bluuebunny/crossref_metadata_2025 huggingface dataset:
An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys
Authors: Parra Marilyn , Booth Ben W. , Weiszmann Richard , Yee Brian , Yeo Gene W. , Brown James B. , Celniker Susan E. , Conboy John G.
Published: March 2018

During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the SF3B1 splicing factor gene, which expresses ~50% of its transcripts in late erythroblasts as a nuclear isoform that retains intron 4. RNA-seq analysis of nonsense-mediated decay (NMD)-inhibited cells revealed previously undescribed splice junctions, rare or not detected in normal cells, that connect constitutive exons 4 and 5 to highly conserved cryptic cassette exons within the intron. Minigene splicing reporter assays showed that these cassettes promote IR. Genome-wide analysis of splice junction reads demonstrated that cryptic noncoding cassettes are much more common in large (>1kb) retained introns than they are in small retained introns or in non-retained introns. Functional assays showed that heterologous cassettes can promote retention of intron 4 in the SF3B1 splicing reporter. Although many of these cryptic exons were spliced inefficiently, they exhibited substantial binding of U2AF1 and U2AF2 adjacent to their splice acceptor sites. We propose that these exons function as decoys that engage the intron-terminal splice sites, blocking cross-intron interactions required for excision. Developmental regulation of decoy function underlies a major component of the erythroblast IR program.
Neural coding of leg proprioception inDrosophila
Authors: Mamiya Akira , Gurung Pralaksha , Tuthill John
Published: March 2018

Animals rely on an internal sense of body position and movement to effectively control motor behavior. This sense of proprioception relies on diverse populations of mechanosensory neurons distributed throughout the body. However, little is known about how proprioceptor neurons collectively encode sensory stimuli. Here, we investigate neural coding of leg proprioception inDrosophila, usingin vivotwo-photon calcium imaging of proprioceptors during controlled movements of the fly tibia. We found that the axons of leg proprioceptors are organized into distinct functional projections that contain topographic representations of specific kinematic features. Using subtype-specific genetic driver lines, we show that one group of axons encodes tibia position (flexion/extension), another encodes movement direction, and a third encodes bidirectional movement and vibration frequency. Thus, proprioceptive sensing of a single leg joint is mediated by multiple subtypes of specialized sensory neurons. This architecture may help to maximize information transmission, processing speed, and robustness, which are critical for feedback control of the limbs during locomotion.
A strategy to study intrinsically mixed folded proteins: The structure in solution of ataxin-3
Authors: Sicorello A. , Kelly G. , Oregioni A. , Nováček J. , Sklenář V. , Pastore A.
Published: March 2018

It has increasingly become clear over the last two decades that proteins can contain both globular domains and intrinsically unfolded regions which both can contribute to function. While equally interesting, the disordered regions are difficult to study because they usually do not crystallize unless bound to partners and are not easily amenable to cryo-electron microscopy studies. Nuclear magnetic resonance spectroscopy remains the best technique to capture the structural features of intrinsically mixed folded proteins and describe their dynamics. These studies rely on the successful assignment of the spectrum, task not easy per se given the limited spread of the resonances of the disordered residues. Here, we describe assignment of the spectrum of ataxin-3, the protein responsible for the neurodegenerative Machado-Joseph disease. We used a 42 kDa construct containing a globular N-terminal josephin domain and a C-terminal tail which comprises thirteen polyglutamine repeats within a low-complexity region. We developed a strategy which allowed us to achieve 87% assignment of the spectrum. We show that the C-terminal tail is flexible with extended helical regions and interacts only marginally with the rest of the protein. We could also, for the first time, deduce the structure of the polyglutamine repeats within the context of the full-length protein and show that it has a strong helical propensity stabilized by the preceding region.
Lipid droplet phase transition in freezing cat embryos and oocytes probed by Raman spectroscopy
Authors: Okotrub K.A. , Mokrousova V.I. , Amstislavsky S.Y. , Surovtsev N.V.
Published: March 2018

Embryo and oocyte cryopreservation is a widely used technology for cryopreservation of genetic resources. One challenging limitation of this technology is the cell damage during freezing associated with the intracellular lipid droplets. We exploit a Raman spectroscopy to investigate the freezing of cumulus-oocyte complexes, mature oocytes and early embryos of a domestic cat. All these cells are rich in lipids. The degree of lipid unsaturation, lipid phase transition from liquid-like disordered to solid-like ordered state (main transition) and triglyceride polymorphic state are studied. For all cells examined, the average degree of lipid unsaturation is estimated about 1.3 (with ±20 % deviation) double bonds per acyl chain. The onset of the main lipid phase transition occurs in a temperature range from −10 to +4 °C and does not depend significantly on the cell type. It is found that lipid droplets in cumulus-oocyte complexes undergo an abrupt lipid crystallization, which not completely correlate with the ordering of lipid molecule acyl chains. In the case of mature oocytes and early embryos obtainedin vitrofrom cumulus-oocyte complexes, the lipid phase transition is broadened. In frozen state lipid droplets inside the cumulus-oocyte complexes have higher content of triglyceride polymorphic β and β′ phases (∼66%) than it is estimated for the mature oocytes and the early embryos (∼50%). For the first time, to our knowledge, temperature evolution of lipid droplets phase state is examined. Raman spectroscopy is proved as a prospective tool forin situmonitoring of lipid phase state in single embryo/oocyte during freezing.
Interaction of diabetes and smoking on stroke: A population-based cross-sectional survey in China
Authors: Lou Heqing , Dong Zongmei , Zhang Pan , Shao Xiaoping , Li Ting , Zhao Chunyan , Zhang Xunbao , Lou Peian
Published: March 2018

Objectives

Diabetes and smoking are known independent risk factors for stroke; however, their interaction concerning stroke is less clear. We aimed to explore such interaction and its influence on stroke in Chinese adults.

