bluuebunny/crossref_metadata_2025 huggingface dataset:
Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2
Authors: Gardner Heather L. , Sivaprakasam Karthigayini , Briones Natalia , Zismann Victoria , Perdigones Nieves , Drenner Kevin , Facista Salvatore , Richholt Ryan , Liang Winnie , Aldrich Jessica , Trent Jeffrey M. , Shields Peter G. , Robinson Nicholas , Johnson Jeremy , Lana Susan , Houghton Peter , Fenger Joelle , Lorch Gwendolen , Janeway Katherine A. , London Cheryl A. , Hendricks William P. D.
Published: July 2019

Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing (n = 24) and whole exome sequencing (WES;n = 13) of primary tumors and matched normal tissue, WES (n = 10) of matched primary/metastatic/normal samples and RNA sequencing (n = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequentTP53(71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somaticSETD2(42%) andDMD(50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.
A cascade-reaction enabled synergistic cancer starvation/ROS-mediated/chemo-therapy with an enzyme modified Fe-based MOF
Authors: Liu Zongjun , Li Tuo , Han Fang , Wang You , Gan Yang , Shi Junhui , Wang Tianran , Akhtar Muhammad Luqman , Li Yu
Published: July 2019

A cascade-reaction enabled synergistic starvation/ROS-mediated/chemo-therapy was developed, and it exhibits a remarkable therapeutic efficacy without any external intervention.
Intermetallic species in the Negishi coupling and their involvement in inhibition pathways
Authors: Polynski Mikhail V. , Pidko Evgeny A.
Published: July 2019

The formation of M–Zn-intermetallic species (M = Ni, Pd) in the course of the Negishi reaction in THF solvent and their potential impact on in situ catalyst inhibition were investigated by DFT calculations carried out at two levels of theory.
Diameter-optimized high-order waveguide nanorods for fluorescence enhancement applied in ultrasensitive bioassays
Authors: Du Baosheng , Tang Chengchun , Zhao Dan , Zhang Hong , Yu Dengfeng , Yu Miao , Balram Krishna C. , Gersen Henkjan , Yang Bin , Cao Wenwu , Gu Changzhi , Besenbacher Flemming , Li Junjie , Sun Ye
Published: July 2019

High fluorescence enhancement has been realized by optimizing the evanescent field of ZnO nanorods.
Effect of hydrogen chloride etching on carrier recombination processes of indium phosphide nanowires
Authors: Su Xiaojun , Zeng Xulu , Němec Hynek , Zou Xianshao , Zhang Wei , Borgström Magnus T. , Yartsev Arkady
Published: July 2019

The effect of hydrogen chloride etching on charge recombination processes of indium phosphide nanowires was studied by means of time-resolved spectroscopy.
Pattern formation of metal–oxide hybrid nanostructuresviathe self-assembly of di-block copolymer blends
Authors: Jung Dae Soo , Bang Jiwon , Park Tae Wan , Lee Seung Hyup , Jung Yun Kyung , Byun Myunghwan , Cho Young-Rae , Kim Kwang Ho , Seong Gi Hun , Park Woon Ik
Published: July 2019

Unusual pattern generation of hybrid nanostructures can be achievedviathe microphase separation of blended di-BCPs. We present a useful method which is capable of forming uniform hybridized BCP patterns consisting of metal and nonmetal materials.
Tuning the NIR downconversion luminescence and photothermal conversion efficiencies of MNdxY1−xF4 (M = Na and Li) nanocrystals for use in anti-counterfeiting labels with opposite displays
Authors: Wu Xiangyang , Yeow Edwin K. L.
Published: July 2019

The inverse relationship between luminescence and photothermal conversion efficiencies is used to enhance anti-counterfeiting applications.
A strategy of tailoring polymorphs and nanostructures to construct self-reinforced nonswelling high-strength bacterial cellulose hydrogels
Authors: Zhang Minghao , Chen Shiyan , Sheng Nan , Wang Baoxiu , Yao Jingjing , Wu Zhuotong , Wang Huaping
Published: July 2019

High strength and non-swelling pure natural hydrogels with nanofiber-network-self-reinforced structures were fabricated through tailoring polymorphs and nanostructures.
Wash-induced multicolor tuning of carbon nano-dot/micro-belt hybrids with full recyclability and stable color convertibility
Authors: Cheng Shuai , Ding Yamei , Chang Qing , Zhong Shunuo , Shen Wei , Mao Huiwu , Zhai Xueting , Lu Gang , Deng Zhengtao , Liu Juqing , Xiu Fei , Huang Wei
Published: July 2019

Novel carbon nano-dot/micro-belt hybrid structures are prepared, featuring wash-induced multicolor tuning ranging from white to green and blue.
3D printable non-isocyanate polyurethanes with tunable material properties
Authors: Warner John J. , Wang Pengrui , Mellor William M. , Hwang Henry H. , Park Ji Hoon , Pyo Sang-Hyun , Chen Shaochen
Published: July 2019

