bluuebunny/crossref_metadata_2025 huggingface dataset:
Volumetric Analysis in Autologous Fat Grafting to the Foot
Authors: Ruane Edward J. , Minteer Danielle M. , Wyse Aaron J. , Gusenoff Beth R. , Gusenoff Jeffrey A.
Published: August 2019

Background:

Pedal fat grafting is a safe, minimally invasive approach to treat pedal fat pad atrophy. Prior randomized controlled trials demonstrate that the fat as measured directly under the metatarsal heads disappears between 2 and 6 months after fat grafting, despite patients having relief for 2 years. The authors aim to use magnetic resonance imaging to further assess three-dimensional volume of fat in the foot after autologous fat grafting to help explain the mechanism for improved pain.

Methods:

A prospective study was performed using magnetic resonance imaging before and at 6 months after pedal fat grafting to assess changes in the three-dimensional morphology of the fat.

Results:

Seventeen patients (six men and 11 women) underwent injections with a mean volume of 5.8 cc per foot. At 6 months, patients demonstrated increased tissue thickness (p = 0.008) and volume (p = 0.04). Improvements were seen in pain (p < 0.05) and activity (p < 0.05). Foot pressures and forces were significantly decreased and positively correlated with increased fat pad volume (p < 0.05).

Conclusions:

Pedal fat grafting significantly increases metatarsal fat pad volume. The distribution of the fat may contribute to lasting clinical relief in these patients.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Nonbiological Microsurgery Simulators in Plastic Surgery Training: A Systematic Review
Authors: Abi-Rafeh Jad , Zammit Dino , Mojtahed Jaberi Mehrad , Al-Halabi Becher , Thibaudeau Stephanie
Published: August 2019

Background:

Simulation has gained notable recognition for its role as an effective training and assessment modality in the present era of competency-based medical education. Despite the well-documented efficacy of both live and cadaveric animal models, several ethical, financial, and accessibility issues persist with their use. Lower fidelity nonbiological simulators have gained recognition for their ability to circumvent these challenges. This systematic review reports on all prosthetic and virtual reality simulators in use for microsurgery training, with an emphasis on each model’s complexity, characteristics, advantages, disadvantages, and validation measures taken.

Methods:

A systematic search was performed using the National Library of Medicine (PubMed), MEDLINE, and Embase databases. Search terms were those pertaining to prosthetic and virtual reality models with relevance to microsurgical training in plastic surgery. Three independent reviewers evaluated all articles retrieved based on strict inclusion and exclusion criteria.

Results:

Fifty-seven articles met the inclusion criteria for review, reporting on 20 basic prosthetic models, 20 intermediate models, 13 advanced models, and six virtual reality simulators.

Conclusions:

A comprehensive summary has been compiled of all nonbiological simulators in use for microsurgery training in plastic surgery, demonstrating efficacy for the acquisition and retention of microsurgical skills. Metrics-based validation efforts, however, were often lacking in the literature. As plastic surgery programs continue to innovate, ensure accountability, and safely meet today’s training standards, prosthetic simulators are set to play a larger role in the development of a standardized, ethical, accessible, and objectively measurable microsurgery training curriculum for the modern-day plastic and reconstructive surgery resident.
Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel
Authors: Olivença Daniel V. , Fonseca Luis L. , Voit Eberhard O. , Pinto Francisco R.
Published: August 2019

The lung epithelium is lined with a layer of airway surface liquid (ASL) that is crucial for healthy lung function. ASL thickness is controlled by two ion channels: epithelium sodium channel (ENaC) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Here, we present a minimal mathematical model of ENaC, CFTR and ASL regulation that sheds light on the control of ENaC by the short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and by phosphatidylinositol 4,5-biphosphate (PI(4,5)P
2
). The model, despite its simplicity, yields a good fit to experimental observations and is an effective tool for exploring the interplay between ENaC, CFTR and ASL. Steady-state data and dynamic information constrain the model's parameters without ambiguities. Testing the hypothesis that PI(4,5)P
2
protects ENaC from ubiquitination suggests that this protection does not improve the model results and that the control of the ENaC opening probability by PI(4,5)P
2
is sufficient to explain all available data. The model analysis further demonstrates that ASL at the steady state is sensitive to small changes in PI(4,5)P
2
abundance, particularly in CF conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for CF patients.
Social cognition, behaviour and therapy adherence in frontal lobe epilepsy: a study combining neuroeconomic and neuropsychological methods
Authors: Javor Andrija , Ciumas Carolina , Ibarrola Danielle , Ryvlin Philippe , Rheims Sylvain
Published: August 2019

Social behaviour of healthy humans and its neural correlates have been extensively studied in social neuroscience and neuroeconomics. Whereas it is well established that several types of epilepsies, such as frontal lobe epilepsy, lead to social cognitive impairments, experimental evidence on how these translate into behavioural symptoms is scarce. Furthermore, it is unclear whether social cognitive or behavioural disturbances have an impact on therapy adherence, which is critical for effective disease management, but generally low in these patients. In order to investigate the relationship between social cognition, social behaviour, and therapy adherence in patients with frontal lobe epilepsies (FLE), we designed a study combining conventional neuropsychological with behavioural economic and functional magnetic resonance imaging (fMRI) methodology. Fifteen patients and 15 healthy controls played a prisoners' dilemma game (an established game to operationalize social behaviour) while undergoing fMRI. Additionally, social cognitive, basic neuropsychological variables, and therapy adherence were assessed. Our results implicate that social behaviour is indeed affected and can be quantified using neuroeconomic methods in patients with FLE. Impaired social behaviour in these patients might be a consequence of altered brain activation in the medial prefrontal cortex and play a role in low therapy adherence. Finally, this study serves as an example of how to integrate neuroeconomic methods in neurology.
Revaluation of magnetic properties of Magneto, MagR and αGFP−TRPV1/GFP−ferritin
Authors: Wang Guangfu , Zhang Peng , Mendu Suresh K. , Wang Yali , Zhang Yajun , Kang Xi , Desai Bimal N. , Zhu J. Julius
Published: August 2019

ABSTRACT AND INTRODUCTION

Magnetic control of neuronal activity offers many obvious advantages over electric, optogenetic and chemogenetic manipulations. A recent series of highly visible papers reported the development of magnetic actuators (i.e., Magneto, MagR and αGFP−TRPV1/GFP−ferritin) that appeared to be effective in controlling neuronal firing1–3, yet their action mechanisms seem to conflict with the principles of physics4. We found that neurons expressing Magneto, MagR and αGFP−TRPV1/GFP−ferritin did not respond to magnetic stimuli with any membrane depolarization (let alone action potential firing), although these neurons frequently generated spontaneous action potentials. Because the previous study did not establish the precise temporal correlation between magnetic stimuli and action potentials in recorded neurons1–3, the reported magnetically-evoked action potentials are likely to represent mismatched spontaneous firings.
RAD-Behavior (Recombining Atomized, Discretized, Behavior): A new framework for the quantitative analysis of behavioral execution
Authors: Ligon Russell A. , Scholes Edwin , Sheehan Michael J.
Published: August 2019

The ability to precisely describe and numerically evaluate organismal phenotypes is a prerequisite for addressing most questions in evolutionary biology and ecology. The quantification and comparison of behavior, loosely defined as an external response to stimuli, is particularly challenging because the myriad axes of variation that exist make comparisons, both within and among species, difficult. Such evaluations often boil down to comparisons of time-budgets (e.g. relative investment in courtship displays) or probabilities (e.g. likelihood of engaging in a class of behaviors in a particular context) – which we refer to as behavioral strategies. A focus on variation in behavioral strategies underlies most research in evolutionary and ecological studies of behavior. Equally important, however, is perhaps the question of ‘how’ animals are actually performing the complex motor sequences that comprise behaviors (i.e. behavioral execution). What are the patterns of movement, the relative transition rates, and kinematics underlying the behaviors exhibited in particular contexts? Understanding how behavioral execution differs among individuals, populations, and species has the potential to provide new insights into the factors shaping variation in behavior and the processes shaping behavioral evolution at different scales. Here, we propose a broad framework for comparing behavioral execution (RAD-behavior: recombining atomized, discretized behavior) that leverages string-matching/bioinformatic tools to understand phenotypic variation in behavioral execution and which holds the potential to yield novel insights about the evolutionary ecology of behavior at multiple scales.
Serial coupling of chromatographic columns having orthogonal selectivity to improve the coverage of oxidised lipidome for mass spectrometry analysis
Authors: Thakker Alpesh , Pitt Andrew , Spickett Corinne
Published: August 2019

1

Phospholipid oxidation (OxPL) generates a wide variety of products with potentially novel biological activities that may be associated with disease pathogenesis. To understand their role in disease requires precise information about their abundance in biological samples. Liquid chromatography-mass spectrometry (LCMS) is a sensitive technique that can provide detailed information about the oxidative lipidome, but challenges remain. Furthermore, variation in charge of the polar head groups and the extreme diversity of oxidised species make analysis of several classes of OxPLs within one analytical run challenging.

The work in this study aims to develop improved methods for detection of OxPLs by improvement of chromatographic separation through the serial coupling of polystyrene-divinylbenzene based monolithic, and mixed-mode hydrophilic interaction (HILIC) with use of semi-targeted mass spectrometry approaches. The results suggests that by serially coupling two columns, HILIC and monolith, provided the better coverage of OxPL species in a single analytical run. We tested in-vitro generated oxidized species for phosphatidylcholine (PC) and phosphatidylethanolamine (PE) class and the combination of orthogonal chromatographic separation allowed separation of oxdised species from both the classes, which otherwise coeluted.
A new variance ratio metric to detect the timescale of compensatory dynamics
Authors: Zhao Lei , Wang Shaopeng , Hallett Lauren M. , Rypel Andrew , Sheppard Lawrence W. , Castorani Max C.N. , Shoemaker Lauren G. , Cottingham Kathryn L. , Suding Katharine , Reuman Daniel C.
Published: August 2019

Understanding the mechanisms governing ecological stability – why a property such as primary productivity is stable in some communities and variable in others – has long been a focus of ecology. Compensatory dynamics, in which anti-synchronous fluctuations between populations buffer against fluctuations at the community level, is a key theoretical mechanism of stability. Classically, compensatory dynamics have been quantified using a “variance ratio” approach that compares the ratio between community variance and aggregate population variance, such that a lower ratio indicates compensation and a higher ratio indicates synchrony among species fluctuations. However, population dynamics may be influenced by different drivers that operate on different timescales, and evidence from aquatic systems indicates that communities can be compensatory on some timescales and synchronous on others. The variance ratio and related metrics cannot reflect this timescale-specificity, yet have remained popular, especially in terrestrial systems. Here, we develop a timescale-specific variance ratio approach that formally decomposes the classical variance ratio according to the timescales of distinct contributions. The approach is implemented in a new R package, called tsvr, that accompanies this paper. We apply our approach to a long-term, multi-site grassland community dataset. Our approach demonstrates that the degree of compensation versus synchrony in community dynamics can vary by timescale. Across sites, population variability was typically greater over longer compared to shorter timescales. At some sites, minimal timescale-specificity in compensatory dynamics translated this pattern of population variability into a similar pattern of greater community variability on longer compared to shorter timescales. But at other sites, differentially stronger compensatory dynamics at longer compared to shorter timescales produced lower-than-expected community variability on longer timescales. Within every site there were plots that exhibited shifts in the strength of compensation between timescales. Our results highlight that compensatory versus synchronous dynamics are intrinsically timescale-dependent concepts, and our timescale-specific variance ratio provides a metric to quantify timescale-specificity and relate it back to the classic variance ratio.
Neutrophils Suppress Mucosal-Associated Invariant T Cells
Authors: Schneider M , Hannaway RF , Lamichhane R , de la Harpe SM , Tyndall JDA , Vernall AJ , Kettle A , Ussher JE
Published: August 2019

Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that are abundant in mucosal tissues and the liver where they can respond rapidly to a broad range of riboflavin producing bacterial and fungal pathogens. Neutrophils, which are recruited early to sites of infection, play a non-redundant role in pathogen clearance and are crucial for controlling infection. The interaction of these two cell types is poorly studied. Here, we investigated both the effect of neutrophils on MAIT cell activation and the effect of activated MAIT cells on neutrophils. We show that neutrophils suppress the activation of MAIT cells by a cell-contact and H2O2dependent mechanism. Moreover, highly activated MAIT cells were able to produce high levels of TNFα that induced neutrophil death. We therefore provide evidence for a negative regulatory feedback mechanism in which neutrophils prevent over-activation of MAIT cells and, in turn, MAIT cells limit neutrophil survival.
A mathematical multi-organ model for bidirectional epithelial-mesenchymal transitions in the metastatic spread of cancer
Authors: Franssen Linnea C. , Chaplain Mark A.J.
Published: August 2019

Cancer invasion and metastatic spread to secondary sites in the body are facilitated by a complex interplay between cancer cells of different phenotypes and their microenvironment. A trade-off between the cancer cells’ ability to invade the tissue and to metastasise, and their ability to proliferate has been observed. This gives rise to the classification of cancer cells into those ofmesenchymalandepithelialphenotype, respectively. Additionally, mixed phenotypic states between these two extremes exist. Cancer cells can transit between these states viaepithelial-mesenchymal transition(EMT) and the reverse process,mesenchymal-epithelial transition(MET). These processes are crucial both for the local tissue invasion and the metastatic spread of cancer cells. To shed light on the role of these phenotypic states and the transitions between them in the invasive and metastatic process, we extend our recently published multi-grid, hybrid, individual-based mathematical metastasis framework (Franssen et al., 2019a). In addition to cancer cells of epithelial and of mesenchymal phenotype, we now also include those of an intermediatepartial-EMTphenotype. Furthermore, we allow for the switching between these phenotypic states via EMT and MET at the biologically appropriate steps of the invasion-metastasis cascade. We also account for the likelihood of spread of cancer cells to the various secondary sites and differentiate between the tissues of the organs involved in our simulations. Finally, we consider the maladaptation of metastasised cancer cells to the new tumour microenvironment at secondary sites as well as the immune response at these sites by accounting for cancer cell dormancy and death. This way, we create a first mathematical multi-organ model that explicitly accounts for EMT-processes in individual cancer cells in the context of the invasion-metastasis cascade.
PlotTwist - a web app for plotting and annotating time-series data
Authors: Goedhart Joachim
Published: August 2019

The results from time-dependent experiments are often used to generate plots that visualize how the data evolves over time. To simplify state-of-the-art data visualization and annotation of data from such experiments, an open source tool was created with R/shiny that does not require coding skills to operate. The freely available web app accepts wide (spreadsheet) and tidy data and offers a range of options to normalize the data. The data from individual objects can be shown in three different ways: (i) lines with unique colors, (ii) small multiples and (iii) heatmap-style display. Next to this, the mean can be displayed with a 95% confidence interval for the visual comparison of different conditions. Several color blind friendly palettes are available to label the data and/or statistics. The plots can be annotated with graphical features and/or text to indicate any perturbations that were applied during the time-lapse experiments. All user-defined settings can be stored for reproducibility of the data visualization. The app is dubbed PlotTwist and is available online: https://huygens.science.uva.nl/PlotTwist
Population Structure, Stratification and Introgression of Human Structural Variation
Authors: Almarri Mohamed A. , Bergström Anders , Prado-Martinez Javier , Yang Fengtang , Fu Beiyuan , Dunham Alistair S. , Chen Yuan , Hurles Matthew E. , Tyler-Smith Chris , Xue Yali
Published: August 2019

Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, yet are still understudied. Here, we present a comprehensive analysis of deletions, duplications, insertions, inversions and non-reference unique insertions in the Human Genome Diversity Project (HGDP-CEPH) panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify in total 126,018 structural variants (25,588 <100 bp in size), of which 78% are novel. Some reach high frequency and are private to continental groups or even individual populations, including a deletion in the maltase-glucoamylase gene MGAM involved in starch digestion, in the South American Karitiana and a deletion in the Central African Mbuti in SIGLEC5, potentially leading to immune hyperactivity. We discover a dynamic range of copy number expansions and find cases of regionally-restricted runaway duplications, for example, 18 copies near the olfactory receptor OR7D2 in East Asia and in the clinically-relevant HCAR2 in Central Asia. We identify highly-stratified putatively introgressed variants from Neanderthals or Denisovans, some of which, like a deletion within AQR in Papuans, are almost fixed in individual populations. Finally, by de novo assembly of 25 genomes using linked-read sequencing we discover 1631 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. These insertions show population structure and some reside in functional regions, illustrating the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.
Residue retention promotes soil carbon accumulation in minimum tillage systems: Implications for conservation tillage
Authors: Li Yuan , Li Zhou , Chang Scott X. , Cui Song , Jagadamma Sindhu , Zhang Qingping , Cai Yanjiang
Published: August 2019

Crop residue retention and minimum tillage (including no-tillage, NT, and reduced tillage, RT) are common conservation tillage practices that have been extensively practised for improving soil health and reducing the negative environmental impact caused by intensive farming. However, the complex effect of conservation tillage practices on soil organic carbon (SOC) storage has not been systematically analyzed, and particularly, the synergistic effect of crop residue retention and minimum tillage on SOC storage remains nonexistent. We conducted a global meta-analysis using a dataset consisting of 823 pairs of data points from 164 studies. We analyzed the effect of crop residue retention and minimum tillage on SOC storage and how the above effects were influenced by various soil/environmental (soil sampling depth, soil texture, and climate) and management conditions (cropping intensity and treatment duration). We found that either residue retention or minimum tillage alone increased SOC stock, while the former increased SOC more. The NT and RT increased SOC stock by 10 and 6%, respectively, in comparison to conventional tillage (CT). The NT plus residue retention (NTS) and RT plus residue retention (RTS) resulted in 20 and 26% more increase in SOC than NT and RT, respectively. Compared with CT, NTS and RTS further increased SOC stock by 29 and 27%, respectively. The above effects were greater in the topsoil than in the subsoil. Availability of initial soil nutrient played a greater role in affecting SOC stock than climatic conditions and management practices. Both residue retention and NT increased SOC rapidly in the first 6 years regardless of soil texture or climate condition, followed by a period of slower sequestration phase before reaching a slow steady rate. Double cropping generally increased SOC stock across all conservation tillage practices as compared to single or multiple cropping. Therefore, we conclude that minimum tillage coupled with residue retention in a double cropping system is the most beneficial management system for increasing cropland SOC storage, which can inform sustainable soil management practices aimed at increasing global C sequestration.
The CTCF Anatomy of Topologically Associating Domains
Authors: Nanni Luca , Wang Cheng , Manders Freek , Groh Laszlo , Haro Paula , Oldenkamp Roel , Ceri Stefano , Logie Colin
Published: August 2019

Topologically associated domains (TADs) are defined as regions of self-interaction. To date, it is unclear how to reconcile TAD structure with CTCF site orientation, which is known to coordinate chromatin loops anchored by Cohesin rings at convergent CTCF site pairs. We first approached this problem by 4C analysis of the FKBP5 locus. This uncovered a CTCF loop encompassing FKBP5 but not its entire TAD. However, adjacent CTCF sites were able to form ‘back-up’ loops and these were located at TAD boundaries. We then analysed the spatial distribution of CTCF patterns along the genome together with a boundary identity conservation ‘gradient’ obtained from primary blood cells. This revealed that divergent CTCF sites are enriched at boundaries and that convergent CTCF sites mark the interior of TADs. This conciliation of CTCF site orientation and TAD structure has deep implications for the further study and engineering of TADs and their boundaries.
The physiological level of rNMPs present in mtDNA does not compromise its stability
Authors: Wanrooij Paulina H. , Tran Phong , Thompson Liam J. , Sharma Sushma , Kreisel Katrin , Navarrete Clara , Feldberg Anna-Lena , Watt Danielle L. , Nilsson Anna Karin , Engqvist Martin K. M. , Clausen Anders R. , Chabes Andrei
Published: August 2019

Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA), although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse lifespan and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent in SAMHD1−/− mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their lifespan. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.
The absence of C-5 DNA methylation in Leishmania donovani allows DNA enrichment from complex samples
Authors: Cuypers B , Dumetz F , Meysman P , Laukens K , De Muylder G , Dujardin J-C , Domagalska MA
Published: August 2019

Cytosine C5 methylation is an important epigenetic control mechanism in a wide array of Eukaryotic organisms and generally carried out by proteins of C-5 DNA methyltransferase family (DNMTs). In several protozoans the status of this mechanism remains elusive, such as in Leishmania, the causative agent of the disease leishmaniasis in humans and a wide array of vertebrate animals. In this work, we show that the Leishmania donovani genome contains a C-5 DNA methyltransferase (DNMT) from the DNMT6 subfamily, of which the function is still unclear, and verified its expression at RNA level. We created viable overexpressor and knock-out lines of this enzyme and characterised their genome-wide methylation patterns using whole-genome bisulfite sequencing, together with promastigote and amastigote control lines. Interestingly, despite DNMT6 presence, we found that methylation levels were equal to or lower than 0.0003% at CpG sites, 0.0005% at CHG sites and 0.0126% at CHH sites at genome scale. As none of the methylated sites were retained after manual verification, we conclude that there is no evidence for DNA methylation in this species. We demonstrate that this difference in DNA methylation between the parasite (no detectable DNA methylation) and the vertebrate host (DNA methylation), allows enrichment of parasite versus host DNA using Methyl-CpG-binding domain columns, readily available in commercial kits. As such, we depleted methylated DNA from mixes of Leishmania promastigote and amastigote DNA with human DNA, resulting in average Leishmania:human enrichments from 62x up to 263x. These results open a promising avenue for unmethylated DNA enrichment as a pre-enrichment step before sequencing Leishmania clinical samples.
Developmental regulation of fear memories by an obesogenic high-saturated fat/high-sugar diet
Authors: Vega-Torres Julio David , Reyes-Rivera Arsenio L. , Figueroa Johnny D.
Published: August 2019

Background

Anxiety and stress-related disorders are strongly linked with obesity and the consumption of obesogenic diets. Paralleling clinical findings, we showed that the consumption of an obesogenic diet during adolescence disrupts the structural integrity of amygdalar and prefrontal cortex circuits underlying emotional responses to stress. These abnormalities were associated with a PTSD-like phenotype, including heightened stress reactivity to predator odor trauma, anxiety-like behaviors, and profound learning deficits. The present follow-up study investigates how an obesogenic diet alters aversion-related associative memories across adolescence.

Methods

Adolescent Lewis rats were fed for eight weeks with an experimental Western-like high-saturated fat/high-sugar diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Acoustic fear-potentiated startle (FPS) responses were assessed longitudinally at weeks 1, 4, and 8 after commencing the diets to determine the effects of the WD on cued fear conditioning, fear extinction learning, and fear extinction retention.

Results

We found that the rats that consumed the WD exhibited substantial attenuation of fear extinction and fear extinction retention when remote memory was tested. One-week WD consumption was sufficient to induce impairments in fear extinction learning. This phenotype was associated with reduced dopamine receptor 1 mRNA levels in the prefrontal cortex. Interestingly, our reconditioning paradigm revealed that early-acquired fear memories were resistant to the disruptive effects of chronic WD consumption on cued fear learning.

Conclusions

Our findings demonstrate that consumption of an obesogenic WD during adolescence heightens behavioral vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience and that fear extinction principles are the foundation of psychological treatments for PTSD, understanding how obesity and obesogenic diets affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance.

HIGHLIGHTS

Acute WD consumption impairs cued fear extinction learning in a fear-potentiated startle paradigm.

WD consumption attenuates fear extinction memory retention

WD consumption during adolescence increases acoustic startle responsivity over time

Chronic WD consumption decreases dopamine receptor D1 mRNA levels in the prefrontal cortex.
System-wide analyses of the fission yeast poly(A)+ RNA interactome reveal insights into organisation and function of RNA-protein complexes
Authors: Kilchert Cornelia , Kecman Tea , Priest Emily , Hester Svenja , Kus Krzysztof , Castello Alfredo , Mohammed Shabaz , Vasiljeva Lidia
Published: August 2019

Production, function, and turnover of mRNA are orchestrated by multi-subunit machineries that play a central role in gene expression. Within these molecular machines, interactions with the target mRNA are mediated by RNA-binding proteins (RBPs), and the accuracy and dynamics of these RNA-protein interactions are essential for their function. Here, we show that fission yeast whole cell poly(A)+ RNA-protein crosslinking data provides system-wide information on the organisation and function of the RNA-protein complexes. We evaluate relative enrichment of cellular RBPs on poly(A)+ RNA to identify interactors with high RNA-binding activity and provide key information about the RNA-binding properties of large multi-protein complexes, such as the mRNA 3’ end processing machinery (cleavage and polyadenylation factor, CPF) and the RNA exosome. We demonstrate that different functional modules within CPF differ in their ability to interact with RNA. Importantly, we reveal that CPF forms additional contacts with RNA via the Fip1 subunit of the polyadenylation module and two subunits of the nuclease module. In addition, our data highlights the central role of the RNA helicase Mtl1 in RNA degradation by the exosome as mutations in Mtl1 lead to disengagement of the exosome from RNA. We examine how routes of substrate access to the complex are affected upon mutation of exosome subunits. Our results provide important insights into how different components of the exosome contribute to engagement of the complex with substrate RNA. Overall, our data uncover how multi-subunit cellular machineries interact with RNA, on a proteome-wide scale.
BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation
Authors: Shen Hongtao , Li Jing , Xie Xiujie , Yang Huan , Zhang Mengxue , Wang Bowen , Kent K. Craig , Plutzky Jorge , Guo Lian-Wang
Published: August 2019

Traditionally a pharmacologic target for antipsychotic treatment, the sigma-2 receptor (S2R) was recently implicated in cholesterol homeostasis. Here we investigated the transcriptional regulation of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, 4) upon cholesterol perturbation.

Cytosolic cholesterol deprivation was induced using an export blocker of lysosomal cholesterol in ARPE19 cells. This condition upregulated mRNA and protein levels of S2R, and of SREBP2 but not SREBP1, transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD4 (though widely deemed as a master regulator) or BRD3 prevented S2R upregulation induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, BRD2 co-immunoprecipitated with the SREBP2 transcription-active N-terminal domain, and chromatin immunoprecipitation-qPCR showed a BRD2 occupancy at the S2R gene promoter.

In summary, this study reveals a novel BRD2/SREBP2 cooperative regulation of S2R transcription in response to cytosolic cholesterol deprivation, thus shedding new light on epigenetic control of cholesterol biology.
Subcellular metabolic pathway kinetics are revealed by correcting for artifactual post harvest metabolism
Authors: Trefely Sophie , Liu Joyce , Huber Katharina , Doan Mary T. , Jiang Helen , Singh Jay , von Krusenstiern Eliana , Bostwick Anna , Xu Peining , Bogner-Strauss Juliane , Wellen Kathryn E. , Snyder Nathaniel W.
Published: August 2019

OBJECTIVE

The dynamic regulation of metabolic pathways can be monitored by stable isotope tracing. Yet, many metabolites are part of distinct processes within different subcellular compartments. Standard isotope tracing experiments relying on analyses in whole cells may not accurately reflect compartmentalized metabolic processes. Analysis of compartmentalized metabolism and the dynamic interplay between compartments can potentially be achieved by stable isotope tracing followed by subcellular fractionation. Although it is recognized that metabolism can take place during biochemical fractionation of cells, a clear understanding of how such post-harvest metabolism impacts the interpretation of subcellular isotope tracing data and methods to correct for this are lacking. We set out to directly assess artifactual metabolism, enabling us to develop and test strategies to correct for it. We apply these techniques to examine the compartment-specific metabolic kinetics of 13C-labeled substrates targeting central metabolic pathways.

METHODS

We designed a stable isotope tracing strategy to interrogate post-harvest metabolic activity during subcellular fractionation using liquid chromatography-mass spectrometry (LC-MS).

RESULTS

We show that post-harvest metabolic activity occurs rapidly (within seconds) upon cell harvest. With further characterization we reveal that this post-harvest metabolism is enzymatic, and reflects the metabolic capacity of the sub-cellular compartment analyzed; but is limited in the extent of its propagation into downstream metabolites in metabolic pathways. We also propose and test a post-labeling strategy to assess the amount of post-harvest metabolism occurring in an experiment and then to adjust data to account for this. We validate this approach for both mitochondrial and cytosolic metabolic analyses.

CONCLUSIONS

Our data indicate that isotope tracing coupled with sub-cellular fractionation can reveal distinct and dynamic metabolic features of cellular compartments, and that confidence in such data can be improved by applying a post-labeling correction strategy. We examine compartmentalized metabolism of acetate and glutamine and show that acetyl-CoA is turned over rapidly in the cytosol and acts as a pacemaker of anabolic metabolism in this compartment.
VAMP8 contributes to TRIM6-mediated type-I interferon antiviral response during West Nile virus infection
Authors: van Tol Sarah , Atkins Colm , Bharaj Preeti , Johnson Kendra N. , Hage Adam , Freiberg Alexander N. , Rajsbaum Ricardo
Published: August 2019

Several members of the tripartite motif (TRIM) family of E3 ubiquitin ligases regulate immune pathways including the antiviral type I interferon (IFN-I) system. Previously, we demonstrated that TRIM6 is involved in IFN-I induction and signaling. In the absence of TRIM6, optimal IFN-I signaling is reduced, allowing increased replication of interferon-sensitive viruses. Despite having evolved numerous mechanisms to restrict the vertebrate host’s IFN-I response, West Nile Virus (WNV) replication is sensitive to pre-treatment with IFN-I. However, the regulators and products of the IFN-I pathway that are important in regulating WNV replication are incompletely defined. Consistent with WNV’s sensitivity to IFN-I, we found that in TRIM6 knockout (TRIM6-KO) A549 cells WNV replication is significantly increased and IFN-I induction and signaling is impaired compared to wild-type (wt) cells. IFNβ pre-treatment was more effective in protecting against subsequent WNV infection in wt cells as compared to TRIM6-KO, indicating that TRIM6 contributes to the establishment of an IFN-induced antiviral response against WNV. Using next generation sequencing, we identified VAMP8 as a potential factor involved in this TRIM6-mediated antiviral response. VAMP8 knockdown resulted in reduced Jak1 and STAT1 phosphorylation and impaired induction of several ISGs following WNV infection or IFNβ treatment. Furthermore, VAMP8-mediated STAT1 phosphorylation required the presence of TRIM6. Therefore, the VAMP8 protein is a novel regulator of IFN-I signaling, and its expression and function is dependent on TRIM6 activity. Overall, these results provide evidence that TRIM6 contributes to the antiviral response against WNV and identified VAMP8 as a novel regulator of the IFN-I system.

IMPORTANCE

WNV is a mosquito-borne flavivirus that poses threat to human health across large discontinuous areas throughout the world. Infection with WNV results in febrile illness, which can progress to severe neurological disease. Currently, there are no approved treatment options to control WNV infection. Understanding the cellular immune responses that regulate viral replication is important in diversifying the resources available to control WNV. Here we show that the elimination of TRIM6 in human cells results in an increase in WNV replication and alters the expression and function of other components of the IFN-I pathway through VAMP8. Dissecting the interactions between WNV and host defenses both informs basic molecular virology and promotes the development of host- and viral-targeted antiviral strategies.
Crystal structure of UDP-glucose pyrophosphorylase fromYersinia pestis, a potential therapeutic target against plague
Authors: Gibbs Morgan E. , Lountos George T. , Gumpena Rajesh , Waugh David S.
Published: August 2019

Yersinia pestis, the causative agent of bubonic plague, is one of the most lethal pathogens in recorded human history. Today, the concern is the possible misuse ofY. pestisas an agent in bioweapons and bioterrorism. Current therapies for the treatment of plague include the use of a small number of antibiotics, but clinical cases of antibiotic resistance have been reported in some areas of the world. Therefore, the discovery of new drugs is required to combat potentialY. pestisinfection. Here, the crystal structure of theY. pestisUDP-glucose pyrophosphorylase (UGP), a metabolic enzyme implicated in the survival ofY. pestisin mouse macrophages, is described at 2.17 Å resolution. The structure provides a foundation that may enable the rational design of inhibitors and open new avenues for the development of antiplague therapeutics.
Probiotic creamy soy sauce with Lactobacillus plantarum BG 112
Authors: Moraes Filho Marsilvio Lima , Busanello Marli , Garcia Sandra
Published: August 2019

Purpose

The purpose of this paper is to apply okara flour in the elaboration of a product, verifying the effect of the fermentation by Lactobacillus plantarum BG 112 on the antihypertensive activity and to develop probiotic sauce with gums and low lipid content.

Design/methodology/approach

During the fermentation process, the inhibitory activity of angiotensin-converting enzyme (ACE) and production of organic acids were determined. The simplex-centroid mixture of guar gum, xanthan gum and pregelatinized cassava starch was used for studying the variables water holding capacity, viscosity and firmness. Counts of probiotics and in vitro survival of probiotics in simulated gastrointestinal conditions were made.

Findings

The fermented soymilk showed ACE inhibition capacity above 50 percent with 32 h of fermentation, increasing the levels of lactic acid and acetic acid progressively. Based on the regression analysis and response surfaces, the binary mixture with guar gum and xanthan was chosen as the most suitable for the formulation of the sauce, having over 30 days of storage counts above 8.5 log CFU.g−1 and above 6 log CFU.g−1 after simulation of gastrointestinal conditions. The global acceptance was 7.0 corresponding to the moderately liked.

Practical implications

The findings suggest that the sauce developed has been well accepted by potential consumers and can be incorporated into the diet and can result in health benefits for the consumer when regularly ingested. The fermentation process of soymilk promoted an increase in antihypertensive capacity. Despite the reduction in viable cell counts throughout storage, counts remained high in the product, having a high survival rate after exposure under simulated gastrointestinal conditions.

Originality/value

The use of okara flour in the diet is viable and helps to improve the nutritional composition of foods. The use of okara flour in sauce showed potential applicability and could be incorporated into different products. The fermentation process of soymilk with okara flour produces benefits beyond the sensorial characteristics. The elaborated probiotic sauce presented physical–chemical and microbiological stability throughout the storage, being an alternative for people with food restrictions.
Evaluating PDA using financial analysis for streaming videos: a case study at a US academic library
Authors: Falloon Kerry A.
Published: August 2019

Purpose

The purpose of this study is to evaluate the pre and post success of patron-driven acquisition (PDA) streaming video projects using financial analysis, thus comparing PDA as a collection building tool against other legacy purchasing practices.

Design/methodology/approach

This is primarily a quantitative study based on deductive data derived; however, it does include qualitative findings. Hence, it is a mixed study.

Findings

The study approaches this topic from the viewpoint that ongoing evaluations of PDA projects, based on savings and benefits derived, can be practically conducted and are useful for CD decision-making by purchasing agents in academic libraries.

Research limitations/implications

Caution should be used when generalizing this study due to its specificity of its library’s collection development (CD) needs and methodology. The study is not intended to be original research, but it builds upon other case studies in this area.

Practical implications

In addition to improving CD strategies, libraries could use this study to develop a financial valuation methodology, which can help guide purchasing practices.

Social implications

This study has implications to all library stakeholders.

Originality/value

Few studies have compared and analyzed streaming video PDA programs using financial analysis in a practical manner to aid library acquisitions.
Trust, distrust and translation in a disaster
Authors: Cadwell Patrick
Published: August 2019

Purpose

The purpose of this paper is to describe, explain and provide context for relationships between translation, trust and distrust using accounts of the 2011 Great East Japan Earthquake given by foreign residents who experienced the disaster.

Design/methodology/approach

This research provides a qualitative analysis of ethnographic interview data drawn from a broader study of communication in the 2011 disaster using the cases of 28 foreign residents of the disaster zone from 12 different countries of origin.

Findings

The study confirms the general importance, the linguistic challenges and the context dependency of trust in disaster-related communication at the response phase. It found that translation was involved in some trust reasoning carried out by foreign residents and that translation was anad hocact undertaken by linguistically and culturally proficient acquaintances and friends.

Research limitations/implications

The research examines a limited range of trust phenomena and research participants: only reason-based, social trust described by documented foreign residents of the 2011 disaster zone in Japan was considered. Furthermore, generalisations from the case study data should be approached with caution.

Originality/value

This paper adds to the literature on trust and disaster response as opposed to trust and disaster preparedness, which has already been comprehensively studied. It responds to calls for more studies of the role of context in the understanding of trust and for greater attention to be paid in research to relationships between trust and other phenomena.
Entrepreneurial orientation and innovation performance: insights from Korean ventures
Authors: Seo Ribin
Published: August 2019

Purpose

The purpose of this paper is to explore the curvilinear relationship between entrepreneurial orientation (EO) and innovation performance in ventures of Korea, where this topic has been unexplored.

Design/methodology/approach

This study used 1,837 ventures’ responses in a panel data of the 2015 Korea’s Venture Business Investigation Survey. The measurements of EO based on the Miller/Covin and Slevin scale were used from the survey. The author adopted and independently measured three different indicators of innovation performance: technology innovation, product innovation and sales growth.

Findings

The results of the regression analysis show the significant curvilinear relationships of EO with technology innovation and product innovation, while the relationship between EO and sales growth remains linear. The author also found that multiplicative EO construct explains the changes inR2better than the summative EO construct for the improvement of innovations in technology and product.

Originality/value

This paper provides empirical evidence on the EO–innovation performance relationships from Korean ventures – an underexplored area of research. It also takes into account the curvilinear relationships of summative and multiplicative EO constructs with different performance indicators. Future research can benefit from the use of the multiplicative EO estimation and multiple performance indicators to capture a clearer picture of the causal relationships.