Design

Cross-sectional study.

Setting

Community-based investigation in Xuzhou, China.

Participants

A total of 39,887 Chinese adults who fulfilled the inclusion criteria were included.

Methods

Participants were selected using a multi-stage stratified cluster method, and completed self-reported questionnaires on stroke and smoking. Type 2 diabetes mellitus (DM2) was assessed by fasting blood glucose or use of antidiabetic medication. Interaction, relative excess risk owing to interaction (RERI), attributable proportion (AP), and synergy index (S) were evaluated using a logistic regression model.

Results

After adjustment for age, sex, marital status, educational level, occupation, physical activity, body mass index, hypertension, family history of stroke, alcohol use, and blood lipids, the relationships between DM2 and stroke, and between smoking and stroke, were still significant: odds ratios were 2.75 (95% confidence interval [CI]: 2.03–3.73) and 1.70 (95% CI: 1.38–2.10), respectively. In subjects with DM2 who smoked, the RERI, AP, and S values (and 95% CIs) were 1.80 (1.24–3.83), 0.52 (0.37–0.73), and 1.50 (1.18–1.84), respectively.

Conclusions

The results suggest there are additive interactions between DM2 and smoking and that these affect stroke in Chinese adults.

Article Summary: Strengths and limitations of this study

The strengths of this study were that a large sample population was randomly selected from the general population of Xuzhou and many confounding risk factors were adjusted for.

Owing to the cross-sectional design, we could not determine a causal combined relationship among diabetes, smoking and stroke.

We were not able to control for some important and well-known risk factors of diabetes, such as heart rate and cardiovascular causes.

We did not measure fresh fruit consumption, which is causally related to stroke.
An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort 1936
Authors: Hamilton Olivia KL , Zhang Qian , McRae Allan F , Walker Rosie M , Morris Stewart W , Redmond Paul , Campbell Archie , Murray Alison D , Porteous David J , Evans Kathryn L , McIntosh Andrew M , Deary Ian J , Marioni Riccardo E
Published: March 2018

Background

The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. Additionally, it is of interest whether such contributions are independent of those attributed by the most widely used clinical measure of body mass – the Body Mass Index (BMI).

Method

We tested whether an epigenetic BMI score accounts for inter-individual variation in health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian Birth Cohort 1936 (n=903). Weights for the epigenetic BMI score were derived using penalised regression on methylation data from unrelated Generation Scotland participants (n=2566).

Results

The Epigenetic BMI score was associated with variables related to poor physical health (R2 ranges from 0.02-0.10), metabolic syndrome (R2 ranges from 0.01-0.09), lower crystallised intelligence (R2=0.01), lower health-related quality of life (R2=0.02), physical inactivity (R2=0.02), and social deprivation (R2=0.02). The epigenetic BMI score (per SD) was also associated with self-reported type 2 diabetes (OR 2.25, 95 % CI 1.74, 2.94), cardiovascular disease (OR 1.44, 95 % CI 1.23, 1.69) and high blood pressure (OR 1.21, 95% CI 1.13, 1.48; all at p<0.0011 after Bonferroni correction).

Conclusions

Our results show that regression models with epigenetic and phenotypic BMI scores as predictors account for a greater proportion of all outcome variables than either predictor alone, demonstrating independent and additive effects of epigenetic and phenotypic BMI scores.
Big data approaches to decomposing heterogeneity across the autism spectrum
Authors: Lombardo Michael V. , Lai Meng-Chuan , Baron-Cohen Simon
Published: March 2018

Autism is a diagnostic label based on behavior. While the diagnostic criteria attempts to maximize clinical consensus, it also masks a wide degree of heterogeneity between and within individuals at multiple levels of analysis. Understanding this multi-level heterogeneity is of high clinical and translational importance. Here we present organizing principles to frame the work examining multi-level heterogeneity in autism. Theoretical concepts such as ‘spectrum’ or ‘autisms’ reflect non-mutually exclusive explanations regarding continuous/dimensional or categorical/qualitative variation between and within individuals. However, common practices of small sample size studies and case-control models are suboptimal for tackling heterogeneity. Big data is an important ingredient for furthering our understanding heterogeneity in autism. In addition to being ‘feature-rich’, big data should be both ‘broad’ (i.e. large sample size) and ‘deep’ (i.e. multiple levels of data collected on the same individuals). These characteristics help ensure the results from a population are more generalizable and facilitate evaluation of the utility of different models of heterogeneity. A model’s utility can be shown by its ability to explain clinically or mechanistically important phenomena, but also by explaining how variability manifests across different levels of analysis. The directionality for explaining variability across levels can be bottom-up or top-down, and should include the importance of development for characterizing change within individuals. While progress can be made with ‘supervised’ models built upon a priori or theoretically predicted distinctions or dimensions of importance, it will become increasingly important to complement such work with unsupervised data-driven discoveries that leverage unknown and multivariate distinctions within big data. Without a better understanding of how to model heterogeneity between autistic people, progress towards the goal of precision medicine may be limited.
25 Years of Molecular Biology Databases: A Study of Proliferation, Impact, and Maintenance
Authors: Imker Heidi J.
Published: March 2018

