bluuebunny/crossref_metadata_2025 huggingface dataset:
Polycyclic Aromatic Hydrocarbons and Endocrine Disruption: Role of Testicular Gap Junctional Intercellular Communication and Connexins
Authors: Kubincová Petra , Sychrová Eliška , Raška Jan , Basu Amrita , Yawer Affiefa , Dydowiczová Aneta , Babica Pavel , Sovadinová Iva
Published: January 2019

Ambient air pollution and smoking are well-documented risk factors for male infertility. Prevalent air pollutants and cigarette smoke components, polycyclic aromatic hydrocarbons (PAHs), are environmental and occupational toxicants that act as chemicals disrupting endocrine regulation and reproductive potential in males. Testicular gap junctional intercellular communication (GJIC) is critical for normal development and function of testicular tissue, thus we assessed GJIC as a process potentially targeted by PAHs in testes. Lower MW PAHs with a bay or bay-like region rapidly dysregulated GJIC in Leydig TM3 cells by relocalization of major testicular gap junctional protein connexin 43 (Cx43) from plasma membrane to cytoplasm. This was associated with colocalization between Cx43 and ubiquitin in intracellular compartments, but without any effect on Cx43 degradation rate or steady-state Cx43 mRNA levels. A longer exposure to active PAHs decreased steady-state levels of full-length Cx43 protein and its 2 N-truncated isoforms. Inhibition of GJIC by PAHs, similarly to a prototypic GJIC-inhibitor TPA, was mediated via the MAP kinase-Erk1/2 and PKC pathways. Polycyclic aromatic hydrocarbon-induced GJIC dysregulation in testes was cell-type-specific because neither PAH dysregulated GJIC in Sertoli TM4 cells, despite PAHs were rapidly taken up by both Leydig TM3 as well as Sertoli TM4 cells. Because TPA effectively dysregulated GJIC in both testicular cell types, a unique regulator of GJIC targeted by PAHs might exist in Leydig TM3 cells. Our results indicate that PAHs could be a potential etiological agent contributing to reproductive dysfunctions in males through an impairment of testicular GJIC and junctional and/or nonjunctional functions of Cx43.
The visual social environment affects non-additively neighbor spacing and interaction time in zebrafish
Authors: Pita Diana , Fernández-Juricic Esteban
Published: January 2019

Many fish form schools and visually track the position of their neighbors in a 3D environment. In this study, we assessed whether zebrafish modified their spacing behavior and interaction time in an additive or multiplicative way relative to multiple sources of visual social information using video playbacks. We simultaneously manipulated: (a) the magnitude of the social cues (by varying the size of the virtual fish), (b) the level of social risk (low, high based on the position of the virtual fish in the water column), and (c) the perceived depth of the social cues (visual horizon absent or present). Each of these factors independently affected spacing behavior (zebrafish increased the separation distance with larger virtual fish, under lower visual social risk, and when depth perception was enhanced), but they did not affect interaction time. However, some of these factors interacted significantly, such that their effects on social behavior depended on each other. For instance, zebrafish decreased their separation distance under high vs. low risk conditions when the virtual fish was the same or smaller size, but this risk effect disappeared with larger virtual fish likely to avoid aggression. Also, zebrafish increased their separation distance when perceived depth was enhanced under low risk, but the perceived depth effect became less pronounced under high risk probably due to dilution effects. Overall, the effects of certain visual social parameters depend on the intensity of other visual social parameters, ultimately tuning up or down different social behavioral responses. We discuss the implications for the spatial organization of fish schools.

Significance Statement

Many fish form schools and visually track the position of their neighbors in a 3D environment. We found that zebrafish consider multiple visual social sources of information simultaneously to modify their neighbor distance. Thus, their spacing behavior appears to follow multiplicative rules, whereby the spacing response to a visual social parameter depend on the intensity of a different visual social parameter.
Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis
Authors: Thériault Sébastien , Dina Christian , Messika-Zeitoun David , Scouarnec Solena Le , Capoulade Romain , Gaudreault Nathalie , Rigade Sidwell , Li Zhonglin , Simonet Floriane , Lamontagne Maxime , Clavel Marie-Annick , Arsenault Benoit J. , Boureau Anne-Sophie , Lecointe Simon , Baron Estelle , Bonnaud Stéphanie , Karakachoff Matilde , Charpentier Eric , Fellah Imen , Roussel Jean-Christian , Verhoye Jean Philippe , Baufreton Christophe , Probst Vincent , Roussel Ronan ,   the D.E.S.I.R. Study Group, Redon Richard , Dagenais François , Pibarot Philippe , Mathieu Patrick , Tourneau Thierry Le , Bossé Yohan , Schott Jean-Jacques
Published: January 2019

To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcific aortic valve stenosis (CAVS) using genome-wide and transcriptome-wide association study (TWAS). To identify additional susceptibility genes for CAVS, we performed a GWAS meta-analysis totaling 5,115 cases and 354,072 controls of European descent. Four loci achieved genome-wide significance, including two new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating an eQTL study of 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Association results at the genome-wide scale showed genetic correlation with coronary artery disease and cardiovascular risk factors. Our study highlights three new loci implicating inflammation, mineralization and blood vessel integrity in CAVS pathogenesis and supports shared genetic etiology with cardiovascular traits.
In VivoMonitoring of Rare Circulating Tumor Cell and Cluster Dissemination in a Multiple Myeloma Xenograft Model
Authors: Patil Roshani , Tan Xuefei , Bartosik Peter , Detappe Alexandre , Runnels Judith , Ghobrial Irene , Lin Charles P. , Niedre Mark
Published: January 2019

We recently developed ‘Diffusein vivoFlow Cytometry’ (DiFC), a new pre-clinical research tool for enumerating extremely rare fluorescently-labeled circulating cells directlyin vivo. In this paper, we developed a green fluorescent protein (GFP) compatible version of DiFC, and used it to non-invasively monitor the circulating tumor cell (CTC) burden over time in a multiple myeloma disseminated xenograft model. We show that DiFC allowed counting of CTCs at estimated concentrations below 1 cell per mL in peripheral blood with a negligible false alarm rate. DiFC also revealed the presence of CTC clusters in circulation to our knowledge for the first time in this model, and allowed us to calculate their size, kinetics, and frequency of shedding. We anticipate that the unique capabilities of DiFC will have many applications in the study of hematogenous metastasis, and as a powerful complementary methodology to liquid biopsy assays.
Delta/Notch signaling controls neuroepithelial morphogenesis in the zebrafish spinal cord
Authors: Sharma Priyanka , Saraswathy Vishnu Muraleedharan , Xiang Li , Fürthauer Maximilian
Published: January 2019

The morphogenesis of the nervous system requires coordinating the specification and differentiation of neural precursor cells, the establishment of neuroepithelial tissue architecture and the execution of specific cellular movements. How these aspects of neural development are linked is incompletely understood. Here we inactivate a major regulator of embryonic neurogenesis - the Delta/Notch pathway - and analyze the effect on zebrafish central nervous system morphogenesis. While some parts of the nervous system can establish neuroepithelial tissue architecture independently of Notch, Notch signaling is essential for spinal cord morphogenesis. In this tissue, Notch signaling is required to repress neuronal differentiation and promote neuroepithelial apico-basal polarity. Concomitant with a loss of their neuroepithelial properties, Notch signaling deficient cells also alter their morphogenetic behavior. In the wild-type zebrafish neural tube, cells divide at the organ midline to contribute one daughter cell to each organ half. Notch deficient animals fail to display this behavior and therefore form a misproportioned spinal cord. Taken together, our findings show that Notch signaling governs not only the cellular composition but also the morphogenetic shaping of the zebrafish spinal cord.
Hunter-gatherer genomes reveal diverse demographic trajectories following the rise of farming in East Africa
Authors: Gopalan Shyamalika , Berl Richard E.W. , Belbin Gillian , Gignoux Christopher R. , Feldman Marcus W. , Hewlett Barry S. , Henn Brenna M.
Published: January 2019

A major outstanding question in human prehistory is the fate of hunting and gathering populations following the rise of agriculture and pastoralism. Genomic analysis of ancient and contemporary Europeans suggests that autochthonous groups were either absorbed into or replaced by expanding farmer populations. Many of the hunter-gatherer populations persisting today live in Africa, perhaps because agropastoral transitions occurred later on the continent. Here, we present the first genomic data from the Chabu, a relatively isolated and marginalized hunting-and-gathering group from the Southwestern Ethiopian highlands. The Chabu are a distinct genetic population that carry the highest levels of Southwestern Ethiopian ancestry of any extant population studied thus far. This ancestry has been in situ for at least 4,500 years. We show that the Chabu are undergoing a severe population bottleneck which began around 40 generations ago. We also study other Eastern African populations and demonstrate divergent patterns of historical population size change over the past 60 generations between even closely related groups. We argue that these patterns demonstrate that, unlike in Europe, Africans hunter-gatherers responded to agropastoralism with diverse strategies.
HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome
Authors: Asquith Mark , Sternes Peter R. , Costello Mary-Ellen , Karstens Lisa , Diamond Sarah , Martin Tammy M. , Spector Timothy D. , Cao Kim-Anh le , Rosenbaum James T. , Brown Matthew A.
Published: January 2019

Objectives

HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms to account for these genotype-disease associations are largely unknown. HLA-alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and faecal microbiome signatures. Whether these changes are cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examine the effect ofHLA-B27andHLA-DRB1RA-risk alleles on the composition of the intestinal microbiome in healthy individuals.

Methods

568 samples from 6 intestinal sites were collected from 107 otherwise healthy unrelated subjects and stool samples from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S rRNA bacterial marker gene. All patients were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data.

Results

Association was observed betweenHLA-B27genotype, and RA-riskHLA-DRB1alleles, and overall microbial composition (P=0.0002 and P=0.00001 respectively). These associations were replicated in the TwinsUK cohort stool samples (P=0.023 and P=0.033 respectively).

Conclusions

This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects ofHLA-B27and –DRB1on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome, and suggest that therapies targeting the microbiome may be effective in their prevention and/or treatment.
Cell Fate Determining Molecular Switches and Signaling Pathway in Pax7-expressing Somitic Mesoderm
Authors: Fung Cheuk Wang , Zhu Han , Zhou Shao Pu , Wu Zhenguo , Wu Angela R.
Published: January 2019

Pax7-expressing progenitor cells in the somitic mesoderm differentiate into multiple lineages, such as brown adipose tissue, dorsal dermis, as well as muscle in the dorsal trunk and the diaphragm; however, the key molecular switches that determine and control the process of lineage commitment and cell fate are unknown. To probe the mechanisms behind mesoderm development, Pax7creER/R26-stop-EYFP embryos were tamoxifen-induced at E9.5 to label Pax7+ cells for lineage tracing and collected at later time points for analysis. The YFP-labelled cells which belonged to the Pax7 lineage were enriched by fluorescence-activated cell sorting (FACS) and subject to single-cell RNA profiling. We observed that a subpopulation of cells differentiated into the myogenic lineage, showing Myf5 expression as early as E12.5, whereas the rest of the population was fibroblast-like and appeared to be the early stage of the adipogenic and dermal lineages. Cells at E14.5 had distinct myogenic populations that expressed Myod1 and Myog; we also identified other populations with Ebf2 or Twist2 expression, which could belong to adipogenic or dermal lineages, respectively. Cell surface markers were also found for each specific lineage, providing insights in sorting strategy for lineage-of-interest for further functional evaluation. Adipogenic lineage was successfully sorted with a combination of Pdgfra and Thy1 antibodies. In addition, we found that upregulation of Wnt signaling pathway activity is dynamically regulated in dermal lineage. Finally, transcription factors that could potentially drive, or reprogram cell fate, were identified at different developmental time points.

Summary statement

Investigation of Pax7 lineage transcriptomic profile at single-cell level identified multiple cell types, fate commitment time point, surface markers, transcription factors and signaling pathways that determine cell fate.
Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
Authors: Burmistrova Olga , Olias-Arjona Ana , Eremeeva Tatiana , Shishov Dmitry , Zakurdaeva Kristina , Almeida Angeles , Fedichev Peter O. , Bolaños Juan P.
Published: January 2019

The glycolytic rate in neurons is low in order to allow glucose to be metabolized through the pentose-phosphate pathway (PPP), which regenerates NADPH to preserve the glutathione redox status and survival. This is controlled by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), the pro-glycolytic enzyme that forms fructose-2,6-bisphosphate, a powerful allosteric activator of 6-phosphofructo-1-kinase. In neurons, PFKFB3 protein is physiologically inactive due to its proteasomal degradation. However, upon an excitotoxic stimuli, PFKFB3 becomes stabilized to activate glycolysis, thus hampering PPP mediated protection of redox status leading to neurode-generation. Here, we show that selective inhibition of PFKFB3 activity in neurons by the small molecule AZ67 prevents the NADPH oxidation, redox stress and apoptotic neuronal death caused by activation of glycolysis upon excitotoxic stimuli. Furthermore,in vivoadministration of AZ67 to mice significantly alleviated the motor discoordination and brain infarct injury in the middle carotid artery occlusion ischemia/reperfusion model. These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy for excitotoxic-related neurological diseases.
Deep neural networks for interpreting RNA binding protein target preferences
Authors: Ghanbari Mahsa , Ohler Uwe
Published: January 2019

Deep learning has become a powerful paradigm to analyze the binding sites of regulatory factors including RNA-binding proteins (RBPs), owing to its strength to learn complex features from possibly multiple sources of raw data. However, the interpretability of these models, which is crucial to improve our understanding of RBP binding preferences and functions, has not yet been investigated in significant detail. We have designed a multitask and multimodal deep neural network for characterizing in vivo RBP binding preferences. The model incorporates not only the sequence but also the region type of the binding sites as input, which helps the model to boost the prediction performance. To interpret the model, we quantified the contribution of the input features to the predictive score of each RBP. Learning across multiple RBPs at once, we are able to avoid experimental biases and to identify the RNA sequence motifs and transcript context patterns that are the most important for the predictions of each individual RBP. Our findings are consistent with known motifs and binding behaviors of RBPs and can provide new insights about the regulatory functions of RBPs.
Structural basis for functional interactions in dimers of SLC26 transporters
Authors: Chang Yung-Ning , Jaumann Eva A. , Reichel Katrin , Hartmann Julia , Oliver Dominik , Hummer Gerhard , Joseph Benesh , Geertsma Eric R.
Published: January 2019