A green chemistry-based non-isocyanate polyurethanes with tunable material properties are synthesized by cyclic carbonate and click chemistry. Their excellent photopolymerization property enables light-based 3D printing of functional biomedical devices using polyurethanes.
p-Doping of organic hole transport layers in p–i–n perovskite solar cells: correlating open-circuit voltage and photoluminescence quenching
Authors: Du Tian , Xu Weidong , Daboczi Matyas , Kim Jinhyun , Xu Shengda , Lin Chieh-Ting , Kang Hongkyu , Lee Kwanghee , Heeney Martin J. , Kim Ji-Seon , Durrant James R. , McLachlan Martyn A.
Published: July 2019

Reduction in p-doping of the organic hole transport layer (HTL) leads to substantial improvements in PV performance in planar p–i–n perovskite solar cells.
Recent advances and challenges in divalent and multivalent metal electrodes for metal–air batteries
Authors: Sun Yangting , Liu Xiaorui , Jiang Yiming , Li Jin , Ding Jia , Hu Wenbin , Zhong Cheng
Published: July 2019

This review highlights the critical challenges and the corresponding strategies for different metal electrodes in metal–air batteries.
Fmoc-diphenylalanine as a suitable building block for the preparation of hybrid materials and their potential applications
Authors: Diaferia Carlo , Morelli Giancarlo , Accardo Antonella
Published: July 2019

Due to its capability to self-assemble in self-supporting hydrogels (HG) under physiological conditions, Fmoc-FF is one of the most studied ultra-short peptide. This feature pushed towards the development of novel Fmoc-FF multicomponent systems.
Sending messages in moving cells: mRNA localization and the regulation of cell migration
Authors: Herbert Shane P. , Costa Guilherme
Published: July 2019

Cell migration is a fundamental biological process involved in tissue formation and homeostasis. The correct polarization of motile cells is critical to ensure directed movement, and is orchestrated by many intrinsic and extrinsic factors. Of these, the subcellular distribution of mRNAs and the consequent spatial control of translation are key modulators of cell polarity. mRNA transport is dependent on cis-regulatory elements within transcripts, which are recognized by trans-acting proteins that ensure the efficient delivery of certain messages to the leading edge of migrating cells. At their destination, translation of localized mRNAs then participates in regional cellular responses underlying cell motility. In this review, we summarize the key findings that established mRNA targetting as a critical driver of cell migration and how the characterization of polarized mRNAs in motile cells has been expanded from just a few species to hundreds of transcripts. We also describe the molecular control of mRNA trafficking, subsequent mechanisms of local protein synthesis and how these ultimately regulate cell polarity during migration.
Using pressure to probe thermodynamic anomalies in tetrahedrally-bonded materials
Authors: Nie Jihui , Porowski Sylwester , Keblinski Pawel
Published: July 2019

Tetrahedrally-bonded materials, such as silicon, diamond, or gallium nitride, are characterized by a low coordination number of 4 in the crystalline phase and, in general, can exhibit a liquid phase with higher density and coordination. This leads to interesting thermodynamic behavior, including the lowering of the melting temperature with increasing pressure and the possible existence of distinct low- and high-density liquid phases. Using molecular dynamics simulations, we explored the role of pressure and the degree of tetrahedrality on the structure and phase equilibria between the crystalline and liquid phases of tetrahedrally-bonded materials. In addition to the thermodynamic melting point, we determined the temperature of mechanical stability (spinodal temperature) as a function of pressure. The latter temperature is relevant to the laser pulse rapid melting of tetrahedrally-bonded materials. The results of our simulations indicate the possibility of the existence of a thermodynamically stable low-density liquid phase of silicon at high pressures. Our simulation also suggests that GaN is unlikely to exhibit anomalous thermodynamic behavior due to a high degree of tetragonality preventing the formation of high-density liquid, even at high pressures.
The commodification of TEFL in the context of tourism.
Authors: Stainton H.
Published: July 2019

This chapter examines the progressive changes seen within the industry of teaching English as a foreign language (TEFL) and the way in which commercial, public and NGO bodies operate within it. It is indicated that while the ideals of TEFL may lie in the likes of philanthropy and community development, this is now being replaced by profit-orientated and hedonistic motivations. Also discussed is the application of the four Ps of marketing in TEFL tourism marketing.
Introduction.
Authors: Vidal-Casellas D. , Aulet S. , Crous-Costa N.
Published: July 2019

This chapter recognizes tourism, and particularly religious tourism, as a form of intercultural interaction. It also offers background discussion on (i) pilgrims and religious tourists and their motivations and expectations, (ii) secularization and the loss of the notion of 'sacred'; and (iii) the role of interpretation in religious tourism.
Religious tourism, pilgrimage: manifestation of peace and enlightenment in contemporary religions with special reference to Islam.
Authors: Elhadary T.
Published: July 2019

This chapter claims that religious tourism or pilgrimage not only has the common advantages of tourism in general but also leads to enlightenment and peace. Focusing on the annual Islamic pilgrimage of the Hajj, the chapter explores the impact of pilgrimage on people's lives in general and Muslim lives in particular.
Pilgrimage tourism and social media: A way forward in the 21st century?
Authors: Paschinger E.
Published: July 2019

This chapter reveals a shift in the demand characteristics for religious/pilgrimage tourism with the advent of the "experience economy" and the proliferation of social media. The management implications of the advent of social media for religious/pilgrimage tourism are also discussed, including the use of social media marketing in the context of pilgrimage tourism development. A case study is presented of the 'Peregrino Lebaniego Digital', a project that digitalizes a part of the Way of Saint James.
Taking part in a pilgrimage by hosting pilgrims.
Authors: Ambrósio V.
Published: July 2019

This chapter's focus is on accommodation provided by local people without charge or for a small amount of money and how it contributes to the strengthening of the pilgrimage spirit and success. Examining three pilgrimages in Portugal, the research supports the idea that the locals who host pilgrims believe that they live the pilgrimage without walking the road and each one of them feels that they are taking part in the pilgrimage. On the other side, pilgrims feel that they are spreading the pilgrimage spirit along the way mainly when they have personal contact with locals and spend the night in their houses or in the lodgings they provide.
North Atlantic right whale (Eubalaena glacialis) and its food: (II) interannual variations in biomass of Calanus spp. on western North Atlantic shelves
Authors: Sorochan Kevin A , Plourde StÉphane , Morse Ryan , Pepin Pierre , Runge Jeffrey , Thompson Cameron , Johnson Catherine L
Published: July 2019

The North Atlantic right whale (NARW), Eubalaena glacialis, feeds on zooplankton, particularly copepods of the genus Calanus. We quantified interannual variation in anomalies of abundance and biomass of Calanus spp. and near-surface and near-bottom ocean temperature and salinity from 19 subregions spanning the Gulf of Maine–Georges Bank (GoM–GBK), Scotian Shelf (SS), Gulf of St. Lawrence (GSL) and Newfoundland and Labrador Shelves. We analyzed time series from 1977 to 2016 in GoM–GBK, 1982 to 2016 in southwest GSL and 1999 to 2016 in remaining areas. Calanus finmarchicus dominated abundance and biomass, except in the GSL where Calanus hyperboreus was abundant. The biomass of Calanus spp. declined in many subregions over years 1999–2016 and was negatively correlated with sea surface temperature in GoM–GBK and on the SS. We detected ``regime shifts” to lower biomass of Calanus spp. in the GoM–GBK in 2010 and on the SS in 2011. In the GoM–GBK, shifts to lower biomass of C. finmarchicus coincided with shifts to warmer ocean temperature and with published reports of changes in spatial distribution and reduced calving rate of NARW. We hypothesize that warming has negatively impacted population levels of Calanus spp. near their southern range limit, reducing the availability of prey to NARW.
Tomato bHLH132 Transcription Factor Controls Growth and Defense and Is Activated by Xanthomonas euvesicatoria Effector XopD During Pathogenesis
Authors: Kim Jung-Gun , Mudgett Mary Beth
Published: July 2019

Effector-dependent manipulation of host transcription is a key virulence mechanism used by Xanthomonas species causing bacterial spot disease in tomato and pepper. Transcription activator-like (TAL) effectors employ novel DNA-binding domains to directly activate host transcription, whereas the non-TAL effector XopD uses a small ubiquitin-like modifier (SUMO) protease activity to represses host transcription. The targets of TAL and non-TAL effectors provide insight to the genes governing susceptibility and resistance during Xanthomonas infection. In this study, we investigated the extent to which the X. euvesicatoria non-TAL effector strain Xe85-10 activates tomato transcription to gain new insight to the transcriptional circuits and virulence mechanisms associated with Xanthomonas euvesicatoria pathogenesis. Using transcriptional profiling, we identified a putative basic helix-loop-helix (bHLH) transcription factor, bHLH132, as a pathogen-responsive gene that is moderately induced by microbe-associated molecular patterns and defense hormones and is highly induced by XopD during X. euvesicatoria infection. We also found that activation of bHLH132 transcription requires the XopD SUMO protease activity. Silencing bHLH132 mRNA expression results in stunted tomato plants with enhanced susceptibility to X. euvesicatoria infection. Our work suggests that bHLH132 is required for normal vegetative growth and development as well as resistance to X. euvesicatoria. It also suggests new transcription-based models describing XopD virulence and recognition in tomato.
ORANGE: A CRISPR/Cas9-based genome editing toolbox for epitope tagging of endogenous proteins in neurons
Authors: Willems Jelmer , de Jong Arthur P.H. , Scheefhals Nicky , MacGillavry Harold D.
Published: July 2019