Online resources enable unfettered access to and analysis of scientific data and are considered crucial for the advancement of modern science. Despite the clear power of online data resources, including web-available databases, proliferation can be problematic due to challenges in sustainability and long-term persistence. As areas of research become increasingly dependent on access to collections of data, an understanding of the scientific community’s capacity to develop and maintain such resources is needed.

The advent of the Internet coincided with expanding adoption of database technologies in the early 1990s, and the molecular biology community was at the forefront of using online databases to broadly disseminate data. The journalNucleic Acids Researchhas long published articles dedicated to the description of online databases, as either debut or update articles. Snapshots throughout the entire history of online databases can be found in the pages ofNucleic Acids Research‘s “Database Issue.” Given the prominence of the Database Issue in the molecular biology and bioinformatics communities and the relative rarity of consistent historical documentation, database articles published in Database Issues provide a particularly unique opportunity for longitudinal analysis.

To take advantage of this opportunity, the study presented here first identifies each unique database described in 3055Nucleic Acids ResearchDatabase Issue articles published between 1991-2016 to gather a rich dataset of databases debuted during this time frame, regardless of current availability. In total, 1727 unique databases were identified and associated descriptive statistics were gathered for each, including year debuted in a Database Issue and the number of all associated Database Issue publications and accompanying citation counts. Additionally, each database identified was assessed for current availability through testing of all associated URLs published. Finally, to assess maintenance, database websites were inspected to determine the last recorded update. The resulting work allows for an examination of the overall historical trends, such as the rate of database proliferation and attrition as well as an evaluation of citation metrics and on-going database maintenance.
Zebrafish as a model to investigate the effects of exercise in cancer
Authors: Yin Alexandra , Campbell Nathaniel R. , Jones Lee W. , White Richard M.
Published: March 2018

Emerging data indicates that exercise may regulate cancer pathogenesis, but the mechanisms underpinning how it regulates the tumor as well as surrounding microenvironment are poorly understood. Dissecting this complex, highly integrated physiology requires model systems which accurately recapitulate key aspects of human response to exercise, yet permit rapid and unbiased genetic interrogation of relevant pathways. The zebrafish has emerged as a new model for cancer due to its high resolution in vivo imaging and capacity for large-scale, unbiased screening approaches. Here, we have developed a set of tools to study the effects of exercise in a zebrafish model of melanoma. Using a flow chamber, we studied the effects of endurance exercise bouts (3-6 hour/d, 5d/wk for 1 to 3 wks) in both larval and adult zebrafish. The regimen was well tolerated, with no unexpected toxicities or changes in survival. When the zebrafish were transplanted with ZMEL1-GFP melanoma cells, we found that endurance exercise over a 2-week period led to a significant decrease in cancer growth in the larval zebrafish. As zebrafish cancer models show strong conservation in human disease, our findings have direct application to understanding the human exercise/cancer relationship.
Dystroglycan proteolysis is conformationally-regulated and disrupted by disease-associated mutations
Authors: Hayward Amanda N. , Gordon Wendy R.
Published: March 2018

The adhesion receptor dystroglycan provides a critical mechanical link between the extracellular matrix (ECM) and the actin cytoskeleton to help muscle cells withstand contraction and neural cells maintain the blood brain barrier. Disrupting the link is associated with diseases such as cancer and muscular dystrophy. Proteolysis of dystroglycan by Matrix Metalloproteases (MMPs) also breaks the mechanical anchor and is amplified in several pathogenic states. We use a combination of biochemical and cell-based assays to show that dystroglycan proteolysis is conformationally regulated by an extracellular, juxtamembrane “proteolysis domain”, comprised of tandem Ig-like and SEA-like domains. The intact proteolysis domain is resistant to MMP cleavage, but structurally-disruptive muscular dystrophy-related mutations sensitize dystroglycan to proteolysis. Moreover, increased dystroglycan proteolysis correlates with faster cell migration, linking proteolysis to a disease-relevant cellular phenotype. Intriguingly, previously uncharacterized cancer-associated mutations that map to the proteolysis domain similarly lead to increases in proteolysis and rates of cell migration, potentially revealing a new pathogenic mechanism in cancer.
Effect of tributyltin chloride (TBT-Cl) exposure on expression ofHSP90β1in the river pufferfish (Takifugu obscurus): evidences for its immunologic function involving in exploring process
Authors: Dong-po Xu , Di-an Fang , Chang-sheng Zhao , Shu-lun Jiang , Hao-yuan Hu
Published: March 2018

HSP90β1(known as GP96) is a vital endoplasmic reticulum depended chaperonin among the HSPs family. It plays important roles in regulating the growth, development, differentiation, and apoptosis of cells. Furthermore, it always processes and presents antigen of the tumor and keeps balance for the intracellular environment. In the present study, we explored the effect of tributyltin chloride (TBT-Cl) exposure onHSP90β1expression in river pufferfish,Takifugu obscurus. The full length ofTo-HSP90β1was gained with 2775 bp in length, an ORF obtained with 2412 bp encoding an 803 aa polypeptide. The phylogenetic tree was constructed and showed the close relationship to other fish species. TheHSP90β1mRNA transcript was expressed in all tissues investigated. After the acute and chronic exposure of TBT-Cl, the mRNA level ofTo-HSP90β1significantly up-regulated in tissues of liver and gill. Moreover, the histochemistry study indicated the injury degree of TBT-Cl on liver and gill. Immunohistochemistry (IHC) staining results implied the cytoplasm reorganization after TBT-Cl stress and the function of immunoregulation forTo-HSP90β1. All the results indicated thatHSP90β1may involve in the resistance to the invasion of TBT-Cl for keeping autoimmune homeostasis.
Contribution of structural variation to genome structure: TAD fusion discovery and ranking
Authors: Huynh Linh , Hormozdiari Fereydoun
Published: March 2018

The significant contribution of structural variants to function, disease, and evolution is widely reported. However, in many cases, the mechanism by which these variants contribute to the phenotype is not well understood. Recent studies reported structural variants that disrupted the three-dimensional genome structure by fusing two topologically associating domains (TADs), such that enhancers from one TAD interacted with genes from the other TAD, and could cause severe developmental disorders. However, no computational method exists for directly scoring and ranking structural variations based on their effect on the three-dimensional structure such as the TAD disruption to guide further studies of their biological function. In this paper, we formally define TAD fusion and provide a combinatorial approach for assigning a score to quantify the level of TAD fusion for each deletion denoted as TAD fusion score. We also show that our method outperforms the approaches which use predicted TADs and overlay the deletion on them to predict TAD fusion. Furthermore, we show that deletions that cause TAD fusion are rare and under negative selection in general population. Finally, we show that our method correctly gives higher scores to deletions reported to cause various disorders (developmental disorder and cancer) in comparison to the deletions reported in the 1000 genomes project.
Environmentally controlled curvature of single collagen proteins
Authors: Rezaei Naghmeh , Lyons Aaron , Forde Nancy R.
Published: March 2018

The predominant structural protein in vertebrates is collagen, which plays a key role in extracellular matrix and connective tissue mechanics. Despite its prevalence and physical importance in biology, the mechanical properties of molecular collagen are far from established. The flexibility of its triple helix is unresolved, with descriptions from different experimental techniques ranging from flexible to semirigid. Furthermore, it is unknown how collagen type (homo-vs. heterotrimeric) and source (tissue-derived vs. recombinant) influence flexibility. Using SmarTrace, a chain tracing algorithm we devised, we performed statistical analysis of collagen conformations collected with atomic force microscopy (AFM) to determine the protein’s mechanical properties. Our results show that types I, II and III collagens – the key fibrillar varieties – exhibit molecular flexibilities that are very similar. However, collagen conformations are strongly modulated by salt, transitioning from compact to extended as KCl concentration increases, in both neutral and acidic pH. While analysis with a standard worm-like chain model suggests that the persistence length of collagen can attain almost any value within the literature range, closer inspection reveals that this modulation of collagen’s conformational behaviour is not due to changes in flexibility, but rather arises from the induction of curvature (either intrinsic or induced by interactions with the mica surface). By modifying standard polymer theory to include innate curvature, we show that collagen behaves as an equilibrated curved worm-like chain (cWLC) in two dimensions. Analysis within the cWLC model shows that collagen’s curvature depends strongly on pH and salt, while its persistence length does not. Thus, we find that triple-helical collagen is well described as semiflexible, irrespective of source, type, pH and salt environment. These results demonstrate that collagen is more flexible than its conventional description as a rigid rod, which may have implications for its cellular processing and secretion.
Effect of 5-transisomer of arachidonic acid on model liposomal membranes studied by a combined simulation and experimental approach
Authors: Tremi Ioanna , Anagnostopoulos Dimitrios , Spyratou Ellas , Gkeka Paraskevi , Georgakilas Alexandros G. , Chatgilialoglu Chryssostomos , Cournia Zoe
Published: March 2018

