bluuebunny/crossref_metadata_2025 huggingface dataset:
Geostatistical delta-generalized linear mixed models improve precision for estimated abundance indices for West Coast groundfishes
Authors: Thorson James T. , Shelton Andrew O. , Ward Eric J. , Skaug Hans J.
Published: January 2015

Indices of abundance are the bedrock for stock assessments or empirical management procedures used to manage fishery catches for fish populations worldwide, and are generally obtained by processing catch-rate data. Recent research suggests that geostatistical models can explain a substantial portion of variability in catch rates via the location of samples (i.e. whether located in high- or low-density habitats), and thus use available catch-rate data more efficiently than conventional “design-based” or stratified estimators. However, the generality of this conclusion is currently unknown because geostatistical models are computationally challenging to simulation-test and have not previously been evaluated using multiple species. We develop a new maximum likelihood estimator for geostatistical index standardization, which uses recent improvements in estimation for Gaussian random fields. We apply the model to data for 28 groundfish species off the U.S. West Coast and compare results to a previous “stratified” index standardization model, which accounts for spatial variation using post-stratification of available data. This demonstrates that the stratified model generates a relative index with 60% larger estimation intervals than the geostatistical model. We also apply both models to simulated data and demonstrate (i) that the geostatistical model has well-calibrated confidence intervals (they include the true value at approximately the nominal rate), (ii) that neither model on average under- or overestimates changes in abundance, and (iii) that the geostatistical model has on average 20% lower estimation errors than a stratified model. We therefore conclude that the geostatistical model uses survey data more efficiently than the stratified model, and therefore provides a more cost-efficient treatment for historical and ongoing fish sampling data.
Amplification of small molecule-inducible gene expression via tuning of intracellular receptor densities
Authors: Wang Baojun , Barahona Mauricio , Buck Martin
Published: January 2015

Ligand-responsive transcription factors in prokaryotes found simple small molecule-inducible gene expression systems. These have been extensively used for regulated protein production and associated biosynthesis of fine chemicals. However, the promoter and protein engineering approaches traditionally used often pose significant restrictions to predictably and rapidly tune the expression profiles of inducible expression systems. Here, we present a new unified and rational tuning method to amplify the sensitivity and dynamic ranges of versatile small molecule-inducible expression systems. We employ a systematic variation of the concentration of intracellular receptors for transcriptional control. We show that a low density of the repressor receptor (e.g. TetR and ArsR) in the cell can significantly increase the sensitivity and dynamic range, whereas a high activator receptor (e.g. LuxR) density achieves the same outcome. The intracellular concentration of receptors can be tuned in both discrete and continuous modes by adjusting the strength of their cognate driving promoters. We exemplified this approach in several synthetic receptor-mediated sensing circuits, including a tunable cell-based arsenic sensor. The approach offers a new paradigm to predictably tune and amplify ligand-responsive gene expression with potential applications in synthetic biology and industrial biotechnology.
Interaction between the RNA-dependent ATPase and poly(A) polymerase subunits of the TRAMP complex is mediated by short peptides and important for snoRNA processing
Authors: Losh Jillian S. , King Alejandra Klauer , Bakelar Jeremy , Taylor Lacy , Loomis John , Rosenzweig Jason A. , Johnson Sean J. , van Hoof Ambro
Published: January 2015

The RNA exosome is one of the main 3′ to 5′ exoribonucleases in eukaryotic cells. Although it is responsible for degradation or processing of a wide variety of substrate RNAs, it is very specific and distinguishes between substrate and non-substrate RNAs as well as between substrates that need to be 3′ processed and those that need to be completely degraded. This specificity does not appear to be determined by the exosome itself but rather by about a dozen other proteins. Four of these exosome cofactors have enzymatic activity, namely, the nuclear RNA-dependent ATPase Mtr4, its cytoplasmic paralog Ski2 and the nuclear non-canonical poly(A) polymerases, Trf4 and Trf5. Mtr4 and either Trf4 or Trf5 assemble into a TRAMP complex. However, how these enzymes assemble into a TRAMP complex and the functional consequences of TRAMP complex assembly remain unknown. Here, we identify an important interaction site between Mtr4 and Trf5, and show that disrupting the Mtr4/Trf interaction disrupts specific TRAMP and exosome functions, including snoRNA processing.
Synergistic Inhibition of β2-adrenergic Receptor–mediated Alveolar Epithelial Fluid Transport by Interleukin-8 and Transforming Growth Factor-β
Authors: Wagener Brant M. , Roux Jérémie , Carles Michel , Pittet Jean-Francois
Published: January 2015

AbstractAbstract

In human and rat alveolar epithelial cells, combined exposure to interleukin-8 and transforming growth factor-β1 synergistically inhibited β2-adrenergic agonist–mediated Cl− transport, important to fluid removal.

Supplemental Digital Content is available in the text.

