bluuebunny/crossref_metadata_2025 huggingface dataset:
Condition-specific target prediction from motifs and expression
Authors: Meng Guofeng , Vingron Martin
Published: February 2014

Motivation: It is commonplace to predict targets of transcription factors (TFs) by sequence matching with their binding motifs. However, this ignores the particular condition of the cells. Gene expression data can provide condition-specific information, as is, e.g. exploited in Motif Enrichment Analysis.

Results: Here, we introduce a novel tool named condition-specific target prediction (CSTP) to predict condition-specific targets for TFs from expression data measured by either microarray or RNA-seq. Based on the philosophy of guilt by association, CSTP infers the regulators of each studied gene by recovering the regulators of its co-expressed genes. In contrast to the currently used methods, CSTP does not insist on binding sites of TFs in the promoter of the target genes. CSTP was applied to three independent biological processes for evaluation purposes. By analyzing the predictions for the same TF in three biological processes, we confirm that predictions with CSTP are condition-specific. Predictions were further compared with true TF binding sites as determined by ChIP-seq/chip. We find that CSTP predictions overlap with true binding sites to a degree comparable with motif-based predictions, although the two target sets do not coincide.

Availability and implementation: CSTP is available via a web-based interface at http://cstp.molgen.mpg.de.

Contact:  meng@molgen.mpg.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
LPmerge: an R package for merging genetic maps by linear programming
Authors: Endelman Jeffrey B. , Plomion Christophe
Published: February 2014

Summary: Consensus genetic maps constructed from multiple populations are an important resource for both basic and applied research, including genome-wide association analysis, genome sequence assembly and studies of evolution. The LPmerge software uses linear programming to efficiently minimize the mean absolute error between the consensus map and the linkage maps from each population. This minimization is performed subject to linear inequality constraints that ensure the ordering of the markers in the linkage maps is preserved. When marker order is inconsistent between linkage maps, a minimum set of ordinal constraints is deleted to resolve the conflicts.

Availability and implementation: LPmerge is on CRAN at http://cran.r-project.org/web/packages/LPmerge.

Contact:  endelman@wisc.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
EXTREME: an online EM algorithm for motif discovery
Authors: Quang Daniel , Xie Xiaohui
Published: February 2014

Motivation: Identifying regulatory elements is a fundamental problem in the field of gene transcription. Motif discovery—the task of identifying the sequence preference of transcription factor proteins, which bind to these elements—is an important step in this challenge. MEME is a popular motif discovery algorithm. Unfortunately, MEME’s running time scales poorly with the size of the dataset. Experiments such as ChIP-Seq and DNase-Seq are providing a rich amount of information on the binding preference of transcription factors. MEME cannot discover motifs in data from these experiments in a practical amount of time without a compromising strategy such as discarding a majority of the sequences.

Results: We present EXTREME, a motif discovery algorithm designed to find DNA-binding motifs in ChIP-Seq and DNase-Seq data. Unlike MEME, which uses the expectation-maximization algorithm for motif discovery, EXTREME uses the online expectation-maximization algorithm to discover motifs. EXTREME can discover motifs in large datasets in a practical amount of time without discarding any sequences. Using EXTREME on ChIP-Seq and DNase-Seq data, we discover many motifs, including some novel and infrequent motifs that can only be discovered by using the entire dataset. Conservation analysis of one of these novel infrequent motifs confirms that it is evolutionarily conserved and possibly functional.

Availability and implementation: All source code is available at the Github repository http://github.com/uci-cbcl/EXTREME.

Contact:  xhx@ics.uci.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
ZDOCK server: interactive docking prediction of protein–protein complexes and symmetric multimers
Authors: Pierce Brian G. , Wiehe Kevin , Hwang Howook , Kim Bong-Hyun , Vreven Thom , Weng Zhiping
Published: February 2014

Summary: Protein–protein interactions are essential to cellular and immune function, and in many cases, because of the absence of an experimentally determined structure of the complex, these interactions must be modeled to obtain an understanding of their molecular basis. We present a user-friendly protein docking server, based on the rigid-body docking programs ZDOCK and M-ZDOCK, to predict structures of protein–protein complexes and symmetric multimers. With a goal of providing an accessible and intuitive interface, we provide options for users to guide the scoring and the selection of output models, in addition to dynamic visualization of input structures and output docking models. This server enables the research community to easily and quickly produce structural models of protein–protein complexes and symmetric multimers for their own analysis.

Availability: The ZDOCK server is freely available to all academic and non-profit users at: http://zdock.umassmed.edu. No registration is required.