Unsaturated fatty acids are found in humans predominantly in thecisconfiguration. Fatty acids in thetransconfiguration are primarily the result of human processing (transfats), but can also be formed endogenously by radical stress. Thecis-transisomerization of fatty acids by free radicals could be connected to several pathologies.Transfats have been linked to an increased risk of coronary artery disease; however, the reasons for the resulting pathogenesis remain unclear. Here, we investigate the effect of a monotransisomer of arachidonic acid (C20:4-5trans,8cis,11cis,14cis) produced by free radicals in physiological concentration on a model erythrocyte membrane using a combined experimental and theoretical approach. Molecular Dynamics (MD) simulations of two model lipid bilayers containing arachidonic acid and its 5-transisomer in 3% mol. were carried out for this purpose. The 5-transisomer formation in the phospholipids was catalyzed by HOCH2CH2S• radicals, generated from the corresponding thiol by γ-irradiation, in multilamellar vesicles (MLVs) of SAPC. Large unilamellar vesicles were made by the extrusion method (LUVET) as a biomimetic model forcis-transisomerization. Atomic Force Microscopy and Dynamic Light Scattering were used to measure the average size, morphology, and the z-potential of the liposomes. Both results from MD simulations and experiments are in agreement and indicate that the two model membranes display different physicochemical properties in that the bilayers containing thetransfatty acids were more ordered and more rigid than those containing solely thecisarachidonic acid. Correspondingly, the average size of the liposomes containingtransisomers was smaller than the ones without.
Assessing macrophyte seasonal dynamics using dense time series of medium resolution satellite data
Authors: Villa Paolo , Pinardi Monica , Bolpagni Rossano , Gillier Jean-Marc , Zinke Peggy , Nedelcuţ Florin , Bresciani Mariano
Published: March 2018

Thanks to the improved spatial and temporal resolution of new generation Earth Observation missions, such as Landsat 8 and Sentinel-2, the potential of remote sensing techniques in mapping land surface phenology of terrestrial biomes can now be tested in inland water systems.

We assessed the capabilities of dense time series of medium resolution satellite data to deliver quantitative information about macrophyte phenology metrics, focusing on three temperate European shallow lakes with connected wetlands, located in Italy, France and Romania.

Leaf area index (LAI) maps for floating and emergent macrophyte growth forms were derived from semi-empirical regression modelling based on the best performing spectral index, with an error level around 0.11 m2m-2. Phenology metrics were computed from LAI time series using TIMESAT code and used to analyse macrophyte seasonal dynamics in terms of spatial patterns and species-dependent variability. Peculiar patterns of autochthonous and allochthonous species seasonality across the three study areas were related to the environmental characteristics of each area in terms of ecological and hydrological conditions.

In addition, the influence of satellite dataset characteristics – i.e. cloud cover thresholding, temporal resolution and missing acquisitions – on phenology timing metrics retrieval was assessed. Results have shown that with full resolution (5-day revisit) time series, cloud cover can bias phenology timing metrics by less than 2 days, and that reducing temporal resolution to 15 days (similar to Landsat revisit) still allows for mapping the start and peak of macrophyte growth with an error level around 2–3 days.
The territory of my body: Testosterone prevents limb cooling in the Rubber Hand Illusion
Authors: van der Westhuizen Donné , Page Teneille , Solms Mark , Honk Jack van
Published: March 2018

The Rubber Hand Illusion (RHI) is an experimental paradigm for assessing changes in body ownership. Recent findings in the field suggest that social-emotional variables can influence such changes. Since body ownership is a mechanism that enables subjects to organise information about the environment and interact efficiently in it, changes in body ownership should have important implications for social power. In the current study, we investigated whether 0.5mg of testosterone, a steroid hormone strongly implicated in the achievement of power and dominance, affected the RHI. Forty-nine females participated in a double-blind, placebo-controlled experiment in which the RHI was induced. Compared to placebo, testosterone had no effects on the usual alteration of subjective ownership over the rubber limb or on subjective sense of proprioceptive drift. However, unlike the placebo group, testosterone-treated participants did not display an objective decline in the temperature of their own (hidden) hand following induction of the illusion. These findings suggest that testosterone strengthens implicit but not explicit bodily self-representations. We propose that effective maintenance of implicit body boundaries can be regarded, conceptually, as a primary defensive state facilitating integrity of the self.
KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition
Authors: Magloire Vincent , Cornford Jonathan , Lieb Andreas , Kullmann Dimitri M. , Pavlov Ivan
Published: March 2018

Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of parvalbumin-positive perisomatic-targeting (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain intracellular chloride levels in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.
Analog closed-loop optogenetic modulation of hippocampal pyramidal cells dissociates gamma frequency and amplitude
Authors: Nicholson Elizabeth , Kuzmin Dmitry A , Leite Marco , Akam Thomas E , Kullmann Dimitri M
Published: March 2018

Gamma-band oscillations are implicated in modulation of attention and integration of sensory information. The finding that cross-regional coherence varies with task and performance suggests a role for gamma oscillations in flexible communication among anatomically connected brain areas. How networks become entrained is incompletely understood. Specifically, it is unclear how the spectral and temporal characteristics of network oscillations can be altered on rapid timescales needed for efficient communication. We use closed-loop optogenetic modulation of principal cell excitability to interrogate the dynamical properties of hippocampal oscillations. Gamma frequency and amplitude can be modulated bi-directionally, and dissociated, by phase-advancing or delaying optogenetic feedback to pyramidal cells. Closed-loop modulation alters the synchrony rather than average frequency of action potentials, in principle avoiding disruption of population rate-coding of information. Modulation of phasic excitatory currents in principal neurons is sufficient to manipulate oscillations, suggesting that feed-forward excitation of pyramidal cells has an important role in determining oscillatory dynamics and the ability of networks to couple with one another.
A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain
Authors: Kleaveland Benjamin , Shi Charlie Y. , Stefano Joanna , Bartel David P.
Published: March 2018

