bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redox potential defines functional states of adult hippocampal stem cells
Authors: Adusumilli Vijay S , Walker Tara L , Overall Rupert W , Klatt Gesa M , Zeidan Salma A , Fischer Tim J , Zocher Sara , Sykes Alex M , Reinhardt Susanne , Dahl Andreas , Kirova Dilyana G , Mansfeld Jörg , Rünker Annette E , Kempermann Gerd 
Published: April 2019

SummaryIntracellular redox states regulate the balance between stem cell maintenance and activation. Increased levels of reactive oxygen species (ROS) are linked to proliferation and lineage specification. In contrast to this general principle, we show that in the hippocampus of adult mice it is the quiescent neural stem cells (NSCs) that maintain the highest ROS levels (hiROS). Classifying NSCs based on intracellular ROS content identified subpopulations with distinct molecular profiles, corresponding to functional states. Shifts in ROS content primed cells for a subsequent transition of cellular state, with lower cellular ROS content marking activity and differentiation. Physical activity, a known physiological activator of adult hippocampal neurogenesis, recruited the quiescent hiROS NSCs into proliferation via a transient Nox2-dependent ROS surge. In the absence of Nox2, baseline neurogenesis was unaffected, but the activity-induced increase in proliferation disappeared. These results describe a novel mechanism linking the modulation of cellular ROS by behavioral cues to the maintenance and activation of adult NSCs.HighlightsQuiescent adult hippocampal stem cells are characterized by high intracellular ROSChanges in intracellular ROS content precede changes in cellular stateAcute physical activity recruits quiescent cells into active proliferationThis recruitment is marked by a Nox2-dependent ROS spike in hiROS stem cells and represents an independent mode of cell cycle entryGraphical Abstract
The Central Role of the Tail in Switching Off Myosin II in Cells
Authors: Yang Shixin , Lee Kyoung Hwan , Woodhead John L. , Sato Osamu , Ikebe Mitsuo , Craig Roger 
Published: April 2019

AbstractMyosin II is a motor protein playing an essential role in cell motility. The molecule can exist as a polymer that pulls on actin to generate motion, or as an inactive monomer with a compact structure, in which its tail is folded and its two heads interact with each other. This conformation functions in cells as an energy-conserving storage and transport molecule. The mechanism of inhibition is not fully understood. We have carried out a 3D reconstruction of the switched-off form revealing for the first time multiple interactions between the tail and the two heads that trap ATP hydrolysis products, block actin binding, obstruct head phosphorylation, and prevent filament formation. Blocking these essential features of myosin function can explain the high degree of inhibition of the folded form of myosin, serving its energy-conserving, storage function in cells. The structure also suggests a mechanism for unfolding when activated by phosphorylation.
Sound comparison of seven TMS coils at matched stimulation strength
Authors: Koponen Lari M. , Goetz Stefan M. , Tucci Debara L. , Peterchev Angel V. 
Published: April 2019

AbstractBackgroundAccurate data on the sound emitted by transcranial magnetic stimulation (TMS) coils is lacking.MethodsWe recorded the sound waveforms of seven coils with high bandwidth. We estimated the neural stimulation strength by measuring the induced electric field and applying a strength–duration model to account for different waveforms.ResultsAcross coils, at maximum stimulator output and 25 cm distance, the sound pressure level (SPL) was 98–125 dB(Z) per pulse and 75–97 dB(A) for a 15 Hz pulse train. At 5 cm distance, these values were estimated to increase to 112–139 dB(Z) and 89–111 dB(A), respectively.ConclusionsThe coils’ sound was below, but near, relevant exposure limits for operators and may exceed some limits for the subject. Exposure standards may inadequately capture some risks to hearing. For persons near operating TMS coils we recommend hearing protection, and we consider it essential for the TMS subject.HighlightsCoil click varies by over 20 dB(Z) between TMS coils at matched stimulation strength.Close to TMS coil, sound pressure level may reach nearly 140 dB(Z).For rTMS, the continuous sound level can exceed 110 dB(A).Hearing protection is recommended during TMS, especially for the subject.
Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits
Authors: Tamming Renee J. , Dumeaux Vanessa , Langlois Luana , Ellegood Jacob , Qiu Lily R. , Jiang Yan , Lerch Jason P. , Bérubé Nathalie G. 
Published: April 2019

AbstractMutations in the ATRX chromatin remodeler are associated with syndromic and non-syndromic intellectual disability. Emerging evidence points to key roles for ATRX in preserving neuroprogenitor cell genomic stability, whereas ATRX function in differentiated neurons and memory processes are still unresolved. Here, we show that Atrx deletion in mouse forebrain glutamatergic neurons causes distinct hippocampal structural defects identified by magnetic resonance imaging. Ultrastructural analysis revealed fewer presynaptic vesicles and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. These synaptic defects are associated with impaired long-term contextual memory in male, but not female mice. Mechanistically, we identify ATRX-dependent and sex-specific alterations in synaptic gene expression linked to Mir137 levels, a known regulator of presynaptic processes and spatial memory. We conclude that ablation of Atrx in excitatory forebrain neurons leads to sexually dimorphic outcomes on miR-137 and on spatial memory, identifying a promising therapeutic target for neurological disorders caused by ATRX dysfunction.Summary statementAblation of the ATRX chromatin remodeler specifically in forebrain excitatory neurons of mice causes male-specific deficits in long-term spatial memory associated with miR-137 overexpression, transcriptional changes and structural alterations corresponding to pre- and post-synaptic abnormalities.
Origin of elevational replacements in a clade of nearly flightless birds – most diversity in tropical mountains accumulates via secondary contact following allopatric speciation
Authors: Cadena Carlos Daniel , Céspedes Laura N. 
Published: April 2019

AbstractTropical mountains are biodiversity hotspots. In particular, mountains in the Neotropics exhibit remarkable beta diversity reflecting species turnover along elevational gradients. Elevational replacements of species have been known since early surveys of the tropics, but data on how such replacements arise are scarce, limiting our understanding of mechanisms underlying patterns of diversity. We employed a phylogenetic framework to evaluate hypotheses accounting for the origin of elevational replacements in the genusScytalopus(Rhinocryptidae), a speciose clade of passerine birds with limited dispersal abilities occurring broadly in the Neotropical montane region. We found that species ofScytalopushave relatively narrow elevational ranges, closely related species resemble each other in elevational distributions, and most species replacing each other along elevational gradients are distantly related to each other. Although we cannot reject the hypothesis that a few elevational replacements may reflect parapatric speciation along mountain slopes, we conclude that speciation inScytalopusoccurs predominantly in allopatry within elevational zones, with most elevational replacements resulting from secondary contact of formerly allopatric lineages. Our study suggests that accumulation of species diversity in montane environments reflects colonization processes as opposed toin situdivergence even in dispersal-limited animals.
Impaired KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathogenesis
Authors: Pisella Lucie I. , Gaiarsa Jean-Luc , Diabira Diabé , Zhang Jinwei , Khalilov Ilgam , Duan JingJing , Kahle Kristopher T. , Medina Igor 
Published: April 2019

ABSTRACTKCC2 is a vital neuronal K+/Cl-co-transporter that is implicated in the etiology of numerous neurological diseases. It is subject to developmental dephosphorylation at threonine 906 and 1007, the functional importance of which remains unclear. We engineered mice with heterozygous phospho-mimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (P15) but not juvenile (P30)KCC2E/+mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and higher seizure susceptibility.KCC2E/+mice also had abnormal ultra-sonic vocalizations at P10-P12 and impaired social behavior at P60. Post-natal bumetanide treatment restored network activity at P15 but not social behavior at P60. Our data show that post-translational KCC2 regulation controls the GABAergic developmental sequencein vivo. The post-translational deregulation of KCC2 could be a risk factor for the emergence of neurological pathology and the presence of depolarizing GABA is not essential for manifestation of behavioral changes.
Metabolic and metagenomic profiling of hydrocarbon-degrading microorganisms obtained from the deep biosphere of the Gulf of México
Authors: Moreno-Ulloa Aldo , Diaz Victoria Sicairos , Tejeda-Mora Javier A. , Macias Contreras Marla I. , Díaz Castillo Fernando , Guerrero Abraham , Sanchez Ricardo Gonzales , Duhalt Rafael Vazquez , Licea-Navarro Alexei 
Published: April 2019

AbstractMarine microbes are capable of degrading hydrocarbons; however, those inhabiting the deep biosphere (>1000 m) remain largely unexplored. Microbial metabolism could lead to the generation of diverse chemistries (some with therapeutic activities), but the impact of using hydrocarbons as the sole source of microbial energy in the synthesis of metabolites, remains obscure. Here, we investigated the metagenomic and metabolomic profile of two deep-marine sediments (>1 200 m deep, designated as A7 and B18) collected from the Gulf of México (GM) when grown for 28 days with a simple mixture of 4 hydrocarbons and complex hydrocarbon mixture (petroleum API 40) as their sole source of energy. State of the art techniques and analysis (e.g., Global Natural Products Social Molecular Networking, network annotation propagation [NAP], and MS2LDA) were used to describe the chemistries associated to the microbial utilization of hydrocarbons. The metagenomic sequencing analysis suggests a predominant abundance of Proteobacteria in environmental and API 40-enriched samples, while the abundance of Pseudomonas increased after microbial growth with API 40. The metabolomic analysis suggests the presence of diverse chemistries predominantly associated with lipid and lipid-like and phenyl propanoids and polyketides superclass (Classyfire annotation). Hydrocarbon derivatives were detected as carboxylic acids (e.g., azelaic and sebacic acid) or alcohols, while non-hydrocarbon related chemistries were also detected including tetracycline-related metabolites and sphinganines. Our study provides valuable chemical and microbiological information of microbes inhabiting one of the most understudied ecosystems in the earth, the deep marine biosphere.
Molecular Transport across Lipid Membranes Controls Cell-Free Expression Level and Dynamics
Authors: Caveney Patrick M. , Dabbs Rosemary M. , McClintic William T. , Collier C. Patrick , Simpson Michael L. 
Published: April 2019

SummaryEssential steps toward synthetic cell-like systems require controlled transport of molecular species across the boundary between encapsulated expression and the external environment. When molecular species (e.g. small ions, amino acids) required for expression (i.e. expression resources) may cross this boundary, this transport process plays an important role in gene expression dynamics and expression variability. Here we show how the location (encapsulated or external) of the expression resources controls the level and the dynamics of cell-free protein expression confined in permeable lipid vesicles. Regardless of the concentration of encapsulated resources, external resources were essential for protein production. Compared to resource poor external environments, plentiful external resources increased expression by ~7-fold, and rescued expression when internal resources were lacking. Intriguingly, the location of resources and the membrane transport properties dictated expression dynamics in a manner well predicted by a simple transport-expression model. These results suggest membrane engineering as a means for spatio-temporal control of gene expression in cell-free synthetic biology applications and demonstrate a flexible experimental platform to understand the interplay between membrane transport and expression in cellular systems.
Proton-control of transitions in an amino-acid transporter
Authors: Wu Z. , Alibay I. , Newstead S. , Biggin P. C. 
Published: April 2019

AbstractAmino acid transport into the cell is often coupled to the proton electrochemical gradient, as found in the solute carrier (SLC) 36 family of proton coupled amino acid transporters (PATs). Although no structure of a human PAT exists, the crystal structure of a related homolog, GkApcT, from bacteria has recently been solved in an inward occluded state and allows an opportunity to examine how protons are coupled to amino acid transport. Our working hypothesis is that release of the amino acid substrate is facilitated by deprotonation of a key glutamate residue (E115), located at the bottom of the binding pocket and which forms part of the intracellular gate, allowing the protein to transition from an inward-occluded to an inward-open conformation. During unbiased molecular dynamics, we observed a transition from the inward-occluded state captured in the crystal structure, to a much more open state, which we consider likely to be representative of the inward-open substrate release state. To explore this and the role of protons in these transitions, we have used umbrella sampling to demonstrate that the transition from inward-occluded to inward-open is more energetically favourable when E115 is deprotonated. That E115 is likely to be protonated in the inward-occluded state and deprotonated in the inward-open state is further confirmed via the use of absolute binding free energies. Finally, we also show, via the use of absolute binding free energy calculations, that the affinity of the protein for alanine is very similar regardless of either the state or the protonation of E115, presumably reflecting key interactions deep within the binding cavity. Together, our results give a detailed picture of the role of protons in driving one of the major transitions in this transporter.Significance StatementFor transporter proteins that utilize the proton gradient to drive the uptake of solutes, the precise mechanistic details of proton-coupling remain poorly understood. Structures can only infer the position of protons. All-atom molecular dynamics simulations however, are the ideal complementary tool. Here, we report extensive MD simulations on GkApcT, a proton-coupled transporter. We observe a spontaneous transition from the crystallographically derived inward-occluded state, to an inward-open state, which we then characterise with umbrella sampling and absolute binding free energy calculations. The results suggest that a conserved glutamate is protonated in the inward-occluded state and subsequent deprotonation of this glutamate allows the transporter to move into the inward-open state, thus facilitating substrate release into the cell.
Mutational Analysis of an Intrinsically Disordered Region in the E. coli Phosphatase CheZ, a Regulator of Chemotaxis
Authors: Ward Amber , Kamegne Marilyne , Dillard Paulette , Moore John T. 
Published: April 2019

AbstractAs a model for Intrinsically Disordered Region (IDR) structure-function, we investigated the IDR present in the E. coli chemotaxis regulatory phosphatase CheZ. The CheZ IDR (amino acids 169-200) is attractive for study because CheZ is part of an exceptionally well characterized and easily tractable system and has an available high-resolution crystal structure. The CheZ IDR contains striking evolutionarily conserved regions that are functionally critical as shown by the fact that changes in single specific amino acids in the conserved IDR regions are able to abolish normal chemotaxis. We have focused on identifying suppressor mutations in the coding region of CheZ G188E, a variant with a >80% reduction in chemotactic swarm activity. Our screen identified 6 suppressor mutations that restored swarm activity to wild-type levels. Interestingly, the suppressor mutations were found not in the CheZ coding region, but in CheY, the phosphoprotein substrate of the CheZ phosphatase. The 6 suppressor mutations were restricted to two amino acid codons. Three suppressor mutations were found at position CheY A42 and three at position CheY M60. A model for how the changes in CheY restore CheZ activity is presented. These studies in dissection of the CheZ IDR will be useful in extending our understanding of IDR structure-function. The accumulating knowledge of IDR principles will be a significant component of a broadening understanding of protein biophysics with direct implications in basic protein structure and protein engineering research.
Global analyses of the dynamics of mammalian microRNA metabolism
Authors: Kingston Elena R. , Bartel David P. 
Published: April 2019

AbstractRates of production and degradation together specify microRNA (miRNA) abundance and dynamics. Here, we used approach-to-equilibrium metabolic labeling to assess these rates for 176 miRNAs in contact-inhibited mouse embryonic fibroblasts (MEFs), 182 miRNAs in dividing MEFs, and 136 miRNAs in mouse embryonic stem cells (mESCs). MicroRNA duplexes, each comprising a mature miRNA and its passenger strand, are produced at rates as fast as 114 ± 49 copies/cell per min, which exceeds rates reported for any mRNAs. These duplexes are rapidly loaded into Argonaute, with <10 min typically required for duplex loading and silencing-complex maturation. Within Argonaute, guide strands have stabilities that vary by 100-fold. Half-lives also vary globally between cell lines, with median values ranging from 6.3 to 34 h in mESCs and contact-inhibited MEFs, respectively. Moreover, relative half-lives for individual miRNAs vary between cell types, implying the influence of cell-specific factors in dictating turnover rate. The apparent influence of miRNA regions most important for targeting, together with the effect of one target on miR-7a-5p accumulation, suggest that targets fulfill this role. Analysis of the tailing and trimming of miRNA 3′ termini showed that the flux was typically greatest through the isoform tailed with a single uridine, although changes in this flux did not correspond to changes in stability, which suggested that the processes of tailing and trimming might be independent from that of decay. Together these results establish a framework for describing the dynamics and regulation of miRNAs throughout their lifecycle.
UNI-EM: An Environment for Deep Neural Network-Based Automated Segmentation of Neuronal Electron Microscopic Images
Authors: Urakubo Hidetoshi , Bullmann Torsten , Kubota Yoshiyuki , Oba Shigeyuki , Ishii Shin 
Published: April 2019

AbstractRecently, there has been a rapid expansion in the field of micro-connectomics, which targets the three-dimensional (3D) reconstruction of neuronal networks from a stack of two-dimensional (2D) electron microscopic (EM) images. The spatial scale of the 3D reconstruction grows rapidly owing to deep neural networks (DNNs) that enable automated image segmentation. Several research teams have developed their own software pipelines for DNN-based segmentation. However, the complexity of such pipelines makes their use difficult even for computer experts and impossible for non-experts. In this study, we developed a new software program, called UNI-EM, that enables 2D- and 3D-DNN-based segmentation for non-computer experts. UNI-EM is a software collection for DNN-based EM image segmentation, including ground truth generation, training, inference, postprocessing, proofreading, and visualization. UNI-EM comes with a set of 2D DNNs, i.e., U-Net, ResNet, HighwayNet, and DenseNet. We further wrapped flood-filling networks (FFNs) as a representative 3D DNN-based neuron segmentation algorithm. The 2D- and 3D-DNNs are known to show state-of-the-art level segmentation performance. We then provided two-example workflows: mitochondria segmentation using a 2D DNN as well as neuron segmentation using FFNs. Following these example workflows, users can benefit from DNN-based segmentation without any knowledge of Python programming or DNN frameworks.
Untangling featural and conceptual object representations
Authors: Grootswagers Tijl , Robinson Amanda K. , Shatek Sophia M. , Carlson Thomas A. 
Published: April 2019

AbstractHow are visual inputs transformed into conceptual representations by the human visual system? The contents of human perception, such as objects presented on a visual display, can reliably be decoded from voxel activation patterns in fMRI, and in evoked sensor activations in MEG and EEG. A prevailing question is the extent to which brain activation associated with object categories is due to statistical regularities of visual features within object categories. Here, we assessed the contribution of mid-level features to conceptual category decoding using EEG and a novel fast periodic decoding paradigm. Our study used a stimulus set consisting of intact objects from the animate (e.g., fish) and inanimate categories (e.g., chair) and scrambled versions of the same objects that were unrecognizable and preserved their visual features (Long, Yu, & Konkle, 2018). By presenting the images at different periodic rates, we biased processing to different levels of the visual hierarchy. We found that scrambled objects and their intact counterparts elicited similar patterns of activation, which could be used to decode the conceptual category (animate or inanimate), even for the unrecognizable scrambled objects. Animacy decoding for the scrambled objects, however, was only possible at the slowest periodic presentation rate. Animacy decoding for intact objects was faster, more robust, and could be achieved at faster presentation rates. Our results confirm that the mid-level visual features preserved in the scrambled objects contribute to animacy decoding, but also demonstrate that the dynamics vary markedly for intact versus scrambled objects. Our findings suggest a complex interplay between visual feature coding and categorical representations that is mediated by the visual system’s capacity to use image features to resolve a recognisable object.