Contact:  brian.pierce@umassmed.edu or zhiping.weng@umassmed.edu
How we all kill whales
Authors: Moore Michael J.
Published: February 2014

Today there is enormous popular interest in marine mammals. Western media tend to dwell on the ongoing debate about commercial whaling by Japan, Norway and Iceland. There is, however, relative silence as to how the shipping and fishing industries of many if not all maritime countries are also catching and sometimes killing whales, albeit unintentionally. Thus, western countries have, through the development and increase in fishing and shipping in continental shelf waters, essentially resumed whaling as vessel speeds and fishing gear strength have increased in recent decades. The ways in which these animals die, especially in fixed fishing gear that they become entangled in and swim off with, would raise substantial concern with consumers of seafood were they to be aware of what they were enabling.
Considering the Impact of the ‘Right to Bargain’ Legislation in Ireland: A Review
Authors: Cullinane Niall , Dobbins Anthony
Published: February 2014

Ireland is rare among advanced economies in not having statutory trade union recognition legislation for collective bargaining purposes. The matter has been a source of policy contention over the years with attempts to resolve it encapsulated in the so-called ‘Right to Bargain’ legislation, introduced in 2001. This legislation has sought to circumvent statutory recognition in Ireland by putting in place an alternative mechanism for unions to represent members in non-union firms where collective bargaining is not practiced. This review, based on a mixture of empirical and documentary evidence, demonstrates that this legislation was moderately successful for a short period in generating pay rises, improved employment conditions and better access to procedures for union members in non-unionised firms. Indeed, in some respects, it was a superior institutional mechanism to a statutory recognition regime.
X-ray luminous binaries, metallicity, and the early Universe
Authors: Kaaret Philip
Published: February 2014

High-mass X-ray binaries (HMXBs) may have had a significant impact on the heating of the intergalactic medium in the early Universe. Study of HMXBs in nearby, low-metallicity galaxies that are local analogues to early galaxies can help us understand early HMXBs. The total luminosity of HMXB populations is dominated by sources at high luminosities. These sources exhibit X-ray spectra that show curvature above 2 keV and the same is likely true of HMXB populations at high redshifts. The spectral curvature changes the K-correction for X-rays from HMXBs in a manner that weakens the constraints on X-ray emission of early HMXBs obtained from the soft X-ray background. Applied to deep X-ray surveys of star-forming galaxies, the modified K-correction suggests a moderate increase in the ratio of X-ray luminosity to star formation rate at intermediate redshifts, z = 3–5, and is consistent with a large enhancement at high redshifts, z = 6–7.
A Pilot Study Evaluating Presurgery Neuroanatomical Biomarkers for Postoperative Cognitive Decline after Total Knee Arthroplasty in Older Adults
Authors: Price Catherine C. , Tanner Jared J. , Schmalfuss Ilona , Garvan Cynthia Wilson , Gearen Peter , Dickey David , Heilman Kenneth , McDonagh David L. , Libon David J. , Leonard Christiana , Bowers Dawn , Monk Terri G.
Published: February 2014

Background:

Total knee arthroplasty improves quality of life but is associated with postoperative cognitive dysfunction in older adults. This prospective longitudinal pilot study with a parallel control group tested the hypotheses that (1) nondemented adults would exhibit primary memory and executive difficulties after total knee arthroplasty, and (2) reduced preoperative hippocampus/entorhinal volume would predict postoperative memory change, whereas preoperative leukoaraiosis and lacunae volumes would predict postoperative executive dysfunction.

Methods:

Surgery (n = 40) and age–education-matched controls with osteoarthritis (n = 15) completed pre- and postoperative (3 weeks, 3 months, and 1 yr) memory and cognitive testing. Hypothesized brain regions of interest were measured in patients completing preoperative magnetic resonance scans (surgery, n = 31; control, n = 12). Analyses used reliable change methods to identify the frequency of cognitive change at each time point.

Results:

The incidence of postoperative memory difficulties was shown with delay test indices (i.e., story memory test: 3 weeks = 17%, 3 months = 25%, 1 yr = 9%). Postoperative executive difficulty with measures of inhibitory function (i.e., Stroop Color Word: 3 weeks = 21%, 3 months = 22%, 1 yr = 9%). Hierarchical regression analysis assessing the predictive interaction of group (surgery, control) and preoperative neuroanatomical structures on decline showed that greater preoperative volumes of leukoaraiosis/lacunae were significantly contributed to postoperative executive (inhibitory) declines.

Conclusions:

This pilot study suggests that executive and memory declines occur in nondemented adults undergoing orthopedic surgery. Severity of preoperative cerebrovascular disease may be relevant for understanding executive decline, in particular.
Comparing Robotic Lung Resection with Thoracotomy and Video-Assisted Thoracoscopic Surgery Cases Entered into the Society of Thoracic Surgeons Database
Authors: Farivar Alexander S. , Cerfolio Robert J. , Vallières Eric , Knight Ariel W. , Bryant Ayesha , Lingala Vijaya , Aye Ralph W. , Louie Brian E.
Published: February 2014

Objective

The use of robotic lung surgery has increased dramatically despite being a new, costly technology with undefined benefits over standard of care. There is a paucity of published comparative articles justifying its use or cost. Furthermore, outcomes regarding robotic lung resection are either from single institutions with in-house historical comparisons or based on limited numbers. We compared consecutive robotic anatomic lung resections performed at two institutions with matched data from The Society of Thoracic Surgeons (STS) National Database for all open and video-assisted thoracoscopic surgery (VATS) resections. We sought to define any benefits to a robotic approach versus national outcomes after thoracotomy and VATS.

Methods

Data from all consecutive robotic anatomic lung resections were collected from two institutions (n = 181) from January 2010 until January 2012 and matched against the same variables for anatomic resections via thoracotomy (n = 5913) and VATS (n = 4612) from the STS National Database. Patients with clinical N2, N3, and M1 disease were excluded.

Results

There was a significant decrease in 30-day mortality and postoperative blood transfusion after robotic lung resection relative to VATS and thoracotomy. The patients stayed in the hospital 2 days less after robotic surgery than VATS and 4 days less than after thoracotomy. Robotic surgery led to fewer air leaks, intraoperative blood transfusions, need for perioperative bronchoscopy or reintubation, pneumonias, and atrial arrhythmias compared with thoracotomy.

Conclusions

This is the first comparative analysis using national STS data. It suggests potential benefits of robotic surgery relative to VATS and thoracotomy, particularly in reducing length of stay, 30-day mortality, and postoperative blood transfusion.
Shear Wave Elastography in the Evaluation of Liver Fibrosis in Children
Authors: Tutar Onur , Beşer Ömer F. , Adaletli Ibrahim , Tunc Necmettin , Gulcu Didem , Kantarci Fatih , Mihmanli Ismail , Cokugras Fugen C. , Kutlu Tufan , Ozbay Gulsen , Erkan Tulay
Published: February 2014

Background:

Shear‐wave elastography (SWE) is a novel noninvasive method that involves application of local mechanical compression on soft tissue using focused ultrasonography and acquiring strain images that show tissue response. In this study, our goal was to assess the performance of SWE in the staging of liver fibrosis in children with chronic liver disease.

Methods:

The study involved measuring SWE values in the right lobe of the liver in a patient group of 76 children with chronic liver disease and a control group of 50 healthy subjects. In the patient group, the shear elastic modulus values were correlated with biopsy results according to the Brunt scoring system (F0: portal fibrosis, F1: perisinusoidal or portal/periportal fibrosis, F2: both perisinusoidal and portal/periportal fibrosis, F3: bridging fibrosis, and F4: cirrhosis). Performance of SWE in estimating liver fibrosis in children was determined based on a receiver‐operating characteristics (ROC) analysis.

Results:

Mean SWE values of the control group and F0 group were not statistically significantly different (P = 0.106). The mean SWE values of the F1, F2, F3, and F4 groups were higher than that of the control group (all P < 0.001). Based on kiloPascal measurement values, the area under the ROC curve was 95.2% (95% confidence interval [CI] 92.1–99.5), with a sensitivity for diagnosing liver fibrosis of 91.5%, a specificity of 94.0%, a positive predictive value of 93.1%, and a negative predictive value of 92.6%. Based on meter‐per‐second measurement values, the area under the ROC curve was 96.3% (95% CI 92.7–99.8), with a sensitivity for diagnosing liver fibrosis of 93.2%, a specificity of 94.0%, a positive predictive value of 93.2%, and a negative predictive value of 94.0%. Mean SWE values for patients with nonalcoholic steatohepatitis were higher than those in the remainder of the study group.

Conclusions:

Although liver fibrosis can be detected using SWE, differentiation of fibrosis stages could not be achieved. The presence of steatosis significantly increased the mean SWE values on elastography and so care should be taken when assessing children with nonalcoholic steatohepatitis.
Gaussian solitary waves and compactons in Fermi–Pasta–Ulam lattices with Hertzian potentials
Authors: James Guillaume , Pelinovsky Dmitry
Published: February 2014

We consider a class of fully nonlinear Fermi–Pasta–Ulam (FPU) lattices, consisting of a chain of particles coupled by fractional power nonlinearities of orderα>1. This class of systems incorporates a classical Hertzian model describing acoustic wave propagation in chains of touching beads in the absence of precompression. We analyse the propagation of localized waves whenαis close to unity. Solutions varying slowly in space and time are searched with an appropriate scaling, and two asymptotic models of the chain of particles are derived consistently. The first one is a logarithmic Korteweg–de Vries (KdV) equation and possesses linearly orbitally stable Gaussian solitary wave solutions. The second model consists of a generalized KdV equation with Hölder-continuous fractional power nonlinearity and admits compacton solutions, i.e. solitary waves with compact support. When, we numerically establish the asymptotically Gaussian shape of exact FPU solitary waves with near-sonic speed and analytically check the pointwise convergence of compactons towards the limiting Gaussian profile.
Brittle fracture in a periodic structure with internal potential energy
Authors: Mishuris Gennady S. , Slepyan Leonid I.
Published: February 2014

We consider a brittle fracture taking account of self-equilibrated distributed stresses existing at microlevel in the absence of external forces. To determine how the latter can affect the crack equilibrium and growth, a model of a structured linearly elastic body is introduced, consisting of two equal symmetrically arranged layers (or half-planes) connected by an interface as a prospective crack path. The interface comprises a discrete set of elastic bonds. In the initial state, the bonds are assumed to be stressed in such a way that tensile and compressive forces of the same value alternate. In the general considerations, the layers are assumed to be of an unspecified periodic structure, where such self-equilibrated stresses may also exist. A two-line chain and a lattice are examined as the specified structure. We consider the states of the body-with-a-crack under such microlevel stresses (MS) and under a combined action of the remote forces and MS. Analytical solutions to the considered problems are presented based on the introduction of a selective discrete transform. We demonstrate that MS can increase as well as decrease the crack resistance depending on the internal energy level. We also discuss different scenarios of the crack growth.
Generation of mastitis resistance in cows by targeting human lysozyme gene to β-casein locus using zinc-finger nucleases
Authors: Liu Xu , Wang Yongsheng , Tian Yuchen , Yu Yuan , Gao Mingqing , Hu Guangdong , Su Feng , Pan Shaohui , Luo Yan , Guo Zekun , Quan Fusheng , Zhang Yong
Published: February 2014

Mastitis costs the dairy industry billions of dollars annually and is the most consequential disease of dairy cattle. Transgenic cows secreting an antimicrobial peptide demonstrated resistance to mastitis. The combination of somatic cell gene targeting and nuclear transfer provides a powerful method to produce transgenic animals. Recent studies found that a precisely placed double-strand break induced by engineered zinc-finger nucleases (ZFNs) stimulated the integration of exogenous DNA stretches into a pre-determined genomic location, resulting in high-efficiency site-specific gene addition. Here, we used ZFNs to target human lysozyme (hLYZ) gene to bovine β-casein locus, resulting in hLYZ knock-in of approximately 1% of ZFN-treated bovine fetal fibroblasts (BFFs). Gene-targeted fibroblast cell clones were screened by junction PCR amplification and Southern blot analysis. Gene-targeted BFFs were used in somatic cell nuclear transfer.
In vitro
assays demonstrated that the milk secreted by transgenic cows had the ability to kill
Staphylococcus aureus
. We report the production of cloned cows carrying human lysozyme gene knock-in β-casein locus using ZFNs. Our findings open a unique avenue for the creation of transgenic cows from genetic engineering by providing a viable tool for enhancing resistance to disease and improving the health and welfare of livestock.
Identification of Burkholderia multivorans ATCC 17616 genetic determinants for fitness in soil by using signature-tagged mutagenesis
Authors: Nagata Yuji , Senbongi Junko , Ishibashi Yoko , Sudo Rie , Miyakoshi Masatoshi , Ohtsubo Yoshiyuki , Tsuda Masataka
Published: February 2014

To identify bacterial genetic determinants for fitness in a soil environment, signature-tagged mutagenesis (STM) was applied to a soil bacterium, Burkholderia multivorans ATCC 17616. This strain was randomly mutagenized by each of 36 different signature-tagged plasposons, and 36 mutants with different tags were grouped as a set. A total of 192 sets consisting of 6912 independent mutants were each inoculated into soil and incubated. Two-step STM screening based on quantitative real-time PCR of total DNAs extracted from the resulting soil samples using the tag-specific primers led to the selection of 39 mutant candidates that exhibited a reduction in relative competitive fitness during incubation in the soil, and 32 plasposon-insertion sites were determined. Among them, mutants having plasposon insertion in fur, deaD or hrpA exhibited reduced fitness during incubation in soil when compared with the control strain. The deficiency in the soil fitness of the fur mutant was recovered by the introduction of the wild-type fur gene, indicating that the fur gene is one of the genetic determinants for fitness in the soil.
Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development
Authors: Rodenfels Jonathan , Lavrynenko Oksana , Ayciriex Sophie , Sampaio Julio L. , Carvalho Maria , Shevchenko Andrej , Eaton Suzanne
Published: February 2014

InDrosophilalarvae, growth and developmental timing are regulated by nutrition in a tightly coordinated fashion. The networks that couple these processes are far from understood. Here, we show that the intestine responds to nutrient availability by regulating production of a circulating lipoprotein-associated form of the signaling protein Hedgehog (Hh). Levels of circulating Hh tune the rates of growth and developmental timing in a coordinated fashion. Circulating Hh signals to the fat body to control larval growth. It regulates developmental timing by controlling ecdysteroid production in the prothoracic gland. Circulating Hh is especially important during starvation, when it is also required for mobilization of fat body triacylglycerol (TAG) stores. Thus, we demonstrate that Hh, previously known only for its local morphogenetic functions, also acts as a lipoprotein-associated endocrine hormone, coordinating the response of multiple tissues to nutrient availability.
Synthesis and patterning of tunable multiscale materials with engineered cells
Authors: Chen Allen Y , Seker Urartu O.S. , Lu Michelle Y , Citorik Robert J , Lu Timothy
Published: February 2014

A major challenge in materials science is to create self-assembling, functional, and environmentally responsive materials which can be patterned across multiple length scales. Natural biological systems, such as biofilms, shells, and skeletal tissues, implement dynamic regulatory programs to assemble complex multiscale materials comprised of living and non-living components. Such systems can provide inspiration for the design of heterogeneous functional systems which integrate biotic and abiotic materials via hierarchical self-assembly. Here, we present a synthetic-biology platform for synthesizing and patterning self-assembled functional amyloid materials across multiple length scales with bacterial biofilms. We engineered Escherichia coli curli amyloid production under the tight control of synthetic regulatory circuits and interfaced amyloids with inorganic materials to create a biofilm-based electrical switch whose conductance can be selectively toggled by specific environmental signals. Furthermore, we externally tuned synthetic biofilms to build nanoscale amyloid biomaterials with different structure and composition through the controlled expression of their constituent subunits with artificial gene circuits. By using synthetic cell-cell communication, our engineered biofilms can also autonomously manufacture dynamic materials whose structure and composition change with time. In addition, we show that by combining subunit-level protein engineering, controlled genetic expression of self-assembling subunit proteins, and macroscale spatial gradients, synthetic biofilms can pattern protein biomaterials across multiple length scales. This work lays a foundation for synthesizing, patterning, and controlling composite materials with engineered biological systems. We envision that this approach can be expanded to other cellular and biomaterials contexts for the construction of self-organizing, environmentally responsive, and tunable multiscale composite materials with heterogeneous functionalities. Now published as: Nature Materials, doi:10.1038/nmat3912
Evolutionary rates for multivariate traits: the role of selection and genetic variation
Authors: Pitchers William , Wolf Jason B. , Tregenza Tom , Hunt John , Dworkin Ian
Published: February 2014

A fundamental question in evolutionary biology is the relative importance of selection and genetic architecture in determining evolutionary rates. Adaptive evolution can be described by the multivariate breeders’ equation, which predicts evolutionary change for a suite of phenotypic traitsas a product of directional selection acting on them (β) and the genetic variance-covariance matrix for those traits (G). Despite being empirically challenging to estimate, there are enough published estimates ofGandβto allow for synthesis of general patterns across species. We use published estimates to test the hypotheses that there are systematic differences in the rate of evolution among trait types, and that these differences are in part due to genetic architecture. We find evidence some evidence that sexually selected traits exhibit faster rates of evolution compared to life-history or morphological traits. This difference does not appear to be related to stronger selection on sexually selected traits. Using numerous proposed approaches to quantifying the shape, size and structure ofGwe examine how these parameters relate to one another, and how they vary among taxonomic and trait groupings. Despite considerable variation, they do not explain the observed differences in evolutionary rates.
Neuroanatomical diversity of corpus callosum and brain volume in the Autism Brain Imaging Data Exchange (Abide) project
Authors: Lefebvre Aline , Beggiato Anita , Bourgeron Thomas , Toro Roberto
Published: February 2014

The corpus callosum – the main pathway for long-distance inter-hemispheric integration in the human brain – has been frequently reported to be smaller among autistic patients compared with non-autistic controls. We conducted a meta-analysis of the literature which suggested a statistically significant difference. However, the studies included were heavily underpowered: on average only 20% power to detect differences of 0.3 standard deviations, which makes it difficult to establish the reality of such a difference. We therefore studied the size of the corpus callosum among 694 subjects (328 patients, 366 controls) from the Abide cohort. Despite having achieved 99% power to detect statistically significant differences of 0.3 standard deviations, we did not observe any. To better understand the neuroanatomical diversity of the corpus callosum, and the possible reasons for the previous findings, we analysed the relationship between its size, the size of the brain, intracranial volume and intelligence scores. The corpus callosum appeared to scale non-linearly with brain size, with large brains having a proportionally smaller corpus callosum. Additionally, intelligence scores correlated with brain volume among controls but the correlation was significantly weaker among patients. We used simulations to determine to which extent these two effects could lead to artefactual differences in corpus callosum size within populations. We observed that, were there a difference in brain volume between cases and controls, normalising corpus callosum size by brain volume would not eliminate the brain volume effect, but adding brain volume as a covariate in a linear model would. Finally, we observed that because of the weaker correlation of intelligence scores and brain volume among patients, matching populations by intelligence scores could result in a bias towards including more patients with large brain volumes, inducing an artificial difference. Overall, our results highlight the necessity for open data sharing efforts such as Abide to provide a more solid ground for the discovery of neuroimaging biomarkers, within the context of the wide human neuroanatomical diversity.
Immune stimulation reduces sleep and memory ability inDrosophila melanogaster
Authors: Mallon E. B. , Alghamdi A. , Holdbrook R. T. K. , Rosato E.
Published: February 2014

Psychoneuroimmunology studies the increasing number of connections between neurobiology, immunology and behaviour. We establishDrosophila melanogasteras a tractable model in this field by demonstrating the effects of the immune response on two fundamental behaviours: sleep and memory ability.

We used the Geneswitch system to upregulate peptidoglycan receptor protein (PGRP) expression, thereby stimulating the immune system in the absence of infection. Geneswitch was activated by feeding the steroid RU486, to the flies. We used an aversive classical conditioning paradigm to quantify memory and measures of activity to infer sleep.

Immune stimulated flies exhibited reduced levels of sleep, which could not be explained by a generalised increase in waking activity. The effects on sleep were more pronounced for day compared to night sleep. Immune stimulated flies also showed a reduction in memory abilities.