Noncoding RNAs (ncRNAs) play increasingly appreciated gene-regulatory roles. Here, we describe a regulatory network centered on four ncRNAs—a long ncRNA, a circular RNA, and two microRNAs—using gene editing in mice to probe the molecular consequences of disrupting key components of this network. The long ncRNA Cyrano uses an extensively paired site to miR-7 to trigger destruction of this microRNA. Cyrano-directed miR-7 degradation is much more efficient than previously described examples of target-directed microRNA degradation, which come from studies of artificial and viral RNAs. By reducing miR-7 levels, Cyrano prevents repression of miR-7–targeted mRNAs and enables the accumulation of Cdr1as, a circular RNA known to regulate neuronal activity. Without Cyrano, excess miR-7 causes cytoplasmic destruction of Cdr1as, in part through enhanced slicing of Cdr1as by a second miRNA, miR-671. Thus, several types of ncRNAs can collaborate to establish a sophisticated regulatory network.

HIGHLIGHTS

A long noncoding RNA, a circular RNA, and two microRNAs form a regulatory network

The Cyrano long noncoding RNA directs potent, multiple-turnover destruction of miR-7

Unchecked miR-7 prevents accumulation of Cdr1as circular RNA in cytoplasm of neurons miR-7 prevents this accumulation by enhancing the miR-671-directed slicing of Cdr1as
Effects of Hydrogen‐Donating or Metal‐Chelating Antioxidants on the Oxidative Stability of Organogels Made of Beeswax and Grapeseed Oil Exposed to Light Irradiation
Authors: Hong Seungmi , Kim Mi‐Ja , Park Sungkwon , Lee Suyong , Lee Jonggil , Lee JaeHwan
Published: March 2018

To enhance the oxidative stability of organogels made from grapeseed oil, the antioxidant effects of sesamol, α‐tocopherol, β‐carotene, ethylenediaminetetraacetic acid (EDTA), and citric acid were determined in beeswax‐based organogels stored under light or in the dark conditions at 25 °C. Without the addition of antioxidants, the organogels rapidly oxidized under light irradiation but not during storage in the dark. Sesamol showed the highest antioxidant activity at concentrations of 10 to 40 ppm, whereas the other compounds exhibited no antioxidant activity at 10 ppm. α‐Tocopherol and β‐carotene improved the oxidative stability of organogels at concentrations above 40 and 100 ppm, respectively. The addition of sesamol yielded better oxidative stability than the addition of EDTA or a mixture of sesamol and citric acid. Sesamol can improve the oxidative stability of organogels, which could lead to economic benefits for the food industry.

Practical Application

Recently, interest in organogels has increased due to their properties of maintaining a solid state at room temperature and composition of trans‐free and highly unsaturated fatty acids. However, the addition of antioxidants is necessary due to the high degree of unsaturation in organogels. The results of this study showed that the addition of sesamol significantly enhanced the oxidative stability of organogels under light irradiation. Therefore, the use of sesamol‐supplemented organogels could prolong the shelf‐life of bakery or meat food products.
Efficacy of hypofractionated radiotherapy in patients with non‐melanoma skin cancer: Results of a systematic review
Authors: Gunaratne Dakshika A , Veness Michael J
Published: March 2018

Radiation oncologists are increasingly tasked with the management of elderly patients with non‐melanoma skin cancer, unsuitable for surgical intervention due to inoperable lesions and/or poor performance status. In this cohort, hypofractionated radiotherapy, delivered either daily, alternative daily or once weekly is highly effective. A systematic literature search was conducted of PUBMED, MEDLINE and EMBASE databases using the algorithm (‘radiotherapy’ OR ‘radiation therapy’ OR ‘brachytherapy’) AND (‘hypofraction’ OR ‘hypofractionated’ OR ‘hypofractionation’) AND (‘skin neoplasms’ OR ‘carcinoma’ OR ‘malignancy’) AND (‘skin’ OR ‘epidermis’ OR ‘epidermal’ OR ‘cutaneous’). Forty relevant publications (1983–2017) encompassing 12,337 irradiated lesions were retrieved. Studies documented a mean age of 71.73 years and male predilection (54.5%). Both external beam radiotherapy and brachytherapy were utilized. Tumour subtype was squamous cell carcinoma (23.5%), basal cell carcinoma (75.2%) or others (1.3%). Irradiated lesions were primary (or denovo) (92.6%), located on the head and neck (95.7%) and received definitive therapy (96.5%). Analysis demonstrated a mean weighted total radiotherapy dose (38.15 Gy), dose per fraction (7.95 Gy) and treatments per week (2.98). Despite significant heterogeneity in the study population, the radiotherapy delivered and follow‐up, local recurrence rate (crude or Kaplan–Meier analysis) did not exceed 7.9% in all but three of the 36 publications providing these data. Twenty‐nine publications documented local control exceeding 90%. There is a body of evidence documenting the efficacy of hypofractionated radiotherapy as an option that confers no obvious disadvantage in local control when compared to traditional more protracted radiotherapy schedules.
MiR‐577 suppresses epithelial‐mesenchymal transition and metastasis of breast cancer by targeting Rab25
Authors: Yin Chonggao , Mou Qingjie , Pan Xinting , Zhang Guoxin , Li Hongli , Sun Yunbo
Published: March 2018