The correct subcellular distribution of protein complexes establishes the complex morphology of neurons and is fundamental to their functioning. Thus, determining the dynamic distribution of proteins is essential to understand neuronal processes. Fluorescence imaging, in particular super-resolution microscopy, has become invaluable to investigate subcellular protein distribution. However, these approaches suffer from the limited ability to efficiently and reliably label endogenous proteins. We developed ORANGE: an Open Resource for the Application of Neuronal Genome Editing, that mediates targeted genomic integration of fluorescent tags in neurons. This toolbox includes a knock-in library for in-depth investigation of endogenous protein distribution, and a detailed protocol explaining how knock-in can be developed for novel targets. In combination with super-resolution microscopy, ORANGE revealed the dynamic nanoscale organization of endogenous neuronal signaling molecules, synaptic scaffolding proteins, and neurotransmitter receptors. Thus, ORANGE enables quantitation of expression and distribution for virtually any protein in neurons at high resolution and will significantly further our understanding of neuronal cell biology.
Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: Probing the lipid metabolome
Authors: Mohamed Ahmed , Collins Joel , Jiang Hui , Molendijk Jeffrey , Stoll Thomas , Torta Federico , Wenk Markus R , Bird Robert J , Marlton Paula , Mollee Peter , Markey Kate A , Hill Michelle M
Published: July 2019

Background

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of malignant plasma cells. Though durable remissions are possible, MM is considered incurable, with relapse occurring in almost all patients. There has been limited data reported on the lipid metabolism changes in plasma cells during MM progression. Here, we evaluated the feasibility of concurrent lipidomics and proteomics analyses from patient plasma cells, and report these data on a limited number of patient samples, demonstrating the feasibility of the method, and establishing hypotheses to be evaluated in the future.

Methods

Plasma cells were purified from fresh bone marrow aspirates using CD138 microbeads. Proteins and lipids were extracted using a bi-phasic solvent system with methanol, methyl tert-butyl ether, and water. Untargeted proteomics, untargeted and targeted lipidomics were performed on 7 patient samples using liquid chromatography-mass spectrometry. Two comparisons were conducted: high versus low risk; relapse versus newly diagnosed. Proteins and pathways enriched in the relapsed group was compared to a public transcriptomic dataset from Multiple Myeloma Research Consortium reference collection (n=222) at gene and pathways level.

Results

From one million purified plasma cells, we were able to extract material and complete untargeted (∼6000 and ∼3600 features in positive and negative mode respectively) and targeted lipidomics (313 lipids), as well as untargeted proteomics analysis (∼4100 reviewed proteins). Comparative analyses revealed limited differences between high and low risk groups (according to the standard clinical criteria), hence we focused on drawing comparisons between the relapsed and newly diagnosed patients. Untargeted and targeted lipidomics indicated significant down-regulation of phosphatidylcholines (PCs) in relapsed MM. Although there was limited overlap of the differential proteins/transcripts, 76 significantly enriched pathways in relapsed MM were common between proteomics and transcriptomics data. Further evaluation of transcriptomics data for lipid metabolism network revealed enriched correlation of PC, ceramide, cardiolipin, arachidonic acid and cholesterol metabolism pathways to be exclusively correlated among relapsed but not in newly-diagnosed patients.

Conclusions

This study establishes the feasibility and workflow to conduct integrated lipidomics and proteomics analyses on patient-derived plasma cells. Potential lipid metabolism changes associated with MM relapse warrant further investigation.
The laboratory domestication of zebrafish: from diverse populations to inbred substrains
Authors: Suurväli Jaanus , Whiteley Andrew R , Zheng Yichen , Gharbi Karim , Leptin Maria , Wiehe Thomas
Published: July 2019

The zebrafish (Danio rerio) is a model vertebrate widely used to study disease, development and other aspects of vertebrate biology. Most of the research is performed on laboratory strains, one of which has been fully sequenced in order to derive a reference genome. It is known that the laboratory strains differ genetically from each other, but so far no genome-scale survey of variation between the laboratory and wild zebrafish populations exists.

Here we use Restriction-Associated DNA sequencing (RAD-seq) to characterize three different wild zebrafish lineages from a population genetic viewpoint, and to compare them to four common laboratory strains. For this purpose we combine new genome-wide sequence data obtained from natural samples in India, Nepal and Bangladesh with a previously published dataset. We measured nucleotide diversity, heterozygosity, allele frequency spectra and patterns of gene conversion, and find that wild fish are much more diverse than laboratory strains. Further, in wild zebrafish there is a clear signal of GC-biased gene conversion that is missing in laboratory strains. We also find that zebrafish populations in Nepal and Bangladesh are distinct from all the other strains studied, making them an attractive subject for future studies of zebrafish population genetics and molecular ecology. Finally, isolates of the same strains kept in different laboratories show a clear pattern of ongoing differentiation into genetically distinct substrains. Together, our findings broaden the basis for future genetic and evolutionary studies inDanio rerio.
μDamID: a microfluidic approach for imaging and sequencing protein-DNA interactions in single cells
Authors: Altemose Nicolas , Maslan Annie , Lai Andre , White Jonathan A. , Streets Aaron M.
Published: July 2019

