bluuebunny/crossref_metadata_2025 huggingface dataset:
Linear models enable powerful differential activity analysis in massively parallel reporter assays
Authors: Myint Leslie , Avramopoulos Dimitrios G. , Goff Loyal A. , Hansen Kasper D.
Published: October 2017

Massively parallel reporter assays (MPRAs) have emerged as a popular means for understanding noncoding variation in a variety of conditions. While a large number of experiments have been described in the literature, analysis typically uses ad-hoc methods. There has been little attention to comparing performance of methods across datasets.

We present the mpralm method which we show is calibrated and powerful, by analyzing its performance on multiple MPRA datasets. We show that it outperforms existing statistical methods for analysis of this data type, in the first comprehensive evaluation of statistical methods on several datasets. We investigate theoretical and real-data properties of barcode summarization methods and show an unappreciated impact of summarization method for some datasets. Finally, we use our model to conduct a power analysis for this assay and show substantial improvements in power by performing up to 6 replicates per condition, whereas sequencing depth has smaller impact; we recommend to always use at least 4 replicates. Together, these results inform recommendations for differential analysis, general group comparisons, and power analysis and will help improve design and analysis of MPRA experiments. An R package is available from the Bioconductor project athttps://bioconductor.org/packages/mpra.
A Non-Synonymous SHARPIN Variant is Associated with Limbic Degeneration and Family History of Alzheimer’s Disease
Authors: Soheili-Nezhad Sourena , Jahanshad Neda , Guelfi Sebastian , Khosrowabadi Reza , Saykin Andrew J. , Thompson Paul M. , Beckmann Christian F. , Sprooten Emma , Zarei Mojtaba ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2017

Pharmacological progress, basic science and medical practice can benefit from objective biomarkers that assist in early diagnosis and prognostic stratification of diseases. In the field of Alzheimer’s disease (AD), the clinical presentation of early stage dementia may not fulfill any diagnostic criteria for years, and quantifying structural brain changes by magnetic resonance imaging (MRI) has shown promise in the discovery of sensitive biomarkers. Although hippocampal atrophy is often used as an in vivo measure of AD, data-driven neuroimaging has revealed complex patterns of regional brain vulnerability that may not perfectly map to anatomical boundaries. In addition to aiding diagnosis, decoding genetic influences on neuroimaging measures of the disease can enlighten molecular mechanisms of the underlying pathology in living patients and guide the therapeutic design.

Here, we aimed to extract a data-driven MRI feature of brain atrophy in AD by decomposing structural neuroimages using independent component analysis (ICA), a method for performing unbiased computational search in high dimensional data spaces. Our study of the AD Neuroimaging Initiative dataset (n=1,100 subjects) revealed a disease-vulnerable feature with a network-like topology, comprising amygdala, hippocampus, fornix and the inter-connecting white-matter tracts of the limbic system. Whole-genome sequencing identified a nonsynonymous variant (rs34173062) in SHARPIN, a gene coding for a synaptic protein, as a significant modifier of this new MRI feature (p=2.1×10−10). The risk variant was brought to replication in the UK Biobank dataset (n=8,428 subjects), where it was associated with reduced cortical thickness in areas co-localizing with those of the discovery sample (left entorhinal cortex p=0.002, right entorhinal cortex p=8.6×10−4; same direction), as well as with the history of AD in both parents (p=2.3×10−6; same direction).

In conclusion, our study shows that ICA can transform voxel-wise volumetric measures of the brain into a data-driven feature of neurodegeneration in AD. Structure of the limbic system, as the most vulnerable focus of brain atrophy in AD, is affected by genetic variability of SHARPIN. The elevated risk of dementia in carriers of the minor allele supports engagement of SHARPIN in the disease pathways, and its role in neurotransmitter receptor scaffolding and integrin signaling may inform on new molecular mechanisms of AD pathophysiology.

Abbreviations

Alzheimer’s disease (AD), genome-wide association study (GWAS), independent component analysis (ICA), mild cognitive impairment (MCI), medial temporal circuit (MTC), single-nucleotide polymorphism (SNP), tensor-based morphometry (TBM)
Multiphoton minimal inertia scanning for fast acquisition of neural activity signals
Authors: Schuck Renaud , Go Mary Ann , Garasto Stefania , Reynolds Stephanie , Dragotti Pier Luigi , Schultz Simon R.
Published: October 2017

Multi-photon laser scanning microscopy provides a powerful tool for monitoring the spatiotemporal dynamics of neural circuit activity. It is, however, intrinsically a point scanning technique. Standard raster scanning enables imaging at subcellular resolution; however, acquisition rates are limited by the size of the field of view to be scanned. Recently developed scanning strategies such as Travelling Salesman Scanning (TSS) have been developed to maximize cellular sampling rate by scanning only regions of interest in the field of view corresponding to locations of interest such as somata. However, such strategies are not optimized for the mechanical properties of galvanometric scanners. We describe here the Adaptive Spiral Scanning (SSA) algorithm, which fits a set of near-circular trajectories to the cellular distribution to avoid inertial drifts of galvanometer position. We compare its performance to raster scanning and TSS in terms of cellular sampling frequency and signal-to-noise ratio (SNR). Using surrogate neuron spatial position data, we show that SSA acquisition rates are an order of magnitude higher than those for raster scanning and generally exceed those achieved by TSS for neural densities comparable with those found in the cortex. We show that this result also holds true forin vitrohippocampal mouse brain slices bath loaded with the synthetic calcium dye Cal-520 AM. The ability of TSS to ”park” the laser on each neuron along the scanning trajectory, however, enables higher SNR than SSA when all targets are precisely scanned. Raster scanning has the highest SNR but at a substantial cost in number of cells scanned. To understand the impact of sampling rate and SNR on functional calcium imaging, we used the Cramér-Rao Bound on evoked calcium traces recorded simultaneously with electrophysiology traces to calculate the lower bound estimate of the spike timing occurrence. The results show that TSS and SSA achieve comparable accuracy in spike time estimates compared to raster scanning despite their lower SNR. SSA is an easily implementable way for standard multi-photon laser scanning systems to gain temporal precision in the detection of action potentials while scanning hundreds of active cells.
Conflict between heterozygote advantage and hybrid incompatibility in haplodiploids (and sex chromosomes)
Authors: Ghenu Ana-Hermina , Blanckaert Alexandre , Butlin Roger K. , Kulmuni Jonna , Bank Claudia
Published: October 2017

In many diploid species the sex chromosomes play a special role in mediating reproductive isolation. In haplodiploids, where females are diploid and males haploid, the whole genome behaves similarly to the X/Z chromosomes of diploids. Therefore, haplodiploid systems can serve as a model for the role of sex chromosomes in speciation and hybridization. A previously described population of FinnishFormicawood ants displays genome-wide signs of ploidally and sexually antagonistic selection resulting from hybridization. Here, hybrid females have increased survivorship but hybrid males are inviable. To understand how the unusual hybrid population may be maintained, we developed a mathematical model with hybrid incompatibility, female heterozygote advantage, recombination, and assortative mating. The rugged fitness landscape resulting from the co-occurrence of heterozygote advantage and hybrid incompatibility results in a sexual conflict in haplodiploids, which is caused by the ploidy difference. Thus, whereas heterozygote advantage always promotes long-term polymorphism in diploids, we find various outcomes in haplodiploids in which the population stabilizes either in favor of males, females, or via maximizing the number of introgressed individuals. We discuss these outcomes with respect to the potential long-term fate of the Finnish wood ant population, and provide approximations for the extension of the model to multiple incompatibilities. Moreover, we highlight the general implications of our results for speciation and hybridization in haplodiploids versus diploids, and how the described fitness relationships could contribute to the outstanding role of sex chromosomes as hotspots of sexual antagonism and genes involved in speciation.
JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons
Authors: Roessler Reinhard , Goldmann Johanna , Shivalila Chikdu , Jaenisch Rudolf
Published: October 2017

Phelan-McDermid syndrome (also known as 22q13 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3. However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 (MAPK8IP2) may contribute to a distinct neurodevelopmental phenotype in neural progenitors (NPCs) affecting neuronal maturation. This is most likely due to simultaneous misregulation of JNK proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling is compromised in patient NPCs and neurons. Pharmacological stimulation of neuropilin receptor 1 (NRP1) rescued impaired semaphorin pathway activity and JNK expression in patient neurons. Our results suggest a novel disease-specific mechanism involving the JIP/JNK complex and identify NRP1 as potential therapeutic target.
Modeling the Role of the Striatum in Non-Stationary Bandit Tasks
Authors: Shivkumar Sabyasachi , Srinivasa Chakravarthy V. , Rougier Nicolas P.
Published: October 2017

Decision making in non-stationary and stochastic environments can be interpreted as a variant of non-stationary multi armed bandit task where the optimal decision requires identification of the current context. We formalize the problem using a Bayesian approach taking biological constraints into account (limited memory) that allow us to define a sub-optimal theoretical model. From this theoretical model, we derive a biological model of the striatum based on its micro-anatomy that is able to learn state and action representations. We show that this model matches the theoretical model for low stochasticity in the environment and could be considered as a neural implementation of the theoretical model. Both models are tested on non-stationary multi-armed bandit task and compared to animal performances.

Author Summary

Decision making in changing environments requires knowledge of the current context in order to adapt the response to the environment. Such context identification is based on the recent history of actions and their outcome: when some action used to be rewarded but is not anymore, it might be a sign of a context change. An ideal observer with infinite memory could optimally estimate the current context and act accordingly. Taking biological constraint into account, we show that a model of the striatum, which is the largest nucleus of the basal ganglia, can solve the task in a sub-optimal way as it has been shown to be the case in rats in a T-maze task.
Modulation of high frequency by low-frequency Oscillations in the basal ganglia
Authors: Nouri D. , Ebrahimpour R. , Mirzaei A.
Published: October 2017

Modulation of beta band fioscillatory activity (15-30 Hz) by delta band oscillatory activity (1-3 Hz) in the cortico-basal ganglia loop is important for normal basal ganglia functions. However, the neural mechanisms underlying this modulation are poorly understood. To understand the mechanisms underlying such frequency modulations in the basal ganglia, we use large scale subthalamo-pallidal network model stimulated via a delta-frequency input signal. We show that inhibition of external Globus Pallidus (GPe) and excitation of the Subthalamic nucleus (STN) using the delta-band stimulation leads to the same delta-beta interactions in the network model as the experimental results observed in healthy basal ganglia. In addition, we show that pathological beta oscillations in the network model decorrelates the delta-beta link in the network model. In general, using our simulation results, we propose that striato-pallidal inhibition and cortico-subthalamic excitation are the potential sources of the delta-beta link observed in the intact basal ganglia.
A LaeA- and BrlA-dependent cellular network governs tissue-specific secondary metabolism in the human pathogenAspergillus fumigatus
Authors: Lind Abigail L. , Lim Fang Yun , Soukup Alexandra A. , Keller Nancy P. , Rokas Antonis
Published: October 2017

Biosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. InAspergillusmolds, asexual development is regulated by the BrlA>AbaA>WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, ΔwetAand wild-type strains of the human pathogenAspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of ΔbrlAand ΔlaeAis mediated by a LaeA requirement preventing heterochromatic marks in thebrlApromoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.
Membrane Proteins Significantly Restrict Exosome Mobility
Authors: Skliar Mikhail , Chernyshev Vasiliy S. , Belnap David M. , Al-Hakami Samer M. , Stijleman Inge J. , Rachamadugu Rakesh , Bernard Philip S.
Published: October 2017

Exosomes are membrane nanovesicles that intermediate cell-to-cell signaling through the transfer of their molecular cargo. The exosomes’ small size facilitates rapid migration through the extracellular matrix and into and out of circulation. Here we report that the mobility of the exosomes is much lower than would be expected from the size of their membrane vesicles. The difference is broadly distributed and caused by surface proteins, which significantly impede exosome migration. The observed wide range in the mobility implies that a subpopulation of hydrodynamically small exosomes is more likely to participate in signaling. The extracellular environment amplifies the size-dependent hindrance to the exosomes migration. The significant contribution of surface proteins to the transport resistance make the exosome mobility a dynamic property that changes with the extracellular environment which affects the membrane protein conformation, glycosylation, specific, and non-specific surface adsorption.
Scopoletin 8-hydroxylase: a novel enzyme involved in coumarin biosynthesis and iron-deficiency responses in Arabidopsis
Authors: Siwinska Joanna , Wcisla Kinga , Olry Alexandre , Grosjean Jeremy , Hehn Alain , Bourgaud Frederic , Meharg Andrew A. , Carey Manus , Lojkowska Ewa , Ihnatowicz Anna
Published: October 2017

Highlight

A strongly iron-responsive gene of previously unknown function, At3g12900, encodes a scopoletin 8-hydroxylase involved in coumarin biosynthesis and plays an important role in the iron uptake strategy in Arabidopsis.

Iron (Fe) deficiency represents a serious agricultural problem, particularly in alkaline soils. Secretion of coumarins byArabidopsis thalianaroots is induced under Fe-deficiency. An essential enzyme for the biosynthesis of major Arabidopsis coumarins, scopoletin and its derivatives, is Feruloyl-CoA 6’-Hydroxylase1 (F6′H1) that belongs to a large enzyme family of the 2-oxoglutarate and Fe(II)-dependent dioxygenases. Another member of this family that is a close homologue of F6’H1 and is encoded by a strongly Fe-responsive gene, At3g12900, is functionally characterized in the presented work. We purified the At3g12900 protein heterologously expressed inEscherichia coliand demonstrated that it is involved in the conversion of scopoletin into fraxetinviahydroxylation at the C8-position. Consequently, it was named scopoletin 8-hydroxylase (S8H). Its function in plant cells was confirmed by the transient expression of S8H protein inNicotiana benthamianaleaves followed by the metabolite profiling and the biochemical and ionomic characterization of Arabidopsiss8hknockout lines grown under various regimes of Fe availability. Our results indicate that S8H is involved in coumarin biosynthesis as part of the Fe acquisition machinery.
Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade
Authors: Jelinic Petar , Ricca Jacob , Oudenhove Elke Van , Olvera Narciso , Merghoub Taha , Levine Douglas A. , Zamarin Dmitriy
Published: October 2017

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly aggressive monogenic cancer driven bySMARCA4mutations. Here, we report responses to anti-PD1 immunotherapy in four patients and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors demonstrated PD-L1 expression with strong associated T cell infiltration. PD-L1 expression was detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1 positive cells in some tumors. Transcriptional profiling revealed increased expression of genes related to Th1 and cytotoxic cell function in PD-L1 high tumors, suggesting that PD-L1 acts as a pathway of adaptive immune resistance in SCCOHT. These findings suggest that although SCCOHT are low-mutational-burden tumors, their immunogenic microenvironment that resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade.
The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer
Authors: Zhang Allen W. , McPherson Andrew , Milne Katy , Kroeger David R. , Hamilton Phineas T. , Miranda Alex , Funnell Tyler , Laan Sonya , Cochrane Dawn R. , Lim Jamie L.P. , Yang Winnie , Roth Andrew , Smith Maia A. , de Souza Camila , Ho Julie , Tse Kane , Zeng Thomas , Shlafman Inna , Mayo Michael R. , Moore Richard , Failmezger Henrik , Heindl Andreas , Wang Yi Kan , Bashashati Ali , Brown Scott D. , Lai Daniel , Wan Adrian N. C. , Nielsen Cydney B. , Bouchard-Côté Alexandre , Yuan Yinyin , Wasserman Wyeth W. , Gilks C. Blake , Karnezis Anthony N. , Aparicio Samuel , McAlpine Jessica N. , Huntsman David G. , Holt Robert A. , Nelson Brad H. , Shah Sohrab P.
Published: October 2017

High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.
A Single Mechanosensitive Channel ProtectsFrancisella tularensissubsp.holarcticafrom Hypoosmotic Shock and Promotes Survival in the Aquatic Environment
Authors: Williamson David R. , Dewan Kalyan K. , Patel Tanmay , Wastella Catherine M. , Ning Gang , Kirimanjeswara Girish S.
Published: October 2017

Francisella tularensissubspeciesholarcticais found throughout the northern hemisphere and causes the disease tularemia in humans and animals. An aquatic cycle has been described for this subspecies, which has caused water-borne outbreaks of tularemia in at least 10 countries. In this study, we sought to identify mechanosensitive channel(s) required for the bacterium to survive the transition from mammalian hosts to freshwater, which is likely essential for transmission of the bacterium between susceptible hosts. A singlemechanosensitivechannel MscS (FTL_1753), among the smallest members of the mechanosensitive channel superfamily, was found to protect subsp.holarctiafrom hypoosmotic shock. Deletion of this channel did not affect virulence within the mammalian host, howevermscSwas required to survive the transition from the host niche to fresh water. Deletion ofmscSdid not alter the sensitivity ofF. tularensissubspeciesholarcticato detergents, H2O2, or antibiotics, suggesting that the role of MscS is specific to protection from hypoosmotic shock. Interestingly, deletion ofmscSalso led to reduced average cell size without altering gross cell morphology. The small mechanosensitive channel identified and characterized in this study likely contributes to the transmission of tularemia between hosts by allowing the bacterium to survive the transition from mammalian hosts to fresh water.
Second-order freeriding on antisocial punishment restores the effectiveness of prosocial punishment
Authors: Szolnoki Attila , Perc Matjaž
Published: October 2017

Economic experiments have shown that punishment can increase public goods game contributions over time. However, the effectiveness of punishment is challenged by second-order freeriding and antisocial punishment. The latter implies that non-cooperators punish cooperators, while the former implies unwillingness to shoulder the cost of punishment. Here we extend the theory of cooperation in the spatial public goods game by considering four competing strategies, which are traditional cooperators and defectors, as well as cooperators who punish defectors and defectors who punish cooperators. We show that if the synergistic effects are high enough to sustain cooperation based on network reciprocity alone, antisocial punishment does not deter public cooperation. Conversely, if synergistic effects are low and punishment is actively needed to sustain cooperation, antisocial punishment does act detrimental, but only if the cost-to-fine ratio is low. If the costs are relatively high, cooperation again dominates as a result of spatial pattern formation. Counterintuitively, defectors who do not punish cooperators, and are thus effectively second-order freeriding on antisocial punishment, form an active layer around punishing cooperators, which protects them against defectors that punish cooperators. A stable three-strategy phase that is sustained by the spontaneous emergence of cyclic dominance is also possible via the same route. The microscopic mechanism behind the reported evolutionary outcomes can be explained by the comparison of invasion rates that determine the stability of subsystem solutions. Our results reveal an unlikely evolutionary escape from adverse effects of antisocial punishment, and they provide a rationale for why second-order freeriding is not always an impediment to the evolutionary stability of punishment.
A subcortical circuit linking the cerebellum to the basal ganglia engaged in vocal learning
Authors: Pidoux Ludivine , Leblanc Pascale , Leblois Arthur
Published: October 2017

Speech is a complex sensorimotor skill, and vocal learning involves both the basal ganglia and the cerebellum. These subcortical structures interact indirectly through their respective loops with thalamo-cortical and brainstem networks, and directly via subcortical pathways, but the role of their interaction during sensorimotor learning remains undetermined. While songbirds and their song-dedicated basal ganglia-thalamo-cortical circuitry offer a unique opportunity to study subcortical circuits involved in vocal learning, the cerebellar contribution to avian song learning remains unknown. We demonstrate that the cerebellum provides a strong input to the song-related basal ganglia nucleus in zebra finches. Cerebellar signals are transmitted to the basal ganglia via a disynaptic connection through the thalamus and then conveyed to their cortical target and to the premotor nucleus controlling song production. Finally, cerebellar lesions impair juvenile song learning, opening new opportunities to investigate how subcortical interactions between the cerebellum and basal ganglia contribute to sensorimotor learning.
Temporal profiling of redox-dependent heterogeneity in single cells
Authors: Radzinski Meytal , Fasler Rosi , Yogev Ohad , Breuer William , Shai Nadav , Gutin Jenia , Ravid Tommer , Friedman Nir , Schuldiner Maya , Reichmann Dana
Published: October 2017

Cellular redox status affects diverse cellular functions, including proliferation, protein homeostasis, and aging. Thus, individual differences in redox status can give rise to distinct sub-populations even among cells with identical genetic backgrounds. Here, we have created a novel methodology to track redox status at single cell resolution using the redox-sensitive probe roGFP. Our method allows identification and sorting of sub-populations with different oxidation levels in either the cytosol, mitochondria or peroxisomes. Using this approach we defined redox-dependent heterogeneity of yeast cells, and characterized growth, as well as proteomic and transcriptomic profiles of subpopulations of cells that differ in their redox status, but are similar in age. We report that, starting in late logarithmic growth, cells of the same age have a bi-modal distribution of oxidation status. A comparative proteomic analysis between these populations identified three key proteins, Hsp30, Dhh1, and Pnc1, which affect basal oxidation levels and may serve as first line of defense proteins in redox homeostasis.
No evidence for associations between men’s salivary testosterone and responses on the Intrasexual Competitiveness Scale
Authors: Torrance Jaimie S , Hahn Amanda C , Kandrik Michal , DeBruine Lisa M , Jones Benedict C
Published: October 2017

Many previous studies have investigated relationships between men’s competitiveness and testosterone. For example, the extent of changes in men’s testosterone levels following a competitive task predicts the likelihood of them choosing to compete again. Recent work investigating whether individual differences in men’s testosterone levels predict individual differences in their competitiveness have produced mixed results. Consequently, we investigated whether men’s (N=59) scores on the Intrasexual Competitiveness Scale were related to either within-subject changes or between-subject differences in men’s testosterone levels. Men’s responses on the Intrasexual Competitiveness Scale did not appear to track within-subject changes in testosterone. By contrast with one recent study, men’s Intrasexual Competitiveness Scale also did not appear to be related to between-individual differences in testosterone. Thus, our results present no evidence for associations between men’s testosterone and their responses on the Intrasexual Competitiveness Scale.
Introduction of single nucleotide variations into the promoter region of the mouse kidney anion exchanger 1 gene downstream of a TATA box changes its transcriptional activity
Authors: Takeuchi Takumi , Hattori-Kato Mami
Published: October 2017

(Introduction) Distal renal tubular acidosis (dRTA) is characterized by an impairment of urine acidification and can be caused by variations in genes functioning in α-intercalated cells such as anion exchanger 1 (AE1). AE1 encodes the Cl-/HCO3-exchanger in erythrocytes (eAE1) and α-intercalated cells (kAE1). We previously reported that in human erythroid intron 3 containing the promoter region of human kAE1, a SNP (rs999716) 39 base pairs downstream of the TATA box showed a higher minor allele A frequency in incomplete dRTA patients and such a promoter region showed reduced activities, leading to the hypothesis that those with the A allele may express less kAE1, developing incomplete dRTA. Here, single nucleotide variations were introduced downstream of the TATA box in the murine erythroid intron 3 to investigate changes in the promoter activity for murine kAE1 mRNA. (Methods) The erythroid intron 3 of C57BL/6 was subcloned into the pGL4.17 reporter vector, leading to mu kAE1Pro-pGL4.17. Three types of G to A substitutions were introduced 33, 35, and 36 base pairs downstream of the TATA box in the murine kAE1 promoter region by inverse PCR (Var1, Var2, and Var3, respectively). The HEK 293 cells were transfected with vectors. After 24 hours, the firefly luciferase activity was determined. (Results and Discussion) The promoter activity of Var1, as well as that of Var2 to a lesser extent, was reduced compared with that of the wild-type. The introduction of variations such as Var1 and Var2 into the murine genome by genome editing may help to establish mouse models of incomplete dRTA.
Getting in shape and swimming: the role of cortical forces and membrane heterogeneity in eukaryotic cells
Authors: Wu Hao , de León Marco Avila Ponce , Othmer Hans G.
Published: October 2017

Recent research has shown that motile cells can adapt their mode of propulsion to the mechanical properties of the environment in which they find themselves – crawling in some environments while swimming in others. The latter can involve movement by blebbing or other cyclic shape changes, and both highly-simplified and more realistic models of these modes have been studied previously. Herein we study swimming that is driven by membrane tension gradients that arise from flows in the actin cortex underlying the membrane, and does not involve imposed cyclic shape changes. Such gradients can lead to a number of different characteristic cell shapes, and our first objective is to understand how different distributions of membrane tension influence the shape of cells in a quiescent fluid. We then analyze the effects of spatial variation in other membrane properties, and how they interact with tension gradients to determine the shape. We also study the effect of fluid-cell interactions and show how tension leads to cell movement, how the balance between tension gradients and a variable bending modulus determine the shape and direction of movement, and how the efficiency of movement depends on the properties of the fluid and the distribution of tension and bending modulus in the membrane.

Dedicated to the memory of Karl P. Hadeler, a pioneer in the field of Mathematical Biology and a friend and mentor to many.
The Elastic Network Contact Model applied to RNA: enhanced accuracy for conformational space prediction
Authors: Mailhot Olivier , Frappier Vincent , Major François , Najmanovich Rafael
Published: October 2017

Motivation

The use of Normal Mode Analysis (NMA) methods to study both protein and nucleic acid dynamics is well established. However, the most widely used coarse-grained methods are based on backbone geometry alone and do not take into account the chemical nature of the residues. Elastic Network Contact Model (ENCoM) is a coarse-grained NMA method that includes a pairwise atom-type non-bonded interaction term, which makes it sensitive to the sequence of the studied molecule. We adapted ENCoM to simulate the dynamics of ribonucleic acid (RNA) molecules.

Results

ENCoM outperforms the most commonly used coarse-grained model on RNA, Anisotropic Network Model (ANM), in the prediction of b-factors, in the prediction of conformational change as measured by overlap (a measure of effective prediction of structural transitions) and in the prediction of structural variance from NMR ensembles. These benchmarks were derived from the set of all RNA structures available from the Protein Data Bank (PDB) and contain more total cases than previous studies applying NMA to RNA. We thus established ENCoM as an attractive tool for fast and accurate exploration of the conformational space of RNA molecules.

Availability

ENCoM is open source software available athttps://github.com/NRGlab/ENCoM
Non-AUG translation: a new start for protein synthesis in eukaryotes
Authors: Kearse Michael G. , Wilusz Jeremy E.
Published: October 2017

Although it was long thought that eukaryotic translation almost always initiates at an AUG start codon, recent advancements in ribosome footprint mapping have revealed that non-AUG start codons are used at an astonishing frequency. These non-AUG initiation events are not simply errors but instead are used to generate or regulate proteins with key cellular functions; for example, during development or stress. Misregulation of non-AUG initiation events contributes to multiple human diseases, including cancer and neurodegeneration, and modulation of non-AUG usage may represent a novel therapeutic strategy. It is thus becoming increasingly clear that start codon selection is regulated by many trans-acting initiation factors as well as sequence/structural elements within messenger RNAs and that non-AUG translation has a profound impact on cellular states.
ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression
Authors: Zhou Huanyu , Morales Maria Gabriela , Hashimoto Hisayuki , Dickson Matthew E. , Song Kunhua , Ye Wenduo , Kim Min S. , Niederstrasser Hanspeter , Wang Zhaoning , Chen Beibei , Posner Bruce A. , Bassel-Duby Rhonda , Olson Eric N.
Published: October 2017

Direct reprogramming of fibroblasts to cardiomyocytes represents a potential means of restoring cardiac function following myocardial injury. AKT1 in the presence of four cardiogenic transcription factors, GATA4, HAND2, MEF2C, and TBX5 (AGHMT), efficiently induces the cardiac gene program in mouse embryonic fibroblasts but not adult fibroblasts. To identify additional regulators of adult cardiac reprogramming, we performed an unbiased screen of transcription factors and cytokines for those that might enhance or suppress the cardiogenic activity of AGHMT in adult mouse fibroblasts. Among a collection of inducers and repressors of cardiac reprogramming, we discovered that the zinc finger transcription factor 281 (ZNF281) potently stimulates cardiac reprogramming by genome-wide association with GATA4 on cardiac enhancers. Concomitantly, ZNF281 suppresses expression of genes associated with inflammatory signaling, suggesting the antagonistic convergence of cardiac and inflammatory transcriptional programs. Consistent with an inhibitory influence of inflammatory pathways on cardiac reprogramming, blockade of these pathways with anti-inflammatory drugs or components of the nucleosome remodeling deacetylase (NuRD) complex, which associate with ZNF281, stimulates cardiac gene expression. We conclude that ZNF281 acts at a nexus of cardiac and inflammatory gene programs, which exert opposing influences on fibroblast to cardiac reprogramming.
A novel method for resonant inelastic soft X-ray scatteringviaphotoelectron spectroscopy detection
Authors: Dakovski Georgi L. , Lin Ming-Fu , Damiani Daniel S. , Schlotter William F. , Turner Joshua J. , Nordlund Dennis , Ogasawara Hirohito
Published: October 2017

A method for measuring resonant inelastic X-ray scattering based on the conversion of X-ray photons into photoelectrons is presented. The setup is compact, relies on commercially available detectors, and offers significant flexibility. This method is demonstrated at the Linac Coherent Light Source with ∼0.5 eV resolution at the cobaltL3-edge, with signal rates comparable with traditional grating spectrometers.
Social movement organizations in Spain
Authors: Simsa Ruth , Totter Marion
Published: October 2017

Purpose

The purpose of this paper is to analyze how activists of the Spanish protest movement 15M conceptualize organizational practices in relation to the movement’s goals.

Design/methodology/approach

In order to theoretically understand social movement organizations (SMO), the concept of partial organization is placed within the context of the politics of prefiguration. Empirically, the paper is based on field research conducted in Spain in three consecutive years (2014-2016) that included 82 qualitative interviews and participant observation.

Findings

Activists consider the organizational practices as crucial means to achieve social change. They conceptualize SMO in a meaningful and systematic way as partial organizations, specifically, by aiming at open membership and non-hierarchical structures. As they do this to enact the movement’s goals prefiguratively in their daily organizational practices, the limits and restrictions of the practices of self-organization are widely accepted.

Research limitations/implications

The research focused on studying the relatively young and often very successful organizations of the Spanish movement. It remains open to what extent the prefigurative practices will survive organizational life cycles.

Practical implications

By contributing to a deeper understanding of the underlying philosophy of SMO, this paper is useful for social movement activists and scholars.

Originality/value

This is one of the first papers, which analyzes the organizations of the Spanish protest movement with respect to both empirical and theoretical aspects.
Repertoires of knowledge practices: social movements in times of crisis
Authors: della Porta Donatella , Pavan Elena
Published: October 2017

Purpose

Starting from the assumption that knowledge becomes all the more important for movements in times of crisis, as old structures are challenged and new ones envisaged and proved feasible, the purpose of this paper is to suggest ways to expand the toolkit of social movement studies in order to empirically address knowledge practices as a meaningful part of contemporary progressive activism.

Design/methodology/approach

The authors start by arguing that, in their effort to pursue or resist social and political changes, contemporary progressive social movements form collective spaces of knowledge production that are true laboratories for innovation. For this reason, the authors begin by making a case for accounting more explicitly for knowledge production within social movement studies - not as a substitution for but, rather, as a necessary complement to current cultural approaches. Building on extant literature on the nexus between movements and knowledge, the authors then outline the peculiarities of movement knowledge.

Findings

On these bases, the authors outline the core components of what the authors call repertoires of knowledge practices - that is, the set of practices that foster the coordination of disconnected, local, and highly personal experiences and rationalities within a shared cognitive system able to provide movements and their supporters with a common orientation for making claims and acting collectively to produce social, political, and cultural changes.

Originality/value

The authors conclude by identifying some promising avenues of research to further develop the understanding of movement practices of knowledge production and transmission.
Voicing researched activists with responsive action research
Authors: Varkarolis Orestis , King Daniel
Published: October 2017

Purpose

What it is like to experience being the subject of the research process when you are an actor within a new social movement organization? And what lessons can be learned for researchers engaging with members of New Social Movements? Debates on engagement and the relationship between the researcher and the researched so far have taken the perspective solely of the researcher. Based on insights gained by full participation in a horizontal worker cooperative, the purpose of this paper is to contribute to the facilitation of more fruitful, mutually engaging research relations between organizational theory scholars and members of New Social Movement organizations by voicing the researched in this debate.

Design/methodology/approach

After providing some accounts from the researched point of view, the paper focuses on crafting an appropriate research process based on participatory action research (PAR) ethos and experience.

Findings

Since the research findings suggest that PAR combines elements that both trouble and inspire research participants, namely, workload/availability and relevancy/contribution in practice, the authors introduce and provide a case study of responsive action research that emphasizes adaptation and responsiveness in the research process instead of shared governance.

Originality/value

The originality of this paper lies in voicing the research participants with the aim to aid both scholars and social movements adopt appropriate research designs for the mutual benefit of both theory/action and researchers/researched (even when researchers are already active in the field).
Fungal inoculants in the field: Is the reward greater than the risk?
Authors: Hart Miranda M. , Antunes Pedro M. , Chaudhary Veer Bala , Abbott Lynette K.
Published: October 2017

Biofertilizers are a large part of the global agricultural economy.

Recently, there has been an increase in the number of companies producing fungal inoculants.

Whether these inoculants are useful is not clear; they are difficult to monitor in the field.

The unintended consequences of inoculants in natural systems is not known, but if invasive, they may pose a threat to soil and plant biodiversity and ecosystem functioning.

A plain language summary is available for this article.
Austerity welfare: Social security in the era of finance
Authors: Kar Sohini
Published: October 2017

With the launch of the new financial inclusion programme in 2015, the government of India claimed that more than 90 per cent of households now have access to bank accounts. The programme sought not only to link the poor in India to financial services such as credit and savings, but also to insurance‐based welfare payments. This article examines how the expansion of welfare programmes – a seeming alternative to austerity – in India has simultaneously hinged on arguments of fiscal conservatism. In other words, financial inclusion has also served to curtail government expenditure through payment systems and financial infrastructures. However, as the poor are drawn into new financial products, it raises the question of ‘who benefits’ when welfare systems are streamlined through the banking system.
‘The island is full. Please don't come’: Narratives of austerity and migration in a UK citizenship class
Authors: Tuckett Anna
Published: October 2017

In the lead up to, and aftermath of, the UK referendum on its membership of the European Union, issues relating to migration and entitlement dominated public debates. In a ruthless campaign, the ‘Leave’ camp exploited the implementation of years of austerity policies by explicitly correlating their negative effects with supposedly high migrant numbers. Examining the discourses of scarcity, austerity and deservingness which prevailed during the referendum campaign, this article discusses the way in which UK citizenship classes act as spaces for both the reproduction and subversion of these narratives. On the one hand, migrants in the classes reproduce discourses which scapegoat other migrants for the effects of austerity. On the other, however, powerful messages about the fundamental human right to migrate are also championed.
When ‘Anxious Scrutiny’ of Arms Exports Facilitates Humanitarian Disaster
Authors: Stavrianakis Anna
Published: October 2017

How is it that the UK government continues to export weapons to Saudi Arabia for use in the war in Yemen, despite an explicit commitment to international humanitarian law (IHL)? And how is it that the High Court recently dismissed a case of judicial review, confirming that the government was ‘rationally entitled to conclude’ that arms exports pose no clear risk to IHL in Yemen? In what follows, I explain how a flexible interpretation of risk, reliance on secret information, and deference of the Court to the executive serve to facilitate rather than restrict arms exports. The judges’ decision provides a stamp of approval to an arms export policy that has directly contributed to the deaths of thousands of civilians in Yemen. Attention to the Saudi/Yemen case shows the political and legal manoeuvring that goes into managing the contradictions in government arms export policy.
From loss to repair. A study of body narratives in patient claims for medical injury
Authors: Winance Myriam , Barbot Janine , Parizot Isabelle
Published: October 2017

In this article we examine the body's status in the complaints that patients filed with a compensation agency. Taking a corpus of letters, we analyse the way in which the patients mobilise their bodily experience from the angle of the damage for which they demand compensation. To this end, we articulate an approach in terms of the sociology of complaint with an approach rooted in the sociology of medicine, health and illness. To analyse the body narratives, we use the notion of loss. We highlight the manner in which patients approach their losses as ‘losses in practice’. These losses are defined by the patients putting forward the concrete experience of a body harmed by the treatment received, and by their formulation of expectations in terms of compensation. We therefore identify four ways in which the reality of the damaged body is given a form in terms of expectations of repair: the ‘body‐producer’, the ‘body‐ecological’, the ‘body‐help’ and the ‘body‐self‐image’. Our analysis adds to studies on the status of the body in care and in complaint by showing: the specific influence of the enunciative situation, the plurality of patient evaluations and their temporal dynamic.