Background

MicroRNAs can act as both tumor suppressor genes and oncogenes and participate in cell proliferation, metastasis, and apoptosis. Low levels of miR‐577 are found in several cancers, for example, thyroid carcinoma, glioblastoma, and hepatocellular carcinoma. The aim of this study was to investigate the effect of miR‐577 on breast cancer (BC).

Methods

The relative level of miR‐577 in 120 BC tissues and cells was detected by real‐time PCR. MDA‐MB‐231 cells with upregulated miR‐577 and MCF‐7 cells with downregulated miR‐577 were established. Transwell invasion assays were used to examine the invasiveness of cells. Epithelial‐mesenchymal transition (EMT) markers were evaluated by immunofluorescence and Western blot. Targeted combinations of miR‐577 and Rab25 were analyzed by luciferase assays. Xenograft models were used to examine the effect of miR‐577 on BC metastasis.

Results

MiR‐577 expression was significantly suppressed in BC tissues. Tumor size, tumor stage, and lymphatic metastasis were attributed to miR‐577 expression. Moreover, miR‐577 overexpression strongly inhibited the invasiveness and EMT of BC cells in vitro. MiR‐577 directly regulated Rab25 in BC. Rab25 upregulation by miR‐577 decreased the levels of E‐cadherin and increased the levels of Vimentin. Notably, Rab25 knockdown inhibited BC invasion; however, an increase in Rab25 counteracted the invasive effect of miR‐577 in BC.

Conclusion

Results indicated that miR‐577 suppressed EMT by inhibiting Rab25 expression in BC. MiR‐577 and Rab25 are considered potential targets of BC treatment.
Creation and Implementation of an Outpatient Pathway for Atrial Fibrillation in the Emergency Department Setting: Results of an Expert Panel
Authors: Baugh Christopher W. , Clark Carol L. , Wilson Jason W. , Stiell Ian G. , Kocheril Abraham G. , Luck Krista K. , Myers Troy D. , Pollack Charles V. , Roumpf Steven K. , Tomassoni Gery F. , Williams James M. , Patel Brian B. , Wu Fred , Pines Jesse M.
Published: March 2018

Atrial fibrillation and flutter (AF) is a common condition among emergency department (ED) patients in the United States. Traditionally, ED care for primary complaints related to AF focus on rate control, and patients are often admitted to an inpatient setting for further care. Inpatient care may include further telemetry monitoring and diagnostic testing, rhythm control, a search for identification of AF etiology, and stroke prophylaxis. However, many patients are eligible for safe and effective outpatient management pathways. They are widely used in Canada and other countries but less widely adopted in the United States. In this project, we convened an expert panel to create a practical framework for the process of creating, implementing, and maintaining an outpatient AF pathway for emergency physicians to assess and treat AF patients, safely reduce hospitalization rates, ensure appropriate stroke prophylaxis, and effectively transition patients to longitudinal outpatient treatment settings from the ED and/or observation unit. To support local pathway creation, the panel also reached agreement on a protocol development plan, a sample pathway, consensus recommendations for pathway components, sample pathway metrics, and a structured literature review framework using a modified Delphi technique by a technical expert panel of emergency medicine, cardiology, and other stakeholder groups.
Association Between Excessive Alcohol Consumption and Echocardiographic Parameters According to the Presence of Flushing Reaction in Korean Men: A Community‐Based Study
Authors: Ko Hyeonyoung , Song Yun‐Mi , Lee Sang‐Chol , Park Seung Woo , Sung Joohon , Lee Kayoung , Lee Eunae
Published: March 2018

Background

The objective of this study was to investigate the effect of excessive alcohol consumption on heart reflected by various echocardiographic parameters according to the presence or absence of flushing reaction that might reflect acetaldehyde metabolism.

Methods

A total of 854 Korean men without significant cardiovascular diseases who underwent echocardiography and participated in the Korean Healthy Twin Study were used as subjects of this study. These subjects were classified into 3 categories: nondrinker, moderate drinker (≤196 g/wk), and heavy drinker (>196 g/wk) within 2 strata of flushing reaction to alcohol drinking. Association between echocardiographic measurements and categories of the amount of alcohol consumption considering flushing reaction were evaluated using mixed linear regression model.