Background:

Patients with acute respiratory distress syndrome who retain maximal alveolar fluid clearance (AFC) have better clinical outcomes. The release of endogenous catecholamines associated with shock or the administration of β2-adrenergic receptor (β2AR) agonists enhances AFC via a 3′-5′-cyclic adenosine monophosphate–dependent mechanism. The authors have previously reported that transforming growth factor-β1 (TGF-β1) and interleukin-8 (IL-8), two major mediators of alveolar inflammation associated with the early phase of acute respiratory distress syndrome, inhibit AFC upregulation by β2AR agonists via a phosphoinositol-3-kinase (PI3K)–dependent mechanism. However, whether TGF-β1 and IL-8 cause an additive or synergistic inhibition of AFC is unclear. Thus, the central hypothesis of the study was to determine whether they synergistically inhibit the β2AR-stimulated AFC by activating two different isoforms of PI3K.

Methods:

The effects of TGF-β1 or IL-8 on β2AR agonist–stimulated net alveolar fluid transport were studied using short-circuit current studies. Molecular pathways of inhibition were confirmed by pharmacologic inhibitors and Western blotting of p-Akt, G-protein–coupled receptor kinase 2, protein kinase C-ζ, and phospho-β2AR. Finally, our observations were confirmed by an in vivo model of AFC.

Results:

Combined exposure to TGF-β1 and IL-8/cytokine-induced neutrophil chemoattractant-1 caused synergistic inhibition of β2AR agonist–stimulated vectorial Cl− across alveolar epithelial type II cells (n = 12 in each group). This effect was explained by activation of different isoforms of PI3K by TGF-β1 and IL-8/cytokine-induced neutrophil chemoattractant-1 (n = 12 in each group). Furthermore, the inhibitory effect of TGF-β1 on 3′-5′-cyclic adenosine monophosphate–stimulated alveolar epithelial fluid transport required the presence of IL-8/cytokine-induced neutrophil chemoattractant-1 (n = 12 in each group). Inhibition of cytokine-induced neutrophil chemoattractant-1 prevented TGF-β1–mediated heterologous β2AR downregulation and restored physiologic β2AR agonist–stimulated AFC in rats (n = 6 in each group).

Conclusions:

TGF-β1 and IL-8 have a synergistic inhibitory effect on β2AR-mediated stimulation of pulmonary edema removal by the alveolar epithelium. This result may, in part, explain why a large proportion of the patients with acute respiratory distress syndrome have impaired AFC.
Newer Therapies for Management of Stable Ischemic Heart Disease With Focus on Refractory Angina
Authors: Singh Mukesh , Arora Rohit
Published: January 2015

Ischemic heart disease remains a major public health problem nationally and internationally. Stable ischemic heart disease (SIHD) is one of the clinical manifestations of ischemic heart disease and is generally characterized by episodes of reversible myocardial demand/supply mismatch, related to ischemia or hypoxia, which are usually inducible by exercise, emotion, or other stress and reproducible—but which may also be occurring spontaneously. Improvements in the treatment of acute coronary syndromes along with increasing prevalence of cardiovascular risk factors, including diabetes and obesity, have led to increasing population of patients with SIHD. A significant number of these continue to have severe angina despite medical management and revascularization procedures performed and may progress to refractory angina. This article reviews the newer therapies in the treatment of SIHD with special focus in treating patients with refractory angina.
Valuation and Modeling of EQ-5D-5L Health States Using a Hybrid Approach
Authors: Ramos-Goñi Juan M. , Pinto-Prades Jose L. , Oppe Mark , Cabasés Juan M. , Serrano-Aguilar Pedro , Rivero-Arias Oliver
Published: January 2015

Background:

The EQ-5D instrument is the most widely used preference-based health-related quality of life questionnaire in cost-effectiveness analysis of health care technologies. Recently, a version called EQ-5D-5L with 5 levels on each dimension was developed. This manuscript explores the performance of a hybrid approach for the modeling of EQ-5D-5L valuation data.

Methods:

Two elicitation techniques, the composite time trade-off, and discrete choice experiments, were applied to a sample of the Spanish population (n=1000) using a computer-based questionnaire. The sampling process consisted of 2 stages: stratified sampling of geographic area, followed by systematic sampling in each area. A hybrid regression model combining composite time trade-off and discrete choice data was used to estimate the potential value sets using main effects as starting point. The comparison between the models was performed using the criteria of logical consistency, goodness of fit, and parsimony.

Results:

Twenty-seven participants from the 1000 were removed following the exclusion criteria. The best-fitted model included 2 significant interaction terms but resulted in marginal improvements in model fit compared to the main effects model. We therefore selected the model results with main effects as a potential value set for this methodological study, based on the parsimony criteria. The results showed that the main effects hybrid model was consistent, with a range of utility values between 1 and −0.224.

Conclusion:

This paper shows the feasibility of using a hybrid approach to estimate a value set for EQ-5D-5L valuation data.
Progression to High‐Risk Gastroesophageal Varices in Children With Biliary Atresia With Low‐Risk Signs at First Endoscopy
Authors: Duché Mathieu , Ducot Béatrice , Ackermann Oanez , Jacquemin Emmanuel , Bernard Olivier
Published: January 2015

Objectives:

Biliary atresia carries a risk of bleeding because of portal hypertension. Our goal was to define the factors associated with the emergence of endoscopic signs carrying a high risk of bleeding in children who did not display these signs at the first upper gastrointestinal endoscopy.

Methods:

From 1989 to 2013, a total of 225 children with low‐risk signs at the first endoscopic examination underwent ≥2 upper gastrointestinal endoscopic examinations. The emergence of high‐risk gastroesophageal varices was observed in 76 children in the 10 years following the first endoscopic examination. A survival study using the occurrence of high‐risk varices as an event was performed to identify factors related to the emergence of these varices and to describe the probability of their emergence in 2 groups of children ages older than 18 months and 18 months or younger at the time of the first endoscopy.

Results:

High total serum bilirubin concentration, young age, and high number/grade of esophageal varices at the first endoscopy were significantly related to the emergence of high‐risk varices. The probability of the emergence of high‐risk signs was higher and these signs appeared faster in infants 12 months of age or younger and/or when the first endoscopic examination displayed >1 grade 1 or grade 2 varices. Progression to high‐risk varices was also related to bilirubinemia in children older than 18 months at the first endoscopy.

Conclusions:

The results allow defining a program of repeat endoscopies to detect high‐risk varices and to discuss endoscopic primary prophylaxis of bleeding or hasten liver transplantation when these signs are found.
Indications and Limitations of Bariatric Intervention in Severely Obese Children and Adolescents With and Without Nonalcoholic Steatohepatitis
Authors: Nobili Valerio , Vajro Pietro , Dezsofi Antal , Fischler Bjorn , Hadzic Nedim , Jahnel Joerg , Lamireau Thierry , McKiernan Patrick , McLin Valerie , Socha Piotr , Tizzard Sarah , Baumann Ulrich
Published: January 2015

Morbid obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD), which is one of the most common causes of chronic liver disease worldwide. The present best treatment for NAFLD and nonalcoholic steatohepatitis (NASH) is weight reduction through lifestyle modification. Because of frustrating inefficiency of such a therapeutic approach, bariatric surgery is increasingly performed in adolescents as an alternative option for weight reduction. Standards of care and consensus for indications are, however, scarce. We explore the indications and limitations of bariatric surgery in children with severe obesity with and without NASH and aim to provide guidance for the exceptional indications for adolescents with extreme obesity with major comorbidity that may benefit from these controversial interventions. Present evidence suggests that bariatric surgery can decrease the grade of steatosis, hepatic inflammation, and fibrosis in NASH. Uncomplicated NAFLD is not an indication for bariatric surgery. Roux‐en‐Y gastric bypass is considered a safe and effective option for adolescents with extreme obesity, as long as an appropriate long‐term follow‐up is provided. Laparoscopic adjustable gastric banding has not been approved by the Food and Drug Administration for use in adolescents and therefore should be considered investigational. Finally, sleeve gastrectomy and other types of weight loss surgery that have grown increasingly common in adults, still need to be considered investigational. Temporary devices may be increasingly being used in pediatrics; however, future studies, including a long‐term risk analysis of patients who undergo surgery, are much needed to clarify the exact indications for bariatric surgery in adolescents.
Investigating cell mechanics with atomic force microscopy
Authors: Haase Kristina , Pelling Andrew E.
Published: January 2015

Transmission of mechanical force is crucial for normal cell development and functioning. However, the process of mechanotransduction cannot be studied in isolation from cell mechanics. Thus, in order to understand how cells ‘feel’, we must first understand how they deform and recover from physical perturbations. Owing to its versatility, atomic force microscopy (AFM) has become a popular tool to study intrinsic cellular mechanical properties. Used to directly manipulate and examine whole and subcellular reactions, AFM allows for top-down and reconstitutive approaches to mechanical characterization. These studies show that the responses of cells and their components are complex, and largely depend on the magnitude and time scale of loading. In this review, we generally describe the mechanotransductive process through discussion of well-known mechanosensors. We then focus on discussion of recent examples where AFM is used to specifically probe the elastic and inelastic responses of single cells undergoing deformation. We present a brief overview of classical and current models often used to characterize observed cellular phenomena in response to force. Both simple mechanistic models and complex nonlinear models have been used to describe the observed cellular behaviours, however a unifying description of cell mechanics has not yet been resolved.
Constructor theory of life
Authors: Marletto Chiara
Published: January 2015

Neo-Darwinian evolutionary theory explains how the appearance of purposive design in the adaptations of living organisms can have come about without their intentionally being designed. The explanation relies crucially on the possibility of certain
physical processes
: mainly,
gene replication
and
natural selection
. In this paper, I show that for those processes to be possible without the
design of biological adaptations
being encoded in the laws of physics, those laws must have certain other properties. The theory of what these properties are is not part of evolution theory proper, yet without it the neo-Darwinian theory does not fully achieve its purpose of explaining the appearance of design. To this end, I apply constructor theory's new mode of explanation to express exactly within physics the appearance of design, no-design laws, and the logic of self-reproduction and natural selection. I conclude that self-reproduction, replication and natural selection are possible under no-design laws, the only non-trivial condition being that they allow
digital information
to be physically instantiated. This has an exact characterization in the constructor theory of information. I also show that under no-design laws an accurate replicator
requires
the existence of a ‘vehicle’ constituting, together with the replicator, a self-reproducer.
Demographic buffering: titrating the effects of birth rate and imperfect immunity on epidemic dynamics
Authors: Morris Sinead E. , Pitzer Virginia E. , Viboud Cécile , Metcalf C. Jessica E. , Bjørnstad Ottar N. , Grenfell Bryan T.
Published: January 2015