The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7 + 7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by combining PELDOR distance measurements and biochemical studies with MD simulations and spin-label ensemble refinement. Our structural model reveals a unique interface different from the SLC4 and SLC23 families. The functionally relevant STAS domain exerts a stabilizing effect on regions central in this dimer. Characterization of heterodimers indicates that protomers in the dimer functionally interact. The combined structural and functional data define the framework for a mechanistic understanding of functional cooperativity in SLC26 dimers.
Potential influence of school-based lifestyle strategies among Australian Aboriginal and non-Aboriginal children: a cross-sectional comparison of adiposity and weight related behaviours between 2010 and 2015
Authors: Hardy Louise L , MacNiven Rona , Esgin Tuguy , Mihrshahi Seema
Published: January 2019

Background

In New South Wales (Australia) there has been substantial long term investment in school-based child obesity prevention programs. Whether these programs have led to population level improvements in children’s adiposity and weight-related behaviours in Aboriginal children, who are at greater risk of poorer health outcomes, is yet to be determined. The purpose of this study was to describe changes in adiposity and weight-related behaviours of Aboriginal and non-Aboriginal children and to examine the equality of changes between the two groups.

Methods

Representative cross-sectional population surveys conducted in 2010 and 2015 among children age 5-16 years (n=15,613), stratified by Aboriginality. Indicators of weight-related behaviour (diet, physical activity, school travel, screen-time) were measured by questionnaire with parents responding for children age <10 years and self-report by children age >10 years. Objective measurements included height, weight, waist circumference, cardiorespiratory fitness, and fundamental movement skills.

Results

Adiposity prevalences were significantly higher in 2015, than 2010 among non-Aboriginal children only, however adiposity prevalences were consistently higher among Aboriginal than non-Aboriginal children. There were positive changes towards adopting healthier weight-related behaviours in all children between surveys, which were consistently significant among non-Aboriginal, but not Aboriginal, children. The magnitude of changes and the 2015 prevalences in weight-related behaviours were generally similar for Aboriginal and non-Aboriginal children, however positive changes in fruit consumption and locomotor skills were significantly larger among Aboriginal than non-Aboriginal children. The prevalence of being driven to school in 2015 was significantly higher than 2010 for both groups.

Conclusions

Overall, there are signs that Aboriginal and non-Aboriginal children are shifting towards healthier weight-related behaviours. However, many unhealthy weight-related behaviours remain highly prevalent. Our findings may have utility for the direction of future health policy and service delivery to Aboriginal and non-Aboriginal children and the development of health promotion programs to build on these improvements in health behaviours.
Inflammation and matrix metalloproteinase 9 (Mmp-9) regulate photoreceptor regeneration in adult zebrafish
Authors: Silva Nicholas J. , Nagashima Mikiko , Li Jingling , Kakuk-Atkins Laura , Ashrafzadeh Milad , Hyde David R. , Hitchcock Peter F.
Published: January 2019

Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following sterile photoreceptor ablation anti-inflammatory treatment suppresses both the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia, the intrinsic retinal stem cell, and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the maturation and survival of the regenerated cones. Anti-inflammatory treatment in mutants rescues the defects in cone maturation and survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during photoreceptor regeneration and the requirement of Mmp-9 for the survival of regenerated cones.

Significance Statement

The innate immune system is activated by neuronal death, and recent studies demonstrate that in zebrafish neuroinflammation is required for neuronal regeneration. The roles of inflammatory cytokines are being investigated, however, the function of the inflammatory protease, matrix metalloprotease Mmp-9, in neuronal regeneration is unknown. We show herein that in adult zebrafish retinal inflammation governs the proliferative phase of the stem cell-based regeneration of rod and cone photoreceptors and determine the specific roles for Mmp-9 in photoreceptor regeneration. This study provides the first mechanistic insights into the potential role of Mmp-9 and serves to link neuroinflammation, stem cell-based regeneration of photoreceptors and human photoreceptor disease.
Simulation of the mechanics of actin assembly during endocytosis in yeast
Authors: Nickaeen Masoud , Berro Julien , Pollard Thomas D. , Slepchenko Boris M.
Published: January 2019

We formulated a spatially resolved model to estimate forces exerted by a polymerizing actin meshwork on an invagination of the plasma membrane during endocytosis in yeast cells. The model is a continuous approximation tightly constrained by experimental data. Simulations of the model produce forces that can overcome resistance of turgor pressure in yeast cells. Strong forces emerge due to the high density of polymerized actin in the vicinity of the invagination and because of entanglement of the meshwork due to its dendritic structure and crosslinking. The model predicts forces orthogonal to the invagination that would result in a flask shape that diminishes the net force due to turgor pressure. Simulations of the model with either two rings of nucleation promoting factors as in fission yeast or a single ring of nucleation promoting factors as in budding yeast produce enough force to elongate the invagination against the turgor pressure.
A heuristic feature cluster search algorithm for precise functional brain mapping
Authors: Asadi Nima , Wang Yin , Olson Ingrid , Obradovic Zoran
Published: January 2019

Detecting the most relevant brain regions for explaining the distinction between cognitive conditions is one of the most sought after objectives in neuroimaging research. A popular approach for achieving this goal is the multivariate pattern analysis (MVPA) which is commonly conducted through the searchlight procedure as well as a number of other approaches. This is due to advantages of such methods which include being intuitive and flexible with regards to size of the search space. However, these approaches suffer from a number of limitations that lead to misidentification of truly informative voxels or clusters of voxels which in turn results in imprecise information maps. The limitations of such procedures mainly stem from several factors such as the fact that the information value of the search spheres are assigned to the voxel at the center of them (in case of searchlight), the requirement for manual tuning of parameters such as searchlight radius and shape and other optimization parameters, overlooking the structure and interactions within the regions, and the drawbacks of using regularization methods in analysis of datasets with characteristics of common fMRI data. In this paper, we propose a fully data-driven maximum relevance minimum redundancy search algorithm for detecting precise information value of voxel-level clusters within brain regions while alleviating the above mentioned limitations. In order to make the algorithm efficient, we propose an implementation based on principles of dynamic programming. We evaluate and compare the proposed algorithm with the searchlight procedure using both real and synthetic datasets.
Signal integration and information transfer in an allosterically regulated network
Authors: Shockley Erin M. , Rouzer Carol A. , Marnett Lawrence J. , Deeds Eric J. , Lopez Carlos F.
Published: January 2019

A biological reaction network may serve multiple purposes, processing more than one input and impacting downstream processes via more than one output. These networks operate in a dynamic cellular environment in which the levels of network components may change within cells and across cells. Recent evidence suggests that protein concentration variability could explain cell fate decisions. However, systems with multiple inputs, multiple outputs, and changing input concentrations have not been studied in detail due to their complexity. Here, we take a systems biochemistry approach, combining physiochemical modeling and information theory, to investigate how cyclooxygenase-2 (COX-2) processes simultaneous input signals within a complex interaction network. We find that changes in input levels affect the amount of information transmitted by the network, as does the correlation between those inputs. This, and the allosteric regulation of COX-2 by its substrates, allows it to act as a signal integrator that is most sensitive to changes in relative input levels.
Discovering Data Access and Use Requirements Using the Data Tags Suite (DATS) Model1
Authors: Alter George , Gonzalez-Beltran Alejandra , Ohno-Machado Lucila , Rocca-Serra Philippe
Published: January 2019

This article presents elements in the Data Tags Suite (DATS) metadata schema describing data access, data use conditions, and consent information. DATS is a product of the bioCADDIE Project, which created a data discovery index for searching across all types of biomedical data. The “access and use” metadata items in DATS are designed from the perspective of a researcher who wants to find and re-use existing data. Data reuse is often controlled to protect the privacy of subjects and patients. We focus on the impact of data protection procedures on data users. However, these procedures are part of a larger environment around patient privacy protection, and this article puts DATS metadata into the context of the administrative, legal, and technical systems used to protect confidential data.
BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes
Authors: Ji Changyi , Tang Maoping , Zeidler Claudia , Höhfeld Jörg , Johnson Gail VW
Published: January 2019

A major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes, and are subsequently degraded. MAPT (microtubule associated protein tau) is one of the protein clients of autophagy. Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases. A previous study demonstrated that the HSPA/HSP70 co-chaperone BAG3 (BCL2 associated athanogene 3) facilitates endogenous MAPT clearance through autophagy. These findings prompted us to further investigate the mechanisms underlying BAG3-mediated autophagy in the degradation of endogenous MAPT. Here we demonstrate for the first time that BAG3 plays an important role in autophagic flux in the neuritic processes of mature neurons (20-24 days in vitro [DIV]) through interaction with the post-synaptic cytoskeleton protein SYNPO (synaptopodin). Loss of either BAG3 or SYNPO impeded the fusion of autophagosomes and lysosomes predominantly in the post-synaptic compartment. A block of autophagy leads to accumulation of the autophagic receptor protein SQSTM1/p62 (sequestosome 1) as well as MAPT phosphorylated at Ser262 (p-Ser262). Furthermore, p-Ser262 appears to accumulate in autophagosomes at post-synaptic densities. Overall these data provide evidence of a novel role for the co-chaperone BAG3 in synapses. In cooperation with SYNPO, it functions as part of a surveillance complex that facilitates the autophagic clearance of MAPT p-Ser262, and possibly other MAPT species at the post-synapse. This appears to be crucial for the maintenance of a healthy, functional synapse.
Attention differentially modulates the amplitude of resonance frequencies in the visual cortex
Authors: Gulbinaite Rasa , Roozendaal Diane H. M. , VanRullen Rufin
Published: January 2019

Rhythmic visual stimuli (flicker) elicit rhythmic brain responses at the frequency of the stimulus, and attention generally enhances these oscillatory brain responses (steady state visual evoked potentials, SSVEPs). Although SSVEP responses have been tested for flicker frequencies up to 100 Hz [Herrmann, 2001], effects of attention on SSVEP amplitude have only been reported for lower frequencies (up to ~30 Hz), with no systematic comparison across a wide, finely sampled frequency range. Does attention modulate SSVEP amplitude at higher flicker frequencies (gamma band, 30-80 Hz), and is attentional modulation constant across frequencies? By isolating SSVEP responses from the broadband EEG signal using a multivariate spatiotemporal source separation method, we demonstrate that flicker in the alpha and gamma bands elicit strongest and maximally phase stable brain responses (resonance), on which the effect of attention is opposite: positive for gamma and negative for alpha. Finding subject-specific gamma resonance frequency and a positive attentional modulation of gamma-band SSVEPs points to the untapped potential of flicker as a non-invasive tool for studying the causal effects of interactions between visual gamma-band rhythmic stimuli and endogenous gamma oscillations on perception and attention.
Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain
Authors: Salatino Joseph W. , Kale Arya P. , Purcell Erin K.
Published: January 2019

Microelectrode arrays designed to map and modulate neuronal circuitry have enabled greater understanding and treatment of neurological injury and disease. Reliable detection of neuronal activity over time is critical for the successful application of chronic recording devices. Here, we assess device-related plasticity by exploring local changes in ion channel expression and their relationship to device performance over time. We investigated four voltage-gated ion channels (Kv1.1, Kv4.3, Kv7.2, and Nav1.6) based on their roles in regulating action potential generation, firing patterns, and synaptic efficacy. We found that a progressive increase in potassium channel expression and reduction in sodium channel expression accompanies signal loss over 6 weeks (both LFP amplitude and number of units). This motivated further investigation into a mechanistic role of ion channel expression in recorded signal instability. We employed siRNA in neuronal culture to find that Kv7.2 knockdown (as a model for the transient downregulation observed at 1 day in vivo) mimics excitatory synaptic remodeling around devices. This work provides new insight into the mechanisms underlying signal loss over time.
Homologous recombination substantially delays sequence but not gene content divergence of prokaryotic populations
Authors: Iranzo Jaime , Wolf Yuri I. , Koonin Eugene V. , Sela Itamar
Published: January 2019

Evolution of bacterial and archaeal genomes is a highly dynamic process that involves extensive gain and loss of genes. Therefore, phylogenetic trees of prokaryotes can be constructed both by the traditional sequence-based methods (gene trees) and by comparison of gene compositions (genome trees). Comparing the branch lengths in gene and genome trees with identical topologies for 34 clusters of closely related bacterial and archaeal genomes, we found that the terminal branches of gene trees were systematically compressed compared to those of genome trees. Thus, sequence evolution seems to be significantly delayed with respect to genome evolution by gene gain and loss. The extent of this delay widely differs among bacterial and archaeal lineages. We develop and explore mathematical models demonstrating that the delay of sequence divergence can be explained by sequence homogenization that is caused by homologous recombination. Once evolving genomes become isolated by barriers that impede homologous recombination, gene and genome evolution processes settle into parallel trajectories, and genomes diverge, resulting in speciation. This model of prokaryotic genome evolution gives a mechanistic explanation of our previous finding that archaeal genomes contain a class of genes that turn over rapidly, before significant sequence divergence occurs, and provides a framework for correcting phylogenetic trees, to make them consistent with the dynamics of gene turnover.
Rbm10 facilitates heterochromatin assembly via the Clr6 HDAC complex
Authors: Weigt Martina , Gao Qingsong , Ban Hyoju , He Haijin , Mastrobuoni Guido , Kempa Stefan , Chen Wei , Li Fei
Published: January 2019

Splicing factors have recently been shown to be involved in heterochromatin formation, but their role in controlling heterochromatin structure and function remains poorly understood. In this study, we identified a fission yeast homologue of human splicing factor RBM10, which has been linked to TARP syndrome. Overexpression of Rbm10 in fission yeast leads to strong global intron retention. Rbm10 also interacts with splicing factors in a pattern resembling that of human RBM10, suggesting that the function of Rbm10 as a splicing regulator is conserved. Surprisingly, our deep-sequencing data showed that deletion of Rbm10 caused only minor effect on genome-wide gene expression and splicing. However, the mutant displays severe heterochromatin defects. Further analyses indicated that the heterochromatin defects in the mutant did not result from mis-splicing of heterochromatin factors. Our proteomic data revealed that Rbm10 associates with the histone deacetylase Clr6 complex and chromatin remodelers known to be important for heterochromatin silencing. Deletion of Rbm10 results in significant reduction of Clr6 in heterochromatin. Our work together with previous findings further suggests that different splicing subunits may play distinct roles in heterochromatin regulation.
Nutrient availability affects the prevalence of a microsporidian parasite
Authors: Narr Charlotte F. , Ebert Dieter , Bastille‐Rousseau Guillaume , Frost Paul C.
Published: January 2019

Defining the relationship between nutrients and parasitism is complicated by shifts in host physiology and population density, which can both mediate the effects of host diet on parasites and vice versa.

We examined the relationship between nutrient availability and an abundant parasite capable of both horizontal and vertical transmission (Hamiltosporidium tvaerminnensis) of a planktonic crustacean, Daphnia magna, in rock pools on Baltic Sea Skerry islands.

We found that the relative availability of nutrients directly affected infection prevalence; parasite prevalence was higher in pools with higher particulate N:P ratios. Infection prevalence was not related to Daphnia population densities. A complementary experiment that examined host responses to an N:P gradient in mesocosms indicated that high N:P ratios can increase spore load in the hosts.

We surmise that high N:P food increases Daphnia feeding rate, which increases their contact with parasite spores and leads to higher prevalence and more intense infections. We found no direct evidence that parasite‐induced changes in host nutrient use affected nutrient dynamics in pools. However, the relationship between diet N:P and the parasite's prevalence and load is consistent with previously documented patterns of this parasite's effect on host nutrient use.

Taken together, this study suggests that high N:P ratios in food may benefit the parasite in multiple ways and could create environments that favour horizontal transmission over vertical transmission for parasites capable of both transmission routes. If so, nutrient limitation could have long‐term consequences for host–parasite evolution.
The Construction of the Efficient Office: Scientific Management, Accountability, and the Neo‐Liberal State
Authors: Parker Lee D. , Jeacle Ingrid
Published: January 2019

The office has been a central site of organizational planning, accountability, and control since the 19th century. Yet it has been the subject of relatively little accounting research. Through the dual theoretical lenses of Foucaultian and Labour Process theories, this study employs historical photo‐elicitation methodology to investigate the implementation of management control and accountability in the scientifically managed office which emerged in the United States during the late 19th and early 20th centuries. Our analysis reveals the manner in which accounting records created new modes of disciplinary control and surveillance within the office and how accounting tasks were de‐skilled in a gradually feminized and mechanized office environment. We also witness the role of accounting in the physical structuring of office space through the assembly line arrangement of office furniture to facilitate paper flows and the installation of record‐keeping systems of surveillance. In addition, our visually derived historical account of these transformations in office administration allows us to reflect on some contemporary issues. The production‐line design and efficiency so promoted by scientific management served as a forerunner to today's open‐plan office, as well as influencing contemporary office management philosophies such as Activity‐Based Working. Furthermore, we seek to inform current debates on the role of accounting in contemporary neo‐liberal society. In the history of the scientific office, we gain an early glimpse of the subsequent role that accounting comes to play within a neo‐liberal agenda as a powerful technology of micro‐measurement and micro‐management.
bmotif: A package for motif analyses of bipartite networks
Authors: Simmons Benno I. , Sweering Michelle J. M. , Schillinger Maybritt , Dicks Lynn V. , Sutherland William J. , Di Clemente Riccardo
Published: January 2019

Bipartite networks are widely used to represent a diverse range of species interactions, such as pollination, herbivory, parasitism and seed dispersal. The structure of these networks is usually characterised by calculating one or more indices that capture different aspects of network architecture. While these indices capture useful properties of networks, they are relatively insensitive to changes in network structure. Consequently, variation in ecologically‐important interactions can be missed. Network motifs are a way to characterise network structure that is substantially more sensitive to changes in pairwise interactions and is gaining in popularity. However, there is no software available in R, the most popular programming language among ecologists, for conducting motif analyses in bipartite networks. Similarly, no mathematical formalisation of bipartite motifs has been developed.

Here we introduce bmotif: a package for motif analyses of bipartite networks. Our code is primarily an r package, but we also provide matlab and Python code of the core functionality. The software is based on a mathematical framework where, for the first time, we derive formal expressions for motif frequencies and the frequencies with which species occur in different positions within motifs. This framework means that analyses with bmotif are fast, making motif methods compatible with the permutational approaches often used in network studies, such as null model analyses.

We describe the package and demonstrate how it can be used to conduct ecological analyses, using two examples of plant–pollinator networks. We first use motifs to examine the assembly and disassembly of an Arctic plant–pollinator community and then use them to compare the roles of native and introduced plant species in an unrestored site in Mauritius.

bmotif will enable motif analyses of a wide range of bipartite ecological networks, allowing future research to characterise these complex networks without discarding important meso‐scale structural detail.
AllergoOncology: Microbiota in allergy and cancer—A European Academy for Allergy and Clinical Immunology position paper
Authors: Untersmayr Eva , Bax Heather J. , Bergmann Christoph , Bianchini Rodolfo , Cozen Wendy , Gould Hannah J. , Hartmann Karin , Josephs Debra H. , Levi‐Schaffer Francesca , Penichet Manuel L. , O'Mahony Liam , Poli Aurelie , Redegeld Frank A. , Roth‐Walter Franziska , Turner Michelle C. , Vangelista Luca , Karagiannis Sophia N. , Jensen‐Jarolim Erika
Published: January 2019

The microbiota can play important roles in the development of human immunity and the establishment of immune homeostasis. Lifestyle factors including diet, hygiene, and exposure to viruses or bacteria, and medical interventions with antibiotics or anti‐ulcer medications, regulate phylogenetic variability and the quality of cross talk between innate and adaptive immune cells via mucosal and skin epithelia. More recently, microbiota and their composition have been linked to protective effects for health. Imbalance, however, has been linked to immune‐related diseases such as allergy and cancer, characterized by impaired, or exaggerated immune tolerance, respectively. In this AllergoOncology position paper, we focus on the increasing evidence defining the microbiota composition as a key determinant of immunity and immune tolerance, linked to the risk for the development of allergic and malignant diseases. We discuss novel insights into the role of microbiota in disease and patient responses to treatments in cancer and in allergy. These may highlight opportunities to improve patient outcomes with medical interventions supported through a restored microbiome.
The functional biology of peanut allergens and possible links to their allergenicity
Authors: Ozias‐Akins Peggy , Breiteneder Heimo
Published: January 2019

Peanut is one of the most common food triggers of fatal anaphylaxis worldwide although peanut allergy affects only 1%‐2% of the general population. Peanuts are the source of highly potent allergenic proteins. It is emerging that the allergenicity of certain proteins is linked to their biological function. Peanut is an unusual crop in that it flowers aboveground but produces its seed‐containing pods underground. This so‐called geocarpic fruiting habit exposes pods and seeds during their development to soilborne pathogens and pests. Pest damage can also open routes of entry for opportunistic fungi such as Aspergillus. Although seed proteins have primary functions in nutrient reservoirs, lipid storage bodies, or the cytoskeleton, they have also evolved to act as part of the plant's defense system to enhance fitness and survival of the species. When interacting with pathogens or pests, these proteins modify and damage cells' membranes, interact with immune receptors, and modulate signaling pathways. Moreover, following exposure, the immune system of predisposed individuals reacts to these proteins with the production of specific IgE. This review explores the evolutionary biology of peanut and its seed proteins and highlights possible links between the proteins' biological function and their allergenicity.
Anterior segment optical coherence tomography (AS‐OCT) as a new method of detecting copper deposits forming the Kayser–Fleischer ring in patients with Wilson disease
Authors: Broniek‐Kowalik Karina , Dzieżyc Karolina , Litwin Tomasz , Członkowska Anna , Szaflik Jacek P.
Published: January 2019

Purpose

Kayser–Fleischer ring pathognomonic for Wilson disease (WD) is formed of corneal copper deposits present predominantly within the anterior chamber angle at the Schwalbe's line. The slit‐lamp assessment commonly used as a standard of care cannot detect them early enough, as the angle view is obscured by the corneal limbus. The aim of the research was to evaluate the anterior segment optical coherence tomography (AS‐OCT), as objective diagnostic assessment of copper deposits forming KF ring in patients with WD.

Methods

Twenty‐nine subjects (17 women) and twenty‐nine controls (14 women) were enrolled and underwent slit lamp and AS‐OCT assessment.

Results

Kayser–Fleischer ring was not detected – either with a slit lamp or with AS‐OCT – in any of the controls. Fifteen subjects presenting without KF ring at a slit‐lamp examination were found to have a KF ring when examined with AS‐OCT (p < 0.001), which confirms improved accuracy of AS‐OCT, as compared to the slit‐lamp examination.

Conclusion

Our results support AS‐OCT as a diagnostic procedure to offer better objectivity and accuracy as compared to a slit‐lamp examination, both at the diagnostic stage and when monitoring changes in KF ring during medical therapy to assess its efficacy and patient compliance.