissue level remains unclear. The current pilot study was designed to identify potential correlations between RCM CM types and specific biological characteristics, combining immunohistochemistry (IHC) and molecular analyses. Eighty primary CMs evaluated at patient bedside with RCM (type 1 [19, 24%], type 2 [12, 15%], type 3 [7, 9%] and type 4 [42, 52%]) were retrospectively evaluated by IHC stains (CD271, CD20, CD31, cyclin D1), fluorescence in situ hybridization FISH for MYC gain and CDKN2A loss and molecular analysis for somatic mutations (BRAF, NRAS and KIT). RCM CM types correlated with markers of stemness property, density of intra‐tumoral lymphocytic B infiltrate and cyclin D1 expression, while no significant association was found with blood vessel density nor molecular findings. RCM CM types show a different marker profile expression, suggestive of a progression and an increase in aggressiveness, according to RCM morphologies.
Vitiligo as a skin memory disease: The need for early intervention with immunomodulating agents and a maintenance therapy to target resident memory T cells
Authors: Boniface Katia , Seneschal Julien
Published: January 2019

The understanding of the immune mechanisms of vitiligo has profoundly improved over the past years. The recent discovery of a new population of antigen‐experienced memory T cells called resident memory T cells (TRM) has changed the concept of immune surveillance in peripheral tissue as skin, and the presence of melanocyte‐specific TRM is clearly demonstrated in vitiligo, a disease that could be now seen such as a memory skin disease. This review summarizes the recent knowledge on skin TRM and their role in vitiligo. Future management or therapies for this disease will have the goal to block their migration/differentiation, to dampen their activation and/or their accumulation in the vitiligo skin to prevent flare‐up or to promote repigmentation.
Hypoxia‐related carbonic anhydrase IX expression is associated with unfavourable response to first‐line therapy in classical Hodgkin's lymphoma
Authors: Méhes Gábor , Matolay Orsolya , Beke Livia , Czenke Marianna , Jóna Ádám , Miltényi Zsofia , Illés Árpád , Bedekovics Judit
Published: January 2019

Aims

The present study evaluates the impact of hypoxia‐related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralise intracellular acidosis in classical Hodgkin's lymphoma (cHL).

Methods and results

Eighty‐one primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analysed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia‐related histological and functional data with survival characteristics. Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin–Reed–Sternberg (HRS) cells in 39 of 81 samples (48.1%), while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS cells could be demonstrated in only 18 of 77 samples (23.4%), with significant stromal positivity (50 of 77, 64.9%). The CAIX+ positive phenotype was strongly associated with lymphocyte depletion (four of four, 100%) and nodular sclerosis (29 of 51, 56.9%) subtypes. CAIX/Ki‐67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX+ positive compared to CAIX− negative HRS cells (P < 0.001). Seventy‐two months’ progression‐free survival (PFS) was significantly lower for the CAIX positive group (0.192) compared with the CAIX negative group (0.771) (P < 0.001), while the overall survival (OS) did not differ (P = 0.097).

Conclusion

Hypoxic stress‐related adaptation – highlighted by CAIX expression – results in cellular quiescence in HRS cells, potentially contributing to the short‐term failure of the standard chemotherapy in cHL.
Neoadjuvant chemoradiation for patients with advanced oesophageal cancer – which response grading system best impacts prognostic discrimination?
Authors: Puetz Katharina , Bollschweiler Elfriede , Semrau Robert , Mönig Stefan P , Hölscher Arnulf H , Drebber Uta
Published: January 2019

Aims

Neoadjuvant chemoradiation reduces tumour volume and improves the R0 resection rate, followed by extended survival for patients with advanced oesophageal cancer. The degree of tumour regression has high prognostic relevance. To date, there is still no generally accepted tumour regression grading system. The aim of this study was to compare the prognostic discrimination power of different histological regression grading systems: (i) the fibrosis/tumour ratio within the primary tumour (Mandard classification), (ii) the percentage of residual vital tumour cells (VTC) compared to the original primary tumour (Cologne Regression) and (iii) the ypT category, in patients with cT3 carcinoma of the oesophagus after neoadjuvant chemoradiation.

Methods and results

This study included 216 patients with oesophageal cancer clinically staged as cT3NxM0 and treated from 2009 to 2012 with standardised chemoradiation followed by oesophagectomy [median age 62 years, 176 (81%) male and 138 (64%) adenocarcinoma patients]. The subgroup frequencies of the three classification systems were ypT category: ypT0 = 18%, ypT1 = 14%, ypT2 = 23%, ypT3 = 44%, ypT4 = 1%; Mandard classification: TRG1 = 18%, TRG2 = 26%, TRG3 = 24%, TRG4 = 30%, TRG5 = 2%; and Cologne Regression Scale: no tumour = 18%, 1–10% VTC = 27%, 10–50% VTC = 26% and >50% VTC = 29%. The Mandard and Cologne Regression classifications showed better prognostic differentiation for the subgroups than the ypT category. The four‐tiered Cologne Regression system had a good prognostic relevance. Comparing results of the re‐evaluated Cologne Regression classification with the classification by routine pathological report showed very good inter‐rater agreement, with kappa value 0.891.

Conclusion

Compared to the original primary tumour, the tumour regression grading system using the percentage of residual vital tumour has prognostic relevance.
Predator density influences nest attendance of Yellow‐headed BlackbirdsXanthocephalus xanthocephalus
Authors: Behrens Colby , Ruff Zachary J. , Harms Tyler M. , Dinsmore Stephen J.
Published: January 2019

Nest attendance behaviour in birds is a function of the careful balance between the risk of nest predation and the needs of the parents and nestlings. This attendance must be carefully regulated, as increased parental activity at the nest increases nest predation risk. We tested the long‐standing hypothesis that nest predation risk influences parental behaviour by evaluating the influence of local Marsh WrenCistothorus palustrisdensity on the off‐bout frequency of Yellow‐headed BlackbirdsXanthocephalus xanthocephalus. Marsh Wren density was negatively correlated with Yellow‐headed Blackbird off‐bout frequency during the morning (05:00–10:00 h) and evening (16:00–21:00 h), suggesting that Yellow‐headed Blackbirds alter their nest attendance behaviour in response to a perceived increased risk of nest predation. We suggest that Yellow‐headed Blackbirds are sensitive to nest predation risk and alter their behaviour accordingly to increase overall fitness, although future research is needed to evaluate the influence of Marsh Wren nest predation on the reproductive success of Yellow‐headed Blackbirds.
Mechanisms of anionic surfactant penetration into human skin: Investigating monomer, micelle and submicellar aggregate penetration theories
Authors: Morris Stephanie A. V. , Thompson Ryan T. , Glenn Robert W. , Ananthapadmanabhan K. P. , Kasting Gerald B.
Published: January 2019

Objective

Once penetrated into the stratum corneum, anionic surfactants bind to and denature stratum corneum proteins as well as intercalate into and extract intercellular lipids. With repeated exposures, this leads to skin dryness and irritation, compromising barrier function and skin health. The mechanisms of anionic surfactant penetration into the skin, however, are still widely debated. The objective of this study was to evaluate current theories of surfactant penetration into human skin.

Methods

A test set comprising 15 anionic surfactant systems and one non‐ionic surfactant, all having either dodecyl or lauryl alkyl chains, was tested for surfactant penetration into split‐thickness human cadaver skin in vitro using radiolabelled sodium dodecyl sulphate (14C‐SDS). Select physical properties of these formulations thought to be associated with skin penetration including critical micelle concentration, micelle diameter, filtrate concentration and zeta potential were also measured.

Results

14C‐SDS penetration into human cadaver skin from surfactant systems in vitro was found to correlate well with CMC (R2 = 0.34, P < 0.05), filtrate concentration (R2 = 0.36, P < 0.05) and zeta potential (R2 = 0.76, P < 0.001), but poorly with micelle diameter (R2 = 0.12). Furthermore, the latter measure correlated inversely with penetration compared to what would be expected based on the micelle penetration theory.

Conclusion

Neither monomer nor micelle penetration theories are sufficient to explain anionic surfactant penetration into human skin. Submicellar (or premicellar) aggregate penetration theory is difficult to defend at relevant surfactant concentrations. We propose a new hypothesis for this mechanism in which short‐term penetration is based on monomer concentration and longer term penetration is based on surfactant‐induced damage to the skin barrier.
Evaluating the evolution and function of the dynamic Venom Y protein in ectoparasitoid wasps
Authors: Martinson E. O. , Siebert A. L. , He M. , Kelkar Y. D. , Doucette L. A. , Werren J. H.
Published: January 2019

Venom of the parasitoid wasp Nasonia vitripennis changes the metabolism and gene expression in its fly host Sarcophaga bullata to induce developmental arrest, suppression of the immune response and various other venom effects. Yet, the venom of ectoparasitoid wasps has not been fully characterized. A major component of N. vitripennis venom is an uncharacterized, high‐expressing protein referred to as Venom Y. Here we describe the evolutionary history and possible functions of this venom protein. We found that Venom Y is a relatively young gene that has duplicated to form two distinct paralogue groups. A copy of Venom Y has been recruited as a venom protein in at least five wasp species. Functional analysis found that Venom Y affects detoxification and immunity genes in envenomated fly hosts. Many of these genes are fat‐body specific, suggesting that Venom Y may have a targeted effect on fat body tissue. We also show that Venom Y may mitigate negative effects of other venom proteins. Finally, protein sequencing indicates that Venom Y is post‐translationally modified. This study contributes to elucidating parasitoid venom by using RNA interference knockdown to investigate venom protein function in the context of the whole venom cocktail.