Results

The proportion of flushers among drinkers was 39.5% (278 of 703). In stratified analysis by flushing reaction, nonflushers showed significantly higher left ventricular mass index (β: 4.605; 95% CI: 0.966, 8.243) and significantly lower ratio of peak early diastolic velocities (E peak) over peak late diastolic velocities of mitral inflow (β: −0.103; 95% CI: −0.198, −0.008) in heavy drinkers compared to nondrinkers. Flushers showed significantly higher left atrial (LA) volume index (β: 2.712; 95% CI: 0.456, 4.968) in heavy drinkers and significantly lower ratio of E peak over the peak early diastolic mitral annular velocities (β: −0.493; 95% CI: −0.902, −0.085) in moderate drinkers compared to nondrinkers. However, the interaction according to flushing reaction was only statistically significant for the association between alcohol consumption and LA volume index (p for interaction = 0.004).

Conclusions

Alcohol consumption is associated with changes in cardiac structure and function. Such association might be influenced by acetaldehyde metabolism.
Microstructure of the eye tunics, eyelids and ocular glands of the Sulawesi bear cuscus (Ailurops ursinusTemminck, 1824) (Phalangeridae: Marsupialia) based on anatomical, histological and histochemical studies
Authors: Klećkowska‐Nawrot Joanna E. , Goździewska‐Harłajczuk Karolina , Darska Marta , Barszcz Karolina , Janeczek Maciej
Published: March 2018

This study described the anatomy, histology and the histochemical analysis of the eye tunics, the upper and lower eyelid, the third eyelid, the lacrimal gland and the superficial gland of the third eyelid in adult Sulawesi bear cuscus. The eyeball and the eyelids with the orbital glands were harvested immediately post‐mortem. The eyeball in the Sulawesi bear cuscus had a sphere‐like shape. The pupil was round, and the lens was a circular biconvex body. There was neither tapetum lucidum nor Harderian gland. Similarly, there were no eyelashes in the lower eyelid. The lymphoid follicles and the high endothelial venules (HEV) were found in the lymphoid region only in the third eyelid and in the connective tissue of the superficial gland of the third eyelid. The third eyelid in the bear cuscus resembled the letter “T.” The lacrimal gland and superficial gland of the third eyelid were multilobar tubuloacinar glands. The histological analysis and histochemical studies showed that the lacrimal gland in the Sulawesi bear cuscus produced a mucoserous secretion with predominantly serous cells. In contrast, the superficial gland of the third eyelid produced a serous secretion with a single acinus mucous in character.
Relevance and Application of Read‐Across – Mini Review of European Consensus Platform for Alternatives and Scandinavian Society for Cell Toxicology 2017 Workshop Session
Authors: Stuard Sharon Buring , Heinonen Tuula
Published: March 2018

Structure activity relationship (SAR)‐based read‐across is an effective approach for addressing data gaps in human health risk assessment for ‘data‐poor’ chemicals. In read‐across, available data on chemical structural analogues are used to predict the toxicity potential of the data‐poor chemical. This approach has long been recognized by regulatory agencies and used by industry to evaluate the hazards of chemicals for which there are limited direct data. Construction of a scientifically robust SAR‐based read‐across hazard assessment is a complex and iterative process involving multiple considerations in each step. Traditional in vivo data generated using regulatory guideline compliant study designs typically forms the basis for read‐across assessments. Recently, however, new data streams have been explored and incorporated to enhance read‐across predictivity. These in vitro and omics data streams may be used in different ways involving identification of hazards or to provide insight into modes of action for observed toxicological responses. These ‘new approach methods’ can also enable comparison of biological responses across analogues or a category of structurally related chemicals in order to establish a pattern of biological similarity in addition chemical similarity and/or to help address potency differences across a category. The purpose of this workshop session was to inform on practical considerations in conducting SAR‐based read‐across assessments and to review recent activities related to application of new approach methods to the practice of read‐across.
In vitro and in vivo characterization of the bifunctional μ and δ opioid receptor ligand UFP‐505
Authors: Dietis N , Niwa H , Tose R , McDonald J , Ruggieri V , Filaferro M , Vitale G , Micheli L , Ghelardini C , Salvadori S , Calo G , Guerrini R , Rowbotham D J , Lambert D G
Published: March 2018

Background and Purpose

Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reducing side‐effects. We have evaluated the mixed μ opioid receptor agonist/ δ opioid receptor antagonist UFP‐505 in vitro and in vivo.

Experimental Approach

We measured receptor density and function in single μ, δ and μ /δ receptor double expression systems. GTPγ35S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment. In some experiments, we collected tissues to measure receptor densities.

Key Results

UFP‐505 bound to μ receptors with full agonist activity and to δ receptors as a low efficacy partial agonist At μ, but not δ receptors, UFP‐505 binding recruited arrestin. Unlike morphine, UFP‐505 treatment internalized μ receptors and there was some evidence for internalization of δ receptors. Similar data were obtained in a μ /δ receptor double expression system. In rats, acute UFP‐505 or morphine, injected intrathecally, was antinociceptive. In tissues harvested from these experiments, μ and δ receptor density was decreased after UFP‐505 but not morphine treatment, in agreement with in vitro data. Both morphine and UFP‐505 induced significant tolerance.

Conclusions and Implications

In this study, UFP‐505 behaved as a full agonist at μ receptors with variable activity at δ receptors. This bifunctional compound was antinociceptive in rats after intrathecal administration. In this model, dual targeting provided no advantages in terms of tolerance liability.

Linked Articles

This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc