bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Evolution of Neuromodulation in the Treatment of Chronic Pain: Forward-Looking Perspectives
Authors: Fishman Michael A , Antony Ajay , Esposito Michael , Deer Timothy , Levy Robert 
Published: March 2019

AbstractBackgroundThe field of neuromodulation is continually evolving, with the past decade showing significant advancement in the therapeutic efficacy of neuromodulation procedures. The continued evolution of neuromodulation technology brings with it the promise of addressing the needs of both patients and physicians, as current technology improves and clinical applications expand.DesignThis review highlights the current state of the art of neuromodulation for treating chronic pain, describes key areas of development including stimulation patterns and neural targets, expanding indications and applications, feedback-controlled systems, noninvasive approaches, and biomarkers for neuromodulation and technology miniaturization.Results and ConclusionsThe field of neuromodulation is undergoing a renaissance of technology development with potential for profoundly improving the care of chronic pain patients. New and emerging targets like the dorsal root ganglion, as well as high-frequency and patterned stimulation methodologies such as burst stimulation, are paving the way for better clinical outcomes. As we look forward to the future, neural sensing, novel target-specific stimulation patterns, and approaches combining neuromodulation therapies are likely to significantly impact how neuromodulation is used. Moreover, select biomarkers may influence and guide the use of neuromodulation and help objectively demonstrate efficacy and outcomes.
Size-Dependent elastic response in functionally graded microbeams considering generalized first strain gradient elasticity
Authors: Sidhardh S , Ray M C 
Published: March 2019

Summary
In this article, the size-dependent mechanical response of an isotropic functionally graded (FG) microbeam has been investigated. The size-effects over the elastic response have been modeled by the Mindlin–Toupin strain gradient theory, with the coefficients evaluated from the generalized first strain gradient theory of elasticity. In order to facilitate the derivation of the exact solutions to the governing differential equations of equilibrium, an exponentially graded FG beam is chosen. These exact solutions are derived for a simply supported beam subjected to a sinusoidally distributed mechanical load. Following this, an element-free Galerkin (EFG) model involving moving least squares interpolations across the domain is also developed here. The EFG model is validated with the exact solutions for the exponentially graded beam. Finally, the EFG model is extended to the more general case of a power law-graded beam. The mechanical responses for the power law-graded beams under various loading and boundary conditions are presented here. These results may serve as benchmark for further studies over size-effects in FG beams.
Autoantibodies to a novel Rpp38 (Th/To) derived B-cell epitope are specific for systemic sclerosis and associate with a distinct clinical phenotype
Authors: Koenig Martial , Bentow Chelsea , Satoh Minoru , Fritzler Marvin J , Senécal Jean-Luc , Mahler Michael 
Published: March 2019

Abstract

Objective
Detection of antinuclear antibodies and specific autoantibodies is important in the diagnosis and classification of SSc. Several proteins of the Th/To complex, including Rpp25, Rpp38 and hPop1 are the target of autoantibodies in SSc patients. However, very little is known about the epitope distribution of this autoantigen. Consequently, we screened Rpp25, Rpp38 and hPop1 for B cell epitopes and evaluated their clinical relevance.

Methods
Serum pools with (n = 2) and without (n = 1) anti-Th/To autoantibodies were generated and used for epitope discovery. Identified biomarker candidate sequences were then utilized to synthesize synthetic, biotinylated, soluble peptides. The peptides were tested to determine reactivity with sera from SSc cohorts (n = 202) and controls (n = 159) using a chemiluminescence immunoassay. Additionally, samples were also tested for antibodies to full-length recombinant Rpp25 antibodies by chemiluminescence immunoassay.

Results
Several immunodominant regions were found on the three proteins. The strongest reactivity was observed with an Rpp38 peptide (aa 229–243). Autoantibodies to the Rpp38 peptide were detected in 8/149 (5.4%) limited cutaneous SSc patients, but not in any of 159 controls (P = 0.003 by two-sided Fisher's exact probability test). Although reactivity to the novel antigenic peptide was correlated with the binding to Rpp25 (rho = 0.44; P < 0.0001), subsets of patient sera either reacted strongly with Rpp25 or with the novel Rpp38-derived peptide.

Conclusion
A novel Rpp38 epitope holds promise to increase the sensitivity in the detection of anti-Th/To autoantibodies, thus enhancing the serological diagnosis of SSc.
The TLR5 agonist flagellin modifies phenotypical and enhances functional activation of lung mucosal antigen presenting cells in neonatal mice
Authors: Sharma Pankaj , Levy Ofer , Dowling David J. 
Published: March 2019

AbstractIntranasal mucosal vaccines are of interest in that they may induce protective mucosal immune responses. Activation of lung antigen presenting cells (APCs), a phenotyoically and functionally heterogeneous cell population located at distinct mucosal sites, may be key to the immunogenicity of such vaccines. Characterizing responsiveness of newborn lung APCs to adjuvants may inform design of efficacious intranasal vaccines for early life, when most infections occur. We characterized APCs from neonatal (<7 days of life) and adult (6-8 weeks of age) mice. Neonatal mice displayed a relatively high abundance of alveolar macrophages (AMs), with lower percentages of plasmacytoid dendritic cells (pDCs), CD103+ (cDC1) and CD11b+ (cDC2) DCs. Furthermore, neonatal CD103+ and CD11b+ DC subsets demonstrated an inverse expression of maturation markers as compared to adult mice. Upon stimulation of lung APC subsets with a panel of pattern recognition receptor (PRR), including TLR and STING, agonists, CD11c+ enriched cells from neonatal and adult mice lungs demonstrated distinct maturation profiles. The TLR5 ligand, flagellin, was most effective at activating neonatal lung APCs, inducing significantly higher expression of maturation markers on CD103+ (cDC1) and CD11b+ (cDC2) subsets. Intranasal administration of flagellin induced a distinct migration of CD103+ and CD11b+ DC subsets to the mediastinal lymph nodes (mLNs) of neonatal mice. Overall, these findings highlight age specific differences in the maturation and responsiveness of lung APC subsets to different PRR agonists. The unique efficacy of flagellin in enhancing lung APC activity suggests that it may serve as an effective adjuvant for early life mucosal vaccines.
The protein repertoire in early vertebrate embryogenesis
Authors: Peshkin Leonid , Lukyanov Alexander , Kalocsay Marian , Gage Robert Michael , Wang DongZhuo , Pells Troy J. , Karimi Kamran , Vize Peter D. , Wühr Martin , Kirschner Marc W. 
Published: March 2019

SummaryWe present an unprecedentedly comprehensive characterization of protein dynamics across early development inXenopus laevis, available immediately via a convenient Web portal. This resource allows interrogation of the protein expression data in conjunction with other data modalities such as genome wide mRNA expression. This study provides detailed data for absolute levels of ∼14K uniqueXenopusproteins representing homologues of ∼9K unique human genes – a rich resource for developmental biologists. The purpose of this manuscript is limited to presenting and releasing the data browser.HighlightsRelative protein expression from stage IV oocyte, blastula, gastrula, neurula, and early organogenesisBiological triplicates with confidence intervals on protein expression reflect certainty in dynamic patternsConvenient time-series Web-browser integrated with the multi-media Xenbase portalGene-symbol search and multi-gene protein/mRNA juxtaposition capabilities
Alzheimer disease and Apolipoprotein E4: meningeal brain lymphatics point to new clues in pathogenesis
Authors: Mentis Alexios-Fotios A. , Chrousos George P. 
Published: March 2019

ABSTRACTThe role of the lymphatic system in brain function and/or dysfunction has long been an enigma. However, recent reports that meningeal lymphatic vessels exist within the mouse and human brain, as well as evidence that mouse meningeal lymphatic vessels play a role in clearing the toxic amyloid-beta peptide connected with Alzheimer’s disease (AD), may herald novel diagnostic and therapeutic avenues. Here, we explore new evidence connecting the lymphatic system of the brain with AD. In particular, we focus on new findings showing that meningeal lymphatic vessels play a role in drainage of cerebrospinal fluid and egress of immune cells from the brain, and that disrupting this vessel system leads to accumulation of amyloid - beta peptide and cognitive dysfunction. We also discuss the hypothesis that apolipoprotein E isoform e4 (APO E4) ─ the leading genetic risk for developing AD ─ is involved in meningeal lymphatic vessel function. By reanalyzing previously published RNA-Seq data, we show that APO E4 knock-in microglia cells express lower levels of genes representing lymphatic markers (a phenomenon we call “attenuated lymphaticness”) and of genes in which functional missense mutations are linked to lymphedema. Accordingly, we propose the hypothesis that APO E4 is involved in the shrinkage of lymphatic vessels. This notion could lead, if verified by additional anatomic and mechanistic data, to the concept that APO E4-related AD (such as in late onset AD or trisomy 21-related AD) is related to lymphosclerosis coupled with lymphedema.
A failed top-down control from prefrontal cortex to amygdala in generalized anxiety disorder: evidence from resting-state fMRI with Granger causality analysis
Authors: Dong Mengshi , Xia Likun , Lu Min , Li Chao , Xu Ke , Zhang Lina 
Published: March 2019

AbstractObjectiveIn generalized anxiety disorder (GAD), abnormal top-down control from prefrontal cortex (PFC) to amygdala is a widely accepted hypothesis through which “emotional dysregulation model” may be explained. However, whether and how the PFC directly exerted abnormal top-down control on amygdala remained largely unknown. We aim to investigate the amygdala-based effective connectivity by using Granger causality analysis (GCA).MethodsThirty-five drug-naive patients with GAD and thirty-six healthy controls (HC) underwent resting-state functional MR imaging. We used seed-based Granger causality analysis to examine the effective connectivity between the bilateral amygdala and the whole brain. The amygdala-based effective connectivity was compared between the two groups.ResultsIn HC, the left middle frontal gyrus exerted inhibitory influence on the right amygdala, while in GAD group, this influence was disrupted (single voxel P < 0.001, Gaussian random field corrected with P < 0.01).ConclusionOur finding might provide new insight into the “insufficient top-down control” hypothesis in GAD.
Capsidiol, a defensive sesquiterpene produced by wild tobacco in response to attack from the fungal pathogenAlternaria alternata, is regulated by an ERF2-like transcription factor
Authors: Song Na , Ma Lan , Wang Weiguang , Sun Huanhuan , Wang Lei , Baldwin Ian T. , Wu Jinsong 
Published: March 2019

AbstractCapsidiol is a sesquiterpenoid phytoalexin produced inNicotianaandCapsicumspecies in response to pathogen attack. Whether capsidiol plays a defensive role and how its biosynthesis is regulated in the wild tobaccoNicotiana attenuatawhen the plant is attacked byAlternaria alternata(tobacco pathotype), a notorious necrotrophic fungus causing brown spot disease, is unknown. Transcriptome analysis indicated that a metabolic switch to sesquiterpene biosynthesis occurred in young leaves ofN. attenuataafterA. alternatainoculation: many genes leading to sesquiterpene production were strongly up-regulated, including the capsidiol biosynthetic genes, 5-epi-aristolochene synthase(EAS) and 5-epi-aristolochene hydroxylase(EAH). Consistently, the level of capsidiol was increased dramatically in young leaves after fungal inoculation, from not detectable in mock control to 50.68 ± 3.10 µg/g fresh leaves at 3 days post inoculation. Capsidiol-reduced or capsidiol-depleted plants, which were generated by silencingEAHs orEASs by virus-induced gene silencing, were more susceptible to the fungus. In addition, this sesquiterpene exhibited strong anti-fungal activities againstA. alternata in vitrowhen purified from infected plants and applied to fungal growth. Furthermore, an ERF2-like transcription factor was found to positively regulate capsidiol production and plant resistance through the direct transactivation of a capsidiol biosynthetic geneEAS12. Taken together, our results demonstrate that capsidiol, a phytoalexin highly accumulated inN. attenuataplants in response toA. alternatainfection, plays an important role in pathogen resistance independent of JA and ethylene signaling pathways, and its biosynthesis is transcriptionally regulated by an ERF2-like transcription factor.HighlightOur results demonstrate that capsidiol, a phytoalexin highly accumulated inNicotiana attenuataplants in response toAlternaria alternataattack, plays an important role in pathogen resistance, and its biosynthesis is transcriptionally regulated by an ERF2-like transcription factor.
Sequential compression of gene expression across dimensionalities and methods reveals no single best method or dimensionality
Authors: Way Gregory P. , Zietz Michael , Rubinetti Vincent , Himmelstein Daniel S. , Greene Casey S. 
Published: March 2019

AbstractBackgroundUnsupervised compression algorithms applied to gene expression data extract latent, or hidden, signals representing technical and biological sources of variation. However, these algorithms require a user to select a biologically-appropriate latent dimensionality. In practice, most researchers select a single algorithm and latent dimensionality. We sought to determine the extent by which using multiple dimensionalities across ensemble compression models improves biological representations.ResultsWe compressed gene expression data from three large datasets consisting of adult normal tissue, adult cancer tissue, and pediatric cancer tissue. We compressed these data into many latent dimensionalities ranging from 2 to 200. We observed various tradeoffs across latent dimensionalities and compression models. For example, we observed high model stability between principal components analysis (PCA), independent components analysis (ICA), and non-negative matrix factorization (NMF). We identified more unique biological signatures in ensembles of denoising autoencoder (DAE) and variational autoencoder (VAE) models in intermediate latent dimensionalities. However, we captured the most pathway-associated features using all compressed features across algorithms and dimensionalities. Optimized at different latent dimensionalities, compression models detect generalizable gene expression signatures representing sex, neuroblastoma MYCN amplification, and cell types. In two supervised machine learning tasks, compressed features optimized predictions at different latent dimensionalities.ConclusionsThere is no single best latent dimensionality or compression algorithm for analyzing gene expression data. Instead, using feature ensembles from different compression models across latent space dimensionalities optimizes biological representations.
Conserved residues in the wheat (Triticum aestivum) NAM-A1 NAC domain are required for protein binding and when mutated lead to delayed peduncle and flag leaf senescence
Authors: Harrington Sophie A. , Overend Lauren E. , Cobo Nicolas , Borrill Philippa , Uauy Cristobal 
Published: March 2019

AbstractBackgroundNAC transcription factors contain five highly conserved subdomains which are required for protein dimerisation and DNA binding. Few residues within these subdomains have been identified as essential for protein function, and fewer still have been shown to be of biological relevancein planta. Here we use a positive regulator of senescence in wheat,NAM-A1, to test the impact of missense mutations at specific, highly conserved residues of the NAC domain on protein function.ResultsWe identified missense mutations in five highly conserved residues of the NAC domain ofNAM-A1in a tetraploid TILLING population. TILLING lines containing these mutations, alongside synonymous and non-conserved mutation controls, were grown under glasshouse conditions and scored for senescence. Four of the five mutations showed a significant and consistent delay in peduncle senescence but had no consistent effects on flag leaf senescence. All four mutant alleles with the delayed senescence phenotype also lost the ability to interact with the homoeolog NAM-B1 in a yeast two-hybrid assay. Two of these residues were previously shown to be involved in NAC domain function in Arabidopsis, suggesting conservation of residue function between species. Three of these four alleles led to an attenuated cell death response compared to wild-typeNAM-A1when transiently over-expressed inNicotiana benthamiana. One of these mutations was further tested under field conditions, in which there was a significant and consistent delay in both peduncle and leaf senescence.ConclusionsWe combined field and glasshouse studies of a series of mutant alleles with biochemical analyses to identify four residues of the NAC domain which are required forNAM-A1function and protein interaction. We show that mutations in these residues lead to a gradient of phenotypes, raising the possibility of developing allelic series of mutations for traits of agronomic importance. We also show that mutations inNAM-A1more severely impact peduncle senescence, compared to the more commonly studied flag leaf senescence, highlighting this as an area deserving of further study. The results from this integrated approach provide strong evidence that conserved residues within the functional domains of NAC transcription factors have biological significancein planta.
Structure elucidation of colibactin
Authors: Xue Mengzhao , Kim Chung Sub , Healy Alan R. , Wernke Kevin M. , Wang Zhixun , Frischling Madeline C. , Shine Emilee E. , Wang Weiwei , Herzon Seth B. , Crawford Jason M. 
Published: March 2019

AbstractColibactin is a gut microbiome metabolite of unknown structure that has been implicated in colorectal cancer formation. Several studies now suggest that the tumorgenicity of colibactin derives from interstrand cross-linking of host DNA. Here we use a combination of genetics, isotope labeling, tandem MS, and chemical synthesis to deduce the structure of colibactin. Our structural assignment accounts for all known biosynthetic data and suggests roles for the final unaccounted enzymes in the colibactin gene cluster. DNA cross-link degradation products derived from synthetic and natural colibactin were indistinguishable by tandem MS analysis, thereby confirming the structure prediction. This work reveals the structure of colibactin, which has remained incompletely defined for over a decade.
Propagation of cortical activity via open-loop intrathalamic architectures: a computational analysis
Authors: Brown Jeffrey W. , Taheri Aynaz , Kenyon Robert V. , Berger-Wolf Tanya , Llano Daniel A. 
Published: March 2019

AbstractPropagation of signals across the cerebral cortex is a core component of many cognitive processes and is generally thought to be mediated by direct intracortical connectivity. The thalamus, by contrast, is considered to be devoid of internal connections and organized as a collection of parallel inputs to the cortex. Here, we provide evidence that “open-loop” intrathalamic connections involving the thalamic reticular nucleus (TRN) can support propagation of oscillatory activity across the cortex. Recent studies support the existence of open-loop thalamo-reticulo-thalamic (TC-TRN-TC) synaptic motifs in addition to traditional closed-loop architectures. We hypothesized that open-loop structural modules, when connected in series, might underlie thalamic and, therefore cortical, signal propagation. Using a supercomputing platform to simulate thousands of permutations of a thalamo-reticular-cortical network and allowing select synapses to vary both by class and individually, we evaluated the relative capacities of closed- and open-loop TC-TRN-TC synaptic configurations to support both propagation and oscillation. We observed that 1) signal propagation was best supported in networks possessing strong open-loop TC-TRN-TC connectivity; 2) intrareticular synapses were neither primary substrates of propagation nor oscillation; and 3) heterogeneous synaptic networks supported more robust propagation of oscillation than their homogeneous counterparts. These findings suggest that open-loop heterogeneous intrathalamic architectures complement direct intracortical connectivity to facilitate cortical signal propagation.Significance StatementInteractions between the dorsal thalamus and thalamic reticular nucleus (TRN) are speculated to contribute to phenomena such as arousal, attention, sleep, and seizures. Despite the importance of the TRN, the synaptic microarchitectures forming the basis for dorsal thalamus-TRN interactions are not fully understood. The computational neural model we present incorporates “open-loop” thalamo-reticular-thalamic (TC-TRN-TC) synaptic motifs, which have been experimentally observed. We elucidate how open-loop motifs possess the capacity to shape the propagative properties of signals intrinsic to the thalamus and evaluate the wave dynamics they support relative to closed-loop TC-TRN-TC pathways and intrareticular synaptic connections. Our model also generates predictions regarding how different spatial distributions of reticulothalamic and intrareticular synapses affect these signaling properties.
A pivotal genetic program controlled by thyroid hormone during the maturation of GABAergic neurons in mice
Authors: Richard Sabine , Guyot Romain , Rey-Millet Martin , Prieux Margaux , Markossian Suzy , Aubert Denise , Flamant Frédéric 
Published: March 2019

AbstractIn mammals, brain development is critically dependent on proper thyroid hormone signaling, via the TRα1 nuclear receptor. However, the downstream mechanisms by which TRα1 impacts brain development are currently unknown, notably because this receptor is expressed ubiquitously from early stages of development. In order to better define the function of TRα1 in the developing brain, we used mouse genetics to induce the expression of a dominant-negative mutation of the receptor specifically in GABAergic neurons, the main inhibitory neurons in the brain, which were previously identified as sensitive to hypothyroidism. This triggered post-natal epileptic seizures, reflecting a profound impairment of GABAergic neuron maturation in different brain areas. Analysis of transcriptome and TRα1 cistrome also allowed us to identify a small set of genes, the transcription of which is upregulated by TRα1 in GABAergic neurons during post-natal maturation of the striatum and which probably play an important role during neurodevelopment. Thus, our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction.