An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology

NASA Astrophysics Data System (ADS)

Aravanis, Alexander M.; Wang, Li-Ping; Zhang, Feng; Meltzer, Leslie A.; Mogri, Murtaza Z.; Schneider, M. Bret; Deisseroth, Karl

2007-09-01

Neural interface technology has made enormous strides in recent years but stimulating electrodes remain incapable of reliably targeting specific cell types (e.g. excitatory or inhibitory neurons) within neural tissue. This obstacle has major scientific and clinical implications. For example, there is intense debate among physicians, neuroengineers and neuroscientists regarding the relevant cell types recruited during deep brain stimulation (DBS); moreover, many debilitating side effects of DBS likely result from lack of cell-type specificity. We describe here a novel optical neural interface technology that will allow neuroengineers to optically address specific cell types in vivo with millisecond temporal precision. Channelrhodopsin-2 (ChR2), an algal light-activated ion channel we developed for use in mammals, can give rise to safe, light-driven stimulation of CNS neurons on a timescale of milliseconds. Because ChR2 is genetically targetable, specific populations of neurons even sparsely embedded within intact circuitry can be stimulated with high temporal precision. Here we report the first in vivo behavioral demonstration of a functional optical neural interface (ONI) in intact animals, involving integrated fiberoptic and optogenetic technology. We developed a solid-state laser diode system that can be pulsed with millisecond precision, outputs 20 mW of power at 473 nm, and is coupled to a lightweight, flexible multimode optical fiber, ~200 µm in diameter. To capitalize on the unique advantages of this system, we specifically targeted ChR2 to excitatory cells in vivo with the CaMKIIα promoter. Under these conditions, the intensity of light exiting the fiber (~380 mW mm-2) was sufficient to drive excitatory neurons in vivo and control motor cortex function with behavioral output in intact rodents. No exogenous chemical cofactor was needed at any point, a crucial finding for in vivo work in large mammals. Achieving modulation of behavior with optical control of neuronal subtypes may give rise to fundamental network-level insights complementary to what electrode methodologies have taught us, and the emerging optogenetic toolkit may find application across a broad range of neuroscience, neuroengineering and clinical questions.

Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila

PubMed Central

Aso, Yoshinori; Sitaraman, Divya; Ichinose, Toshiharu; Kaun, Karla R; Vogt, Katrin; Belliart-Guérin, Ghislain; Plaçais, Pierre-Yves; Robie, Alice A; Yamagata, Nobuhiro; Schnaitmann, Christopher; Rowell, William J; Johnston, Rebecca M; Ngo, Teri-T B; Chen, Nan; Korff, Wyatt; Nitabach, Michael N; Heberlein, Ulrike; Preat, Thomas; Branson, Kristin M; Tanimoto, Hiromu; Rubin, Gerald M

2014-01-01

Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ∼2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several associative learning tasks and in sleep regulation, revealing the extent to which information flow is segregated into distinct channels and suggesting possible roles for the multi-layered MBON network. We also show that optogenetic activation of MBONs can, depending on cell type, induce repulsion or attraction in flies. The behavioral effects of MBON perturbation are combinatorial, suggesting that the MBON ensemble collectively represents valence. We propose that local, stimulus-specific dopaminergic modulation selectively alters the balance within the MBON network for those stimuli. Our results suggest that valence encoded by the MBON ensemble biases memory-based action selection. DOI: http://dx.doi.org/10.7554/eLife.04580.001 PMID:25535794

Subject-based discriminative sparse representation model for detection of concealed information.

PubMed

Akhavan, Amir; Moradi, Mohammad Hassan; Vand, Safa Rafiei

2017-05-01

The use of machine learning approaches in concealed information test (CIT) plays a key role in the progress of this neurophysiological field. In this paper, we presented a new machine learning method for CIT in which each subject is considered independent of the others. The main goal of this study is to adapt the discriminative sparse models to be applicable for subject-based concealed information test. In order to provide sufficient discriminability between guilty and innocent subjects, we introduced a novel discriminative sparse representation model and its appropriate learning methods. For evaluation of the method forty-four subjects participated in a mock crime scenario and their EEG data were recorded. As the model input, in this study the recurrence plot features were extracted from single trial data of different stimuli. Then the extracted feature vectors were reduced using statistical dependency method. The reduced feature vector went through the proposed subject-based sparse model in which the discrimination power of sparse code and reconstruction error were applied simultaneously. Experimental results showed that the proposed approach achieved better performance than other competing discriminative sparse models. The classification accuracy, sensitivity and specificity of the presented sparsity-based method were about 93%, 91% and 95% respectively. Using the EEG data of a single subject in response to different stimuli types and with the aid of the proposed discriminative sparse representation model, one can distinguish guilty subjects from innocent ones. Indeed, this property eliminates the necessity of several subject EEG data in model learning and decision making for a specific subject. Copyright © 2017 Elsevier B.V. All rights reserved.

BWTG3 hepatoma cells can acquire phenylalanine hydroxylase, cystathionine synthase and CPS-I without genetic manipulation, but activation of the silent OTC gene requires cell fusion with hepatocytes.

PubMed

Farmer, A A; Goss, S J

1991-04-01

The mouse hepatoma BWTG3 has been tested for its ability to grow in three different media that select for traits normally expressed in adult liver: homocysteine medium to select for cystathionine synthase (CS), tyrosine-free medium for phenylalanine hydroxylase (PH), and ornithine medium for carbamylphosphate synthetase-I (CPS-I) and ornithine transcarbamylase (OTC). In no case were the cells immediately capable of bulk growth, showing that all these traits were in some degree deficient. However, the cultures in homocysteine medium and in tyrosine-free medium both gave rise, spontaneously, to growing clones with frequencies of approximately 10(-3) and 10(-5), respectively. The deficiencies of CS and PH were accordingly excluded from further study, in view of their inherent instability. In contrast, no colonies ever formed in ornithine medium. Though neither CPS-I nor OTC were detectable in stock BWTG3 cells, it was found that CPS-I was readily inducible by hormones. The deficiency of OTC, however, appeared to be totally stable showing no reversion in response either to hormones or to azacytidine treatment. This deficiency was investigated by fusing the hepatoma to OTC+ liver cells prepared from normal or sparse-fur (spf) mice. Sparse-fur mice were used because their OTC is mutant and has a distinctive pH-dependence. OTC+ hybrids were readily produced, without the need for any specific selection for OTC, and, in one case at least, with only minimal chromosome segregation. In all the OTC+ hybrids made with spf cells, there was clear reactivation of the wild-type, hepatoma-derived OTC gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Are V1 Simple Cells Optimized for Visual Occlusions? A Comparative Study

PubMed Central

Bornschein, Jörg; Henniges, Marc; Lücke, Jörg

2013-01-01

Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of ‘globular’ receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of ‘globular’ fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of ‘globular’ fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of ‘globular’ fields well. Our computational study, therefore, suggests that ‘globular’ fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex. PMID:23754938

Metabolic enzymes in glial cells of the honeybee brain and their associations with aging, starvation and food response.

PubMed

Shah, Ashish K; Kreibich, Claus D; Amdam, Gro V; Münch, Daniel

2018-01-01

The honey bee has been extensively studied as a model for neuronal circuit and memory function and more recently has emerged as an unconventional model in biogerontology. Yet, the detailed knowledge of neuronal processing in the honey bee brain contrasts with the very sparse information available on glial cells. In other systems glial cells are involved in nutritional homeostasis, detoxification, and aging. These glial functions have been linked to metabolic enzymes, such as glutamine synthetase and glycogen phosphorylase. As a step in identifying functional roles and potential differences among honey bee glial types, we examined the spatial distribution of these enzymes and asked if enzyme abundance is associated with aging and other processes essential for survival. Using immunohistochemistry and confocal laser microscopy we demonstrate that glutamine synthetase and glycogen phosphorylase are abundant in glia but appear to co-localize with different glial sub-types. The overall spatial distribution of both enzymes was not homogenous and differed markedly between different neuropiles and also within each neuropil. Using semi-quantitative Western blotting we found that rapid aging, typically observed in shortest-lived worker bees (foragers), was associated with declining enzyme levels. Further, we found enzyme abundance changes after severe starvation stress, and that glutamine synthetase is associated with food response. Together, our data indicate that aging and nutritional physiology in bees are linked to glial specific metabolic enzymes. Enzyme specific localization patterns suggest a functional differentiation among identified glial types.

Tonic Inhibitory Control of Dentate Gyrus Granule Cells by α5-Containing GABAA Receptors Reduces Memory Interference.

PubMed

Engin, Elif; Zarnowska, Ewa D; Benke, Dietmar; Tsvetkov, Evgeny; Sigal, Maksim; Keist, Ruth; Bolshakov, Vadim Y; Pearce, Robert A; Rudolph, Uwe

2015-10-07

Interference between similar or overlapping memories formed at different times poses an important challenge on the hippocampal declarative memory system. Difficulties in managing interference are at the core of disabling cognitive deficits in neuropsychiatric disorders. Computational models have suggested that, in the normal brain, the sparse activation of the dentate gyrus granule cells maintained by tonic inhibitory control enables pattern separation, an orthogonalization process that allows distinct representations of memories despite interference. To test this mechanistic hypothesis, we generated mice with significantly reduced expression of the α5-containing GABAA (α5-GABAARs) receptors selectively in the granule cells of the dentate gyrus (α5DGKO mice). α5DGKO mice had reduced tonic inhibition of the granule cells without any change in fast phasic inhibition and showed increased activation in the dentate gyrus when presented with novel stimuli. α5DGKO mice showed impairments in cognitive tasks characterized by high interference, without any deficiencies in low-interference tasks, suggesting specific impairment of pattern separation. Reduction of fast phasic inhibition in the dentate gyrus through granule cell-selective knock-out of α2-GABAARs or the knock-out of the α5-GABAARs in the downstream CA3 area did not detract from pattern separation abilities, which confirms the anatomical and molecular specificity of the findings. In addition to lending empirical support to computational hypotheses, our findings have implications for the treatment of interference-related cognitive symptoms in neuropsychiatric disorders, particularly considering the availability of pharmacological agents selectively targeting α5-GABAARs. Interference between similar memories poses a significant limitation on the hippocampal declarative memory system, and impaired interference management is a cognitive symptom in many disorders. Thus, understanding mechanisms of successful interference management or processes that can lead to interference-related memory problems has high theoretical and translational importance. This study provides empirical evidence that tonic inhibition in the dentate gyrus (DG), which maintains sparseness of neuronal activation in the DG, is essential for management of interference. The specificity of findings to tonic, but not faster, more transient types of neuronal inhibition and to the DG, but not the neighboring brain areas, is presented through control experiments. Thus, the findings link interference management to a specific mechanism, proposed previously by computational models. Copyright © 2015 the authors 0270-6474/15/3513699-15$15.00/0.

Space radiation effects on plant and mammalian cells

NASA Astrophysics Data System (ADS)

Arena, C.; De Micco, V.; Macaeva, E.; Quintens, R.

2014-11-01

The study of the effects of ionizing radiation on organisms is related to different research aims. The current review emphasizes the studies on the effects of different doses of sparsely and densely ionizing radiation on living organisms, with the final purpose of highlighting specific and common effects of space radiation in mammals and plants. This topic is extremely relevant in the context of radiation protection from space environment. The response of different organisms to ionizing radiation depends on the radiation quality/dose and/or the intrinsic characteristics of the living system. Macromolecules, in particular DNA, are the critical targets of radiation, even if there is a strong difference between damages encountered by plant and mammalian cells. The differences in structure and metabolism between the two cell types are responsible for the higher resistance of the plant cell compared with its animal counterpart. In this review, we report some recent findings from studies performed in Space or on Earth, simulating space-like levels of radiation with ground-based facilities, to understand the effect of ionizing radiation on mammalian and plant cells. In particular, our attention is focused on genetic alterations and repair mechanisms in mammalian cells and on structures and mechanisms conferring radioresistance to plant cells.

Beauty is in the efficient coding of the beholder.

PubMed

Renoult, Julien P; Bovet, Jeanne; Raymond, Michel

2016-03-01

Sexual ornaments are often assumed to be indicators of mate quality. Yet it remains poorly known how certain ornaments are chosen before any coevolutionary race makes them indicative. Perceptual biases have been proposed to play this role, but known biases are mostly restricted to a specific taxon, which precludes evaluating their general importance in sexual selection. Here we identify a potentially universal perceptual bias in mate choice. We used an algorithm that models the sparseness of the activity of simple cells in the primary visual cortex (or V1) of humans when coding images of female faces. Sparseness was found positively correlated with attractiveness as rated by men and explained up to 17% of variance in attractiveness. Because V1 is adapted to process signals from natural scenes, in general, not faces specifically, our results indicate that attractiveness for female faces is influenced by a visual bias. Sparseness and more generally efficient neural coding are ubiquitous, occurring in various animals and sensory modalities, suggesting that the influence of efficient coding on mate choice can be widespread in animals.

Structured sparse linear graph embedding.

PubMed

Wang, Haixian

2012-03-01

Subspace learning is a core issue in pattern recognition and machine learning. Linear graph embedding (LGE) is a general framework for subspace learning. In this paper, we propose a structured sparse extension to LGE (SSLGE) by introducing a structured sparsity-inducing norm into LGE. Specifically, SSLGE casts the projection bases learning into a regression-type optimization problem, and then the structured sparsity regularization is applied to the regression coefficients. The regularization selects a subset of features and meanwhile encodes high-order information reflecting a priori structure information of the data. The SSLGE technique provides a unified framework for discovering structured sparse subspace. Computationally, by using a variational equality and the Procrustes transformation, SSLGE is efficiently solved with closed-form updates. Experimental results on face image show the effectiveness of the proposed method. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mesosecrin: a secreted glycoprotein produced in abundance by human mesothelial, endothelial, and kidney epithelial cells in culture

PubMed Central

1987-01-01

Human mesothelial cells, endothelial cells, and type II kidney epithelial cells growing in culture devote approximately 3% of their total protein synthesis to the production of an Mr approximately 46-kD, pI 7.1, secreted glycoprotein (designated Sp46). Fibroblasts make about 1/10th as much Sp46 as these cell types, and their synthesis is dependent upon hydrocortisone. Keratinocytes, urothelial cells, conjunctival epithelial cells, and mammary epithelial cells do not make detectable amounts of Sp46. Mesothelial cells secrete Sp46 onto the substratum, and from there it is subsequently released into the medium. Immunofluorescence analysis using specific antisera discloses that Sp46 is deposited beneath cells as a fine coating on the substratum. In sparse cultures, Sp46 is detected in trails behind motile cells. In contrast, secreted fibronectin coalesces into fibers, most of which remain in contact with and on top of the cells; thus Sp46 does not preferentially bind to fibronectin. About 6 kD of the mass of human Sp46 is N-linked oligosaccharide, which is terminally sialated before secretion. Sp46 has a low glycine content, indicating that it is not a collagenlike protein. Its NH2-terminal sequence over the first 40 amino acids does not resemble any protein for which sequence information is available. Sp46 appears to be a novel extracellular glycoprotein, high- level constitutive expression of which is restricted to mesoderm- derived epithelial and endothelial cells. We therefore propose for it the name "mesosecrin." PMID:3543023

Enteroendocrine K and L cells in healthy and type 2 diabetic individuals.

PubMed

Jorsal, Tina; Rhee, Nicolai A; Pedersen, Jens; Wahlgren, Camilla D; Mortensen, Brynjulf; Jepsen, Sara L; Jelsing, Jacob; Dalbøge, Louise S; Vilmann, Peter; Hassan, Hazem; Hendel, Jakob W; Poulsen, Steen S; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

2018-02-01

Enteroendocrine K and L cells are pivotal in regulating appetite and glucose homeostasis. Knowledge of their distribution in humans is sparse and it is unknown whether alterations occur in type 2 diabetes. We aimed to evaluate the distribution of enteroendocrine K and L cells and relevant prohormone-processing enzymes (using immunohistochemical staining), and to evaluate the mRNA expression of the corresponding genes along the entire intestinal tract in individuals with type 2 diabetes and healthy participants. In this cross-sectional study, 12 individuals with type 2 diabetes and 12 age- and BMI-matched healthy individuals underwent upper and lower double-balloon enteroscopy with mucosal biopsy retrieval from approximately every 30 cm of the small intestine and from seven specific anatomical locations in the large intestine. Significantly different densities for cells positive for chromogranin A (CgA), glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, peptide YY, prohormone convertase (PC) 1/3 and PC2 were observed along the intestinal tract. The expression of CHGA did not vary along the intestinal tract, but the mRNA expression of GCG, GIP, PYY, PCSK1 and PCSK2 differed along the intestinal tract. Lower counts of CgA-positive and PC1/3-positive cells, respectively, were observed in the small intestine of individuals with type 2 diabetes compared with healthy participants. In individuals with type 2 diabetes compared with healthy participants, the expression of GCG and PYY was greater in the colon, while the expression of GIP and PCSK1 was greater in the small intestine and colon, and the expression of PCSK2 was greater in the small intestine. Our findings provide a detailed description of the distribution of enteroendocrine K and L cells and the expression of their products in the human intestinal tract and demonstrate significant differences between individuals with type 2 diabetes and healthy participants. NCT03044860.

Down-regulation of E-cadherin and catenins in human pituitary growth hormone-producing adenomas.

PubMed

Sano, Toshiaki; Rong, Qian Zhi; Kagawa, Noriko; Yamada, Shozo

2004-01-01

Growth hormone (GH)-producing pituitary adenomas can be ultrastructurally divided into two major types: densely granulated and sparsely granulated. The latter type of adenoma characteristically exhibits globular accumulations of cytokeratin filaments known as fibrous bodies, which are immunohistochemically identifiable as juxtanuclear dot-like immunoreactivity. We hypothesize that the formation of fibrous body might be related to dysfunction of adhesion molecules, because of the functional relationship between intermediate filaments and the cadherin-catenin complex and frequent observation of loss of cohesiveness of the adenoma cells. Our recent immunohistochemical study showed that expression of E-cadherin and its undercoat proteins, alpha-, beta- and gamma-catenin, in GH cell adenomas with prominent fibrous bodies was significantly reduced compared with GH cell adenomas without fibrous bodies and the normal adenohypophysial cells. Although no mutation of exon 3 of the beta-catenin gene was found in any GH cell adenomas with fibrous bodies, methylation-specific polymerase chain reaction analysis revealed that the E-cadherin promoter region was methylated in 37.5% of these adenomas, two of which displayed total methylation, but not in GH cell adenomas without fibrous bodies. We conclude that the decreased expression of the E-cadherin-catenin complex and methylation of the E-cadherin gene promoter region are events associated with the formation of fibrous bodies in GH cell adenomas. It remains to be clarified to explain the mechanism by which down-regulation of adhesion molecules is involved in the abnormal assembly of intermediate filaments.

Topography and behavior of Sertoli cells in sparse culture during the transitional remodeling phase.

PubMed

Tung, P S; Choi, A H; Fritz, I B

1988-01-01

We report observations on the behavior of Sertoli cells in sparse culture during the period from the time of plating to the time of initial confluence (the transitional remodeling phase). Changes in shape, structure, and polarity of cells, as well as changes in migration patterns and cell-cell association patterns, have been followed during the transitional remodeling phase with the aid of topographical markers. These markers are based upon differences between ultrastructural features of the basolateral and apicolateral surfaces. The basolateral surface is characterized by plasmalemmal blebs, whereas the apicolateral surface is characterized by filopodial extensions. Structural differences observed in situ remain evident in Sertoli cells isolated by sequential enzymatic treatments that are described. Another marker is provided by laminin-binding sites, which are detected exclusively on the blebbed, basolateral surfaces of freshly prepared Sertoli cell aggregates. The orientation described is sustained during the initial radial migration of Sertoli cells explanted on uncoated glass coverslips. Under these conditions, blebs are detected only on the dorsal surfaces, and filopodial extensions are evident only on the ventral surfaces. In contrast, Sertoli cells sparsely plated on a reconstituted basement membrane (air-dried Matrigel) migrate rapidly, display an extraordinary capacity to form elaborate cytoplasmic extensions for cell-cell and cell-substratum contacts, and readily retract blebs and filopodial extensions. These cells do not form mosaic borders, whereas cells plated on uncoated glass do form a monolayer with mosaic-like borders. Cells sparsely seeded on gelated Matrigel migrate preferentially at gaps between adjacent cell explants, and develop a compact cell-cell association pattern. These cells display few, if any, cytoplasmic extensions. We compare the behavior of Sertoli cells sparsely plated on Matrigel with the behavior of Sertoli cells in situ during different stages of development.

Transmission and scanning electron microscopy study of the characteristics and morphology of pericytes and novel desmin-immunopositive perivascular cells before and after castration in rat anterior pituitary gland.

PubMed

Jindatip, Depicha; Fujiwara, Ken; Kouki, Tom; Yashiro, Takashi

2012-09-01

Pericytes are perivascular cells associated with microcirculation. Typically, they are localized close to the capillary wall, underneath the basement membrane, and have sparse cytoplasm and poorly developed cell organelles. However, the specific properties of pericytes vary by organ and the conditions within organs. We recently demonstrated that pericytes in rat anterior pituitary gland produce type I and III collagens. The present study attempted to determine the morphological characteristics of these pituitary pericytes. Castrated rats were used as a model of hormonal and vascular changes in the gland. Pericytes, as determined by desmin immunohistochemistry, were more numerous and stained more intensely in castrated rats. Transmission electron microscopy revealed that pituitary pericytes displayed the typical characteristics of pericytes. In pituitary sections from castrated rats, the Golgi apparatus of pericytes was well developed and the rough endoplasmic reticulum was elongated. Additionally, scanning electron microscopy revealed four pericyte shapes: oval, elongate, triangular, and multiangular. As compared with normal rats, the proportion of oval pericytes was lower, and the proportions of the other three shapes were higher, in castrated rats. These results suggest that pericytes change their fine structure and cell shape in response to hormonal and vascular changes in the anterior pituitary gland. In addition, a novel type of perivascular cell was found by desmin immunoelectron microscopy. The morphological properties of these cells were dissimilar to those of pericytes. The cells were localized in the perivascular space, had no basement membrane, and contained dilated rough endoplasmic reticulum. This new cell type will require further study of its origin and characteristics.

Inactivation of the tumor suppressor gene on 11q13 in brothers with familial acrogigantism without multiple endocrine neoplasia type 1.

PubMed

Yamada, S; Yoshimoto, K; Sano, T; Takada, K; Itakura, M; Usui, M; Teramoto, A

1997-01-01

Two of three brothers (the second and third brothers) and their uncle (their mother's brother) presented acrogigantism without multiple endocrine neoplasia type 1 (MEN 1). An invasive macroadenoma was found in the second brother, and it was histologically confirmed as a sparsely granulated GH cell adenoma. Two distinct microadenomas were found in the third brother, and these were histologically diagnosed as a mixed GH cell and PRL cell adenoma and a sparsely granulated GH cell adenoma, respectively. The loss of heterozygosity (LOH) was analyzed in two adenomas (GH cell adenoma from the second brother and a mixed GH cell and PRL cell adenoma from the third brother) by determining microsatellite polymorphisms of DNAs from tumors and patients' leukocytes. The LOH was found on the chromosome 11q13, whereas LOH was not detected on 1p31-36, 2p, 3p, 4, 5, 6p, 7, 8, 9p21-22, 12p, and 19q13 in both pituitary adenomas examined. The haplotype analysis showed that the same haplotype on 11q13 was found in their mother and the unaffected first brother as well as in the affected uncle and two brothers. The deleted alleles on chromosome 11q13 in the tumors of two affected brothers were, however, restricted to those transmitted from their unaffected father. These data suggest that inactivation of the MEN 1 gene or other tumor suppressor genes on chromosome 11q13 plays an important role for the development of our familial acrogigantism without MEN 1.

Classification of melanoma lesions using sparse coded features and random forests

NASA Astrophysics Data System (ADS)

Rastgoo, Mojdeh; Lemaître, Guillaume; Morel, Olivier; Massich, Joan; Garcia, Rafael; Meriaudeau, Fabrice; Marzani, Franck; Sidibé, Désiré

2016-03-01

Malignant melanoma is the most dangerous type of skin cancer, yet it is the most treatable kind of cancer, conditioned by its early diagnosis which is a challenging task for clinicians and dermatologists. In this regard, CAD systems based on machine learning and image processing techniques are developed to differentiate melanoma lesions from benign and dysplastic nevi using dermoscopic images. Generally, these frameworks are composed of sequential processes: pre-processing, segmentation, and classification. This architecture faces mainly two challenges: (i) each process is complex with the need to tune a set of parameters, and is specific to a given dataset; (ii) the performance of each process depends on the previous one, and the errors are accumulated throughout the framework. In this paper, we propose a framework for melanoma classification based on sparse coding which does not rely on any pre-processing or lesion segmentation. Our framework uses Random Forests classifier and sparse representation of three features: SIFT, Hue and Opponent angle histograms, and RGB intensities. The experiments are carried out on the public PH2 dataset using a 10-fold cross-validation. The results show that SIFT sparse-coded feature achieves the highest performance with sensitivity and specificity of 100% and 90.3% respectively, with a dictionary size of 800 atoms and a sparsity level of 2. Furthermore, the descriptor based on RGB intensities achieves similar results with sensitivity and specificity of 100% and 71.3%, respectively for a smaller dictionary size of 100 atoms. In conclusion, dictionary learning techniques encode strong structures of dermoscopic images and provide discriminant descriptors.

Social biases determine spatiotemporal sparseness of ciliate mating heuristics.

PubMed

Clark, Kevin B

2012-01-01

Ciliates become highly social, even displaying animal-like qualities, in the joint presence of aroused conspecifics and nonself mating pheromones. Pheromone detection putatively helps trigger instinctual and learned courtship and dominance displays from which social judgments are made about the availability, compatibility, and fitness representativeness or likelihood of prospective mates and rivals. In earlier studies, I demonstrated the heterotrich Spirostomum ambiguum improves mating competence by effecting preconjugal strategies and inferences in mock social trials via behavioral heuristics built from Hebbian-like associative learning. Heuristics embody serial patterns of socially relevant action that evolve into ordered, topologically invariant computational networks supporting intra- and intermate selection. S. ambiguum employs heuristics to acquire, store, plan, compare, modify, select, and execute sets of mating propaganda. One major adaptive constraint over formation and use of heuristics involves a ciliate's initial subjective bias, responsiveness, or preparedness, as defined by Stevens' Law of subjective stimulus intensity, for perceiving the meaningfulness of mechanical pressures accompanying cell-cell contacts and additional perimating events. This bias controls durations and valences of nonassociative learning, search rates for appropriate mating strategies, potential net reproductive payoffs, levels of social honesty and deception, successful error diagnosis and correction of mating signals, use of insight or analysis to solve mating dilemmas, bioenergetics expenditures, and governance of mating decisions by classical or quantum statistical mechanics. I now report this same social bias also differentially affects the spatiotemporal sparseness, as measured with metric entropy, of ciliate heuristics. Sparseness plays an important role in neural systems through optimizing the specificity, efficiency, and capacity of memory representations. The present findings indicate sparseness performs a similar function in single aneural cells by tuning the size and density of encoded computational architectures useful for decision making in social contexts.

Social biases determine spatiotemporal sparseness of ciliate mating heuristics

PubMed Central

2012-01-01

Ciliates become highly social, even displaying animal-like qualities, in the joint presence of aroused conspecifics and nonself mating pheromones. Pheromone detection putatively helps trigger instinctual and learned courtship and dominance displays from which social judgments are made about the availability, compatibility, and fitness representativeness or likelihood of prospective mates and rivals. In earlier studies, I demonstrated the heterotrich Spirostomum ambiguum improves mating competence by effecting preconjugal strategies and inferences in mock social trials via behavioral heuristics built from Hebbian-like associative learning. Heuristics embody serial patterns of socially relevant action that evolve into ordered, topologically invariant computational networks supporting intra- and intermate selection. S. ambiguum employs heuristics to acquire, store, plan, compare, modify, select, and execute sets of mating propaganda. One major adaptive constraint over formation and use of heuristics involves a ciliate’s initial subjective bias, responsiveness, or preparedness, as defined by Stevens’ Law of subjective stimulus intensity, for perceiving the meaningfulness of mechanical pressures accompanying cell-cell contacts and additional perimating events. This bias controls durations and valences of nonassociative learning, search rates for appropriate mating strategies, potential net reproductive payoffs, levels of social honesty and deception, successful error diagnosis and correction of mating signals, use of insight or analysis to solve mating dilemmas, bioenergetics expenditures, and governance of mating decisions by classical or quantum statistical mechanics. I now report this same social bias also differentially affects the spatiotemporal sparseness, as measured with metric entropy, of ciliate heuristics. Sparseness plays an important role in neural systems through optimizing the specificity, efficiency, and capacity of memory representations. The present findings indicate sparseness performs a similar function in single aneural cells by tuning the size and density of encoded computational architectures useful for decision making in social contexts. PMID:22482001

Active inhibition of herpes simplex virus type 1-induced cell fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bzik, D.J.; Person, S.; Read, G.S.

1982-01-01

Previous studies have demonstrated that syn mutant-infected cells fuse less well with nonsyncytial virus-infected cells than with uninfected cells, a phenomenon defined as function inhibition. The present study characterizes the kinetics as well as the requirements for expression of fusion inhibition. Initially, the capacity of sparse syn mutant-infected cells to fuse with uninfected surrounding cells was determined throughout infection. Of seven syn mutants examined, including representatives with alterations in two different viral genes that affect cell fusion, all showed an increase in fusion capacity up to 12 hr after infection and a decrease at later times. Fusion inhibition was examinedmore » in experiments employing sparse syn20-infected cells which had been incubated to a maximum fusion capacity; it was shown that surrounding cells infected with KOS, the parent of syn20, began to inhibit fusion by the syn20-infected cells at about 4 hr after infection, and that the maximum ability to inhibit fusion was attained at about 6 hr after infection. The metabolic blocking agents actinomycin D (RNA), cycloheximide (protein), 2-deoxyglucose, and tunicamycin (glycoslyation of glycoproteins) all showed the ability to inhibit the expression of fusion inhibition by KOS-infected cells if added shortly after infection. It is concluded that fusion inhibition is an active process that requires the synthesis of RNA, proteins, and glycoproteins. 17 references, 3 figures, 2 tables.« less

Human primary mixed brain cultures: preparation, differentiation, characterization and application to neuroscience research.

PubMed

Ray, Balmiki; Chopra, Nipun; Long, Justin M; Lahiri, Debomoy K

2014-09-16

Culturing primary cortical neurons is an essential neuroscience technique. However, most cultures are derived from rodent brains and standard protocols for human brain cultures are sparse. Herein, we describe preparation, maintenance and major characteristics of a primary human mixed brain culture, including neurons, obtained from legally aborted fetal brain tissue. This approach employs standard materials and techniques used in the preparation of rodent neuron cultures, with critical modifications. This culture has distinct differences from rodent cultures. Specifically, a significant numbers of cells in the human culture are derived from progenitor cells, and the yield and survival of the cells grossly depend on the presence of bFGF. In the presence of bFGF, this culture can be maintained for an extended period. Abundant productions of amyloid-β, tau and proteins make this a powerful model for Alzheimer's research. The culture also produces glia and different sub-types of neurons. We provide a well-characterized methodology for human mixed brain cultures useful to test therapeutic agents under various conditions, and to carry forward mechanistic and translational studies for several brain disorders.

Sparse grid techniques for particle-in-cell schemes

NASA Astrophysics Data System (ADS)

Ricketson, L. F.; Cerfon, A. J.

2017-02-01

We propose the use of sparse grids to accelerate particle-in-cell (PIC) schemes. By using the so-called ‘combination technique’ from the sparse grids literature, we are able to dramatically increase the size of the spatial cells in multi-dimensional PIC schemes while paying only a slight penalty in grid-based error. The resulting increase in cell size allows us to reduce the statistical noise in the simulation without increasing total particle number. We present initial proof-of-principle results from test cases in two and three dimensions that demonstrate the new scheme’s efficiency, both in terms of computation time and memory usage.

Hierarchical patch-based co-registration of differently stained histopathology slides

NASA Astrophysics Data System (ADS)

Yigitsoy, Mehmet; Schmidt, Günter

2017-03-01

Over the past decades, digital pathology has emerged as an alternative way of looking at the tissue at subcellular level. It enables multiplexed analysis of different cell types at micron level. Information about cell types can be extracted by staining sections of a tissue block using different markers. However, robust fusion of structural and functional information from different stains is necessary for reproducible multiplexed analysis. Such a fusion can be obtained via image co-registration by establishing spatial correspondences between tissue sections. Spatial correspondences can then be used to transfer various statistics about cell types between sections. However, the multi-modal nature of images and sparse distribution of interesting cell types pose several challenges for the registration of differently stained tissue sections. In this work, we propose a co-registration framework that efficiently addresses such challenges. We present a hierarchical patch-based registration of intensity normalized tissue sections. Preliminary experiments demonstrate the potential of the proposed technique for the fusion of multi-modal information from differently stained digital histopathology sections.

Optogenetic stimulation of a hippocampal engram activates fear memory recall.

PubMed

Liu, Xu; Ramirez, Steve; Pang, Petti T; Puryear, Corey B; Govindarajan, Arvind; Deisseroth, Karl; Tonegawa, Susumu

2012-03-22

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.

Optogenetic stimulation of a hippocampal engram activates fear memory recall

PubMed Central

Liu, Xu; Ramirez, Steve; Pang, Petti T.; Puryear, Corey B.; Govindarajan, Arvind; Deisseroth, Karl; Tonegawa, Susumu

2012-01-01

A specific memory is thought to be encoded by a sparse population of neurons1,2. These neurons can be tagged during learning for subsequent identification3 and manipulation4,5,6. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, a critical question of sufficiency remains: can one elicit the behavioral output of a specific memory by directly activating a population of neurons that was active during learning? Here we show that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior. We labeled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2)7,8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear conditioned mice with cells labeled by EYFP instead of ChR2. Finally, activation of cells labeled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context-specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams. PMID:22441246

Sparse coding can predict primary visual cortex receptive field changes induced by abnormal visual input.

PubMed

Hunt, Jonathan J; Dayan, Peter; Goodhill, Geoffrey J

2013-01-01

Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory experience in visual development comes from receptive field changes in animals reared with abnormal visual input. However, most sparse coding accounts have considered only normal visual input and the development of monocular receptive fields. Here, we applied three sparse coding models to binocular receptive field development across six abnormal rearing conditions. In every condition, the changes in receptive field properties previously observed experimentally were matched to a similar and highly faithful degree by all the models, suggesting that early sensory development can indeed be understood in terms of an impetus towards sparsity. As previously predicted in the literature, we found that asymmetries in inter-ocular correlation across orientations lead to orientation-specific binocular receptive fields. Finally we used our models to design a novel stimulus that, if present during rearing, is predicted by the sparsity principle to lead robustly to radically abnormal receptive fields.

Sparse Coding Can Predict Primary Visual Cortex Receptive Field Changes Induced by Abnormal Visual Input

PubMed Central

Hunt, Jonathan J.; Dayan, Peter; Goodhill, Geoffrey J.

2013-01-01

Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory experience in visual development comes from receptive field changes in animals reared with abnormal visual input. However, most sparse coding accounts have considered only normal visual input and the development of monocular receptive fields. Here, we applied three sparse coding models to binocular receptive field development across six abnormal rearing conditions. In every condition, the changes in receptive field properties previously observed experimentally were matched to a similar and highly faithful degree by all the models, suggesting that early sensory development can indeed be understood in terms of an impetus towards sparsity. As previously predicted in the literature, we found that asymmetries in inter-ocular correlation across orientations lead to orientation-specific binocular receptive fields. Finally we used our models to design a novel stimulus that, if present during rearing, is predicted by the sparsity principle to lead robustly to radically abnormal receptive fields. PMID:23675290

Design principles of the sparse coding network and the role of “sister cells” in the olfactory system of Drosophila

PubMed Central

Zhang, Danke; Li, Yuanqing; Wu, Si; Rasch, Malte J.

2013-01-01

Sensory systems face the challenge to represent sensory inputs in a way to allow easy readout of sensory information by higher brain areas. In the olfactory system of the fly drosopohila melanogaster, projection neurons (PNs) of the antennal lobe (AL) convert a dense activation of glomeruli into a sparse, high-dimensional firing pattern of Kenyon cells (KCs) in the mushroom body (MB). Here we investigate the design principles of the olfactory system of drosophila in regard to the capabilities to discriminate odor quality from the MB representation and its robustness to different types of noise. We focus on understanding the role of highly correlated homotypic projection neurons (“sister cells”) found in the glomeruli of flies. These cells are coupled by gap-junctions and receive almost identical sensory inputs, but target randomly different KCs in MB. We show that sister cells might play a crucial role in increasing the robustness of the MB odor representation to noise. Computationally, sister cells thus might help the system to improve the generalization capabilities in face of noise without impairing the discriminability of odor quality at the same time. PMID:24167488

Role of tumbling in bacterial swarming

NASA Astrophysics Data System (ADS)

Sidortsov, Marina; Morgenstern, Yakov; Be'er, Avraham

2017-08-01

Typical wild-type bacteria swimming in sparse suspensions exhibit a movement pattern called "run and tumble," characterized by straight trajectories (runs) interspersed by shorter, random reorientation (tumbles). This is achieved by rotating their flagella counterclockwise, or clockwise, respectively. The chemotaxis signaling network operates in controlling the frequency of tumbles, enabling navigation toward or away from desired regions in the medium. In contrast, while in dense populations, flagellated bacteria exhibit collective motion and form large dynamic clusters, whirls, and jets, with intricate dynamics that is fundamentally different than trajectories of sparsely swimming cells. Although collectively swarming cells do change direction at the level of the individual cell, often exhibiting reversals, it has been suggested that chemotaxis does not play a role in multicellular colony expansion, but the change in direction stems from clockwise flagellar rotation. In this paper, the effects of cell rotor switching (i.e., the ability to tumble) and chemotaxis on the collective statistics of swarming bacteria are studied experimentally in wild-type Bacillus subtilis and two mutants—one that does not tumble and one that tumbles independently of the chemotaxis system. We show that while several of the parameters examined are similar between the strains, other collective and individual characteristics are significantly different. The results demonstrate that tumbling and/or flagellar directional rotor switching has an important role on the dynamics of swarming, and imply that swarming models of self-propelled rods that do not take tumbling and/or rotor switching into account may be oversimplified.

Projections of Somatosensory Cortex and Frontal Eye Fields onto Incertotectal Neurons in the Cat

PubMed Central

Perkins, Eddie; Warren, Susan; Lin, Rick C.-S.; May, Paul J.

2014-01-01

The goal of this study was to determine whether the input-output characteristics of the zona incerta (ZI) are appropriate for it to serve as a conduit for cortical control over saccade-related activity in the superior colliculus. The study utilized the neuronal tracers wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and biotinylated dextran amine (BDA) in the cat. Injections of WGA-HRP into primary somatosensory cortex (SI) revealed sparse, widespread nontopographic projections throughout ZI. In addition, region-specific areas of more intense termination were present in ventral ZI, although strict topography was not observed. In comparison, the frontal eye fields (FEF) also projected sparsely throughout ZI, but terminated more heavily, medially, along the border between the two sublaminae. Furthermore, retrogradely labeled incertocortical neurons were observed in both experiments. The relationship of these two cortical projections to incertotectal cells was also directly examined by retrogradely labeling incertotectal cells with WGA-HRP in animals that had also received cortical BDA injections. Labeled axonal arbors from both SI and FEF had thin, sparsely branched axons with numerous en passant boutons. They formed numerous close associations with the somata and dendrites of WGA-HRP-labeled incertotectal cells. In summary, these results indicate that both sensory and motor cortical inputs to ZI display similar morphologies and distributions. In addition, both display close associations with incertotectal cells, suggesting direct synaptic contact. From these data, we conclude that inputs from somatosensory and FEF cortex both play a role in controlling gaze-related activity in the superior colliculus by way of the inhibitory incertotectal projection. PMID:17083121

Sparse Coding of Natural Human Motion Yields Eigenmotions Consistent Across People

NASA Astrophysics Data System (ADS)

Thomik, Andreas; Faisal, A. Aldo

2015-03-01

Providing a precise mathematical description of the structure of natural human movement is a challenging problem. We use a data-driven approach to seek a generative model of movement capturing the underlying simplicity of spatial and temporal structure of behaviour observed in daily life. In perception, the analysis of natural scenes has shown that sparse codes of such scenes are information theoretic efficient descriptors with direct neuronal correlates. Translating from perception to action, we identify a generative model of movement generation by the human motor system. Using wearable full-hand motion capture, we measure the digit movement of the human hand in daily life. We learn a dictionary of ``eigenmotions'' which we use for sparse encoding of the movement data. We show that the dictionaries are generally well preserved across subjects with small deviations accounting for individuality of the person and variability in tasks. Further, the dictionary elements represent motions which can naturally describe hand movements. Our findings suggest the motor system can compose complex movement behaviours out of the spatially and temporally sparse activation of ``eigenmotion'' neurons, and is consistent with data on grasp-type specificity of specialised neurons in the premotor cortex. Andreas is supported by the Luxemburg Research Fund (1229297).

Cell-Autonomous Regulation of Dendritic Spine Density by PirB.

PubMed

Vidal, George S; Djurisic, Maja; Brown, Kiana; Sapp, Richard W; Shatz, Carla J

2016-01-01

Synapse density on cortical pyramidal neurons is modulated by experience. This process is highest during developmental critical periods, when mechanisms of synaptic plasticity are fully engaged. In mouse visual cortex, the critical period for ocular dominance (OD) plasticity coincides with the developmental pruning of synapses. At this time, mice lacking paired Ig-like receptor B (PirB) have excess numbers of dendritic spines on L5 neurons; these spines persist and are thought to underlie the juvenile-like OD plasticity observed in adulthood. Here we examine whether PirB is required specifically in excitatory neurons to exert its effect on dendritic spine and synapse density during the critical period. In mice with a conditional allele of PirB (PirB fl/fl ), PirB was deleted only from L2/3 cortical pyramidal neurons in vivo by timed in utero electroporation of Cre recombinase. Sparse mosaic expression of Cre produced neurons lacking PirB in a sea of wild-type neurons and glia. These neurons had significantly elevated dendritic spine density, as well as increased frequency of miniature EPSCs, suggesting that they receive a greater number of synaptic inputs relative to Cre - neighbors. The effect of cell-specific PirB deletion on dendritic spine density was not accompanied by changes in dendritic branching complexity or axonal bouton density. Together, results imply a neuron-specific, cell-autonomous action of PirB on synaptic density in L2/3 pyramidal cells of visual cortex. Moreover, they are consistent with the idea that PirB functions normally to corepress spine density and synaptic plasticity, thereby maintaining headroom for cells to encode ongoing experience-dependent structural change throughout life.

Proliferating fibroblasts and HeLa cells co-cultured in vitro reciprocally influence growth patterns, protein expression, chromatin features and cell survival.

PubMed

Delinasios, John G; Angeli, Flora; Koumakis, George; Kumar, Shant; Kang, Wen-Hui; Sica, Gigliola; Iacopino, Fortunata; Lama, Gina; Lamprecht, Sergio; Sigal-Batikoff, Ina; Tsangaris, George T; Farfarelos, Christos D; Farfarelos, Maria C; Vairaktaris, Eleftherios; Vassiliou, Stavros; Delinasios, George J

2015-04-01

to identify biological interactions between proliferating fibroblasts and HeLa cells in vitro. Fibroblasts were isolated from both normal and tumour human tissues. Coverslip co-cultures of HeLa and fibroblasts in various ratios with medium replacement every 48 h were studied using fixed cell staining with dyes such as Giemsa and silver staining, with immunochemistry for Ki-67 and E-cadherin, with dihydrofolate reductase (DHFR) enzyme reaction, as well as live cell staining for non-specific esterases and lipids. Other techniques included carmine cell labeling, autoradiography and apoptosis assessment. Under conditions of feeding and cell: cell ratios allowing parallel growth of human fibroblasts and HeLa cells, co-cultured for up to 20 days, a series of phenomena occur consecutively: profound affinity between the two cell types and exchange of small molecules; encircling of the HeLa colonies by the fibroblasts and enhanced growth of both cell types at their contact areas; expression of carbonic anhydrase in both cell types and high expression of non-specific esterases and cytoplasmic argyrophilia in the surrounding fibroblasts; intense production and secretion of lipid droplets by the surrounding fibroblasts; development of a complex net of argyrophilic projections of the fibroblasts; E-cadherin expression in the HeLa cells; from the 10th day onwards, an increasing detachment of batches of HeLa cells at the peripheries of colonies and appearance of areas with many multi-nucleated and apoptotic HeLa cells, and small HeLa fragments; from the 17th day, appearance of fibroblasts blocked at the G2-M phase. Co-cultures at approximately 17-20 days display a cell-cell fight with foci of (a) sparse growth of both cell types, (b) overgrowth of the fibroblasts and (c) regrowth of HeLa in small colonies. These results indicate that during their interaction with HeLa cells in vitro, proliferating fibroblasts can be activated against HeLa. This type of activation is not observed if fibroblast proliferation is blocked by contact inhibition of growth at confluency, or by omitting replacement of the nutrient medium. The present observations show that: (a) interaction between proliferating fibroblasts and HeLa cells in vitro drastically influences each other's protein expression, growth pattern, chromatin features and survival; (b) these functions depend on the fibroblast/HeLa ratio, cell topology (cell-cell contact and the architectural pattern developed during co-culture) and frequent medium change, as prerequisites for fibroblast proliferation; (c) this co-culture model is useful in the study of the complex processes within the tumour microenvironment, as well as the in vitro reproduction and display of several phenomena conventionally seen in tumour cytological sections, such as desmoplasia, apoptosis, nuclear abnormalities; and (d) overgrown fibroblasts adhering to the boundaries of HeLa colonies produce and secrete lipid droplets. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Optimization of sparse matrix-vector multiplication on emerging multicore platforms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, Samuel; Oliker, Leonid; Vuduc, Richard

2007-01-01

We are witnessing a dramatic change in computer architecture due to the multicore paradigm shift, as every electronic device from cell phones to supercomputers confronts parallelism of unprecedented scale. To fully unleash the potential of these systems, the HPC community must develop multicore specific optimization methodologies for important scientific computations. In this work, we examine sparse matrix-vector multiply (SpMV) - one of the most heavily used kernels in scientific computing - across a broad spectrum of multicore designs. Our experimental platform includes the homogeneous AMD dual-core and Intel quad-core designs, the heterogeneous STI Cell, as well as the first scientificmore » study of the highly multithreaded Sun Niagara2. We present several optimization strategies especially effective for the multicore environment, and demonstrate significant performance improvements compared to existing state-of-the-art serial and parallel SpMV implementations. Additionally, we present key insights into the architectural tradeoffs of leading multicore design strategies, in the context of demanding memory-bound numerical algorithms.« less

Viscoelastic properties of normal and cancerous human breast cells are affected differently by contact to adjacent cells.

PubMed

Schierbaum, Nicolas; Rheinlaender, Johannes; Schäffer, Tilman E

2017-06-01

Malignant transformation drastically alters the mechanical properties of the cell and its response to the surrounding cellular environment. We studied the influence of the physical contact between adjacent cells in an epithelial monolayer on the viscoelastic behavior of normal MCF10A, non-invasive cancerous MCF7, and invasive cancerous MDA-MB-231 human breast cells. Using an atomic force microscopy (AFM) imaging technique termed force clamp force mapping (FCFM) to record images of the viscoelastic material properties, we found that normal MCF10A cells are stiffer and have a lower fluidity at confluent than at sparse density. Contrarily, cancerous MCF7 and MDA-MB-231 cells do not stiffen and do not decrease their fluidity when progressing from sparse to confluent density. The behavior of normal MCF10A cells appears to be governed by the formation of stable cell-cell contacts, because their disruption with a calcium-chelator (EGTA) causes the stiffness and fluidity values to return to those at sparse density. In contrast, EGTA-treatment of MCF7 and MDA-MB-231 cells does not change their viscoelastic properties. Confocal fluorescence microscopy showed that the change of the viscoelastic behavior in MCF10A cells when going from sparse to confluent density is accompanied by a remodeling of the actin cytoskeleton into thick stress fiber bundles, while in MCF7 and MDA-MB-231 cells the actin cytoskeleton is only composed of thin and short fibers, regardless of cell density. While the observed behavior of normal MCF10A cells might be crucial for providing mechanical stability and thus in turn integrity of the epithelial monolayer, the dysregulation of this behavior in cancerous MCF7 and MDA-MB-231 cells is possibly a central aspect of cancer progression in the epithelium. We measured the viscoelastic properties of normal and cancerous human breast epithelial cells in different states of confluency using atomic force microscopy. We found that confluent normal cells are stiffer and have lower fluidity than sparse normal cells, which appears to be governed by the formation of cell-cell contacts. Contrarily, confluent cancer cells do not stiffen and not have a decreased fluidity compared to sparse cancer cells and their viscoelastic properties are independent of cell-cell contact formation. While the observed behavior of normal cells appears to be crucial for providing the mechanical stability and therefore the integrity of the epithelial monolayer, the dysregulation of this behavior in cancer cells might be a central aspect of early stage cancer progression and metastasis in the epithelium. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Robust Cell Detection of Histopathological Brain Tumor Images Using Sparse Reconstruction and Adaptive Dictionary Selection

PubMed Central

Su, Hai; Xing, Fuyong; Yang, Lin

2016-01-01

Successful diagnostic and prognostic stratification, treatment outcome prediction, and therapy planning depend on reproducible and accurate pathology analysis. Computer aided diagnosis (CAD) is a useful tool to help doctors make better decisions in cancer diagnosis and treatment. Accurate cell detection is often an essential prerequisite for subsequent cellular analysis. The major challenge of robust brain tumor nuclei/cell detection is to handle significant variations in cell appearance and to split touching cells. In this paper, we present an automatic cell detection framework using sparse reconstruction and adaptive dictionary learning. The main contributions of our method are: 1) A sparse reconstruction based approach to split touching cells; 2) An adaptive dictionary learning method used to handle cell appearance variations. The proposed method has been extensively tested on a data set with more than 2000 cells extracted from 32 whole slide scanned images. The automatic cell detection results are compared with the manually annotated ground truth and other state-of-the-art cell detection algorithms. The proposed method achieves the best cell detection accuracy with a F1 score = 0.96. PMID:26812706

Mechanical stretch triggers rapid epithelial cell division through Piezo1.

PubMed

Gudipaty, S A; Lindblom, J; Loftus, P D; Redd, M J; Edes, K; Davey, C F; Krishnegowda, V; Rosenblatt, J

2017-03-02

Despite acting as a barrier for the organs they encase, epithelial cells turn over at some of the fastest rates in the body. However, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How does the number of dying cells match those dividing to maintain constant numbers? When epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. However, it is unclear how epithelial cell division is controlled to balance cell death at the steady state. Here we show that mammalian epithelial cell division occurs in regions of low cell density where cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the Piezo1 channel. To stimulate cell division, stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at the steady state, the type of mechanical force controls the outcome: stretch induces cell division, whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion and apoptosis in crowded regions and cell division in sparse regions.

Analysis of Monte Carlo accelerated iterative methods for sparse linear systems: Analysis of Monte Carlo accelerated iterative methods for sparse linear systems

DOE PAGES

Benzi, Michele; Evans, Thomas M.; Hamilton, Steven P.; ...

2017-03-05

Here, we consider hybrid deterministic-stochastic iterative algorithms for the solution of large, sparse linear systems. Starting from a convergent splitting of the coefficient matrix, we analyze various types of Monte Carlo acceleration schemes applied to the original preconditioned Richardson (stationary) iteration. We expect that these methods will have considerable potential for resiliency to faults when implemented on massively parallel machines. We also establish sufficient conditions for the convergence of the hybrid schemes, and we investigate different types of preconditioners including sparse approximate inverses. Numerical experiments on linear systems arising from the discretization of partial differential equations are presented.

Optimal degrees of synaptic connectivity

PubMed Central

Litwin-Kumar, Ashok; Harris, Kameron Decker; Axel, Richard; Sompolinsky, Haim; Abbott, L. F.

2017-01-01

Summary Synaptic connectivity varies widely across neuronal types. Cerebellar granule cells receive five orders of magnitude fewer inputs than the Purkinje cells they innervate, and cerebellum-like circuits including the insect mushroom body also exhibit large divergences in connectivity. In contrast, the number of inputs per neuron in cerebral cortex is more uniform and large. We investigate how the dimension of a representation formed by a population of neurons depends on how many inputs they each receive and what this implies for learning associations. Our theory predicts that the dimensions of the cerebellar granule-cell and Drosophila Kenyon-cell representations are maximized at degrees of synaptic connectivity that match those observed anatomically, showing that sparse connectivity is sometimes superior to dense connectivity. When input synapses are subject to supervised plasticity, however, dense wiring becomes advantageous, suggesting that the type of plasticity exhibited by a set of synapses is a major determinant of connection density. PMID:28215558

Distant failure prediction for early stage NSCLC by analyzing PET with sparse representation

NASA Astrophysics Data System (ADS)

Hao, Hongxia; Zhou, Zhiguo; Wang, Jing

2017-03-01

Positron emission tomography (PET) imaging has been widely explored for treatment outcome prediction. Radiomicsdriven methods provide a new insight to quantitatively explore underlying information from PET images. However, it is still a challenging problem to automatically extract clinically meaningful features for prognosis. In this work, we develop a PET-guided distant failure predictive model for early stage non-small cell lung cancer (NSCLC) patients after stereotactic ablative radiotherapy (SABR) by using sparse representation. The proposed method does not need precalculated features and can learn intrinsically distinctive features contributing to classification of patients with distant failure. The proposed framework includes two main parts: 1) intra-tumor heterogeneity description; and 2) dictionary pair learning based sparse representation. Tumor heterogeneity is initially captured through anisotropic kernel and represented as a set of concatenated vectors, which forms the sample gallery. Then, given a test tumor image, its identity (i.e., distant failure or not) is classified by applying the dictionary pair learning based sparse representation. We evaluate the proposed approach on 48 NSCLC patients treated by SABR at our institute. Experimental results show that the proposed approach can achieve an area under the characteristic curve (AUC) of 0.70 with a sensitivity of 69.87% and a specificity of 69.51% using a five-fold cross validation.

Evidence for sparse synergies in grasping actions.

PubMed

Prevete, Roberto; Donnarumma, Francesco; d'Avella, Andrea; Pezzulo, Giovanni

2018-01-12

Converging evidence shows that hand-actions are controlled at the level of synergies and not single muscles. One intriguing aspect of synergy-based action-representation is that it may be intrinsically sparse and the same synergies can be shared across several distinct types of hand-actions. Here, adopting a normative angle, we consider three hypotheses for hand-action optimal-control: sparse-combination hypothesis (SC) - sparsity in the mapping between synergies and actions - i.e., actions implemented using a sparse combination of synergies; sparse-elements hypothesis (SE) - sparsity in synergy representation - i.e., the mapping between degrees-of-freedom (DoF) and synergies is sparse; double-sparsity hypothesis (DS) - a novel view combining both SC and SE - i.e., both the mapping between DoF and synergies and between synergies and actions are sparse, each action implementing a sparse combination of synergies (as in SC), each using a limited set of DoFs (as in SE). We evaluate these hypotheses using hand kinematic data from six human subjects performing nine different types of reach-to-grasp actions. Our results support DS, suggesting that the best action representation is based on a relatively large set of synergies, each involving a reduced number of degrees-of-freedom, and that distinct sets of synergies may be involved in distinct tasks.

PLAG1 deficiency impairs spermatogenesis and sperm motility in mice.

PubMed

Juma, Almas R; Grommen, Sylvia V H; O'Bryan, Moira K; O'Connor, Anne E; Merriner, D Jo; Hall, Nathan E; Doyle, Stephen R; Damdimopoulou, Pauliina E; Barriga, Daniel; Hart, Adam H; Van de Ven, Wim J M; De Groef, Bert

2017-07-13

Deficiency in pleomorphic adenoma gene 1 (PLAG1) leads to reduced fertility in male mice, but the mechanism by which PLAG1 contributes to reproduction is unknown. To investigate the involvement of PLAG1 in testicular function, we determined (i) the spatial distribution of PLAG1 in the testis using X-gal staining; (ii) transcriptomic consequences of PLAG1 deficiency in knock-out and heterozygous mice compared to wild-type mice using RNA-seq; and (iii) morphological and functional consequences of PLAG1 deficiency by determining testicular histology, daily sperm production and sperm motility in knock-out and wild-type mice. PLAG1 was sparsely expressed in germ cells and in Sertoli cells. Genes known to be involved in spermatogenesis were downregulated in the testes of knock-out mice, as well as Hsd17b3, which encodes a key enzyme in androgen biosynthesis. In the absence of Plag1, a number of genes involved in immune processes and epididymis-specific genes were upregulated in the testes. Finally, loss of PLAG1 resulted in significantly lowered daily sperm production, in reduced sperm motility, and in several animals, in sloughing of the germinal epithelium. Our results demonstrate that the subfertility seen in male PLAG1-deficient mice is, at least in part, the result of significantly reduced sperm output and sperm motility.

The neuronal structure of paramamillary nuclei in Bison bonasus: Nissl and Golgi pictures.