Host demography can alter the dynamics of infectious disease. In the case of perfectly immunizing infections, observations of strong sensitivity to demographic variation have been mechanistically explained through analysis of the susceptible–infected–recovered (SIR) model that assumes lifelong immunity following recovery from infection. When imperfect immunity is incorporated into this framework via the susceptible–infected–recovered–susceptible (SIRS) model, with individuals regaining full susceptibility following recovery, we show that rapid loss of immunity is predicted to buffer populations against the effects of demographic change. However, this buffering is contrary to the dependence on demography recently observed for partially immunizing infections such as rotavirus and respiratory syncytial virus. We show that this discrepancy arises from a key simplification embedded in the SIR(S) framework, namely that the potential for differential immune responses to repeat exposures is ignored. We explore the minimum additional immunological information that must be included to reflect the range of observed dependencies on demography. We show that including partial protection and lower transmission following primary infection is sufficient to capture more realistic reduced levels of buffering, in addition to changes in epidemic timing, across a range of partially and fully immunizing infections. Furthermore, our results identify key variables in this relationship, includingR0.
Creating the brain and interacting with the brain: an integrated approach to understanding the brain
Authors: Morimoto Jun , Kawato Mitsuo
Published: January 2015

In the past two decades, brain science and robotics have made gigantic advances in their own fields, and their interactions have generated several interdisciplinary research fields. First, in the ‘understanding the brain by creating the brain’ approach, computational neuroscience models have been applied to many robotics problems. Second, such brain-motivated fields as cognitive robotics and developmental robotics have emerged as interdisciplinary areas among robotics, neuroscience and cognitive science with special emphasis on humanoid robots. Third, in brain–machine interface research, a brain and a robot are mutually connected within a closed loop. In this paper, we review the theoretical backgrounds of these three interdisciplinary fields and their recent progress. Then, we introduce recent efforts to reintegrate these research fields into a coherent perspective and propose a new direction that integrates brain science and robotics where the decoding of information from the brain, robot control based on the decoded information and multimodal feedback to the brain from the robot are carried out in real time and in a closed loop.
Fluid-flow-induced mesenchymal stem cell migration: role of focal adhesion kinase and RhoA kinase sensors
Authors: Riehl Brandon D. , Lee Jeong Soon , Ha Ligyeom , Lim Jung Yul
Published: January 2015

The study of mesenchymal stem cell (MSC) migration under flow conditions with investigation of the underlying molecular mechanism could lead to a better understanding and outcome in stem-cell-based cell therapy and regenerative medicine. We used peer-reviewed open source software to develop methods for efficiently and accurately tracking, measuring and processing cell migration as well as morphology. Using these tools, we investigated MSC migration under flow-induced shear and tested the molecular mechanism with stable knockdown of focal adhesion kinase (FAK) and RhoA kinase (ROCK). Under steady flow, MSCs migrated following the flow direction in a shear stress magnitude-dependent manner, as assessed by root mean square displacement and mean square displacement, motility coefficient and confinement ratio. Silencing FAK in MSCs suppressed morphology adaptation capability and reduced cellular motility for both static and flow conditions. Interestingly, ROCK silencing significantly increased migration tendency especially under flow. Blocking ROCK, which is known to reduce cytoskeletal tension, may lower the resistance to skeletal remodelling during the flow-induced migration. Our data thus propose a potentially differential role of focal adhesion and cytoskeletal tension signalling elements in MSC migration under flow shear.
Sinomonas susongensis sp. nov., isolated from the surface of weathered biotite
Authors: Bao Yuan-Yuan , Huang Zhi , Mao Dong-Mei , Sheng Xia-Fang , He Lin-Yan
Published: January 2015

A novel actinomycete, designated strain A31T, was isolated from the surface of weathered biotite in Susong, Anhui Province, China. The organism grew optimally at 30 °C, at pH 8.0 and with 1 % (w/v) NaCl. Strain A31T had A3α as the cell-wall peptidoglycan type and galactose, mannose and rhamnose as whole-cell sugars. Anteiso-C15 : 0 and anteiso-C17 : 0 were the major cellular fatty acids and MK-9(H2) was the predominant respiratory quinone. In addition, the total polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylmonomethylethanolamine and four glycolipids. The genomic DNA G+C content of strain A31T was 70.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain A31T was related most closely to

Sinomonas albida

LC13T (98.3 % similarity),

Sinomonas atrocyanea

DSM 20127T (98.2 %),

Sinomonas soli

CW 59T (98.1 %),

Sinomonas flava

CW 108T (97.8 %), ‘Sinomonas
mesophila’ MPKL 26 (97.3 %),

Sinomonas echigonensis

LC10T (97.1 %) and ‘

Sinomonas notoginsengisoli

’ SYP-B575 (96.7 %). DNA–DNA hybridization studies with the new isolate showed relatedness values of 16.0–56.6 % with its six closest neighbours. Based on phenotypic, chemotaxonomic and phylogenetic analysis, strain A31T represents a novel species of the genus

Sinomonas

, for which the name Sinomonas
susongensis sp. nov. is proposed. The type strain is A31T ( = DSM 28245T = CCTCC AB 2014068T).
SCIE: Information Extraction for Spinal Cord Injury Preclinical Experiments – A Webservice and Open Source Toolkit
Authors: Stöckel Andreas , Paassen Benjamin , Dickfelder Raphael , Göpfert Jan Philip , Brazda Nicole , Müller Hans Werner , Cimiano Philipp , Hartung Matthias , Klinger Roman
Published: January 2015

Translational neuroscience in the field of spinal cord injuries (SCI) faces a strong disproportion between immense preclinical research efforts and a lack of therapeutic approaches successful in human patients: Currently, preclinical research on SCI yields more than 3,000 new publications per year (8,000 when including the whole central nervous system, growing at an exponential rate), whereas none of the resulting therapeutic concepts has led to functional recovery of neural tissue in humans. Improving clinical researchers’ information access therefore carries the potential to support more effective selection of promising therapy candidates from preclinical studies. Thus, automated information extraction from scientific publications contributes to enabling meta studies and therapy grading by aggregating relevant information from the entire body of previous work on SCI.

We present SCIE, an automated information extraction pipeline capable of detecting relevant information in SCI publications based on ontological entity and probabilistic relation detection. The input are plain text or PDF documents. As output, the user choses between an online visualization or a machine-readable format. Compared to human gold standard annotations, our system achieves an average extraction performance of 76 % precision and 52 % recall (F1-measure 0.59).

An instance of the webservice is available athttp://scie.sc.cit-ec.uni-bielefeld.de/. SCIE is free software licensed under the AGPL and can be downloaded for local installation athttp://opensource.cit-ec.de/projects/scie/.
A Spatial Framework for Understanding Population Structure and Admixture.
Authors: Bradburd Gideon , Ralph Peter L. , Coop Graham
Published: January 2015

Geographic patterns of genetic variation within modern populations, produced by complex histories of migration, can be difficult to infer and visually summarize. A general consequence of geographically limited dispersal is that samples from nearby locations tend to be more closely related than samples from distant locations, and so genetic covariance often recapitulates geographic proximity. We use genome-wide polymorphism data to build ``geogenetic maps,'' which, when applied to stationary populations, produces a map of the geographic positions of the populations, but with distances distorted to reflect historical rates of gene flow. In the underlying model, allele frequency covariance is a decreasing function of geogenetic distance, and nonlocal gene flow such as admixture can be identified as anomalously strong covariance over long distances. This admixture is explicitly co-estimated and depicted as arrows, from the source of admixture to the recipient, on the geogenetic map. We demonstrate the utility of this method on a circum-Tibetan sampling of the greenish warbler (Phylloscopus trochiloides), in which we find evidence for gene flow between the adjacent, terminal populations of the ring species. We also analyze a global sampling of human populations, for which we largely recover the geography of the sampling, with support for significant histories of admixture in many samples. This new tool for understanding and visualizing patterns of population structure is implemented in a Bayesian framework in the program SpaceMix.
Neurospora heterokaryons with complementary duplications and deficiencies in their constituent nuclei provide an approach to identify nucleus-limited genes
Authors: Giri Dev Ashish , Rekha S. , Kasbekar Durgadas P.
Published: January 2015

Introgression is the transfer of genes or genomic regions from one species into another via hybridization and back-crosses. We have introgressed four translocations (EB4,IBj5,UK14-1, andB362i) fromNeurospora crassaintoN. tetrasperma. This enabled us to construct heterokaryotic [T+N] and [Dp+Df] strains in which themat-Aandmat-anuclei have different genotypes. Self-crosses of the heterokaryons again produced [T+N] and [Dp+Df] progeny. From conidia (vegetative spores) produced by the heterokaryotic mycelia we obtained self-fertile (heterokaryotic) and self-sterile (homokaryotic) derivative strains. [T+N] heterokaryons produced homokaryotic derivatives of both mating types, but [Dp+Df] heterokaryons produced viable homokaryons of only the mating type of theDpnucleus. All the four [T+N] heterokaryons, and three [Dp+Df] heterokaryons, produced both self-sterile and self-fertile conidial derivatives, but the [Dp(B362i)+Df(B362i)] heterokaryons produced only self-sterile ones. Conceivably, theDf(B362i)nuclei may be deleted for a nucleus-limited gene required for efficient mitosis or nuclear division, and whose deficit is not complemented by the neighboringDp(B362i)nuclei. Repeat-induced point mutation (RIP) was shown to occur in aDp-heterozygous cross, therefore RIP-alteration of a translocated segment would depend on relative numbers of self-crosses undergone in [Dp+Df] versus [T+N] ancestors.
Widespread localisation of lncRNA to ribosomes: Distinguishing features and evidence for regulatory roles
Authors: Carlevaro-Fita Juna , Rahim Anisa , Guigo Roderic , Vardy Leah A. , Johnson Rory
Published: January 2015

The function of long noncoding RNAs (lncRNAs) depends on their location within the cell. While most studies to date have concentrated on their nuclear roles in transcriptional regulation, evidence is mounting that lncRNA also have cytoplasmic roles. Here we comprehensively map the cytoplasmic and ribosomal lncRNA population in a human cell. Three-quarters (74%) of lncRNAs are detected in the cytoplasm, the majority of which (62%) preferentially cofractionate with polyribosomes. Ribosomal lncRNA are highly expressed across tissues, under purifying evolutionary selection, and have cytoplasmic-to-nuclear ratios comparable to mRNAs and consistent across cell types. LncRNAs may be classified into three groups by their ribosomal interaction: non-ribosomal cytoplasmic lncRNAs, and those associated with either heavy or light polysomes. A number of mRNA-like features destin lncRNA for light polysomes, including capping and 5’UTR length, but not cryptic open reading frames or polyadenylation. Surprisingly, exonic retroviral sequences antagonise recruitment. In contrast, it appears that lncRNAs are recruited to heavy polysomes through basepairing to mRNAs. Finally, we show that the translation machinery actively degrades lncRNA. We propose that light polysomal lncRNAs are translationally engaged, while heavy polysomal lncRNAs are recruited indirectly. These findings point to extensive and reciprocal regulatory interactions between lncRNA and the translation machinery.
Olfactory receptors are sensitive to molecular volume of odorants
Authors: Saberi Majid , Seyed-allaei Hamed
Published: January 2015

To study olfaction,  first we should know which physical or chemical properties of odorant molecules determine   the response of olfactory receptor neurons,   and then we should study the effect of those properties on the combinatorial encoding in olfactory system.    In this work we show that the response of an olfactory receptor neuron in Drosophila depends on molecular volume of an odorant;   The molecular volume determines the upper limits of the neural response,   while the actual neural response may depend on other properties of the molecules.  Each olfactory receptor prefers a particular volume,   with some degree of flexibility.  These two parameters predict the volume and flexibility of the binding-pocket of the olfactory receptors,   which are the targets of structural biology studies.     At the end we argue that the molecular volume can affects the quality of perceived smell of an odorant via the combinatorial encoding,  molecular volume may mask other underlying relations between properties of molecules and neural responses   and we suggest a way to improve the selection of odorants in further experimental studies.
The origin and evolution of maize in the American Southwest
Authors: da Fonseca Rute R , Smith Bruce D , Wales Nathan , Cappellini Enrico , Skoglund Pontus , Fumagalli Matteo , Samaniego José Alfredo , Carøe Christian , Ávila-Arcos María C , Hufnagel David E , Korneliussen Thorfinn Sand , Vieira Filipe Garrett , Jakobsson Mattias , Arriaza Bernardo , Willerslev Eske , Nielsen Rasmus , Hufford Matthew B , Albrechtsen Anders , Ross-Ibarra Jeffrey , Gilbert M Thomas P
Published: January 2015

Maize offers an ideal system through which to demonstrate the potential of ancient population genomic techniques for reconstructing the evolution and spread of domesticates. The diffusion of maize from Mexico into the North American Southwest (SW) remains contentious with the available evidence being restricted to morphological studies of ancient maize plant material. We captured 1 Mb of nuclear DNA from 32 archaeological maize samples spanning 6000 years and compared them with modern landraces including those from the Mexican West coast and highlands. We found that the initial diffusion of domesticated maize into the SW is likely to have occurred through a highland route. However, by 2000 years ago a Pacific coastal corridor was also being used. Furthermore, we could distinguish between genes that were selected for early during domestication (such as zagl1 involved in shattering) from genes that changed in the SW context (e.g. related to sugar content and adaptation to drought) likely as a response to the local arid environment and new cultural uses of maize.
SWS2 visual pigment evolution as a test of historically contingent patterns of plumage color evolution in Warblers
Authors: Bloch Natasha I. , Morrow James M. , Chang Belinda S.W. , Price Trevor D.
Published: January 2015

Distantly related clades that occupy similar environments may differ due to the lasting imprint of their ancestors – historical contingency. The New World warblers (Parulidae) and Old World warblers (Phylloscopidae) are ecologically similar clades that differ strikingly in plumage coloration. We studied genetic and functional evolution of the short-wavelength sensitive visual pigments (SWS2 and SWS1) to ask if altered color perception could contribute to the plumage color differences between clades. We show SWS2 is short-wavelength shifted in birds that occupy open environments, such as finches, compared to those in closed environments, including warblers. Sequencing of opsin genes and phylogenetic reconstructions indicate New World warblers were derived from a finch-like form that colonized from the Old World 15-20Ma. During this process the SWS2 gene accumulated 6 substitutions in branches leading to New World warblers, inviting the hypothesis that passage through a finch-like ancestor resulted in SWS2 evolution. In fact, we show spectral tuning remained similar across warblers as well as the finch ancestor. Results reject the hypothesis of historical contingency based on opsin spectral tuning, but point to evolution of other aspects of visual pigment function. Using the approach outlined here, historical contingency becomes a generally testable theory in systems where genotype and phenotype can be connected.
On The Organization Of Human T Cell Receptor Loci
Authors: Toor Amir A. , Toor Abdullah A. , Manjili Masoud H.
Published: January 2015

The human T cell repertoire is complex and is generated by the rearrangement of variable (V), diversity (D) and joining (J) segments on the T cell receptor (TCR) loci. The T cell repertoire demonstrates selfsimilarity in terms clonal frequencies when defined by V, D and J gene segment usage; therefore to determine whether the structural ordering of these gene segments on the TCR loci contributes to the observed clonal frequencies, the TCR loci were examined for self-similarity and periodicity in terms of gene segment organization. Logarithmic transformation of numeric sequence order demonstrated that the V and J gene segments for both T cell receptor α (TRA) and β (TRB) loci were arranged in a selfsimilar manner when the spacing between the adjacent segments was considered as a function of the size of the neighboring gene segment, with an average fractal dimension of ͠1.5. The ratio of genomic distance between either the J (in TRA) or D (in TRB) segments and successive V segments on these loci declined logarithmically with a slope of similar magnitude. Accounting for the gene segments occurring on helical DNA molecules in a logarithmic distribution, sine and cosine functions of the log transformed angular coordinates of the start and stop nucleotides of successive TCR gene segments showed an ordered progression from the 5’ to the 3’ end of the locus, supporting a log-periodic organization. T cell clonal frequencies, based on V and J segment usage, from three normal stem cell donors were plotted against the V and J segment on TRB locus and demonstrated a periodic distribution. We hypothesize that this quasi-periodic variation in gene-segment representation in the T cell clonal repertoire may be influenced by the location of the gene segments on the periodic-logarithmically scaled TCR loci. Interactions between the two strands of DNA in the double helix may influence the probability of gene segment usage by means of either constructive or destructive interference resulting from the superposition of the two helices.
Reprogramming LCLs to iPSCs Results in Recovery of Donor-Specific Gene Expression Signature
Authors: Thomas Samantha M. , Kagan Courtney , Pavlovic Bryan J. , Burnett Jonathan , Patterson Kristen , Pritchard Jonathan K. , Gilad Yoav
Published: January 2015

Renewablein vitrocell cultures, such as lymphoblastoid cell lines (LCLs), have facilitated studies that contributed to our understanding of genetic influence on human traits. However, the degree to which cell lines faithfully maintain differences in donor-specific phenotypes is still debated. We have previously reported that standard cell line maintenance practice results in a loss of donor-specific gene expression signatures in LCLs. An alternative to the LCL model is the induced pluripotent stem cell (iPSC) system, which carries the potential to model tissue-specific physiology through the use of differentiation protocols. Still, existing LCL banks represent an important source of starting material for iPSC generation, and it is possible that the disruptions in gene regulation associated with long-term LCL maintenance could persist through the reprogramming process. To address this concern, we studied the effect of reprogramming mature LCLs to iPSCs on the ensuing gene expression patterns within and between six unrelated donor individuals. We show that the reprogramming process results in a recovery of donor-specific gene regulatory signatures. Since environmental contributions are unlikely to be a source of individual variation in our system of highly passaged cultured cell lines, our observations suggest that the effect of genotype on gene regulation is more pronounced in the iPSCs than in the LCL precursors. Our findings indicate that iPSCs can be a powerful model system for studies of phenotypic variation across individuals in general, and the genetic association with variation in gene regulation in particular. We further conclude that LCLs are an appropriate starting material for iPSC generation.
A pooling-based approach to mapping genetic variants associated with DNA methylation
Authors: Kaplow Irene M. , MacIsaac Julia L. , Mah Sarah M. , McEwen Lisa M. , Kobor Michael S. , Fraser Hunter B.
Published: January 2015

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover less than 2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified over 2,000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.
Putative G-quadruplex forming sequence signatures in genes differentially transcribed upon loss of BLM or WRN helicases
Authors: Smestad John , James Maher L.
Published: January 2015

Putative G-quadruplex-forming sequences (PQS) have long been implicated in regulation of DNA replication and transcription, though their actual roles are unknown. To gain insight into potential PQS transcriptional function, we map and analyze PQS motifs in promoters of genes differentially-expressed in Bloom Syndrome (BS) and Werner Syndrome (WS), two human genetic disorders resulting in loss of PQS-interacting RecQ helicases. Non-B-DNA structures at PQS might be stabilized in these syndromes. For BS and WS we demonstrate that PQS promoter abundance is generally higher in down-regulated genes and lower in up-regulated genes, and show that these effects are position-dependent. To interpret these correlations we determined genome-wide PQS correlations with transcription using epigenetic information to predict gene expression. We report that 33% and 35% of analyzed PQS positions in promoter antisense and sense strands, respectively, displayed statistically-significant correlation with gene expression. Of these statistically-significant positions, 100% and 84% on antisense and sense strands, respectively, were correlated with reduced expression. This suggests that promoter PQS repress transcription. Finally, we report neural network clustering analysis of PQS motifs to demonstrate that genes differentially-expressed in BS and WS are significantly biased in their PQS motifs, suggesting an unappreciated biological relationship between PQS, RecQ helicases, and transcription.