Genome regulation depends on carefully programmed protein-DNA interactions that maintain or alter gene expression states, often by influencing chromatin organization. Most studies of these interactions to date have relied on bulk methods, which in many systems cannot capture the dynamic single-cell nature of these interactions as they modulate cell states. One method allowing for sensitive single-cell mapping of protein-DNA interactions is DNA adenine methyltransferase identification (DamID), which records a protein’s DNA-binding history by methylating adenine bases in its vicinity, then selectively amplifies and sequences these methylated regions. These interaction sites can also be visualized using fluorescent proteins that bind to methyladenines. Here we combine these imaging and sequencing technologies in an integrated microfluidic platform (μDamID) that enables single-cell isolation, imaging, and sorting, followed by DamID. We apply this system to generate paired single-cell imaging and sequencing data from a human cell line, in which we map and validate interactions between DNA and nuclear lamina proteins, providing a measure of 3D chromatin organization and broad gene regulation patterns. μDamID provides the unique ability to compare paired imaging and sequencing data for each cell and between cells, enabling the joint analysis of the nuclear localization, sequence identity, and variability of protein-DNA interactions.
ER membranes exhibit phase behavior at sites of organelle contact
Authors: King Christopher , Sengupta Prabuddha , Seo Arnold , Lippincott-Schwartz Jennifer
Published: July 2019

The plasma membrane of cells exhibits phase behavior that allows transient concentration of specific proteins and lipids, giving rise to functionally dynamic and diverse nanoscopic domains. This phase behavior is observable in giant plasma membrane-derived vesicles, in which microscopically visible, liquid-ordered (Lo) and liquid-disordered (Ld) lipid domains form upon a shift to low temperatures. The extent such phase behavior exists in the membrane of the endoplasmic reticulum (ER) of cells remains unclear. To explore the phase behavior of the ER membrane in cells, we used hypotonic cell swelling to generate Large Intra-Cellular Vesicles (LICVs) from the ER in cells. ER LICVs retained their lumenal protein content, could be retubulated into an ER network, and maintained stable inter-organelle contacts, where protein tethers are concentrated at these contacts. Notably, upon temperature reduction, ER LICVs underwent reversible phase separation into microscopically-visible Lo and Ld lipid domains. The Lo lipid domains marked ER contact sites with other organelles. These findings demonstrate that LICVs provide an important model system for studying the biophysical properties of intracellular organelles in cells.

Significance Statement

Prior work has demonstrated that the plasma membrane can phase separate into microscopically visible Lo and Ld domains with distinct lipid and protein content. However, such behavior on the ER membrane has not been experimentally observed, even though the ER contacts every organelle of the cell, exchanging lipids and metabolites in a highly regulated manner at these contacts. We find here that hypotonic treatment generates Large Intra-Cellular Vesicles from the endoplasmic reticulum and other membrane-bound organelles in cells, enabling the study of phase behavior on the ER membrane. We show that ER membranes can be reversibly phase separated into microscopically-observable, Lo and Ld domains. ER LICVs also maintained stable inter-organelle contact sites in cells, with organelle tethers concentrated at these contacts.
Germ Granules Coordinate RNA-based Epigenetic Inheritance Pathways
Authors: Dodson Anne E. , Kennedy Scott
Published: July 2019

Germ granules are biomolecular condensates that promote germ cell totipotency in most, if not all, animals. InC. elegans, MEG-3 and MEG-4 are two intrinsically disordered proteins that are redundantly required for the phase separations that drive germ granule assembly in germline blastomeres. Here, we show that animals lacking MEG-3/4 exhibit defects in dsRNA-mediated gene silencing (RNAi) that are due, at least in part, to defects in systemic RNAi. Interestingly, these RNAi defects are transgenerationally disconnected frommeg-3/4genotype: RNAi defects do not arise until 5-9 generations after animals become mutant formeg-3/4, and RNAi defects persist for 9-11 generations aftermeg-3/4genotype is restored to wild type. Similar non-Mendelian patterns of inheritance are associated with other mutations that disrupt germ granule formation, indicating that germ granule disruption is the likely cause of genotype/phenotype disconnects. Loss of germ granules is associated with the production of aberrant populations of endogenous siRNAs, which, remarkably, are propagated for ≅10 generations in wild-type descendants of animals that lacked germ granules.sid-1, which encodes a factor required for systemic RNAi inC. elegans, is inappropriately and heritably silenced by aberrantly expressedsid-1endogenous siRNAs, suggesting that transgenerational silencing ofsid-1likely underlies the heritable defect in RNAi. We conclude that one function of germ granules is to organize RNA-based epigenetic inheritance pathways and that failure to assemble germ granules has consequences that persist across many generations.
Beyond the Motor Cortex: Theta Burst Stimulation of the Anterior Midcingulate Cortex
Authors: Baker Travis E. , Lin Mei-Heng , Parikh Seema , Bauer Neeta , Cocuzza Carrisa
Published: July 2019

Intermittent Theta Burst Stimulation (TBS) applied to the left dorsolateral prefrontal cortex suppressed reward-related signaling in the anterior midcingulate cortex (aMCC), resulting in a change in goal-directed behavior. Continuous TBS had no effect. While these results are inconsistent with reported TBS effects on motor cortex, the present findings offer normative insights into the magnitude and time course of TBS-induced changes in aMCC excitability during goal-directed behavior.
Functional plasticity and reversible growth behavior of patients’ acute myeloid leukemia stem cells growing in mice
Authors: Ebinger Sarah , Zeller Christina , Carlet Michela , Senft Daniela , Liu Wen-Hsin , Rothenberg-Thurley Maja , Metzeler Klaus H. , Spiekermann Karsten , Vick Binje , Jeremias Irmela
Published: July 2019

Resistance against chemotherapy remains a major obstacle in treating patients with acute myeloid leukemia (AML). Novel therapeutic concepts are especially desired to target and eliminate resistant AML stem cells. Here we show that AML stem cells harbor the plasticity to switch from a low-cycling, chemotherapy resistant state into an actively proliferating state associated with treatment response. We used patient-derived xenograft (PDX) cells from patients with high risk or relapsed AML, which were lentivirally transduced for marker expression, stained with the proliferation-sensitive dye Carboxyfluorescein succinimidyl ester (CFSE), and re-transplanted into next-recipient mice. A rare subpopulation of AML cells displayed reduced proliferation in vivo, associated with increased treatment resistance. The proportion of AML cells with stem cell potential was identical in both, the highly and lowly proliferative sub-fraction. In re-transplantation experiments, proliferation behavior proved reversible, and AML stem cells were able to switch between a high and low proliferation state. Our data indicate that AML stem cells display functional plasticity in vivo, which might be exploited for therapeutic purposes, to prevent AML relapse and ultimately improve the prognosis of patients with AML.
Neural Taskonomy: Inferring the Similarity of Task-Derived Representations from Brain Activity
Authors: Wang Aria Y. , Wehbe Leila , Tarr Michael J.
Published: July 2019

Convolutional neural networks (CNNs) trained for object recognition have been widely used to account for visually-driven neural responses in both the human and primate brains. However, because of the generality and complexity of the task of object classification, it is often difficult to make precise inferences about neural information processing using CNN representations from object classification despite the fact that these representations are effective for predicting brain activity. To better understand underlying the nature of the visual features encoded in different brain regions of the human brain, we predicted brain responses to images using fine-grained representations drawn from 19 specific computer vision tasks. Individual encoding models for each task were constructed and then applied to BOLD5000—a large-scale dataset comprised of fMRI scans collected while observers viewed over 5000 naturalistic scene and object images. Because different encoding models predict activity in different brain regions, we were able to associate specific vision tasks with each region. For example, within scene-selective brain regions, features from 3D tasks such as 3D keypoints and 3D edges explain greater variance as compared to 2D tasks—a pattern that replicates across the whole brain. Using results across all 19 task representations, we constructed a “task graph” based on the spatial layout of well-predicted brain areas from each task. We then compared the brain-derived task structure with the task structure derived from transfer learning accuracy in order to assess the degree of shared information between the two task spaces. These computationally-driven results—arising out of state-of-the-art computer vision methods—begin to reveal the task-specific architecture of the human visual system.
Stroke prevents exercise-induced gains in bone microstructure but not composition in mice
Authors: Hanne Nicholas J. , Steward Andrew J. , Sessions Marci R. , Thornburg Hannah L. , Sheng Huaxin , Cole Jacqueline H.
Published: July 2019

Ischemic stroke induces rapid loss in bone mineral density that is up to 13 times greater than during normal aging, leading to a markedly increased risk of fracture. Little is known about skeletal changes following stroke beyond density loss. In this study we use a mild-moderate middle cerebral artery occlusion model to determine the effects of ischemic stroke without bedrest on bone microstructure, dynamic bone formation, and tissue composition. Twenty-seven 12-week-old male C57Bl/6J mice received either a stroke or sham surgery and then either received daily treadmill exercise or remained sedentary for four weeks. All mice were ambulatory immediately following stroke, and limb coordination during treadmill exercise was unaffected by stroke, indicating similar mechanical loading across limbs for both stroke and sham groups. Stroke did not directly detriment microstructure, but exercise only stimulated adaptation in the sham group, not the stroke group, with increased bone volume fraction and trabecular thickness in the sham distal femoral metaphysis. Stroke differentially decreased cortical area in the affected limb relative to the unaffected limb of the distal femoral metaphysis, as well as endosteal bone formation rate in the affected tibial diaphysis. Although exercise failed to improve bone microstructure following stroke, exercise increased mineral-to-matrix content in stroke but not sham. Together, these results show that stroke inhibits exercise-induced changes to femoral microstructure but not tibial composition, even without changes to gait. Similarly, affected-unaffected limb differences in cortical bone structure and bone formation rate in ambulatory mice show that stroke affects bone health even without bedrest.
Assaying Chlamydia pneumoniae persistence in monocyte-derived macrophages identifies schisandrin lignans as phenotypic switchers
Authors: Taavitsainen Eveliina , Kortesoja Maarit , Hanski Leena
Published: July 2019

Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. Taking persisters into account in susceptibility assays is thus an essential success factor in antibacterial drug discovery. The virulence of the obligate intracellular bacterium Chlamydia pneumoniae is tightly linked to its propensity for persistence, but current susceptibility screening on this gram-negative respiratory pathogen relies on permissive epithelial cells. To establish an improved antichlamydial susceptibility assay allowing the analysis of both actively growing and persister bacteria, we studied C. pneumoniae clinical isolate CV-6 infection kinetics in THP-1 macrophages by qPCR and quantitative culture. Indicated by the steady increase of chlamydial genome copy numbers and infectious progeny as well as the failure of azithromycin to eradicate the intracellular forms of the bacterium, the macrophages were found to harbor a subpopulation of persister C. pneumoniae cells. The potential of the assay for the discovery of anti-persister molecules against intracellular bacteria was demonstrated by the identification of the differential effects of two dibenzocyclooctadiene lignans on C. pneumoniae infection. While schisandrin reverted C. pneumoniae persistence and promoted productive infection, schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection. The phenotypic switch was associated with the suppression of cellular glutathione pools, implying that targeting glutathione homeostasis may provide a novel means for intracellular bacteria resuscitation. In conclusion, these data highlight the value of macrophages over permissive cell lines in anti-persister agent discovery on intracellular bacteria and targeting host cell redox status to fight persistent infections.
A straightforward approach for bioorthogonal labeling of proteins and organelles in live mammalian cells, using a short peptide tag
Authors: Segal Inbar , Nachmias Dikla , Arbely Eyal , Elia Natalie
Published: July 2019

In the high-resolution microscopy era, genetic code expansion (GCE)-based bioorthogonal labeling offers an elegant way for direct labeling of proteins in live cells with fluorescent dyes. This labeling approach is currently not broadly used live cell applications, partly because it needs to be adjusted to the specific protein under study. Here, we present a generic, 14-residues long, N-terminal tag for GCE-based labeling of proteins in live mammalian cells. Using this tag, we generated a library of GCE-based organelle markers, demonstrating the applicability of the tag for labeling a plethora of proteins and organelles. Finally, we show that the HA epitope, used as a backbone in our tag, can be substituted with other epitopes and, in some cases, can be completely removed, reducing the tag length to 5 residues. The GCE-tag presented here offers a powerful, easy-to-implement tool for live cell labeling of cellular proteins with small and bright probes.
Regulation of melanocyte development by ligand-dependent BMP signaling underlies oncogenic BMP signaling in melanoma
Authors: Gramann Alec K. , Venkatesan Arvind M. , Guerin Melissa , Ceol Craig J.
Published: July 2019

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligandGDF6as a novel melanoma oncogene showedGDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles forGDF6orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligandgdf6a, a zebrafish ortholog of humanGDF6, during the development of melanocytes from the neural crest. We establish that the loss ofgdf6aor inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends onmitfa, an ortholog ofMITF, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development.
Cellular innate and adaptive immunity are affected by chronic exercise: implication of the cannabinergic system
Authors: Valencia-Sánchez Salvador , Nava-Castro Karen , Palacios-Arreola M. Isabel , Prospéro-García Oscar , Morales-Montor Jorge , Drucker-Colín René
Published: July 2019

The impact of performing exercise on the immune system presents contrasting effects on health when performed at different intensities. In addition, the consequences of performing chronic exercise have not been sufficiently studied in contrast to the effects of acute bouts of exercise. Our findings shed light on the effects that chronic exercise elicits on several immune cell subpopulations, from the innate to the adaptive immunity. For this study male Wistar rats performed treadmill running 5 times a week for a period of 10 weeks, speed and duration in each exercise bout was gradually increased until reaching 40 minutes at 15 m/min. Our results showed a significant decrease in lymphocyte subpopulations (CD4+, Tγδ, and CD45 RA+ cells) and also indicate an alteration in the cannabinoid receptors expression in some of these cells subsets. Although functional assays did not reveal any variation in total immunoglobulin production or NK cells cytotoxic activity, proliferative capability of total splenocytes increased in trained rats. Our results further support the notion that exercise affects the immunological system and extends the description of underlying mechanisms mediating such effects. Altogether, our results contribute to the understanding of the benefits of exercise on the practitioner’s general health.
PECLIDES Neuro A Personalisable Clinical Decision Support System for Neurological Diseases
Authors: Müller Tamara , Lio’ Pietro
Published: July 2019

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s impact millions of people worldwide. Early diagnosis has proven to greatly increase the chances of slowing down the diseases’ progression. Correct diagnosis often relies on the analysis of large amounts of patient data, and thus lends itself well to support from machine learning algorithms, which are able to learn from past diagnosis and see clearly through the complex interactions of a patient’s symptoms. Unfortunately, many contemporary machine learning techniques fail to reveal details about how they reach their conclusions, a property considered fundamental when providing a diagnosis. This is one reason why we introduce our Personalisable Clinical Decision Support SystemPECLIDESthat provides a clear insight into the decision making process on top of the diagnosis. Our algorithm enriches the fundamental work of Masheyekhi and Gras in data integration, personal medicine, usability, visualisation and interactivity.

Our decision support system is an operation of translational medicine. It is based on random forests, is personalisable and allows a clear insight into the decision making process. A well-structured rule set is created and every rule of the decision making process can be observed by the user (physician). Furthermore, the user has an impact on the creation of the final rule set and the algorithm allows the comparison of different diseases as well as regional differences in the same disease1.
High-efficiency X-ray multilayer-coated blazed gratings with shifted boundaries
Authors: Lubov Maxim , Goray Leonid
Published: July 2019

A new design for a high-efficiency multilayer-coated blazed X-ray grating with horizontal-shifted (non-conformal) boundary profiles is proposed. The investigation of the grating design is carried out using an integrated approach based on rigorous numerical calculations of light diffraction by gratings with realistic boundary profiles obtained from simulations of multilayer grating growth. By varying the incidence angle of the deposition flux, one can set the direction and magnitude of the boundary profile shifts over a wide range of values. It is shown that the diffraction efficiency of the blazed gratings with shifted boundary profiles may be substantially higher than the efficiency of gratings with conformal boundaries, which are, moreover, much more difficult to produce. High-efficiency gratings with shifted boundaries can be obtained when the deposition is mainly on the blaze facet with a high inclination of the deposition flux, as opposed to widely used near-normal deposition methods. The maximum absolute efficiency of a W/B4C 2500 mm−1 grating with a blaze angle of 1.76° and an anti-blaze angle of 20°, working at a blaze wavelength of 1.3 nm and having shifted realistic boundary profiles, obtained using our integrated approach is 23.3%, while that of a grating with the ideal (triangular) boundary profile and the same shifts is 25.3%, and that of an ideal conformal profile is only 22.2%. The maximum absolute efficiency of 40.2% of a 2500 mm Cr/C grating with a blaze angle of 1.05° and a realistic anti-blaze angle of 10°, working at a blaze wavelength of 0.83 nm and having ideal shifted boundaries, is higher than the maximum efficiency of the similar grating having ideal conformal boundaries with a non-realistic anti-blaze angle of 80°.
Poly[[μ4-4-(carboxylatomethyl)benzoato]zinc(II)]
Authors: Jia Jason , LaDuca Robert L.
Published: July 2019

In the title compound, [Zn(C9H6O4)]
n
, the ZnII cations are coordinated in a tetrahedral fashion by carboxylate O-atom donors belonging to four 4-(carboxymethyl) benzoate (4-cmb) ligands. Each 4-cmb ligand binds to four ZnII cations in an exotetradentate fashion to create a non-interpenetrated [Zn(4-cmb)]
n
three-dimensional coordination polymer network with a new non-diamondoid 66 topology. The crystal studied was refined as an inversion twin.
Social well-being and transformative service research: evidence from China
Authors: Feng Kuo , Altinay Levent , Olya Hossein
Published: July 2019

Purpose

This empirical study aims to investigate the influence of socially supportive services provided by commercial senior living services on older customers’ social well-being. This study seeks to test the moderating role of social connectedness on the above associations. It explores necessary conditions and causal recipes from the combination of interactions and social connectedness to predict customers’ social well-being.

Design/methodology/approach

Data were collected from 190 older customers residing in commercial senior living services in Beijing, Shanghai and Shenyang in China. The proposed structural and configurational models were tested using structural equation modelling and fuzzy-set qualitative comparative analysis (fsQCA).

Findings

The results of the model testing illustrate that peers have no influence on the social well-being of older customers. However, positive interactions with employees and outsiders are supportive resources that increase older customers’ social well-being. Social connectedness moderates the relationship between interaction with peers and the social well-being of customers. fsQCA results revealed that complex combinations of interactions and social connectedness predict social well-being. Interactions with employees, peers and outsiders appeared as necessary conditions to achieve social well-being.

Originality/value

This study provides evidence for how commercial senior living services can serve as a space to exchange socially supportive resources with employees and outsiders, which enhance older customers’ social well-being.
Rheumatologists' insight into medication adherence in patients with rheumatoid arthritis: A qualitative study
Authors: Heidari Parvaneh , Cross Wendy , Weller Carolina , Team Victoria , Nazarinia Mohammadali , Crawford Kimberley
Published: July 2019

Background

Medication non‐adherence is prevalent among patients with rheumatoid arthritis (RA). Rheumatologists are specialists in medication prescribing and counselling for RA, but their insights regarding medication adherence have not been studied.

Objective

To explore rheumatologists' insights into medication adherence in patients with RA.

Methods

A qualitative study using semi‐structured interviews with 10 rheumatologists in Iran was undertaken. Thematic analysis was conducted to identify how rheumatologists assess medication adherence and their perceived determinants of adherence. The identified determinants of adherence were mapped according to the Andersen's Behavioral Model of Health Service Use.

Results

Six participants were male, and the mean age was 47 years. The mean years of experience as a rheumatologist was 8.6 (SD = 7.1) years. Rheumatologists did not use a validated tool for medication adherence assessment. They assessed medication adherence either by asking their patients simple questions or using laboratory test results. The identified determinants of adherence were divided into 3 groups: patient‐, rheumatologist‐ and healthcare organization‐related determinants. The proposed suggestions to improve adherence were: (a) to understand a patient's financial situation before prescribing more expensive medications; (b) to employ a dose‐reducing strategy; (c) to give hope to patients regarding remission; and (d) to arrange a session with the nurse educator.

Conclusion

The findings of this study provide insight into rheumatologists' perspectives on medication adherence of patients with RA. The identified determinants of adherence could be considered when developing initiatives to improve medication adherence in this group of patients.