These are important results as they establishDrosophilaas a model for immune-neural interactions and provide a possible role for sleep in the interplay between the immune response and memory.
Fluorescent sensors for activity and regulation of the nitrate transceptor CHL1/NRT1.1 and oligopeptide transporters
Authors: Ho Cheng-Hsun , Frommer Wolf B.
Published: February 2014

To monitor nitrate and peptide transport activityin vivo, we converted the dual-affinity nitrate transceptor CHL1/NRT1.1/NPF6.3 and four related oligopeptide transporters PTR1, 2, 4 and 5 into fluorescence activity sensors (NiTrac1, PepTrac). Substrate addition to yeast expressing transporter fusions with yellow fluorescent protein and mCerulean triggered substrate-dependent donor quenching or resonance energy transfer. Fluorescence changes were nitrate/peptide-specific, respectively. Like CHL1, NiTrac1 had biphasic kinetics. Mutation of T101A eliminated high-affinity transport and blocked the fluorescence response to low nitrate. NiTrac was used for characterizing side chains considered important for substrate interaction, proton coupling, and regulation. We observed a striking correlation between transport activity and sensor output. Coexpression of NiTrac with known calcineurin-like proteins (CBL1, 9; CIPK23) and candidates identified in an interactome screen (CBL1, KT2, WNKinase 8) blocked NiTrac1 responses, demonstrating the suitability forin vivoanalysis of activity and regulation. The new technology is applicable in plant and medical research.
ESCRT-0 is not required for ectopic Notch activation and tumor suppression inDrosophila
Authors: Tognon Emiliana , Wollscheid Nadine , Cortese Katia , Tacchetti Carlo , Vaccari Thomas
Published: February 2014

Multivesicular endosome (MVE) sorting depends on proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) family. These are organized in four complexes (ESCRT-0, -I, -II, -III) that act in a sequential fashion to deliver ubiquitylated cargoes into the internal luminal vesicles (ILVs) of the MVE.Drosophilagenes encoding ESCRT-I, -II, -III components function in sorting signaling receptors, including Notch and the JAK/STAT signaling receptor Domeless. Loss of ESCRT-I, -II, -III inDrosophilaepithelia causes altered signaling and cell polarity, suggesting that ESCRTs genes are tumor suppressors. However, the nature of the tumor suppressive function of ESCRTs, and whether tumor suppression is linked to receptor sorting is unclear. Unexpectedly, a null mutant inHrs,encoding one of components of the ESCRT-0 complex, which acts upstream of ESCRT-I, -II, -III in MVE sorting is dispensable for tumor suppression. Here, we report that twoDrosophilaepithelia lacking activity ofStam, the other known components of the ESCRT-0 complex, or of bothHrsandStamfail to degrade signaling receptors. However, mutant tissue surprisingly maintains normal apico-basal polarity and proliferation control and does not display ectopic Notch signaling activation, unlike cells that lack ESCRT-I, -II, -III activity. Overall, ourin vivodata indicate that the ESCRT-0 complex plays no crucial role in regulation of tumor suppression, and suggest re-evaluation of the relationship of signaling modulation in endosomes and tumorigenesis.
Migration and interaction in a contact zone: mtDNA variation among Bantu-speakers in southern Africa
Authors: Barbieri Chiara , Vicente Mário , Oliveira Sandra , Bostoen Koen , Rocha Jorge , Stoneking Mark , Pakendorf Brigitte
Published: February 2014

Bantu speech communities expanded over large parts of sub-Saharan Africa within the last 4000-5000 years, reaching different parts of southern Africa 1200-2000 years ago. The Bantu languages subdivide in several major branches, with languages belonging to the Eastern and Western Bantu branches spreading over large parts of Central, Eastern, and Southern Africa. There is still debate whether this linguistic divide is correlated with a genetic distinction between Eastern and Western Bantu speakers. During their expansion, Bantu speakers would have come into contact with diverse local populations, such as the Khoisan hunter-gatherers and pastoralists of southern Africa, with whom they may have intermarried. In this study, we analyze complete mtDNA genome sequences from over 900 Bantu-speaking individuals from Angola, Zambia, Namibia, and Botswana to investigate the demographic processes at play during the last stages of the Bantu expansion. Our results show that most of these Bantu-speaking populations are genetically very homogenous, with no genetic division between speakers of Eastern and Western Bantu languages. Most of the mtDNA diversity in our dataset is due to different degrees of admixture with autochthonous populations. Only the pastoralist Himba and Herero stand out due to high frequencies of particular L3f and L3d lineages; the latter are also found in the neighboring Damara, who speak a Khoisan language and were foragers and small-stock herders. In contrast, the close cultural and linguistic relatives of the Herero and Himba, the Kuvale, are genetically similar to other Bantu-speakers. Nevertheless, as demonstrated by resampling tests, the genetic divergence of Herero, Himba, and Kuvale is compatible with a common shared ancestry with high levels of drift and differential female admixture with local pre-Bantu populations.
The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration
Authors: Dey Bijan K. , Pfeifer Karl , Dutta Anindya
Published: February 2014

Regulated expression of the H19 long noncoding RNA gene has been well characterized as a paradigm for genomic imprinting, but the H19 RNA's biological function remains largely unclear. H19 is abundantly expressed maternally in embryonic tissues but is strongly repressed after birth, and significant transcription persists only in skeletal muscle. Thus, we examined the role of the H19 RNA in skeletal muscle differentiation and regeneration. Knockdown of H19 RNA in myoblast cells and H19 knockout mouse satellite cells decreases differentiation. H19 exon1 encodes two conserved microRNAs, miR-675-3p and miR-675-5p, both of which are induced during skeletal muscle differentiation. The inhibition of myogenesis by H19 depletion during myoblast differentiation is rescued by exogenous expression of miR-675-3p and miR-675-5p. H19-deficient mice display abnormal skeletal muscle regeneration after injury, which is rectified by reintroduction of miR-675-3p and miR-675-5p. miR-675-3p and miR-675-5p function by directly targeting and down-regulating the anti-differentiation Smad transcription factors critical for the bone morphogenetic protein (BMP) pathway and the DNA replication initiation factor Cdc6. Therefore, the H19 long noncoding RNA has a critical trans-regulatory function in skeletal muscle differentiation and regeneration that is mediated by the microRNAs encoded within H19.
The Rad50 hook domain regulates DNA damage signaling and tumorigenesis
Authors: Roset Ramon , Inagaki Akiko , Hohl Marcel , Brenet Fabienne , Lafrance-Vanasse Julien , Lange Julian , Scandura Joseph M. , Tainer John A. , Keeney Scott , Petrini John H.J.
Published: February 2014

The Mre11 complex (Mre11, Rad50, and Nbs1) is a central component of the DNA damage response (DDR), governing both double-strand break repair and DDR signaling. Rad50 contains a highly conserved Zn2+-dependent homodimerization interface, the Rad50 hook domain. Mutations that inactivate the hook domain produce a null phenotype. In this study, we analyzed mutants with reduced hook domain function in an effort to stratify hook-dependent Mre11 complex functions. One of these alleles, Rad5046, conferred reduced Zn2+ affinity and dimerization efficiency. Homozygous Rad5046/46 mutations were lethal in mice. However, in the presence of wild-type Rad50, Rad5046 exerted a dominant gain-of-function phenotype associated with chronic DDR signaling. At the organismal level, Rad50+/46 exhibited hydrocephalus, liver tumorigenesis, and defects in primitive hematopoietic and gametogenic cells. These outcomes were dependent on ATM, as all phenotypes were mitigated in Rad50+/46Atm+/− mice. These data reveal that the murine Rad50 hook domain strongly influences Mre11 complex-dependent DDR signaling, tissue homeostasis, and tumorigenesis.
The less things change, the more they are different: contributions of long-term synaptic plasticity and homeostasis to memory
Authors: Schacher Samuel , Hu Jiang-Yuan
Published: February 2014

An important cellular mechanism contributing to the strength and duration of memories is activity-dependent alterations in the strength of synaptic connections within the neural circuit encoding the memory. Reversal of the memory is typically correlated with a reversal of the cellular changes to levels expressed prior to the stimulation. Thus, for stimulus-induced changes in synapse strength and their reversals to be functionally relevant, cellular mechanisms must regulate and maintain synapse strength both prior to and after the stimuli inducing learning and memory. The strengths of synapses within a neural circuit at any given moment are determined by cellular and molecular processes initiated during development and those subsequently regulated by the history of direct activation of the neural circuit and system-wide stimuli such as stress or motivational state. The cumulative actions of stimuli and other factors on an already modified neural circuit are attenuated by homeostatic mechanisms that prevent changes in overall synaptic inputs and excitability above or below specific set points (synaptic scaling). The mechanisms mediating synaptic scaling prevent potential excitotoxic alterations in the circuit but also may attenuate additional cellular changes required for learning and memory, thereby apparently limiting information storage. What cellular and molecular processes control synaptic strengths before and after experience/activity and its reversals? In this review we will explore the synapse-, whole cell-, and circuit level-specific processes that contribute to an overall zero sum-like set of changes and long-term maintenance of synapse strengths as a consequence of the accommodative interactions between long-term synaptic plasticity and homeostasis.
Infantile amnesia: forgotten but not gone
Authors: Li Stella , Callaghan Bridget L. , Richardson Rick
Published: February 2014

Unlike adult memories that can be remembered for many years, memories that are formed early in life are more fragile and susceptible to being forgotten (a phenomenon known as “infantile” or “childhood” amnesia). Nonetheless, decades of research in both humans and nonhuman animals demonstrate the importance of early life experiences on later physical, mental, and emotional functioning. This raises the question of how early memories can be so influential if they cannot be recalled. This review presents one potential solution to this paradox by considering what happens to an early memory after it has been forgotten. Specifically, we describe evidence showing that these forgotten early-acquired memories have not permanently decayed from storage. Instead, there appears to be a memory “trace” that persists in the face of forgetting which continues to affect a variety of behavioral responses later in life. Excitingly, the discovery of this physical trace will allow us to explore previously untestable issues in new ways, from whether forgetting is due to a failure in retrieval or storage to how memories can be recovered after extended periods of time. A greater understanding of the characteristics of this memory trace will provide novel insights into how some memories are left behind in childhood while others are carried with us, at least in some form, for a lifetime.
Stochastic reinforcement benefits skill acquisition
Authors: Dayan Eran , Averbeck Bruno B. , Richmond Barry J. , Cohen Leonardo G.
Published: February 2014

Learning complex skills is driven by reinforcement, which facilitates both online within-session gains and retention of the acquired skills. Yet, in ecologically relevant situations, skills are often acquired when mapping between actions and rewarding outcomes is unknown to the learning agent, resulting in reinforcement schedules of a stochastic nature. Here we trained subjects on a visuomotor learning task, comparing reinforcement schedules with higher, lower, or no stochasticity. Training under higher levels of stochastic reinforcement benefited skill acquisition, enhancing both online gains and long-term retention. These findings indicate that the enhancing effects of reinforcement on skill acquisition depend on reinforcement schedules.
Interaction between theGROWTH-REGULATING FACTORandKNOTTED1-LIKE HOMEOBOXFamilies of Transcription Factors
Authors: Kuijt Suzanne J.H. , Greco Raffaella , Agalou Adamantia , Shao Jingxia , ‘t Hoen Corine C.J. , Övernäs Elin , Osnato Michela , Curiale Serena , Meynard Donaldo , van Gulik Robert , Maraschin Simone de Faria , Atallah Mirna , de Kam Rolf J. , Lamers Gerda E.M. , Guiderdoni Emmanuel , Rossini Laura , Meijer Annemarie H. , Ouwerkerk Pieter B.F.
Published: February 2014

KNOTTED1-LIKE HOMEOBOX (KNOX) genes are important regulators of meristem function, and a complex network of transcription factors ensures tight control of their expression. Here, we show that members of the GROWTH-REGULATING FACTOR (GRF) family act as players in this network. A yeast (Saccharomyces cerevisiae) one-hybrid screen with the upstream sequence of the KNOX gene Oskn2 from rice (Oryza sativa) resulted in isolation of OsGRF3 and OsGRF10. Specific binding to a region in the untranslated leader sequence of Oskn2 was confirmed by yeast and in vitro binding assays. ProOskn2:β-glucuronidase reporter expression was down-regulated by OsGRF3 and OsGRF10 in vivo, suggesting that these proteins function as transcriptional repressors. Likewise, we found that the GRF protein BGRF1 from barley (Hordeum vulgare) could act as a repressor on an intron sequence in the KNOX gene Hooded/Barley Knotted3 (Bkn3) and that AtGRF4, AtGRF5, and AtGRF6 from Arabidopsis (Arabidopsis thaliana) could repress KNOTTED-LIKE FROM ARABIDOPSIS THALIANA2 (KNAT2) promoter activity. OsGRF overexpression phenotypes in rice were consistent with aberrant meristematic activity, showing reduced formation of tillers and internodes and extensive adventitious root/shoot formation on nodes. These effects were associated with down-regulation of endogenous Oskn2 expression by OsGRF3. Conversely, RNA interference silencing of OsGRF3, OsGRF4, and OsGRF5 resulted in dwarfism, delayed growth and inflorescence formation, and up-regulation of Oskn2. These data demonstrate conserved interactions between the GRF and KNOX families of transcription factors in both monocot and dicot plants.
Thinking about changing mobility practices: how a social practice approach can help
Authors: Nettleton Sarah , Green Judith
Published: February 2014

Policy efforts directed at encouraging physical activity have had minimal success to date. Drawing on Bourdieu's theory of practice, we suggest that a social practice framing might provide useful ways of thinking about why and how some practices do and could change. This article takes three case studies of transformations in mobility practices to explore conditions of possibility for change, using a secondary analysis of qualitative data from studies on cycling in London and fell running in the English Lake District. Three modes of transformation: unthinkable, thwarted and resisted, are rooted in differential interrelationships of field, habitus and doxa in these contrasting cases. We suggest that the notion of tacit, practical knowledge is more useful to understanding why change is thinkable or unthinkable than participants’ reasoned accounts of their practice; that where new social fields are available that are congruent with habitus, change is possible and that where field and habitus are tightly aligned, the conditions of possibility for change are reduced. Efforts directed at changing practice might usefully focus not on behaviour or environments but on identifying the social fields in which mobility practices are likely to be malleable. The sociology of public health needs to focus less on health behaviour and more on social practice.
Providers’ constructions of pregnant and early parenting women who use substances
Authors: Benoit Cecilia , Stengel Camille , Marcellus Lenora , Hallgrimsdottir Helga , Anderson John , MacKinnon Karen , Phillips Rachel , Zazueta Pilar , Charbonneau Sinead
Published: February 2014

The research literature indicates that problematic substance use as a form of health behaviour is poorly understood, being sometimes viewed as deviance, at other times as a disease, and most often as a combination of these states. The use of substances by women who are pregnant or new parents is often conceptualised within an individualised framework. Yet drinking alcohol and using other drugs during pregnancy and early parenthood cuts across social divisions and is shaped by socio‐structural contexts including health care. There is a growing body of literature that critically examines public health interventions that are aimed at implementing harm reduction and health promotion techniques in service delivery to help pregnant and early parenting women who are identified as problem substance users. We examine qualitative data from representatives of a recent harm reduction intervention, focusing, in particular, on providers’ individual conceptualisations of the problematic behaviour. Our results show that most study participants regard any substance use during pregnancy, birth and the postpartum period as fundamentally unacceptable. This framing of problematic substance use is accomplished via gendered responsibilisation of women as foetal incubators and primary caregivers of infants. We discuss our results in light of the current literature and suggest policy implications.