bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tim-3 Regulates Tregs’ Ability to Resolve the Inflammation and Proliferation of Acute Lung Injury by Modulating Macrophages Polarization
Authors: Liu Xiandong , Jiang Sen , Zhang Qian , Xu Shumin , Bao Xiaowei , Cao Wei , Bai Jianwen , Tang Lunxian 
Published: November 2017

ABSTRACT
We recently reported that CD4+CD25+ regulatory T cells (Tregs) contributed to the recovery of patients with acute lung injury (ALI) by upregulating T cell immunoglobulin and mucin-domain containing-3 (Tim-3). However, the molecular mechanism by which Tim-3 regulates Tregs’ function in the resolution and fibroproliferation after ALI remains unknown. In this study, we adoptively transferred Tim-3+Tregs or Tim-3−Tregs into lipopolysaccharide -induced ALI mice model. Data demonstrated that Tim-3+Tregs not only decreased indices of lung inflammation and injury but also mitigated lung fibrosis after ALI. Furthermore, we observed that the transfer of Tim-3+Tregs led to M2-like macrophage differentiation as demonstrated by significantly upregulated levels of M2-associated phenotypic markers as well as downregulated expressions of M1-related markers in both the profibrotic lung tissue and sorted pulmonary monocytes after ALI. In addition, cytokines such as interleukin (IL)-10 and IL-4 were also upregulated in lung tissues after Tim-3+Tregs transferring. In vitro experiments further demonstrated that cell-contact cocultures with Tregs lacking Tim-3 presented decreased polarization of M2-like macrophages partially mediated by a decreased expression and function of STAT-3. Therefore, these data demonstrate a previously unrecognized function of Tim-3 on Tregs in their ability to repress the fibroproliferation of ALI by inducing alternative macrophages polarization. Moreover, the data highlight that Tim-3+Tregs-mediated induction of M2-like macrophages may be a novel treatment modality with transitional potential.
Time calibrated tree of Dioscorea (Dioscoreaceae) indicate four origins of yams in the Neotropics since the Eocene
Authors: Couto Ricardo S. , Martins Aline C. , Bolson Mônica , Lopes Rosana C. , Smidt Eric C. , Braga João M. A. 
Published: November 2017

ABSTRACTThe yam genus Dioscorea comprises circa 650 species of tropical vines with starch rich tubers, usefull as an energy source and often containing secondary metabolites. The Neotropical Region holds the highest diversity of species and morphology of yams. We generated a time-calibrated tree for Dioscorea using, for the first time, a dense sampling of Neotropical species (64 sp., 20% of all Neotropical sp. and 22 sections) to trace the biogeography of these plants in this region. Four origins of Dioscorea in the neotropics were estimated since the Eocene. The two most diverse lineages originated between the Eocene and Oligocene, respectively in the Southern Andes and eastern South America. Both lineages occupied the South American ‘Dry Diagonal’ after the Miocene, but New World II clade remained associated with forest habitats. Several exchanges between Dry Diagonal and adjacent forested biomes occurred, corroborating the interchange between these vegetation types. Dispersals to Central America occurred before the closure of the Panama Isthmus. We highlight two important events of long distance dispersal, the colonization of Central American before the closure of Isthmus of Panama and the dispersal of D. antaly lineage to Madagascar. In addition, our phylogenetic tree evidenced the unnatural nature of the classical infrageneric classification of Dioscorea. The taxonomic implications of our results are also discussed.
Toward Machine Learning-based Data-driven Functional Protein Studies: Understanding Colour Tuning Rules and Predicting the Absorption Wavelengths of Microbial Rhodopsins
Authors: Karasuyama Masayuki , Inoue Keiichi , Kandori Hideki , Takeuchi Ichiro 
Published: November 2017

AbstractThe light-dependent ion-transport function of microbial rhodopsin has been widely used in optogenetics for optical control of neural activity. In order to increase the variety of rhodopsin proteins having a wide range of absorption wavelengths, the light absorption properties of various wild-type rhodopsins and their artificially mutated variants were investigated in the literature. Here, we demonstrate that a machine-learning-based (ML-based) data-driven approach is useful for understanding and predicting the light-absorption properties of microbial rhodopsin proteins. We constructed a database of 796 proteins consisting of microbial rhodopsin wildtypes and their variants. We then proposed an ML method that produces a statistical model describing the relationship between amino-acid sequences and absorption wavelengths and demonstrated that the fitted statistical model is useful for understanding colour tuning rules and predicting absorption wavelengths. By applying the ML method to the database, two residues that were not considered in previous studies are newly identified to be important to colour shift.
Electrophysiological properties of human β-cell lines EndoC-βH1 and -βH2 conform with human β-cells
Authors: Hastoy Benoît , Godazgar Mahdieh , Clark Anne , Nylander Vibe , Spiliotis Ioannis , van de Bunt Martijn , Chibalina Margarita , Barrett Amy , Burrows Carla , Tarasov Andrei , Scharfmann Raphael , Gloyn Anna L. , Rorsman Patrik 
Published: November 2017

AbstractThe electrophysiological and secretory properties of the human β-cell lines EndoC-βH1 and EndoC-βH2 were investigated. Both cell lines respond to glucose (6-20mM) with 2-to 3-fold stimulation of insulin secretion, an effect that was mimicked by tolbutamide (0.2mM) and reversed by diazoxide (0.5mM). Glucose-induced insulin release correlated with an elevation of [Ca2+]i, membrane depolarization and increased action potential firing. KATP channel activity at 1mM glucose is low and increasing glucose to 6 or 20mM reduced KATP channel activity to the same extent as application of the KATP channel blocker tolbutamide (0.2mM). The upstroke of the action potentials in EndoC-βH1 and −βH2 cells observed at high glucose principally reflects activation of L- and P/Q-type Ca2+ channels with some small contribution of TTX-sensitive Na+ channels. Action potential repolarization involves activation of voltage-gated Kv2.2 channels and large-conductance Ca2+-activated K+ channels. Exocytosis (measured by measurements of membrane capacitance) was triggered by membrane depolarizations >10ms to membrane potentials above -30mV. Both cell lines were well-granulated (6,000-15,000 granules/cell) and granules consisted of a central insulin core surrounded by a clear halo. We conclude that the EndoC-βH1 and -βH2 cells share many features of primary human β-cells and that they represent a useful experimental model.
UV-Induced Keratin 1 Proteolysis Mediates UV-Induced Skin Damage
Authors: Zhang Mingchao , Maharjan Dhruba Tara , He Hao , Li Yujia , Yan Wei , Yan Weixin , Zhu Yujie , Ying Weihai 
Published: November 2017

AbstractKeratins play critical roles in intermediate filament formation, inflammatory responses and cellular signaling in epithelium. While keratins is a major epidermal fluorophore, the mechanisms underlying the autofluorescence (AF) of keratins and its biomedical implications have remained unknown. Our study used mouse skin as a model to study these topics, showing that UV dose-dependently induced increases in green AF at the spinous layer of the epidermis of mouse within 6 hr of the UV exposures, which may be used for non-invasive prediction of UV-induced skin damage. The UV-induced AF appears to be induced by cysteine protease-mediated keratin 1 proteolysis: 1) UV rapidly induced significant keratin 1 degradation; 2) administration of keratin 1 siRNA largely decreased the UV-induced AF; and 3) administration of E-64, a cysteine protease inhibitor, significantly attenuated the UV-induced AF and keratin 1 degradation. Our study has also suggested that the UV-induced keratin 1 proteolysis may be a novel crucial pathological factor in UV-induced skin damage, which is supported by both the findings that indicate critical biological roles of keratin 1 in epithelium and our observation that prevention of UV-induced keratin 1 proteolysis can lead to decreased UV-induced skin damage. Collectively, our study has suggested that UV-induced keratin 1 proteolysis may be a novel and valuable target for diagnosis, prevention and treatment of UV-induced skin damage.
Identification and Targeting of Cortical Ensembles
Authors: Carrillo-Reid Luis , Han Shuting , Taralova Ekaterina , Jebara Tony , Yuste Rafael 
Published: November 2017

AbstractBreaking the neural code requires the characterization of physiological and behavioral correlates of neuronal ensemble activity. To understand how the emergent properties of neuronal ensembles allow an internal representation of the external world, it is necessary to generate empirically grounded models that fully capture ensemble dynamics. We used machine learning techniques, often applied in big data pattern recognition, to identify and target cortical ensembles from mouse primary visual cortex in vivo leveraging recent developments in optical techniques that allowed the simultaneous recording and manipulation of neuronal ensembles with single-cell precision. Conditional random fields (CRFs) allowed us not only to identify cortical ensembles representing visual stimuli, but also to individually target neurons that are functionally key for pattern completion. These results represent the proof-of-principle that machine learning techniques could be used to design close-loop behavioral experiments that involve the precise manipulation of functional cortical ensembles.
Learning a neural response metric for retinal prosthesis
Authors: Shah Nishal P. , Madugula Sasidhar , Chichilnisky E.J. , Shlens Jonathon , Singer Yoram 
Published: November 2017

ABSTRACTRetinal prostheses for treating incurable blindness are designed to electrically stimulate surviving retinal neurons, causing them to send artificial visual signals to the brain. However, electrical stimulation generally cannot precisely reproduce typical patterns of neural activity in the retina. Therefore, an electrical stimulus must be selected so as to produce a neural response as close as possible to the desired response. This requires a technique for computing the distance between a desired response and an achievable response that is meaningful in terms of the visual signal being conveyed. We propose a method to learn a metric on neural responses directly from recorded light responses of a population of retinal ganglion cells (RGCs) in the primate retina. The learned metric produces a measure of similarity of RGC population responses that accurately reflects the similarity of visual inputs. Using data from electrical stimulation experiments, we demonstrate that the learned metric could produce improvements in the performance of a retinal prosthesis.
ShuTu: Open-Source Software for Efficient and Accurate Reconstruction of Dendritic Morphology
Authors: Jin Dezhe Z. , Zhao Ting , Hunt David L. , Tillage Rachel P. , Hsu Ching-Lung , Spruston Nelson 
Published: November 2017

AbstractNeurons perform computations by integrating inputs from thousands of synapses – mostly in the dendritic tree – to drive action potential firing in the axon. One fruitful approach to understanding this process is to record from neurons using patch-clamp electrodes, fill the recorded neuron with a substance that allows subsequent staining, reconstruct the three-dimensional architecture of the dendrites, and use the resulting functional and structural data to develop computer models of dendritic integration. Accurately producing quantitative reconstructions of dendrites is typically a tedious process taking many hours of manual inspection and measurement. Here we present ShuTu, a new software package that facilitates accurate and efficient reconstruction of dendrites imaged using bright-field microscopy. The program operates in two steps: (1) automated identification of dendritic process, and (2) manual correction of errors in the automated reconstruction. This approach allows neurons with complex dendritic morphologies to be reconstructed rapidly and efficiently, thus facilitating the use of computer models to study dendritic structure-function relationships and the computations performed by single neurons.Significance StatementWe developed a software package – ShuTu – that integrates automated reconstruction of stained neurons with manual error correction. This package facilitates rapid reconstruction of the three-dimensional geometry of neuronal dendritic trees, often needed for computational simulations of the functional properties of these structures.
Altered sensitivity to motion of area MT neurons following long-term V1 lesions
Authors: Hagan Maureen A. , Chaplin Tristan A. , Huxlin Krystel R. , Rosa Marcello G. P. , Lui Leo L. 
Published: November 2017

AbstractThe middle temporal area (MT) receives its main afferents from the striate cortex (V1). However, MT also receives direct thalamic projections, which have been hypothesized to play a crucial role in residual vision after V1 lesions. MT neurons continue to respond shortly after V1 lesions, but human clinical work has shown that lesion effects can take up to six months to stabilize, making it important to understand MT responses after long-term deprivation of V1 inputs. We recorded neuronal responses in MT to moving dot stimuli in adult marmoset monkeys, 7-11 months after unilateral V1 lesions. Fewer MT neurons were direction selective, including neurons whose locations corresponded to the intact parts of V1. Firing rates were higher and more variable, and increased with motion strength regardless of direction. These properties could be re-created by a network model with imbalanced inhibition and excitation, providing the first insights into functional implications of long-term plasticity in MT following V1 lesions.
Effective polyploidy causes phenotypic delay and influences bacterial evolvability
Authors: Sun Lei , Alexander Helen K. , Bogos Balazs , Kiviet Daniel J. , Ackermann Martin , Bonhoeffer Sebastian 
Published: November 2017

Whether mutations in bacteria exhibit a noticeable delay before expressing their corresponding mutant phenotype was discussed intensively in the 1940s-50s, but the discussion eventually waned for lack of supportive evidence and perceived incompatibility with observed mutant distributions in fluctuation tests. Phenotypic delay in bacteria is widely assumed to be negligible, despite lack of direct evidence. Here we revisited the question using recombineering to introduce antibiotic resistance mutations intoE. coliat defined time points and then tracking expression of the corresponding mutant phenotype over time. Contrary to previous assumptions, we found a substantial median phenotypic delay of 3-4 generations. We provided evidence that the primary source of this delay is multifork replication causing cells to be effectively polyploid, whereby wild-type gene copies transiently mask the phenotype of recessive mutant gene copies in the same cell. Using modeling and simulation methods, we explored the consequences of effective polyploidy for mutation rate estimation by fluctuation tests and sequencing-based methods. For recessive mutations, despite the substantial phenotypic delay, theper-copyorper-genomemutation rate is accurately estimated. However, theper-cellrate cannot be estimated by existing methods. Finally, with a mathematical model, we showed that effective polyploidy increases the frequency of costly recessive mutations in the standing genetic variation, and thus their potential contribution to evolutionary adaptation, while drastically reducing the chance thatde novorecessive mutations can rescue populations facing a harsh environmental change such as antibiotic treatment. Overall, we have identified phenotypic delay and effective polyploidy as previously overlooked but essential components in bacterial evolvability, including antibiotic resistance evolution.Author summaryWhat is the time delay between the occurrence of a genetic mutation in a bacterial cell and manifestation of its phenotypic effect? We show that antibiotic resistance mutations inE.colishow a remarkably long phenotypic delay of 3-4 bacterial generations. The primary underlying mechanism of this delay is effective polyploidy. In a polyploid cell with multiple chromosomes, once a mutation arises on one of the chromosomes, the presence of non-mutated, wild-type gene copies on other chromosomes may mask the phenotype of the mutation. One implication of this finding is that conventional methods to determine the mutation rates of bacteria do not detect polyploidy and thus underestimate their potential for adaptation. More generally, the effect that a new mutation may become useful only in the “grand-children of the grand-children” suggests that pre-existing mutations are more important for surviving sudden environmental catastrophe.
A quantitative PCR based environmental DNA assay for detecting Atlantic salmon (Salmo salar L.)
Authors: Atkinson Siobhán , Carlsson Jeannette E.L. , Ball Bernard , Egan Damian , Kelly-Quinn Mary , Whelan Ken , Carlsson Jens 
Published: November 2017

AbstractThe Atlantic salmon (Salmo salar L.) has worldwide ecological, cultural and economic importance. The species has undergone extensive decline across its native range, yet concerns have been raised about its invasive potential in the Pacific. Knowledge on the distribution of this species is vital for addressing conservation goals.This study presents an eDNA assay to detect S. salar in water samples, using quantitative PCR (qPCR) technology. Species-specific primers and a minor groove binding (MGB) probe were designed for the assay, based on the mitochondrial cytochrome oxidase I (COI) gene.The results of this study indicate that eDNA is a highly sensitive tool for detecting S. salar in situ, and could potentially provide an alternative, non-invasive method for determining the distribution of this species.
Transcriptome-wide interrogation of the functional intronome by spliceosome profiling
Authors: Chen Weijun , Moore Jill , Ozadam Hakan , Shulha Hennady P. , Rhind Nicholas , Weng Zhiping , Moore Melissa J. 
Published: November 2017

SUMMARYFull understanding of eukaryotic transcriptomes and how they respond to different conditions requires deep knowledge of all sites of intron excision. Although RNA-Seq provides much of this information, the low abundance of many spliced transcripts (often due to their rapid cytoplasmic decay) limits the ability of RNA-Seq alone to reveal the full repertoire of spliced species. Here we present “spliceosome profiling”, a strategy based on deep sequencing of RNAs co-purifying with late stage spliceosomes. Spliceosome profiling allows for unambiguous mapping of intron ends to single nucleotide resolution and branchpoint identification at unprecedented depths. Our data reveal hundreds of new introns inS. pombeand numerous others that were previously misannotated. By providing a means to directly interrogate sites of spliceosome assembly and catalysis genome-wide, spliceosome profiling promises to transform our understanding of RNA processing in the nucleus much like ribosome profiling has transformed our understanding mRNA translation in the cytoplasm.
Reciprocal Disruptions in Thalamic and Hippocampal Resting-State Functional Connectivity in Youth with 22q11.2 Deletions
Authors: Schleifer Charles , Lin Amy , Kushan Leila , Ji Jie Lisa , Yang Genevieve , Bearden Carrie E. , Anticevic Alan 
Published: November 2017

ABSTRACT22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant (CNV) with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional MRI (rs-fMRI) studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of young men and women with 22q11DS (n=42) and demographically matched healthy controls (n=39). Neuroimaging data were acquired via single-band protocols, and analyzed in line with methods provided by the Human Connectome Project (HCP). We computed functional relationships between individual-specific anatomically-defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain type I error protection was achieved through nonparametric permutation-based methods. 22q11DS patients displayed reciprocal disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamo-cortical coupling was increased in sensorimotor cortex, and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to sensory and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggest that high genetic risk for psychiatric illness is linked with disruptions in large-scale cortico-subcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect CNVs for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.SIGNIFICANCE STATEMENTInvestigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders, and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a reciprocal fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.
Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls
Authors: Esparza Thomas J. , Gangolli Mihika , Cairns Nigel J. , Brody David L. 
Published: November 2017

AbstractAn unanswered question regarding Alzheimer disease dementia (ADD) is whether amyloid-beta (Aβ) plaques sequester toxic soluble Aβ species early in the pathological progression. We previously reported that the concentration of soluble Aβ aggregates from patients with mild dementia was higher than soluble Aβ aggregates from patients with modest Aβ plaque burden but no dementia. The ratio of soluble Aβ aggregate concentration to Aβ plaque area fully distinguished these groups of patients. We hypothesized that initially plaques may serve as a reservoir or sink for toxic soluble Aβ aggregates, sequestering them from other targets in the extracellular space and thereby preventing their toxicity. To initially test a generalized version of this hypothesis, we have performed binding assessments using biotinylated synthetic Aβ1-42 peptide. Aβ1-42-biotin peptide was incubated on unfixed frozen sections from non-demented high plaque pathology controls and patients with dementia of the Alzheimer type. The bound peptide was measured using ELISA and confocal microscopy. We observed no quantitative difference in Aβ binding between the groups using either method. Further testing of the buffering hypothesis using various forms of synthetic and human derived soluble Aβ aggregates will be required to definitively address the role of plaque buffering as it relates to ADD.