REVIEWER LINKS TO DEPOSITED DATA

ftp://www.jsmes.net/PQS_Genomics
Estimating stem cell fractions in hierarchically organized tumors
Authors: Werner Benjamin , Scott Jacob G. , Sottoriva Andrea , Anderson Alexander R.A. , Traulsen Arne , Altrock Philipp M.
Published: January 2015

Cancers arise as a result of genetic and epigenetic alterations. These accumulate in cells during the processes of tissue development, homeostasis and repair. Many tumor types are hierarchically organized and driven by a sub-population of cells often called cancer stem cells. Cancer stem cells are uniquely capable of recapitulating the tumor and can be highly resistant to radio-and chemotherapy treatment. We investigate tumor growth patterns from a theoretical standpoint and show how significant changes in pre-and post-therapy tumor dynamics are tied to the dynamics of cancer stem cells. We identify two characteristic growth regimes of a tumor population that can be leveraged to estimate cancer stem cell fractionsin vivousing simple linear regression. Our method is a mathematically exact result, parameter free and does not require any microscopic knowledge of the tumor properties. A more accurate quantification of the direct link between the sub-population driving tumor growth and treatment response promises new ways to individualize treatment strategies.

Significance Statement

Under the cancer stem cell hypothesis a tumor population is driven by a fraction of self-renewing cancer stem cells. Absolute and relative size of this population in human cancers at any stage of the disease remains unknown. We formulate a mathematical model that describes the tumor cell population’s growth dynamics and response to therapy. This allows to estimate cancer stem cell fraction from longitudinal measurements of tumor size (often available from imaging). Such estimates are critical because treatment outcome and risk of relapse depend on the tumor’s capacity to self-renew. Ideally, by tailoring patient treatment strategies based on the relative abundance of cancer stem cells could lead to radically different therapeutic regime and to the successful eradication of the disease.
Evolutionary processes make invasion speed difficult to predict
Authors: Phillips Ben L.
Published: January 2015

1

A capacity to predict the spread rate of populations is critical for understanding the impacts of climate change and invasive species. Despite sophisticated theory describing how populations spread, the prediction of spread rate remains a formidable challenge. As well as the inherent stochasticity in the spread process, spreading populations are subject to strong evolutionary forces (operating on dispersal and reproductive rates) that can cause accelerating spread. Despite these strong evolutionary forces, serial founder events and drift on the expanding range edge mean that evolutionary trajectories in the invasion vanguard may be highly stochastic. Here I develop a model of spatial spread in continuous space that incorporates evolution of continuous traits under a quantitative genetic model of inheritance. I use this model to investigate the potential role of evolution on the variation in spread rate between replicate model realisations. Models incorporating evolution exhibited more than four times the variance in spread rate across replicate invasions compared with nonevolving scenarios. Results suggest that the majority of this increase in variation is driven by evolutionary stochasticity on the invasion front rather than initial founder events: in many cases evolutionary stochasticity on the invasion front contributed more than 90% of the variance in spread rate over 30 generations. Our uncertainty around predicted spread rates - whether for invasive species or those shifting under climate change - may be much larger than we expect when the spreading population contains heritable variation in rates of dispersal and reproduction.
Selection-, age-, and exercise-dependence of skeletal muscle gene expression patterns in a rat model of metabolic fitness
Authors: Ren Yu-yu , Koch Lauren G. , Britton Steven L. , Qi Nathan R. , Treutelaar Mary K. , Burant Charles F. , Li Jun Z.
Published: January 2015

Aerobic exercise capacity can influence many complex traits including obesity and type 2 diabetes. We established two rat lines by divergent selection of intrinsic aerobic capacity. The high capacity runners (HCR) and low capacity runners (LCR) differed by ~9-fold in aerobic capacity after 32 generations, and diverged in body fat, blood glucose, and other health indicators. To study the interplay among genetic differentiation, age, and strenuous exercise, we performed microarray-based gene expression analyses in skeletal muscle with a 2×2×2 design to compare HCR and LCR, old and young animals, and between rest and exhaustion, for a total of eight groups (n=6 each). Transcripts for mitochondrial function are expressed higher in HCR than LCR at both rest and exhaustion, for both age groups. Extracellular matrix components decrease with age in both lines and both rest and exhaustion. Interestingly, age-effects in many pathways are more pronounced in LCR, suggesting that HCR’s higher innate aerobic capacity underlies both increased lifespan and heathspan.