PubMed

Robak, A; Szteyn, S; Równiak, M

1998-01-01

The studies were carried out on the hypothalamus of bison bonasus aged 2 and 3 months. Sections were made by means of Bagiński's technique and Nissl and Klüver-Barrera methods. Four types of neurons were distinguished in the paramamillary nuclei: nucleus supramamillaris (Sm) and nucleus tuberomammillaris pars posterior (Tmp). Type I, small and medium-size, triangular or fusiform cells, which have 2-3 slender, poorly ramified dendrites; typical leptodendritic neurons. Type II, medium size neurons with quadrangular or spindle-shaped perikaryons. Most of them have 3-4 thick dendritic trunks with ramifying relatively long dendrites. These cells show stalked-appearance and possess different appendages sparsely distributed. Type III is similar to type II, but is made of medium-size to large multipolar cells having quadrangular, triangular or fusiform perikaryons and relatively short dendrites. Type IV, small and medium-size, globular cells with 2 or 3 dendritic trunks, which dichotomously subdivide into quaternary dendrites. In all types of neurons, axons emerge from the perikaryon or initial portion of a dendritic trunk. Type I was found in both studied nuclei. Types II and III constitute mainly the nucleus tuberomamillaris pars posterior. Type IV preponderate in the nucleus supramamillaris. The characteristic feature of Tmp cells, in Nissl picture was irregular contour of their somas and clumps of rough Nisls granules, which appear to lie outside the perikaryons. In Sm there were also lightly stained small rounded cells having both small amount of the cytoplasm and tigroid matter.

Apoptotic death in cerebral hemisphere cells is density dependent and modulated by transient oxygen and glucose deprivation.

PubMed

Yavin, E; Billia, D M

1997-03-01

Flow cytometry, light and fluorescence microscopy, and designated biochemical techniques were used to examine the type of death which occurs in cerebral cortex cells when grown under crowded vs. sparse conditions or after brief anoxia/hypoglycemia. A 4 hr episode of anoxia combined with glucose deprivation enhanced apoptotic cell death as assessed by 4',6-diamidino-2-phenylindole (DAPI) staining and reduced neutral red eye uptake. An additional form of cell death involving exclusion of the nucleus was recorded by time lapse cinematography and DAPI stain. The presence of the endonuclease inhibitor aurintricarboxylic acid (0.1 mM) reduced cell death by 56.6%, while the protein and RNA synthesis inhibitors actinomycin D and cycloheximide (each at 5 micrograms/ml) effectively decreased cell death by 83.3% and 90.6%, respectively. In contrast, 5 mM glutamate had no effect on cell death in accord with the immature state of the cells. Growth of cells under crowded conditions improved cell survival; after 2 h or 4 days in culture, cells seeded at high density (34 microgram cellular DNA/cm2) showed a nearly 3-fold decline in the amount of cell death in comparison to cells seeded at low density (5 micrograms cellular DNA/cm2). At high cell density, anoxic episodes enhanced cell death most likely by preventing a cell density-mediated rescue. Neutral red dye uptake, an index for cell viability, was enhanced with increasing cell density and in vitro maturation, but was reduced in dense cultures exposed to anoxic/hypoglycemic conditions. The data suggest that cell density may play a critical role in brain organogenesis and that anoxic stress is more deleterious in dense than sparse cell assemblies.

Mechanisms and Disease Associations of Haplotype-Dependent Allele-Specific DNA Methylation

PubMed Central

Do, Catherine; Lang, Charles F.; Lin, John; Darbary, Huferesh; Krupska, Izabela; Gaba, Aulona; Petukhova, Lynn; Vonsattel, Jean-Paul; Gallagher, Mary P.; Goland, Robin S.; Clynes, Raphael A.; Dwork, Andrew; Kral, John G.; Monk, Catherine; Christiano, Angela M.; Tycko, Benjamin

2016-01-01

Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A∗-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders. PMID:27153397

Sparse Regression as a Sparse Eigenvalue Problem

NASA Technical Reports Server (NTRS)

Moghaddam, Baback; Gruber, Amit; Weiss, Yair; Avidan, Shai

2008-01-01

We extend the l0-norm "subspectral" algorithms for sparse-LDA [5] and sparse-PCA [6] to general quadratic costs such as MSE in linear (kernel) regression. The resulting "Sparse Least Squares" (SLS) problem is also NP-hard, by way of its equivalence to a rank-1 sparse eigenvalue problem (e.g., binary sparse-LDA [7]). Specifically, for a general quadratic cost we use a highly-efficient technique for direct eigenvalue computation using partitioned matrix inverses which leads to dramatic x103 speed-ups over standard eigenvalue decomposition. This increased efficiency mitigates the O(n4) scaling behaviour that up to now has limited the previous algorithms' utility for high-dimensional learning problems. Moreover, the new computation prioritizes the role of the less-myopic backward elimination stage which becomes more efficient than forward selection. Similarly, branch-and-bound search for Exact Sparse Least Squares (ESLS) also benefits from partitioned matrix inverse techniques. Our Greedy Sparse Least Squares (GSLS) generalizes Natarajan's algorithm [9] also known as Order-Recursive Matching Pursuit (ORMP). Specifically, the forward half of GSLS is exactly equivalent to ORMP but more efficient. By including the backward pass, which only doubles the computation, we can achieve lower MSE than ORMP. Experimental comparisons to the state-of-the-art LARS algorithm [3] show forward-GSLS is faster, more accurate and more flexible in terms of choice of regularization

Combining DCQGMP-Based Sparse Decomposition and MPDR Beamformer for Multi-Type Interferences Mitigation for GNSS Receivers.

PubMed

Guo, Qiang; Qi, Liangang

2017-04-10

In the coexistence of multiple types of interfering signals, the performance of interference suppression methods based on time and frequency domains is degraded seriously, and the technique using an antenna array requires a large enough size and huge hardware costs. To combat multi-type interferences better for GNSS receivers, this paper proposes a cascaded multi-type interferences mitigation method combining improved double chain quantum genetic matching pursuit (DCQGMP)-based sparse decomposition and an MPDR beamformer. The key idea behind the proposed method is that the multiple types of interfering signals can be excised by taking advantage of their sparse features in different domains. In the first stage, the single-tone (multi-tone) and linear chirp interfering signals are canceled by sparse decomposition according to their sparsity in the over-complete dictionary. In order to improve the timeliness of matching pursuit (MP)-based sparse decomposition, a DCQGMP is introduced by combining an improved double chain quantum genetic algorithm (DCQGA) and the MP algorithm, and the DCQGMP algorithm is extended to handle the multi-channel signals according to the correlation among the signals in different channels. In the second stage, the minimum power distortionless response (MPDR) beamformer is utilized to nullify the residuary interferences (e.g., wideband Gaussian noise interferences). Several simulation results show that the proposed method can not only improve the interference mitigation degree of freedom (DoF) of the array antenna, but also effectively deal with the interference arriving from the same direction with the GNSS signal, which can be sparse represented in the over-complete dictionary. Moreover, it does not bring serious distortions into the navigation signal.

Combining DCQGMP-Based Sparse Decomposition and MPDR Beamformer for Multi-Type Interferences Mitigation for GNSS Receivers

PubMed Central

Guo, Qiang; Qi, Liangang

2017-01-01

In the coexistence of multiple types of interfering signals, the performance of interference suppression methods based on time and frequency domains is degraded seriously, and the technique using an antenna array requires a large enough size and huge hardware costs. To combat multi-type interferences better for GNSS receivers, this paper proposes a cascaded multi-type interferences mitigation method combining improved double chain quantum genetic matching pursuit (DCQGMP)-based sparse decomposition and an MPDR beamformer. The key idea behind the proposed method is that the multiple types of interfering signals can be excised by taking advantage of their sparse features in different domains. In the first stage, the single-tone (multi-tone) and linear chirp interfering signals are canceled by sparse decomposition according to their sparsity in the over-complete dictionary. In order to improve the timeliness of matching pursuit (MP)-based sparse decomposition, a DCQGMP is introduced by combining an improved double chain quantum genetic algorithm (DCQGA) and the MP algorithm, and the DCQGMP algorithm is extended to handle the multi-channel signals according to the correlation among the signals in different channels. In the second stage, the minimum power distortionless response (MPDR) beamformer is utilized to nullify the residuary interferences (e.g., wideband Gaussian noise interferences). Several simulation results show that the proposed method can not only improve the interference mitigation degree of freedom (DoF) of the array antenna, but also effectively deal with the interference arriving from the same direction with the GNSS signal, which can be sparse represented in the over-complete dictionary. Moreover, it does not bring serious distortions into the navigation signal. PMID:28394290

Sparse and Specific Coding during Information Transmission between Co-cultured Dentate Gyrus and CA3 Hippocampal Networks

PubMed Central

Poli, Daniele; Thiagarajan, Srikanth; DeMarse, Thomas B.; Wheeler, Bruce C.; Brewer, Gregory J.

2017-01-01

To better understand encoding and decoding of stimulus information in two specific hippocampal sub-regions, we isolated and co-cultured rat primary dentate gyrus (DG) and CA3 neurons within a two-chamber device with axonal connectivity via micro-tunnels. We tested the hypothesis that, in these engineered networks, decoding performance of stimulus site information would be more accurate when stimuli and information flow occur in anatomically correct feed-forward DG to CA3 vs. CA3 back to DG. In particular, we characterized the neural code of these sub-regions by measuring sparseness and uniqueness of the responses evoked by specific paired-pulse stimuli. We used the evoked responses in CA3 to decode the stimulation sites in DG (and vice-versa) by means of learning algorithms for classification (support vector machine, SVM). The device was placed over an 8 × 8 grid of extracellular electrodes (micro-electrode array, MEA) in order to provide a platform for monitoring development, self-organization, and improved access to stimulation and recording at multiple sites. The micro-tunnels were designed with dimensions 3 × 10 × 400 μm allowing axonal growth but not migration of cell bodies and long enough to exclude traversal by dendrites. Paired-pulse stimulation (inter-pulse interval 50 ms) was applied at 22 different sites and repeated 25 times in each chamber for each sub-region to evoke time-locked activity. DG-DG and CA3-CA3 networks were used as controls. Stimulation in DG drove signals through the axons in the tunnels to activate a relatively small set of specific electrodes in CA3 (sparse code). CA3-CA3 and DG-DG controls were less sparse in coding than CA3 in DG-CA3 networks. Using all target electrodes with the three highest spike rates (14%), the evoked responses in CA3 specified each stimulation site in DG with optimum uniqueness of 64%. Finally, by SVM learning, these evoked responses in CA3 correctly decoded the stimulation sites in DG for 43% of the trials, significantly higher than the reverse, i.e., how well-recording in DG could predict the stimulation site in CA3. In conclusion, our co-cultured model for the in vivo DG-CA3 hippocampal network showed sparse and specific responses in CA3, selectively evoked by each stimulation site in DG. PMID:28321182

Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B).

PubMed

Igawa, Satomi; Kishibe, Mari; Honma, Masaru; Murakami, Masamoto; Mizuno, Yuki; Suga, Yasushi; Seishima, Mariko; Ohguchi, Yuka; Akiyama, Masashi; Hirose, Kenji; Ishida-Yamamoto, Akemi; Iizuka, Hajime

2013-10-01

Atopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components' localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. To determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components' distribution and corneocytes surface areas. Corneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. The corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell-cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. This method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non-invasive diagnostic test. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

A versatile Multisite Gateway-compatible promoter and transgenic line collection for cell type-specific functional genomics in Arabidopsis

PubMed Central

Platre, Matthieu Pierre; Barberon, Marie; Caillieux, Erwann; Colot, Vincent

2016-01-01

Summary Multicellular organisms are composed of many cell types that acquire their specific fate through a precisely controlled pattern of gene expression in time and space dictated in part by cell type-specific promoter activity. Understanding the contribution of highly specialized cell types in the development of a whole organism requires the ability to isolate or analyze different cell types separately. We have characterized and validated a large collection of root cell type-specific promoters and have generated cell type-specific marker lines. These benchmarked promoters can be readily used to evaluate cell type-specific complementation of mutant phenotypes, or to knockdown gene expression using targeted expression of artificial miRNA. We also generated vectors and characterized transgenic lines for cell type-specific induction of gene expression and cell type-specific isolation of nuclei for RNA and chromatin profiling. Vectors and seeds from transgenic Arabidopsis plants will be freely available, and will promote rapid progress in cell type-specific functional genomics. We demonstrate the power of this promoter set for analysis of complex biological processes by investigating the contribution of root cell types in the IRT1-dependent root iron uptake. Our findings revealed the complex spatial expression pattern of IRT1 in both root epidermis and phloem companion cells and the requirement for IRT1 to be expressed in both cell types for proper iron homeostasis. PMID:26662936

Morphology and histology of the alimentary canal of Lygus hesperus (Heteroptera: Cimicomoropha: Miridae)

USGS Publications Warehouse

Habibi, J.; Coudron, T.A.; Backus, E.A.; Brandt, S.L.; Wagner, R.M.; Wright, M.K.; Huesing, J.E.

2008-01-01

Microdissection and transverse semithin sections were used to perform a light microscopy survey of the gross morphology and cellular anatomy of the alimentary canal, respectively, of Lygus hesperus Knight, a key pest of cotton (Gossypium hirsutum L.), alfalfa (Medicago sativa L.), and other crops. The gross morphology of the alimentary canal showed a relatively unadorned tube compared with other hemipterans, with variably shaped compartments and one small diverticulum. However, the epithelial cell anatomy of the gut was relatively complex, with the midgut having the most diverse structure and cell types. The midgut was typical of the "Lygus-type gut" seen in the older literature, i.e., it consisted of three major regions, the first (descending), second (ascending), and third (descending) ventriculi, with different variants of three major epithelial cell types in each region. Our light microscopy (LM) study suggests that the three cell types are nondifferentiated regenerative cells (which sparsely occurred throughout the midgut but were abundant in the anterior region of the first ventriculus), endocrine cells, and columnar cells. Although the Lygus gut cells strongly resemble those cell types seen in other insects, their identification should be confirmed via transmission electron microscopy to be considered definitive. These cell types differed in the size and opacity of vesicles, geometry of cell surface in the gut lumen, and size, shape, and concentration of brush-border microvilli and location within the gut. Comparison of gut structure in L. hesperus with that of other hemipterans, especially in relation to hemipteran phylogeny and feeding strategies, is discussed.

Improving EEG-Based Driver Fatigue Classification Using Sparse-Deep Belief Networks.

PubMed

Chai, Rifai; Ling, Sai Ho; San, Phyo Phyo; Naik, Ganesh R; Nguyen, Tuan N; Tran, Yvonne; Craig, Ashley; Nguyen, Hung T

2017-01-01

This paper presents an improvement of classification performance for electroencephalography (EEG)-based driver fatigue classification between fatigue and alert states with the data collected from 43 participants. The system employs autoregressive (AR) modeling as the features extraction algorithm, and sparse-deep belief networks (sparse-DBN) as the classification algorithm. Compared to other classifiers, sparse-DBN is a semi supervised learning method which combines unsupervised learning for modeling features in the pre-training layer and supervised learning for classification in the following layer. The sparsity in sparse-DBN is achieved with a regularization term that penalizes a deviation of the expected activation of hidden units from a fixed low-level prevents the network from overfitting and is able to learn low-level structures as well as high-level structures. For comparison, the artificial neural networks (ANN), Bayesian neural networks (BNN), and original deep belief networks (DBN) classifiers are used. The classification results show that using AR feature extractor and DBN classifiers, the classification performance achieves an improved classification performance with a of sensitivity of 90.8%, a specificity of 90.4%, an accuracy of 90.6%, and an area under the receiver operating curve (AUROC) of 0.94 compared to ANN (sensitivity at 80.8%, specificity at 77.8%, accuracy at 79.3% with AUC-ROC of 0.83) and BNN classifiers (sensitivity at 84.3%, specificity at 83%, accuracy at 83.6% with AUROC of 0.87). Using the sparse-DBN classifier, the classification performance improved further with sensitivity of 93.9%, a specificity of 92.3%, and an accuracy of 93.1% with AUROC of 0.96. Overall, the sparse-DBN classifier improved accuracy by 13.8, 9.5, and 2.5% over ANN, BNN, and DBN classifiers, respectively.

Improving EEG-Based Driver Fatigue Classification Using Sparse-Deep Belief Networks

PubMed Central

Chai, Rifai; Ling, Sai Ho; San, Phyo Phyo; Naik, Ganesh R.; Nguyen, Tuan N.; Tran, Yvonne; Craig, Ashley; Nguyen, Hung T.

2017-01-01

This paper presents an improvement of classification performance for electroencephalography (EEG)-based driver fatigue classification between fatigue and alert states with the data collected from 43 participants. The system employs autoregressive (AR) modeling as the features extraction algorithm, and sparse-deep belief networks (sparse-DBN) as the classification algorithm. Compared to other classifiers, sparse-DBN is a semi supervised learning method which combines unsupervised learning for modeling features in the pre-training layer and supervised learning for classification in the following layer. The sparsity in sparse-DBN is achieved with a regularization term that penalizes a deviation of the expected activation of hidden units from a fixed low-level prevents the network from overfitting and is able to learn low-level structures as well as high-level structures. For comparison, the artificial neural networks (ANN), Bayesian neural networks (BNN), and original deep belief networks (DBN) classifiers are used. The classification results show that using AR feature extractor and DBN classifiers, the classification performance achieves an improved classification performance with a of sensitivity of 90.8%, a specificity of 90.4%, an accuracy of 90.6%, and an area under the receiver operating curve (AUROC) of 0.94 compared to ANN (sensitivity at 80.8%, specificity at 77.8%, accuracy at 79.3% with AUC-ROC of 0.83) and BNN classifiers (sensitivity at 84.3%, specificity at 83%, accuracy at 83.6% with AUROC of 0.87). Using the sparse-DBN classifier, the classification performance improved further with sensitivity of 93.9%, a specificity of 92.3%, and an accuracy of 93.1% with AUROC of 0.96. Overall, the sparse-DBN classifier improved accuracy by 13.8, 9.5, and 2.5% over ANN, BNN, and DBN classifiers, respectively. PMID:28326009

Sparse orthogonal population representation of spatial context in the retrosplenial cortex.

PubMed

Mao, Dun; Kandler, Steffen; McNaughton, Bruce L; Bonin, Vincent

2017-08-15

Sparse orthogonal coding is a key feature of hippocampal neural activity, which is believed to increase episodic memory capacity and to assist in navigation. Some retrosplenial cortex (RSC) neurons convey distributed spatial and navigational signals, but place-field representations such as observed in the hippocampus have not been reported. Combining cellular Ca 2+ imaging in RSC of mice with a head-fixed locomotion assay, we identified a population of RSC neurons, located predominantly in superficial layers, whose ensemble activity closely resembles that of hippocampal CA1 place cells during the same task. Like CA1 place cells, these RSC neurons fire in sequences during movement, and show narrowly tuned firing fields that form a sparse, orthogonal code correlated with location. RSC 'place' cell activity is robust to environmental manipulations, showing partial remapping similar to that observed in CA1. This population code for spatial context may assist the RSC in its role in memory and/or navigation.Neurons in the retrosplenial cortex (RSC) encode spatial and navigational signals. Here the authors use calcium imaging to show that, similar to the hippocampus, RSC neurons also encode place cell-like activity in a sparse orthogonal representation, partially anchored to the allocentric cues on the linear track.

Distilled single-cell genome sequencing and de novo assembly for sparse microbial communities.

PubMed

Taghavi, Zeinab; Movahedi, Narjes S; Draghici, Sorin; Chitsaz, Hamidreza

2013-10-01

Identification of every single genome present in a microbial sample is an important and challenging task with crucial applications. It is challenging because there are typically millions of cells in a microbial sample, the vast majority of which elude cultivation. The most accurate method to date is exhaustive single-cell sequencing using multiple displacement amplification, which is simply intractable for a large number of cells. However, there is hope for breaking this barrier, as the number of different cell types with distinct genome sequences is usually much smaller than the number of cells. Here, we present a novel divide and conquer method to sequence and de novo assemble all distinct genomes present in a microbial sample with a sequencing cost and computational complexity proportional to the number of genome types, rather than the number of cells. The method is implemented in a tool called Squeezambler. We evaluated Squeezambler on simulated data. The proposed divide and conquer method successfully reduces the cost of sequencing in comparison with the naïve exhaustive approach. Squeezambler and datasets are available at http://compbio.cs.wayne.edu/software/squeezambler/.

Sparsely Ionizing Diagnostic and Natural Background Radiations are Likely Preventing Cancer and Other Genomic-Instability-Associated Diseases

PubMed Central

Scott, Bobby R.; Di Palma, Jennifer

2007-01-01

Routine diagnostic X-rays (e.g., chest X-rays, mammograms, computed tomography scans) and routine diagnostic nuclear medicine procedures using sparsely ionizing radiation forms (e.g., beta and gamma radiations) stimulate the removal of precancerous neo-plastically transformed and other genomically unstable cells from the body (medical radiation hormesis). The indicated radiation hormesis arises because radiation doses above an individual-specific stochastic threshold activate a system of cooperative protective processes that include high-fidelity DNA repair/apoptosis (presumed p53 related), an auxiliary apoptosis process (PAM process) that is presumed p53-independent, and stimulated immunity. These forms of induced protection are called adapted protection because they are associated with the radiation adaptive response. Diagnostic X-ray sources, other sources of sparsely ionizing radiation used in nuclear medicine diagnostic procedures, as well as radioisotope-labeled immunoglobulins could be used in conjunction with apopto-sis-sensitizing agents (e.g., the natural phenolic compound resveratrol) in curing existing cancer via low-dose fractionated or low-dose, low-dose-rate therapy (therapeutic radiation hormesis). Evidence is provided to support the existence of both therapeutic (curing existing cancer) and medical (cancer prevention) radiation hormesis. Evidence is also provided demonstrating that exposure to environmental sparsely ionizing radiations, such as gamma rays, protect from cancer occurrence and the occurrence of other diseases via inducing adapted protection (environmental radiation hormesis). PMID:18648608

Effect of Climate Change on Vegetation Phenology of Different Land Cover Types on the Tibetan Plateau

NASA Astrophysics Data System (ADS)

Cheng, M.; Jin, J.

2017-12-01

Vegetation phenology is one of the most sensitive bio-indicators of climate change, and it has received increasing interests in the context of global warming. As one of the most sensitive areas to global change, the Tibetan Plateau is a unique region to study the trends in vegetation phenology in response to climate change because of its unique vegetation composition, climate features and low-level human disturbance. Although some studies have aroused wide controversies about the actual plant phenology patterns in the Tibetan Plateau, yet the reasons remain unclear. In particular, the phenology characteristics of sparse herbaceous or sparse shrub and evergreen forest that are mostly located in the northwest and southeast of the Tibetan Plateau remain less studied. In this study, the spatio-temporal patterns of the start (SOS), end (EOS) and length (LOS) of the vegetation growing season for six vegetation types in the Tibetan Plateau, including evergreen broadleaf forests, evergreen coniferous forests, evergreen shrub, meadow, steppe and sparse herbaceous or sparse shrub, were quantified from 1982 to 2014 using NOAA/AVHRR NDVI data set at a spatial resolution of 0.05°×0.05° and 7-day intervals using NDVI relative change rate threshold and sixth order polynomial fit models. Assisted with the monthly precipitation and temperature data, the relative effects of changing climates on the variability of phenology were also examined. Diverse phenological changes were observed for different land cover types, with an advancing start of growing season (SOS), delaying end of growing season (EOS) and increasing length of growing season (LOS) in the eastern Tibetan Plateau where meadow was the dominant vegetation type, but with the opposite changes in the steppe and sparse herbaceous or sparse shrub regions which are mostly located in the northwestern and western edges of the Tibetan Plateau. Correlation analysis indicated that sufficient preseason precipitation may delay the SOS of evergreen forests in the southeastern Plateau and advance the SOS of steppe and sparse herbaceous or sparse shrub in relatively arid areas, while the advance of SOS in meadow areas could be related to higher preseason temperature.

Dissecting local circuits in vivo: integrated optogenetic and electrophysiology approaches for exploring inhibitory regulation of cortical activity.

PubMed

Cardin, Jessica A

2012-01-01

Local cortical circuit activity in vivo comprises a complex and flexible series of interactions between excitatory and inhibitory neurons. Our understanding of the functional interactions between these different neural populations has been limited by the difficulty of identifying and selectively manipulating the diverse and sparsely represented inhibitory interneuron classes in the intact brain. The integration of recently developed optical tools with traditional electrophysiological techniques provides a powerful window into the role of inhibition in regulating the activity of excitatory neurons. In particular, optogenetic targeting of specific cell classes reveals the distinct impacts of local inhibitory populations on other neurons in the surrounding local network. In addition to providing the ability to activate or suppress spiking in target cells, optogenetic activation identifies extracellularly recorded neurons by class, even when naturally occurring spike rates are extremely low. However, there are several important limitations on the use of these tools and the interpretation of resulting data. The purpose of this article is to outline the uses and limitations of optogenetic tools, along with current methods for achieving cell type-specific expression, and to highlight the advantages of an experimental approach combining optogenetics and electrophysiology to explore the role of inhibition in active networks. To illustrate the efficacy of these combined approaches, I present data comparing targeted manipulations of cortical fast-spiking, parvalbumin-expressing and low threshold-spiking, somatostatin-expressing interneurons in vivo. Copyright © 2011 Elsevier Ltd. All rights reserved.

Urban land use of the Sao Paulo metropolitan area by automatic analysis of LANDSAT data

NASA Technical Reports Server (NTRS)

Parada, N. D. J. (Principal Investigator); Niero, M.; Foresti, C.

1983-01-01

The separability of urban land use classes in the metropolitan area of Sao Paulo was studied by means of automatic analysis of MSS/LANDSAT digital data. The data were analyzed using the media K and MAXVER classification algorithms. The land use classes obtained were: CBD/vertical growth area, residential area, mixed area, industrial area, embankment area type 1, embankment area type 2, dense vegetation area and sparse vegetation area. The spectral analysis of representative samples of urban land use classes was done using the "Single Cell" analysis option. The classes CBD/vertical growth area, residential area and embankment area type 2 showed better spectral separability when compared to the other classes.

Optimization of Sparse Matrix-Vector Multiplication on Emerging Multicore Platforms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, Samuel; Oliker, Leonid; Vuduc, Richard

2008-10-16

We are witnessing a dramatic change in computer architecture due to the multicore paradigm shift, as every electronic device from cell phones to supercomputers confronts parallelism of unprecedented scale. To fully unleash the potential of these systems, the HPC community must develop multicore specific-optimization methodologies for important scientific computations. In this work, we examine sparse matrix-vector multiply (SpMV) - one of the most heavily used kernels in scientific computing - across a broad spectrum of multicore designs. Our experimental platform includes the homogeneous AMD quad-core, AMD dual-core, and Intel quad-core designs, the heterogeneous STI Cell, as well as one ofmore » the first scientific studies of the highly multithreaded Sun Victoria Falls (a Niagara2 SMP). We present several optimization strategies especially effective for the multicore environment, and demonstrate significant performance improvements compared to existing state-of-the-art serial and parallel SpMV implementations. Additionally, we present key insights into the architectural trade-offs of leading multicore design strategies, in the context of demanding memory-bound numerical algorithms.« less

Revealing the Hidden Relationship by Sparse Modules in Complex Networks with a Large-Scale Analysis

PubMed Central

Jiao, Qing-Ju; Huang, Yan; Liu, Wei; Wang, Xiao-Fan; Chen, Xiao-Shuang; Shen, Hong-Bin

2013-01-01

One of the remarkable features of networks is module that can provide useful insights into not only network organizations but also functional behaviors between their components. Comprehensive efforts have been devoted to investigating cohesive modules in the past decade. However, it is still not clear whether there are important structural characteristics of the nodes that do not belong to any cohesive module. In order to answer this question, we performed a large-scale analysis on 25 complex networks with different types and scales using our recently developed BTS (bintree seeking) algorithm, which is able to detect both cohesive and sparse modules in the network. Our results reveal that the sparse modules composed by the cohesively isolated nodes widely co-exist with the cohesive modules. Detailed analysis shows that both types of modules provide better characterization for the division of a network into functional units than merely cohesive modules, because the sparse modules possibly re-organize the nodes in the so-called cohesive modules, which lack obvious modular significance, into meaningful groups. Compared with cohesive modules, the sizes of sparse ones are generally smaller. Sparse modules are also found to have preferences in social and biological networks than others. PMID:23762457

Molecular modeling of biomolecules by paramagnetic NMR and computational hybrid methods.

PubMed

Pilla, Kala Bharath; Gaalswyk, Kari; MacCallum, Justin L

2017-11-01

The 3D atomic structures of biomolecules and their complexes are key to our understanding of biomolecular function, recognition, and mechanism. However, it is often difficult to obtain structures, particularly for systems that are complex, dynamic, disordered, or exist in environments like cell membranes. In such cases sparse data from a variety of paramagnetic NMR experiments offers one possible source of structural information. These restraints can be incorporated in computer modeling algorithms that can accurately translate the sparse experimental data into full 3D atomic structures. In this review, we discuss various types of paramagnetic NMR/computational hybrid modeling techniques that can be applied to successful modeling of not only the atomic structure of proteins but also their interacting partners. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. Copyright © 2017 Elsevier B.V. All rights reserved.

Discover mouse gene coexpression landscapes using dictionary learning and sparse coding.

PubMed

Li, Yujie; Chen, Hanbo; Jiang, Xi; Li, Xiang; Lv, Jinglei; Peng, Hanchuan; Tsien, Joe Z; Liu, Tianming

2017-12-01

Gene coexpression patterns carry rich information regarding enormously complex brain structures and functions. Characterization of these patterns in an unbiased, integrated, and anatomically comprehensive manner will illuminate the higher-order transcriptome organization and offer genetic foundations of functional circuitry. Here using dictionary learning and sparse coding, we derived coexpression networks from the space-resolved anatomical comprehensive in situ hybridization data from Allen Mouse Brain Atlas dataset. The key idea is that if two genes use the same dictionary to represent their original signals, then their gene expressions must share similar patterns, thereby considering them as "coexpressed." For each network, we have simultaneous knowledge of spatial distributions, the genes in the network and the extent a particular gene conforms to the coexpression pattern. Gene ontologies and the comparisons with published gene lists reveal biologically identified coexpression networks, some of which correspond to major cell types, biological pathways, and/or anatomical regions.

Estimating Highway Volumes Using Vehicle Probe Data - Proof of Concept: Preprint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hou, Yi; Young, Stanley E; Sadabadi, Kaveh

This paper examines the feasibility of using sampled commercial probe data in combination with validated continuous counter data to accurately estimate vehicle volume across the entire roadway network, for any hour during the year. Currently either real time or archived volume data for roadways at specific times are extremely sparse. Most volume data are average annual daily traffic (AADT) measures derived from the Highway Performance Monitoring System (HPMS). Although methods to factor the AADT to hourly averages for typical day of week exist, actual volume data is limited to a sparse collection of locations in which volumes are continuously recorded.more » This paper explores the use of commercial probe data to generate accurate volume measures that span the highway network providing ubiquitous coverage in space, and specific point-in-time measures for a specific date and time. The paper examines the need for the data, fundamental accuracy limitations based on a basic statistical model that take into account the sampling nature of probe data, and early results from a proof of concept exercise revealing the potential of probe type data calibrated with public continuous count data to meet end user expectations in terms of accuracy of volume estimates.« less

An efficient sparse matrix multiplication scheme for the CYBER 205 computer

NASA Technical Reports Server (NTRS)

Lambiotte, Jules J., Jr.

1988-01-01

This paper describes the development of an efficient algorithm for computing the product of a matrix and vector on a CYBER 205 vector computer. The desire to provide software which allows the user to choose between the often conflicting goals of minimizing central processing unit (CPU) time or storage requirements has led to a diagonal-based algorithm in which one of four types of storage is selected for each diagonal. The candidate storage types employed were chosen to be efficient on the CYBER 205 for diagonals which have nonzero structure which is dense, moderately sparse, very sparse and short, or very sparse and long; however, for many densities, no diagonal type is most efficient with respect to both resource requirements, and a trade-off must be made. For each diagonal, an initialization subroutine estimates the CPU time and storage required for each storage type based on results from previously performed numerical experimentation. These requirements are adjusted by weights provided by the user which reflect the relative importance the user places on the two resources. The adjusted resource requirements are then compared to select the most efficient storage and computational scheme.

Three invariant Hi-C interaction patterns: Applications to genome assembly.

PubMed

Oddes, Sivan; Zelig, Aviv; Kaplan, Noam

2018-06-01

Assembly of reference-quality genomes from next-generation sequencing data is a key challenge in genomics. Recently, we and others have shown that Hi-C data can be used to address several outstanding challenges in the field of genome assembly. This principle has since been developed in academia and industry, and has been used in the assembly of several major genomes. In this paper, we explore the central principles underlying Hi-C-based assembly approaches, by quantitatively defining and characterizing three invariant Hi-C interaction patterns on which these approaches can build: Intrachromosomal interaction enrichment, distance-dependent interaction decay and local interaction smoothness. Specifically, we evaluate to what degree each invariant pattern holds on a single locus level in different species, cell types and Hi-C map resolutions. We find that these patterns are generally consistent across species and cell types but are affected by sequencing depth, and that matrix balancing improves consistency of loci with all three invariant patterns. Finally, we overview current Hi-C-based assembly approaches in light of these invariant patterns and demonstrate how local interaction smoothness can be used to easily detect scaffolding errors in extremely sparse Hi-C maps. We suggest that simultaneously considering all three invariant patterns may lead to better Hi-C-based genome assembly methods. Copyright © 2018 Elsevier Inc. All rights reserved.

Histological and Immunological Description of the Leishmanin Skin Test in Ibizan Hounds.

PubMed

Ordeix, L; Silva, J E Dos S; Llull, J; Quirola, P; Montserrat-Sangrà, S; Martínez-Orellana, P; Solano-Gallego, L

2018-01-01

The leishmanin skin test (LST), a delayed-type hypersensitivity (DTH) reaction to Leishmania infantum, can specifically identify dogs that have made a cell-mediated immune response to L. infantum infection. The Ibizan hound appears to be more resistant to L. infantum infection than other breeds of dog. The aim of this study was to describe the histological and immunohistochemical changes induced by the LST in Ibizan hounds living in an area highly endemic for leishmaniosis. The majority of dogs were apparently healthy, lacked serum antibody to L. infantum and blood parasitaemia, but had marked specific interferon gamma production after in-vitro blood stimulation with L. infantum. Leishmanin (3 × 10 8 killed promastigotes of L. infantum/ml) was injected intradermally and biopsy samples were obtained from a positive reaction at 72 h from nine Ibizan hounds. A moderate to intense, perivascular to interstitial dermatitis and panniculitis characterized the inflammatory response at the injection site. In addition, three samples had diffuse inflammation in the deep dermis and panniculus. Oedema and necrosis were present in the deep dermis and panniculus. Congestion and haemorrhage were observed in five biopsies. T lymphocytes (CD3 + ) and large mononuclear cells (lysozyme - ) were the most prevalent cells. CD3 + cells were significantly more numerous than CD20 + B cells and lysozyme + cells. B cells were sparsely distributed, especially in the deep dermis and panniculus. Rare neutrophils and macrophages (lysozyme + ) were observed with few eosinophils. Toll-like receptor (TLR)-2 protein was expressed in large mononuclear cells mainly located in the superficial dermis. Leishmania immunohistochemistry was negative and quantitative polymerase chain reaction was positive in all cases. The intradermal injection of killed L. infantum promastigotes in Ibizan hounds causes similar histological and immunohistochemical findings to those described for human subjects and are indicative of a DTH response. Moreover, TLR2 protein is expressed in inflammatory cells similar to findings in clinically affected skin biopsy samples. Copyright © 2017 Elsevier Ltd. All rights reserved.

Automated deconvolution of structured mixtures from heterogeneous tumor genomic data

PubMed Central

Roman, Theodore; Xie, Lu

2017-01-01

With increasing appreciation for the extent and importance of intratumor heterogeneity, much attention in cancer research has focused on profiling heterogeneity on a single patient level. Although true single-cell genomic technologies are rapidly improving, they remain too noisy and costly at present for population-level studies. Bulk sequencing remains the standard for population-scale tumor genomics, creating a need for computational tools to separate contributions of multiple tumor clones and assorted stromal and infiltrating cell populations to pooled genomic data. All such methods are limited to coarse approximations of only a few cell subpopulations, however. In prior work, we demonstrated the feasibility of improving cell type deconvolution by taking advantage of substructure in genomic mixtures via a strategy called simplicial complex unmixing. We improve on past work by introducing enhancements to automate learning of substructured genomic mixtures, with specific emphasis on genome-wide copy number variation (CNV) data, as well as the ability to process quantitative RNA expression data, and heterogeneous combinations of RNA and CNV data. We introduce methods for dimensionality estimation to better decompose mixture model substructure; fuzzy clustering to better identify substructure in sparse, noisy data; and automated model inference methods for other key model parameters. We further demonstrate their effectiveness in identifying mixture substructure in true breast cancer CNV data from the Cancer Genome Atlas (TCGA). Source code is available at https://github.com/tedroman/WSCUnmix PMID:29059177

Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form.

PubMed

Obari, Abdulkader; Sano, Toshiaki; Ohyama, Kenichi; Kudo, Eiji; Qian, Zhi Rong; Yoneda, Akiko; Rayhan, Nasim; Mustafizur Rahman, Muhammad; Yamada, Shozo

2008-01-01

Pituitary adenomas producing almost exclusively growth hormones (GH) have been ultrastructurally classified into two distinct types: densely granulated somatotroph (DG) adenomas and sparsely granulated (SG) adenomas. Fibrous body (FB), an intracytoplasmic globular aggregation of cytokeratin (CK) filaments, is a hallmark of SG adenomas. Under light microscope, FB could be identified by CK immunohistochemistry as a dot-pattern immunoreaction versus a perinuclear pattern for cells without FB. However, it has been noted that numerous adenomas contain mixed populations of the two patterns. To clarify clinicopathological characteristics of the adenomas with mixed populations ("intermediate type" adenomas) and to confirm clinicopathological differences between strictly defined DG-type and SG-type adenomas, we performed this study on 104 GH cell adenomas. Having segregated "intermediate-type" adenomas (26 cases), we found significant differences between typical DG-type (47 cases) and SG-type adenomas (31 cases); SG-type adenomas had younger ages (44 vs. 50), higher frequency of macroadenomas (86% vs. 58%), invasiveness (65% vs. 38%), advanced grades (3 or 4) in Knosp's classification (50% vs. 24%), and weaker immunoreaction for GH, beta-TSH, alpha-subunit, E-cadherin, and beta-catenin. Clinicopathological characteristics of "intermediate-type" adenomas were identical to those of DG-type adenomas. These findings confirm that SG-type adenoma is a distinct section of GH cell adenomas with special properties and biological behavior, and suggest that intermediate-phenotype adenomas are enrolled in DG-type adenomas. Special properties and biological behavior of SG-type adenomas may appear after the majority of tumor cells possess a fully developed fibrous body.

Relationships between milk culture results and treatment for clinical mastitis or culling in Norwegian dairy cattle.

PubMed

Reksen, O; Sølverød, L; Branscum, A J; Osterås, O

2006-08-01

In quarter milk samples from 2,492 randomly sampled cows that were selected without regard to their current or previous udder health status, the relationships between the following outcome variables were studied: treatment of clinical mastitis; the joint event of either treatment or culling for mastitis; culling for all reasons; culling specifically for mastitis; and the covariates of positive milk culture for Staphylococcus aureus, Streptococcus spp., and coagulase-negative Staphylococcus spp., or other pathogens, or of negative culture for mastitis pathogens. Microbiological diagnoses were assigned at the cow level, and altogether 3,075 diagnoses were related to the outcome variables. The relation between the absence of pathogens and rich (>1,500 cfu/mL of milk) or sparse (

Dermal Aged and Fetal Fibroblasts Realign in Response to Mechanical Strain

NASA Technical Reports Server (NTRS)

Sawyer, Christine; Grymes, Rose; Alvarez, Teresa (Technical Monitor)

1994-01-01

Integrins specifically recognize and bind extracellular matrix components, providing physical anchor points and functional setpoints. Focal adhesion complexes, containing integrin and cytoskeletal proteins, are potential mechanoreceptors, poised to distribute applied forces through the cytoskeleton. Pursuing the hypothesis that cells both perceive and respond to external force, we applied a stretch/relaxation regimen to normal human fetal and aged dermal fibroblast monolayers cultured on flexible membranes. The frequency and magnitude of the applied force is precisely controlled by the Flexercell Unit(Trademark). A protocol of stretch (20% elongation of the monolayer) at a frequency of 6 cycles/min caused a progressive change from a randomly distributed pattern of cells to a symmetric, radial distribution with cells aligned parallel to the applied force. We have coined the term 'orienteering' as the process of active alignment of cells in response to applied force. Cytochalasin D was added in graded doses to investigate the role of the actin cytoskeleton in force perception and transmission. A clear dose response was found; at high concentrations orienteering was abolished; and the drug's impact was reversible. The two cell strains used were similar in their alignment behavior and in their responses to cytochalasin D. Orienteering was influenced by cell density, and the cell strains studied differed in this respect. Fetal cells, unlike their aged counterparts, failed to orient at high cell density. In both cell strains, mid-density cultures aligned rapidly and sparse cultures lagged. These results indicate that both cell-cell adhesion and cytoskeleton integrity are critical in mediating the orienteering response. Differences between these two cell strains may relate to their expression of extracellular matrix molecules (fibronectin, collagen type 1) integrins and their relative binding affinities.

Sparse Regression Based Structure Learning of Stochastic Reaction Networks from Single Cell Snapshot Time Series.

PubMed

Klimovskaia, Anna; Ganscha, Stefan; Claassen, Manfred

2016-12-01

Stochastic chemical reaction networks constitute a model class to quantitatively describe dynamics and cell-to-cell variability in biological systems. The topology of these networks typically is only partially characterized due to experimental limitations. Current approaches for refining network topology are based on the explicit enumeration of alternative topologies and are therefore restricted to small problem instances with almost complete knowledge. We propose the reactionet lasso, a computational procedure that derives a stepwise sparse regression approach on the basis of the Chemical Master Equation, enabling large-scale structure learning for reaction networks by implicitly accounting for billions of topology variants. We have assessed the structure learning capabilities of the reactionet lasso on synthetic data for the complete TRAIL induced apoptosis signaling cascade comprising 70 reactions. We find that the reactionet lasso is able to efficiently recover the structure of these reaction systems, ab initio, with high sensitivity and specificity. With only < 1% false discoveries, the reactionet lasso is able to recover 45% of all true reactions ab initio among > 6000 possible reactions and over 102000 network topologies. In conjunction with information rich single cell technologies such as single cell RNA sequencing or mass cytometry, the reactionet lasso will enable large-scale structure learning, particularly in areas with partial network structure knowledge, such as cancer biology, and thereby enable the detection of pathological alterations of reaction networks. We provide software to allow for wide applicability of the reactionet lasso.

Cloud-In-Cell modeling of shocked particle-laden flows at a ``SPARSE'' cost

NASA Astrophysics Data System (ADS)

Taverniers, Soren; Jacobs, Gustaaf; Sen, Oishik; Udaykumar, H. S.

2017-11-01

A common tool for enabling process-scale simulations of shocked particle-laden flows is Eulerian-Lagrangian Particle-Source-In-Cell (PSIC) modeling where each particle is traced in its Lagrangian frame and treated as a mathematical point. Its dynamics are governed by Stokes drag corrected for high Reynolds and Mach numbers. The computational burden is often reduced further through a ``Cloud-In-Cell'' (CIC) approach which amalgamates groups of physical particles into computational ``macro-particles''. CIC does not account for subgrid particle fluctuations, leading to erroneous predictions of cloud dynamics. A Subgrid Particle-Averaged Reynolds-Stress Equivalent (SPARSE) model is proposed that incorporates subgrid interphase velocity and temperature perturbations. A bivariate Gaussian source distribution, whose covariance captures the cloud's deformation to first order, accounts for the particles' momentum and energy influence on the carrier gas. SPARSE is validated by conducting tests on the interaction of a particle cloud with the accelerated flow behind a shock. The cloud's average dynamics and its deformation over time predicted with SPARSE converge to their counterparts computed with reference PSIC models as the number of Gaussians is increased from 1 to 16. This work was supported by AFOSR Grant No. FA9550-16-1-0008.

Brief announcement: Hypergraph parititioning for parallel sparse matrix-matrix multiplication

DOE PAGES

Ballard, Grey; Druinsky, Alex; Knight, Nicholas; ...

2015-01-01

The performance of parallel algorithms for sparse matrix-matrix multiplication is typically determined by the amount of interprocessor communication performed, which in turn depends on the nonzero structure of the input matrices. In this paper, we characterize the communication cost of a sparse matrix-matrix multiplication algorithm in terms of the size of a cut of an associated hypergraph that encodes the computation for a given input nonzero structure. Obtaining an optimal algorithm corresponds to solving a hypergraph partitioning problem. Furthermore, our hypergraph model generalizes several existing models for sparse matrix-vector multiplication, and we can leverage hypergraph partitioners developed for that computationmore » to improve application-specific algorithms for multiplying sparse matrices.« less

Unified commutation-pruning technique for efficient computation of composite DFTs

NASA Astrophysics Data System (ADS)

Castro-Palazuelos, David E.; Medina-Melendrez, Modesto Gpe.; Torres-Roman, Deni L.; Shkvarko, Yuriy V.

2015-12-01

An efficient computation of a composite length discrete Fourier transform (DFT), as well as a fast Fourier transform (FFT) of both time and space data sequences in uncertain (non-sparse or sparse) computational scenarios, requires specific processing algorithms. Traditional algorithms typically employ some pruning methods without any commutations, which prevents them from attaining the potential computational efficiency. In this paper, we propose an alternative unified approach with automatic commutations between three computational modalities aimed at efficient computations of the pruned DFTs adapted for variable composite lengths of the non-sparse input-output data. The first modality is an implementation of the direct computation of a composite length DFT, the second one employs the second-order recursive filtering method, and the third one performs the new pruned decomposed transform. The pruned decomposed transform algorithm performs the decimation in time or space (DIT) data acquisition domain and, then, decimation in frequency (DIF). The unified combination of these three algorithms is addressed as the DFTCOMM technique. Based on the treatment of the combinational-type hypotheses testing optimization problem of preferable allocations between all feasible commuting-pruning modalities, we have found the global optimal solution to the pruning problem that always requires a fewer or, at most, the same number of arithmetic operations than other feasible modalities. The DFTCOMM method outperforms the existing competing pruning techniques in the sense of attainable savings in the number of required arithmetic operations. It requires fewer or at most the same number of arithmetic operations for its execution than any other of the competing pruning methods reported in the literature. Finally, we provide the comparison of the DFTCOMM with the recently developed sparse fast Fourier transform (SFFT) algorithmic family. We feature that, in the sensing scenarios with sparse/non-sparse data Fourier spectrum, the DFTCOMM technique manifests robustness against such model uncertainties in the sense of insensitivity for sparsity/non-sparsity restrictions and the variability of the operating parameters.

Inverse problems with nonnegative and sparse solutions: algorithms and application to the phase retrieval problem

NASA Astrophysics Data System (ADS)

Quy Muoi, Pham; Nho Hào, Dinh; Sahoo, Sujit Kumar; Tang, Dongliang; Cong, Nguyen Huu; Dang, Cuong

2018-05-01

In this paper, we study a gradient-type method and a semismooth Newton method for minimization problems in regularizing inverse problems with nonnegative and sparse solutions. We propose a special penalty functional forcing the minimizers of regularized minimization problems to be nonnegative and sparse, and then we apply the proposed algorithms in a practical the problem. The strong convergence of the gradient-type method and the local superlinear convergence of the semismooth Newton method are proven. Then, we use these algorithms for the phase retrieval problem and illustrate their efficiency in numerical examples, particularly in the practical problem of optical imaging through scattering media where all the noises from experiment are presented.

The mathematics of tanning

PubMed Central

Thingnes, Josef; Øyehaug, Leiv; Hovig, Eivind; Omholt, Stig W

2009-01-01

Background The pigment melanin is produced by specialized cells, called melanocytes. In healthy skin, melanocytes are sparsely spread among the other cell types in the basal layer of the epidermis. Sun tanning results from an UV-induced increase in the release of melanin to neighbouring keratinocytes, the major cell type component of the epidermis as well as redistribution of melanin among these cells. Here we provide a mathematical conceptualization of our current knowledge of the tanning response, in terms of a dynamic model. The resolution level of the model is tuned to available data, and its primary focus is to describe the tanning response following UV exposure. Results The model appears capable of accounting for available experimental data on the tanning response in different skin and photo types. It predicts that the thickness of the epidermal layer and how far the melanocyte dendrites grow out in the epidermal layers after UV exposure influence the tanning response substantially. Conclusion Despite the paucity of experimental validation data the model is constrained enough to serve as a foundation for the establishment of a theoretical-experimental research programme aimed at elucidating the more fine-grained regulatory anatomy underlying the tanning response. PMID:19505344

Testing of Error-Correcting Sparse Permutation Channel Codes

NASA Technical Reports Server (NTRS)

Shcheglov, Kirill, V.; Orlov, Sergei S.

2008-01-01

A computer program performs Monte Carlo direct numerical simulations for testing sparse permutation channel codes, which offer strong error-correction capabilities at high code rates and are considered especially suitable for storage of digital data in holographic and volume memories. A word in a code of this type is characterized by, among other things, a sparseness parameter (M) and a fixed number (K) of 1 or "on" bits in a channel block length of N.

Statistics of single unit responses in the human medial temporal lobe: A sparse and overdispersed code

NASA Astrophysics Data System (ADS)

Magyar, Andrew

The recent discovery of cells that respond to purely conceptual features of the environment (particular people, landmarks, objects, etc) in the human medial temporal lobe (MTL), has raised many questions about the nature of the neural code in humans. The goal of this dissertation is to develop a novel statistical method based upon maximum likelihood regression which will then be applied to these experiments in order to produce a quantitative description of the coding properties of the human MTL. In general, the method is applicable to any experiments in which a sequence of stimuli are presented to an organism while the binary responses of a large number of cells are recorded in parallel. The central concept underlying the approach is the total probability that a neuron responds to a random stimulus, called the neuronal sparsity. The model then estimates the distribution of response probabilities across the population of cells. Applying the method to single-unit recordings from the human medial temporal lobe, estimates of the sparsity distributions are acquired in four regions: the hippocampus, the entorhinal cortex, the amygdala, and the parahippocampal cortex. The resulting distributions are found to be sparse (large fraction of cells with a low response probability) and highly non-uniform, with a large proportion of ultra-sparse neurons that possess a very low response probability, and a smaller population of cells which respond much more frequently. Rammifications of the results are discussed in relation to the sparse coding hypothesis, and comparisons are made between the statistics of the human medial temporal lobe cells and place cells observed in the rodent hippocampus.

Specific inhibition of antenna bacteriochlorophyll synthesis in Chlorobium vibrioforme by anesthetic gases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ormerod, J.G.; Nesbakken, T.; Beale, S.I.

1990-03-01

The green sulfur bacterium Chlorobium vibrioforme contains two types of bacteriochlorophll (Bchl). The minor pigment, Bchl a, is associated primarily with the cell membrane and its reaction centers; and the major light-harvesting antenna pigment, Bchl d, is found primarily in the chlorosomes, which are attached to the inner surface of the cell membrane. Anesthetic gases, such as N{sub 2}O, ethylene, and acetylene, were found to inhibit the synthesis of Bchl d, but not of Bchl a, thus allowing the cells to grow at high light intensities with a greatly diminished content of antenna pgiment. Chlorosomes were absent or sparse inmore » inhibited cells. Porphyrins accumulated in the inhibited cells. Result suggest that the gases act at a step in pigment biosynthesis that affect the utilization of the major one was identified as the Bchl precursor magnesium-protoporphyrin IX monomethyl ester (Mg-PPME) for isocyclic ring formation. Synthesis of Bchl d and Bchl a may be differentially affected by the gases because of compartmentation of their biosynthetic apparatus or because competition for precursors favors Bchl a synthesis. An ethephon-resistant mutant strain was isolated by selection for growth in dim, long-wavelength light. The mutant cells were also resistant to acetylene, but not to N{sub 2}O. The ability to reversibly generate viable Chlorobium cells that lack antenna pigments may be useful in photosynthesis research. The ethephon-and acetylene-resistant strain may be useful in the study of the enzymes and genes that are involved in the biosynthetic step that the gases affect.« less

Sparsely sampling the sky: Regular vs. random sampling

NASA Astrophysics Data System (ADS)

Paykari, P.; Pires, S.; Starck, J.-L.; Jaffe, A. H.

2015-09-01

Aims: The next generation of galaxy surveys, aiming to observe millions of galaxies, are expensive both in time and money. This raises questions regarding the optimal investment of this time and money for future surveys. In a previous work, we have shown that a sparse sampling strategy could be a powerful substitute for the - usually favoured - contiguous observation of the sky. In our previous paper, regular sparse sampling was investigated, where the sparse observed patches were regularly distributed on the sky. The regularity of the mask introduces a periodic pattern in the window function, which induces periodic correlations at specific scales. Methods: In this paper, we use a Bayesian experimental design to investigate a "random" sparse sampling approach, where the observed patches are randomly distributed over the total sparsely sampled area. Results: We find that in this setting, the induced correlation is evenly distributed amongst all scales as there is no preferred scale in the window function. Conclusions: This is desirable when we are interested in any specific scale in the galaxy power spectrum, such as the matter-radiation equality scale. As the figure of merit shows, however, there is no preference between regular and random sampling to constrain the overall galaxy power spectrum and the cosmological parameters.

Cnidarian Cell Type Diversity and Regulation Revealed by Whole-Organism Single-Cell RNA-Seq.

PubMed

Sebé-Pedrós, Arnau; Saudemont, Baptiste; Chomsky, Elad; Plessier, Flora; Mailhé, Marie-Pierre; Renno, Justine; Loe-Mie, Yann; Lifshitz, Aviezer; Mukamel, Zohar; Schmutz, Sandrine; Novault, Sophie; Steinmetz, Patrick R H; Spitz, François; Tanay, Amos; Marlow, Heather

2018-05-31

The emergence and diversification of cell types is a leading factor in animal evolution. So far, systematic characterization of the gene regulatory programs associated with cell type specificity was limited to few cell types and few species. Here, we perform whole-organism single-cell transcriptomics to map adult and larval cell types in the cnidarian Nematostella vectensis, a non-bilaterian animal with complex tissue-level body-plan organization. We uncover eight broad cell classes in Nematostella, including neurons, cnidocytes, and digestive cells. Each class comprises different subtypes defined by the expression of multiple specific markers. In particular, we characterize a surprisingly diverse repertoire of neurons, which comparative analysis suggests are the result of lineage-specific diversification. By integrating transcription factor expression, chromatin profiling, and sequence motif analysis, we identify the regulatory codes that underlie Nematostella cell-specific expression. Our study reveals cnidarian cell type complexity and provides insights into the evolution of animal cell-specific genomic regulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Adult Mouse Cortical Cell Taxonomy by Single Cell Transcriptomics

PubMed Central

Tasic, Bosiljka; Menon, Vilas; Nguyen, Thuc Nghi; Kim, Tae Kyung; Jarsky, Tim; Yao, Zizhen; Levi, Boaz; Gray, Lucas T.; Sorensen, Staci A.; Dolbeare, Tim; Bertagnolli, Darren; Goldy, Jeff; Shapovalova, Nadiya; Parry, Sheana; Lee, Changkyu; Smith, Kimberly; Bernard, Amy; Madisen, Linda; Sunkin, Susan M.; Hawrylycz, Michael; Koch, Christof; Zeng, Hongkui

2016-01-01

Nervous systems are composed of various cell types, but the extent of cell type diversity is poorly understood. Here, we construct a cellular taxonomy of one cortical region, primary visual cortex, in adult mice based on single cell RNA-sequencing. We identify 49 transcriptomic cell types including 23 GABAergic, 19 glutamatergic and seven non-neuronal types. We also analyze cell-type specific mRNA processing and characterize genetic access to these transcriptomic types by many transgenic Cre lines. Finally, we show that some of our transcriptomic cell types display specific and differential electrophysiological and axon projection properties, thereby confirming that the single cell transcriptomic signatures can be associated with specific cellular properties. PMID:26727548

Heterogeneous expression of Ca(2+) handling proteins in rabbit sinoatrial node.

PubMed

Musa, Hanny; Lei, Ming; Honjo, Hauro; Jones, Sandra A; Dobrzynski, Halina; Lancaster, Mathew K; Takagishi, Yoshiko; Henderson, Zaineb; Kodama, Itsuo; Boyett, Mark R

2002-03-01

We investigated the densities of the L-type Ca(2+) current, i(Ca,L), and various Ca(2+) handling proteins in rabbit sinoatrial (SA) node. The density of i(Ca,L), recorded with the whole-cell patch-clamp technique, varied widely in sinoatrial node cells. The density of i(Ca,L) was significantly (p<0.001) correlated with cell capacitance (measure of cell size) and the density was greater in larger cells (likely to be from the periphery of the SA node) than in smaller cells (likely to be from the center of the SA node). Immunocytochemical labeling of the L-type Ca(2+) channel, Na(+)-Ca(2+) exchanger, sarcoplasmic reticulum Ca(2+) release channel (RYR2), and sarcoplasmic reticulum Ca(2+) pump (SERCA2) also varied widely in SA node cells. In all cases there was significantly (p<0.05) denser labeling of cells from the periphery of the SA node than of cells from the center. In contrast, immunocytochemical labeling of the Na(+)-K(+) pump was similar in peripheral and central cells. We conclude that Ca(2+) handling proteins are sparse and poorly organized in the center of the SA node (normally the leading pacemaker site), whereas they are more abundant in the periphery (at the border of the SA node with the surrounding atrial muscle).

Local structure preserving sparse coding for infrared target recognition

PubMed Central

Han, Jing; Yue, Jiang; Zhang, Yi; Bai, Lianfa

2017-01-01

Sparse coding performs well in image classification. However, robust target recognition requires a lot of comprehensive template images and the sparse learning process is complex. We incorporate sparsity into a template matching concept to construct a local sparse structure matching (LSSM) model for general infrared target recognition. A local structure preserving sparse coding (LSPSc) formulation is proposed to simultaneously preserve the local sparse and structural information of objects. By adding a spatial local structure constraint into the classical sparse coding algorithm, LSPSc can improve the stability of sparse representation for targets and inhibit background interference in infrared images. Furthermore, a kernel LSPSc (K-LSPSc) formulation is proposed, which extends LSPSc to the kernel space to weaken the influence of the linear structure constraint in nonlinear natural data. Because of the anti-interference and fault-tolerant capabilities, both LSPSc- and K-LSPSc-based LSSM can implement target identification based on a simple template set, which just needs several images containing enough local sparse structures to learn a sufficient sparse structure dictionary of a target class. Specifically, this LSSM approach has stable performance in the target detection with scene, shape and occlusions variations. High performance is demonstrated on several datasets, indicating robust infrared target recognition in diverse environments and imaging conditions. PMID:28323824

Push-Pull Receptive Field Organization and Synaptic Depression: Mechanisms for Reliably Encoding Naturalistic Stimuli in V1

PubMed Central

Kremkow, Jens; Perrinet, Laurent U.; Monier, Cyril; Alonso, Jose-Manuel; Aertsen, Ad; Frégnac, Yves; Masson, Guillaume S.

2016-01-01

Neurons in the primary visual cortex are known for responding vigorously but with high variability to classical stimuli such as drifting bars or gratings. By contrast, natural scenes are encoded more efficiently by sparse and temporal precise spiking responses. We used a conductance-based model of the visual system in higher mammals to investigate how two specific features of the thalamo-cortical pathway, namely push-pull receptive field organization and fast synaptic depression, can contribute to this contextual reshaping of V1 responses. By comparing cortical dynamics evoked respectively by natural vs. artificial stimuli in a comprehensive parametric space analysis, we demonstrate that the reliability and sparseness of the spiking responses during natural vision is not a mere consequence of the increased bandwidth in the sensory input spectrum. Rather, it results from the combined impacts of fast synaptic depression and push-pull inhibition, the later acting for natural scenes as a form of “effective” feed-forward inhibition as demonstrated in other sensory systems. Thus, the combination of feedforward-like inhibition with fast thalamo-cortical synaptic depression by simple cells receiving a direct structured input from thalamus composes a generic computational mechanism for generating a sparse and reliable encoding of natural sensory events. PMID:27242445

Accounting for cell lineage and sex effects in the identification of cell-specific DNA methylation using a Bayesian model selection algorithm.

PubMed

White, Nicole; Benton, Miles; Kennedy, Daniel; Fox, Andrew; Griffiths, Lyn; Lea, Rodney; Mengersen, Kerrie

2017-01-01

Cell- and sex-specific differences in DNA methylation are major sources of epigenetic variation in whole blood. Heterogeneity attributable to cell type has motivated the identification of cell-specific methylation at the CpG level, however statistical methods for this purpose have been limited to pairwise comparisons between cell types or between the cell type of interest and whole blood. We developed a Bayesian model selection algorithm for the identification of cell-specific methylation profiles that incorporates knowledge of shared cell lineage and allows for the identification of differential methylation profiles in one or more cell types simultaneously. Under the proposed methodology, sex-specific differences in methylation by cell type are also assessed. Using publicly available, cell-sorted methylation data, we show that 51.3% of female CpG markers and 61.4% of male CpG markers identified were associated with differential methylation in more than one cell type. The impact of cell lineage on differential methylation was also highlighted. An evaluation of sex-specific differences revealed differences in CD56+NK methylation, within both single and multi- cell dependent methylation patterns. Our findings demonstrate the need to account for cell lineage in studies of differential methylation and associated sex effects.

Boosting multi-state models.

PubMed

Reulen, Holger; Kneib, Thomas

2016-04-01

One important goal in multi-state modelling is to explore information about conditional transition-type-specific hazard rate functions by estimating influencing effects of explanatory variables. This may be performed using single transition-type-specific models if these covariate effects are assumed to be different across transition-types. To investigate whether this assumption holds or whether one of the effects is equal across several transition-types (cross-transition-type effect), a combined model has to be applied, for instance with the use of a stratified partial likelihood formulation. Here, prior knowledge about the underlying covariate effect mechanisms is often sparse, especially about ineffectivenesses of transition-type-specific or cross-transition-type effects. As a consequence, data-driven variable selection is an important task: a large number of estimable effects has to be taken into account if joint modelling of all transition-types is performed. A related but subsequent task is model choice: is an effect satisfactory estimated assuming linearity, or is the true underlying nature strongly deviating from linearity? This article introduces component-wise Functional Gradient Descent Boosting (short boosting) for multi-state models, an approach performing unsupervised variable selection and model choice simultaneously within a single estimation run. We demonstrate that features and advantages in the application of boosting introduced and illustrated in classical regression scenarios remain present in the transfer to multi-state models. As a consequence, boosting provides an effective means to answer questions about ineffectiveness and non-linearity of single transition-type-specific or cross-transition-type effects.

Compilation of 1985 Annual Reports of the Navy ELF (Extremely Low Frequency) Communications System Ecological Monitoring Program. Volume 1. Tabs A-C.

DTIC Science & Technology

1986-07-01

and straight when short, but spindly and often crooked when long, ususally somewhat constricted at the base. Microscopic -- Surface hyphae sparse, 2-3... hyphae with conspicuous interlocking, "jig-saw puzzle-like" pattern; cortical cells red-brown except over apex where they are colorless; Hartig net hyphae ...Type S Macroscopic -- Black, sometimes with lighter apex; usually fuzzy, with abundant attached, coarse hyphae ; 1-3 mm long X 0.5-1.0 mm diameter; mono

Parallel RNAi screens across different cell lines identify generic and cell type-specific regulators of actin organization and cell morphology.

PubMed

Liu, Tao; Sims, David; Baum, Buzz

2009-01-01

In recent years RNAi screening has proven a powerful tool for dissecting gene functions in animal cells in culture. However, to date, most RNAi screens have been performed in a single cell line, and results then extrapolated across cell types and systems. Here, to dissect generic and cell type-specific mechanisms underlying cell morphology, we have performed identical kinome RNAi screens in six different Drosophila cell lines, derived from two distinct tissues of origin. This analysis identified a core set of kinases required for normal cell morphology in all lines tested, together with a number of kinases with cell type-specific functions. Most significantly, the screen identified a role for minibrain (mnb/DYRK1A), a kinase associated with Down's syndrome, in the regulation of actin-based protrusions in CNS-derived cell lines. This cell type-specific requirement was not due to the peculiarities in the morphology of CNS-derived cells and could not be attributed to differences in mnb expression. Instead, it likely reflects differences in gene expression that constitute the cell type-specific functional context in which mnb/DYRK1A acts. Using parallel RNAi screens and gene expression analyses across cell types we have identified generic and cell type-specific regulators of cell morphology, which include mnb/DYRK1A in the regulation of protrusion morphology in CNS-derived cell lines. This analysis reveals the importance of using different cell types to gain a thorough understanding of gene function across the genome and, in the case of kinases, the difficulties of using the differential gene expression to predict function.

Exhaustive Search for Sparse Variable Selection in Linear Regression

NASA Astrophysics Data System (ADS)

Igarashi, Yasuhiko; Takenaka, Hikaru; Nakanishi-Ohno, Yoshinori; Uemura, Makoto; Ikeda, Shiro; Okada, Masato

2018-04-01

We propose a K-sparse exhaustive search (ES-K) method and a K-sparse approximate exhaustive search method (AES-K) for selecting variables in linear regression. With these methods, K-sparse combinations of variables are tested exhaustively assuming that the optimal combination of explanatory variables is K-sparse. By collecting the results of exhaustively computing ES-K, various approximate methods for selecting sparse variables can be summarized as density of states. With this density of states, we can compare different methods for selecting sparse variables such as relaxation and sampling. For large problems where the combinatorial explosion of explanatory variables is crucial, the AES-K method enables density of states to be effectively reconstructed by using the replica-exchange Monte Carlo method and the multiple histogram method. Applying the ES-K and AES-K methods to type Ia supernova data, we confirmed the conventional understanding in astronomy when an appropriate K is given beforehand. However, we found the difficulty to determine K from the data. Using virtual measurement and analysis, we argue that this is caused by data shortage.

Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic Excitation and Inhibition

PubMed Central

Migliore, Michele; Hines, Michael L.; Shepherd, Gordon M.

2014-01-01

The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral–granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID:25297097

Effects of cholera toxin and isobutylmethylxanthine on growth of human fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Espinoza, B.; Wharton, W.

1986-08-01

Cholera toxin produced a dose-dependent decrease in the restimulation of G0/G1 traverse in density-arrested human fibroblasts but did not inhibit the stimulation of cells arrested in G0 after serum starvation at low density. In addition, cholera toxin did not inhibit the proliferation of sparse logarithmically growing human fibroblasts, even when low concentrations of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) were also present. However, the final density to which sparse cells grew was limited by cholera toxin, when added either alone or together with low concentrations of IBMX. In contrast, high concentrations of the phosphodiesterase inhibitor alone produced a profound inhibition inmore » the growth of sparse human fibrobasts. IBMX produced an inhibition both in the G1 and in the G2 phases of the cell cycle by a mechanism(s) that was not related to the magnitude of the increases in adenosine 3,5-cyclic monophosphate concentrations.« less

Heterogeneity of transverse-axial tubule system in mouse atria: Remodeling in atrial-specific Na+-Ca2+ exchanger knockout mice.

PubMed

Yue, Xin; Zhang, Rui; Kim, Brian; Ma, Aiqun; Philipson, Kenneth D; Goldhaber, Joshua I

2017-07-01

Transverse-axial tubules (TATs) are commonly assumed to be sparse or absent in atrial myocytes from small animals. Atrial myocytes from rats, cats and rabbits lack TATs, which results in a characteristic "V"-shaped Ca release pattern in confocal line-scan recordings due to the delayed rise of Ca in the center of the cell. To examine TAT expression in isolated mouse atrial myocytes, we loaded them with the membrane dye Di-4-ANEPPS to label TATs. We found that >80% of atrial myocytes had identifiable TATs. Atria from male mice had a higher TAT density than female mice, and TAT density correlated with cell width. Using the fluorescent Ca indicator Fluo-4-AM and confocal imaging, we found that wild type (WT) mouse atrial myocytes generate near-synchronous Ca transients, in contrast to the "V"-shaped pattern typically reported in other small animals such as rat. In atrial-specific Na-Ca exchanger (NCX) knockout (KO) mice, which develop sinus node dysfunction and atrial hypertrophy with dilation, we found a substantial loss of atrial TATs in isolated atrial myocytes. There was a greater loss of transverse tubules compared to axial tubules, resulting in a dominance of axial tubules. Consistent with the overall loss of TATs, NCX KO atrial myocytes displayed a "V"-shaped Ca transient with slower and reduced central (CT) Ca release and uptake in comparison to subsarcolemmal (SS) Ca release. We compared chemically detubulated (DT) WT cells to KO, and found similar slowing of CT Ca release and uptake. However, SS Ca transients in the WT DT cells had faster uptake kinetics than KO cells, consistent with the presence of NCX and normal sarcolemmal Ca efflux in the WT DT cells. We conclude that the remodeling of NCX KO atrial myocytes is accompanied by a loss of TATs leading to abnormal Ca release and uptake that could impact atrial contractility and rhythm. Copyright © 2017 Elsevier Ltd. All rights reserved.

The influence of biomechanical properties and cannabinoids on tumor invasion.

PubMed

Hohmann, Tim; Grabiec, Urszula; Ghadban, Chalid; Feese, Kerstin; Dehghani, Faramarz

2017-01-02

Cannabinoids are known to have an anti-tumorous effect, but the underlying mechanisms are only sparsely understood. Mechanical characteristics of tumor cells represent a promising marker to distinguish between tumor cells and the healthy tissue. We tested the hypothesis whether cannabinoids influence the tumor cell specific mechanical and migratory properties and if these factors are a prognostic marker for the invasiveness of tumor cells. 3 different glioblastoma cell lines were treated with cannabinoids and changes of mechanical and migratory properties of single cells were measured using atomic force microscopy and time lapse imaging. The invasiveness of cell lines was determined using a co-culture model with organotypic hippocampal slice cultures. We found that cannabinoids are capable of influencing migratory and mechanical properties in a cell line specific manner. A network analysis revealed a correlation between a "generalized stiffness" and the invasiveness for all tumor cell lines after 3 and 4 d of invasion time: r 3d = -0.88 [-0.52;-0.97]; r 4d = -0.90 [-0.59;-0.98]. Here we could show that a "generalized stiffness" is a profound marker for the invasiveness of a tumor cell population in our model and thus might be of high clinical relevance for drug testing. Additionally cannabinoids were shown to be of potential use for therapeutic approaches of glioblastoma.

The HTM Spatial Pooler-A Neocortical Algorithm for Online Sparse Distributed Coding.

PubMed

Cui, Yuwei; Ahmad, Subutai; Hawkins, Jeff

2017-01-01

Hierarchical temporal memory (HTM) provides a theoretical framework that models several key computational principles of the neocortex. In this paper, we analyze an important component of HTM, the HTM spatial pooler (SP). The SP models how neurons learn feedforward connections and form efficient representations of the input. It converts arbitrary binary input patterns into sparse distributed representations (SDRs) using a combination of competitive Hebbian learning rules and homeostatic excitability control. We describe a number of key properties of the SP, including fast adaptation to changing input statistics, improved noise robustness through learning, efficient use of cells, and robustness to cell death. In order to quantify these properties we develop a set of metrics that can be directly computed from the SP outputs. We show how the properties are met using these metrics and targeted artificial simulations. We then demonstrate the value of the SP in a complete end-to-end real-world HTM system. We discuss the relationship with neuroscience and previous studies of sparse coding. The HTM spatial pooler represents a neurally inspired algorithm for learning sparse representations from noisy data streams in an online fashion.

Liver segmentation from CT images using a sparse priori statistical shape model (SP-SSM).

PubMed

Wang, Xuehu; Zheng, Yongchang; Gan, Lan; Wang, Xuan; Sang, Xinting; Kong, Xiangfeng; Zhao, Jie

2017-01-01

This study proposes a new liver segmentation method based on a sparse a priori statistical shape model (SP-SSM). First, mark points are selected in the liver a priori model and the original image. Then, the a priori shape and its mark points are used to obtain a dictionary for the liver boundary information. Second, the sparse coefficient is calculated based on the correspondence between mark points in the original image and those in the a priori model, and then the sparse statistical model is established by combining the sparse coefficients and the dictionary. Finally, the intensity energy and boundary energy models are built based on the intensity information and the specific boundary information of the original image. Then, the sparse matching constraint model is established based on the sparse coding theory. These models jointly drive the iterative deformation of the sparse statistical model to approximate and accurately extract the liver boundaries. This method can solve the problems of deformation model initialization and a priori method accuracy using the sparse dictionary. The SP-SSM can achieve a mean overlap error of 4.8% and a mean volume difference of 1.8%, whereas the average symmetric surface distance and the root mean square symmetric surface distance can reach 0.8 mm and 1.4 mm, respectively.

Inflammatory myofibroblastic tumors of the lung carrying a chimeric A2M-ALK gene: report of 2 infantile cases and review of the differential diagnosis of infantile pulmonary lesions.

PubMed

Tanaka, Mio; Kohashi, Kenichi; Kushitani, Kei; Yoshida, Misa; Kurihara, Sho; Kawashima, Masumi; Ueda, Yuka; Souzaki, Ryota; Kinoshita, Yoshiaki; Oda, Yoshinao; Takeshima, Yukio; Hiyama, Eiso; Taguchi, Tomoaki; Tanaka, Yukichi

2017-08-01

We report 2 infantile cases of pulmonary tumor carrying a chimeric A2M-ALK gene. A2M-ALK is a newly identified anaplastic lymphoma kinase (ALK)-related chimeric gene from a tumor diagnosed as fetal lung interstitial tumor (FLIT). FLIT is a recently recognized infantile pulmonary lesion defined as a mass-like lesion that morphologically resembles the fetal lung. Grossly, FLIT characteristically appears as a well-circumscribed spongy mass, whereas the tumors in these patients were solid and firm. Histologically, the tumors showed intrapulmonary lesions composed of densely proliferating polygonal or spindle-shaped mesenchymal cells with diffuse and dense infiltrations of inflammatory cells forming microcystic or micropapillary structures lined by thyroid transcription factor 1-positive pneumocytes, favoring inflammatory myofibroblastic tumor rather than FLIT. The proliferating cells were immunoreactive for ALK, and A2M-ALK was identified in both tumors with reverse-transcription polymerase chain reaction. The dense infiltration of inflammatory cells, immunoreactivity for ALK, and identification of an ALK-related chimeric gene suggested a diagnosis of inflammatory myofibroblastic tumor. Histologically, most reported FLITs show sparse inflammatory infiltrates and a relatively low density of interstitial cells in the septa, although prominent infiltration of inflammatory cells and high cellularity of interstitial cells are seen in some FLITs. The present cases suggest that ALK rearrangements, including the chimeric A2M-ALK gene, may be present in these infantile pulmonary lesions, especially those with inflammatory cell infiltration. We propose that these infantile pulmonary lesions containing a chimeric A2M-ALK gene be categorized as a specific type of inflammatory myofibroblastic tumor that develops exclusively in neonates and infants. Copyright © 2017 Elsevier Inc. All rights reserved.

Cell-mediated immunity to herpes simplex virus: recognition of type-specific and type-common surface antigens by cytotoxic T cell populations.

PubMed Central

Eberle, R; Russell, R G; Rouse, B T

1981-01-01

In this communication, we examine the specificity of anti-herpes simplex virus (HSV) cytotoxic T lymphocytes (CTL). Serological studies of the two related HSV serotypes (HSV-1 and HSV-2) have revealed both type-specific and cross-reactive antigenic determinants in the viral envelope and on the surface of infected cells. By analysis of cytotoxicity of CTL, generated in vitro by restimulation of splenocytes from mice primed with one or the other HSV serotype, the recognition of both type-specific and cross-reactive determinants on infected target cells by anti-HSV CTL was detectable. Thus, effector cells generated by priming and restimulating with the same virus recognized both type-specific and cross-reactive determinants on target cells infected with the homologous virus, but only cross-reactive determinants on target cells infected with the heterologous HSV serotype. CTL generated by restimulation with the heterologous virus were capable of recognizing only the cross-reactive determinants on either HSV-1- or HSV-2-infected target cells. These results indicate that two subpopulations of CTL exist in a population of anti-HSV immune spleen cells--those which recognize type-specific determinants and those specific for cross-reactive antigenic determinants present on the surface of HSV infected cells. The type-specific subset of anti-HSV CTL was shown to recognize the gC glycoprotein of HSV-1 infected target cells. In addition to the gC glycoprotein, at least one other type-specific surface antigen was also recognized by anti-HSV CTL in addition to the cross-reactive determinants recognized by anti-HSV CTL. PMID:6277790

Discriminative Dictionary Learning With Two-Level Low Rank and Group Sparse Decomposition for Image Classification.

PubMed

Wen, Zaidao; Hou, Zaidao; Jiao, Licheng

2017-11-01

Discriminative dictionary learning (DDL) framework has been widely used in image classification which aims to learn some class-specific feature vectors as well as a representative dictionary according to a set of labeled training samples. However, interclass similarities and intraclass variances among input samples and learned features will generally weaken the representability of dictionary and the discrimination of feature vectors so as to degrade the classification performance. Therefore, how to explicitly represent them becomes an important issue. In this paper, we present a novel DDL framework with two-level low rank and group sparse decomposition model. In the first level, we learn a class-shared and several class-specific dictionaries, where a low rank and a group sparse regularization are, respectively, imposed on the corresponding feature matrices. In the second level, the class-specific feature matrix will be further decomposed into a low rank and a sparse matrix so that intraclass variances can be separated to concentrate the corresponding feature vectors. Extensive experimental results demonstrate the effectiveness of our model. Compared with the other state-of-the-arts on several popular image databases, our model can achieve a competitive or better performance in terms of the classification accuracy.

β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure

PubMed Central

McLaren, James E.; Dolton, Garry; Matthews, Katherine K.; Gostick, Emma; Kronenberg-Versteeg, Deborah; Eichmann, Martin; Knight, Robin R.; Heck, Susanne; Powrie, Jake; Bingley, Polly J.; Dayan, Colin M.; Miles, John J.; Sewell, Andrew K.

2015-01-01

Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high definition polychromatic flow cytometry with ultrasensitive peptide-human leukocyte antigen class I (pHLAI) tetramer staining to quantify and characterize β-cell-specific CD8 T cell populations in patients with recent onset type 1 diabetes and healthy controls. Remarkably, we found that β-cell-specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy controls, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the β-cell-specific CD8 T cell compartment. Molecular analysis of selected β-cell-specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor (TCR) repertoires comprising exclusively private clonotypes. Collectively, these data identify novel and distinctive features of disease-relevant CD8 T cells that inform the immunopathogenesis of type 1 diabetes. PMID:25249579

Biclustering sparse binary genomic data.

PubMed

van Uitert, Miranda; Meuleman, Wouter; Wessels, Lodewyk

2008-12-01

Genomic datasets often consist of large, binary, sparse data matrices. In such a dataset, one is often interested in finding contiguous blocks that (mostly) contain ones. This is a biclustering problem, and while many algorithms have been proposed to deal with gene expression data, only two algorithms have been proposed that specifically deal with binary matrices. None of the gene expression biclustering algorithms can handle the large number of zeros in sparse binary matrices. The two proposed binary algorithms failed to produce meaningful results. In this article, we present a new algorithm that is able to extract biclusters from sparse, binary datasets. A powerful feature is that biclusters with different numbers of rows and columns can be detected, varying from many rows to few columns and few rows to many columns. It allows the user to guide the search towards biclusters of specific dimensions. When applying our algorithm to an input matrix derived from TRANSFAC, we find transcription factors with distinctly dissimilar binding motifs, but a clear set of common targets that are significantly enriched for GO categories.

Crooked fingers and sparse hair: an interesting case of trichorhinophalangeal syndrome type 1.

PubMed

Narayanan, Ramakrishna; Chennareddy, Srinivasa

2015-01-27

Trichorhinophalangeal syndrome type 1 is a rare skeletal dysplasia of autosomal-dominant inheritance due to defects in the TRPS-1 gene. The syndrome is characterised by sparse slow-growing hair, a bulbous pear-shaped nose, cone-shaped epiphyses and deformities of the interphalangeal joints resembling those in rheumatoid arthritis. We present a case of trichorhinophalangeal syndrome in a 23-year-old man who presented with symmetrical painless progressive deformity of the fingers in both hands. 2015 BMJ Publishing Group Ltd.

The Hadley circulation: assessing NCEP/NCAR reanalysis and sparse in-situ estimates

NASA Astrophysics Data System (ADS)

Waliser, D. E.; Shi, Zhixiong; Lanzante, J. R.; Oort, A. H.

We present a comparison of the zonal mean meridional circulations derived from monthly in situ data (i.e. radiosondes and ship reports) and from the NCEP/NCAR reanalysis product. To facilitate the interpretation of the results, a third estimate of the mean meridional circulation is produced by subsampling the reanalysis at the locations where radiosonde and surface ship data are available for the in situ calculation. This third estimate, known as the subsampled estimate, is compared to the complete reanalysis estimate to assess biases in conventional, in situ estimates of the Hadley circulation associated with the sparseness of the data sources (i.e., radiosonde network). The subsampled estimate is also compared to the in situ estimate to assess the biases introduced into the reanalysis product by the numerical model, initialization process and/or indirect data sources such as satellite retrievals. The comparisons suggest that a number of qualitative differences between the in situ and reanalysis estimates are mainly associated with the sparse sampling and simplified interpolation schemes associated with in situ estimates. These differences include: (1) a southern Hadley cell that consistently extends up to 200 hPa in the reanalysis, whereas the bulk of the circulation for the in situ and subsampled estimates tends to be confined to the lower half of the troposphere, (2) more well-defined and consistent poleward limits of the Hadley cells in the reanalysis compared to the in-situ and subsampled estimates, and (3) considerably less variability in magnitude and latitudinal extent of the Ferrel cells and southern polar cell exhibited in the reanalysis estimate compared to the in situ and subsampled estimates. Quantitative comparison shows that the subsampled estimate, relative to the reanalysis estimate, produces a stronger northern Hadley cell ( 20%), a weaker southern Hadley cell ( 20-60%), and weaker Ferrel cells in both hemispheres. These differences stem from poorly measured oceanic regions which necessitate significant interpolation over broad regions. Moreover, they help to pinpoint specific shortcomings in the present and previous in situ estimates of the Hadley circulation. Comparisons between the subsampled and in situ estimates suggest that the subsampled estimate produces a slightly stronger Hadley circulation in both hemispheres, with the relative differences in some seasons as large as 20-30%. 6These differences suggest that the mean meridional circulation associated with the NCEP/NCAR reanalysis is more energetic than observations suggest. Examination of ENSO-related changes to the Hadley circulation suggest that the in situ and subsampled estimates significantly overestimate the effects of ENSO on the Hadley circulation due to the reliance on sparsely distributed data. While all three estimates capture the large-scale region of low-level equatorial convergence near the dateline that occurs during El Nino, the in situ and subsampled estimates fail to effectively reproduce the large-scale areas of equatorial mass divergence to the west and east of this convergence area, leading to an overestimate of the effects of ENSO on the zonal mean circulation.

Input dependent cell assembly dynamics in a model of the striatal medium spiny neuron network.

PubMed

Ponzi, Adam; Wickens, Jeff

2012-01-01

The striatal medium spiny neuron (MSN) network is sparsely connected with fairly weak GABAergic collaterals receiving an excitatory glutamatergic cortical projection. Peri-stimulus time histograms (PSTH) of MSN population response investigated in various experimental studies display strong firing rate modulations distributed throughout behavioral task epochs. In previous work we have shown by numerical simulation that sparse random networks of inhibitory spiking neurons with characteristics appropriate for UP state MSNs form cell assemblies which fire together coherently in sequences on long behaviorally relevant timescales when the network receives a fixed pattern of constant input excitation. Here we first extend that model to the case where cortical excitation is composed of many independent noisy Poisson processes and demonstrate that cell assembly dynamics is still observed when the input is sufficiently weak. However if cortical excitation strength is increased more regularly firing and completely quiescent cells are found, which depend on the cortical stimulation. Subsequently we further extend previous work to consider what happens when the excitatory input varies as it would when the animal is engaged in behavior. We investigate how sudden switches in excitation interact with network generated patterned activity. We show that sequences of cell assembly activations can be locked to the excitatory input sequence and outline the range of parameters where this behavior is shown. Model cell population PSTH display both stimulus and temporal specificity, with large population firing rate modulations locked to elapsed time from task events. Thus the random network can generate a large diversity of temporally evolving stimulus dependent responses even though the input is fixed between switches. We suggest the MSN network is well suited to the generation of such slow coherent task dependent response which could be utilized by the animal in behavior.

Input Dependent Cell Assembly Dynamics in a Model of the Striatal Medium Spiny Neuron Network

PubMed Central

Ponzi, Adam; Wickens, Jeff

2012-01-01

The striatal medium spiny neuron (MSN) network is sparsely connected with fairly weak GABAergic collaterals receiving an excitatory glutamatergic cortical projection. Peri-stimulus time histograms (PSTH) of MSN population response investigated in various experimental studies display strong firing rate modulations distributed throughout behavioral task epochs. In previous work we have shown by numerical simulation that sparse random networks of inhibitory spiking neurons with characteristics appropriate for UP state MSNs form cell assemblies which fire together coherently in sequences on long behaviorally relevant timescales when the network receives a fixed pattern of constant input excitation. Here we first extend that model to the case where cortical excitation is composed of many independent noisy Poisson processes and demonstrate that cell assembly dynamics is still observed when the input is sufficiently weak. However if cortical excitation strength is increased more regularly firing and completely quiescent cells are found, which depend on the cortical stimulation. Subsequently we further extend previous work to consider what happens when the excitatory input varies as it would when the animal is engaged in behavior. We investigate how sudden switches in excitation interact with network generated patterned activity. We show that sequences of cell assembly activations can be locked to the excitatory input sequence and outline the range of parameters where this behavior is shown. Model cell population PSTH display both stimulus and temporal specificity, with large population firing rate modulations locked to elapsed time from task events. Thus the random network can generate a large diversity of temporally evolving stimulus dependent responses even though the input is fixed between switches. We suggest the MSN network is well suited to the generation of such slow coherent task dependent response which could be utilized by the animal in behavior. PMID:22438838

Sparse graph regularization for robust crop mapping using hyperspectral remotely sensed imagery with very few in situ data

NASA Astrophysics Data System (ADS)

Xue, Zhaohui; Du, Peijun; Li, Jun; Su, Hongjun

2017-02-01

The generally limited availability of training data relative to the usually high data dimension pose a great challenge to accurate classification of hyperspectral imagery, especially for identifying crops characterized with highly correlated spectra. However, traditional parametric classification models are problematic due to the need of non-singular class-specific covariance matrices. In this research, a novel sparse graph regularization (SGR) method is presented, aiming at robust crop mapping using hyperspectral imagery with very few in situ data. The core of SGR lies in propagating labels from known data to unknown, which is triggered by: (1) the fraction matrix generated for the large unknown data by using an effective sparse representation algorithm with respect to the few training data serving as the dictionary; (2) the prediction function estimated for the few training data by formulating a regularization model based on sparse graph. Then, the labels of large unknown data can be obtained by maximizing the posterior probability distribution based on the two ingredients. SGR is more discriminative, data-adaptive, robust to noise, and efficient, which is unique with regard to previously proposed approaches and has high potentials in discriminating crops, especially when facing insufficient training data and high-dimensional spectral space. The study area is located at Zhangye basin in the middle reaches of Heihe watershed, Gansu, China, where eight crop types were mapped with Compact Airborne Spectrographic Imager (CASI) and Shortwave Infrared Airborne Spectrogrpahic Imager (SASI) hyperspectral data. Experimental results demonstrate that the proposed method significantly outperforms other traditional and state-of-the-art methods.

Receptive Field Inference with Localized Priors

PubMed Central

Park, Mijung; Pillow, Jonathan W.

2011-01-01

The linear receptive field describes a mapping from sensory stimuli to a one-dimensional variable governing a neuron's spike response. However, traditional receptive field estimators such as the spike-triggered average converge slowly and often require large amounts of data. Bayesian methods seek to overcome this problem by biasing estimates towards solutions that are more likely a priori, typically those with small, smooth, or sparse coefficients. Here we introduce a novel Bayesian receptive field estimator designed to incorporate locality, a powerful form of prior information about receptive field structure. The key to our approach is a hierarchical receptive field model that flexibly adapts to localized structure in both spacetime and spatiotemporal frequency, using an inference method known as empirical Bayes. We refer to our method as automatic locality determination (ALD), and show that it can accurately recover various types of smooth, sparse, and localized receptive fields. We apply ALD to neural data from retinal ganglion cells and V1 simple cells, and find it achieves error rates several times lower than standard estimators. Thus, estimates of comparable accuracy can be achieved with substantially less data. Finally, we introduce a computationally efficient Markov Chain Monte Carlo (MCMC) algorithm for fully Bayesian inference under the ALD prior, yielding accurate Bayesian confidence intervals for small or noisy datasets. PMID:22046110

Multi-threaded Sparse Matrix Sparse Matrix Multiplication for Many-Core and GPU Architectures.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deveci, Mehmet; Trott, Christian Robert; Rajamanickam, Sivasankaran

Sparse Matrix-Matrix multiplication is a key kernel that has applications in several domains such as scientific computing and graph analysis. Several algorithms have been studied in the past for this foundational kernel. In this paper, we develop parallel algorithms for sparse matrix- matrix multiplication with a focus on performance portability across different high performance computing architectures. The performance of these algorithms depend on the data structures used in them. We compare different types of accumulators in these algorithms and demonstrate the performance difference between these data structures. Furthermore, we develop a meta-algorithm, kkSpGEMM, to choose the right algorithm and datamore » structure based on the characteristics of the problem. We show performance comparisons on three architectures and demonstrate the need for the community to develop two phase sparse matrix-matrix multiplication implementations for efficient reuse of the data structures involved.« less

Research on segmentation based on multi-atlas in brain MR image

NASA Astrophysics Data System (ADS)

Qian, Yuejing

2018-03-01

Accurate segmentation of specific tissues in brain MR image can be effectively achieved with the multi-atlas-based segmentation method, and the accuracy mainly depends on the image registration accuracy and fusion scheme. This paper proposes an automatic segmentation method based on the multi-atlas for brain MR image. Firstly, to improve the registration accuracy in the area to be segmented, we employ a target-oriented image registration method for the refinement. Then In the label fusion, we proposed a new algorithm to detect the abnormal sparse patch and simultaneously abandon the corresponding abnormal sparse coefficients, this method is made based on the remaining sparse coefficients combined with the multipoint label estimator strategy. The performance of the proposed method was compared with those of the nonlocal patch-based label fusion method (Nonlocal-PBM), the sparse patch-based label fusion method (Sparse-PBM) and majority voting method (MV). Based on our experimental results, the proposed method is efficient in the brain MR images segmentation compared with MV, Nonlocal-PBM, and Sparse-PBM methods.

Cell Specific eQTL Analysis without Sorting Cells

PubMed Central

Esko, Tõnu; Peters, Marjolein J.; Schurmann, Claudia; Schramm, Katharina; Kettunen, Johannes; Yaghootkar, Hanieh; Fairfax, Benjamin P.; Andiappan, Anand Kumar; Li, Yang; Fu, Jingyuan; Karjalainen, Juha; Platteel, Mathieu; Visschedijk, Marijn; Weersma, Rinse K.; Kasela, Silva; Milani, Lili; Tserel, Liina; Peterson, Pärt; Reinmaa, Eva; Hofman, Albert; Uitterlinden, André G.; Rivadeneira, Fernando; Homuth, Georg; Petersmann, Astrid; Lorbeer, Roberto; Prokisch, Holger; Meitinger, Thomas; Herder, Christian; Roden, Michael; Grallert, Harald; Ripatti, Samuli; Perola, Markus; Wood, Andrew R.; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Knight, Julian C.; Melchiotti, Rossella; Lee, Bernett; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Wang, De Yun; van den Berg, Leonard H.; Veldink, Jan H.; Rotzschke, Olaf; Makino, Seiko; Salomaa, Veikko; Strauch, Konstantin; Völker, Uwe; van Meurs, Joyce B. J.; Metspalu, Andres; Wijmenga, Cisca; Jansen, Ritsert C.; Franke, Lude

2015-01-01

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus. PMID:25955312

Robust visual tracking via multiscale deep sparse networks

NASA Astrophysics Data System (ADS)

Wang, Xin; Hou, Zhiqiang; Yu, Wangsheng; Xue, Yang; Jin, Zefenfen; Dai, Bo

2017-04-01

In visual tracking, deep learning with offline pretraining can extract more intrinsic and robust features. It has significant success solving the tracking drift in a complicated environment. However, offline pretraining requires numerous auxiliary training datasets and is considerably time-consuming for tracking tasks. To solve these problems, a multiscale sparse networks-based tracker (MSNT) under the particle filter framework is proposed. Based on the stacked sparse autoencoders and rectifier linear unit, the tracker has a flexible and adjustable architecture without the offline pretraining process and exploits the robust and powerful features effectively only through online training of limited labeled data. Meanwhile, the tracker builds four deep sparse networks of different scales, according to the target's profile type. During tracking, the tracker selects the matched tracking network adaptively in accordance with the initial target's profile type. It preserves the inherent structural information more efficiently than the single-scale networks. Additionally, a corresponding update strategy is proposed to improve the robustness of the tracker. Extensive experimental results on a large scale benchmark dataset show that the proposed method performs favorably against state-of-the-art methods in challenging environments.

Glutamic Acid - Amino Acid, Neurotransmitter, and Drug - Is Responsible for Protein Synthesis Rhythm in Hepatocyte Populations in vitro and in vivo.

PubMed

Brodsky, V Y; Malchenko, L A; Konchenko, D S; Zvezdina, N D; Dubovaya, T K

2016-08-01

Primary cultures of rat hepatocytes were studied in serum-free media. Ultradian protein synthesis rhythm was used as a marker of cell synchronization in the population. Addition of glutamic acid (0.2 mg/ml) to the medium of nonsynchronous sparse cultures resulted in detection of a common protein synthesis rhythm, hence in synchronization of the cells. The antagonist of glutamic acid metabotropic receptors MCPG (0.01 mg/ml) added together with glutamic acid abolished the synchronization effect; in sparse cultures, no rhythm was detected. Feeding rats with glutamic acid (30 mg with food) resulted in protein synthesis rhythm in sparse cultures obtained from the rats. After feeding without glutamic acid, linear kinetics of protein synthesis was revealed. Thus, glutamic acid, a component of blood as a non-neural transmitter, can synchronize the activity of hepatocytes and can form common rhythm of protein synthesis in vitro and in vivo. This effect is realized via receptors. Mechanisms of cell-cell communication are discussed on analyzing effects of non-neural functions of neurotransmitters. Glutamic acid is used clinically in humans. Hence, a previously unknown function of this drug is revealed.

Sensorimotor Representations in Cerebellar Granule Cells in Larval Zebrafish Are Dense, Spatially Organized, and Non-temporally Patterned.

PubMed

Knogler, Laura D; Markov, Daniil A; Dragomir, Elena I; Štih, Vilim; Portugues, Ruben

2017-05-08

A fundamental question in neurobiology is how animals integrate external sensory information from their environment with self-generated motor and sensory signals in order to guide motor behavior and adaptation. The cerebellum is a vertebrate hindbrain region where all of these signals converge and that has been implicated in the acquisition, coordination, and calibration of motor activity. Theories of cerebellar function postulate that granule cells encode a variety of sensorimotor signals in the cerebellar input layer. These models suggest that representations should be high-dimensional, sparse, and temporally patterned. However, in vivo physiological recordings addressing these points have been limited and in particular have been unable to measure the spatiotemporal dynamics of population-wide activity. In this study, we use both calcium imaging and electrophysiology in the awake larval zebrafish to investigate how cerebellar granule cells encode three types of sensory stimuli as well as stimulus-evoked motor behaviors. We find that a large fraction of all granule cells are active in response to these stimuli, such that representations are not sparse at the population level. We find instead that most responses belong to only one of a small number of distinct activity profiles, which are temporally homogeneous and anatomically clustered. We furthermore identify granule cells that are active during swimming behaviors and others that are multimodal for sensory and motor variables. When we pharmacologically change the threshold of a stimulus-evoked behavior, we observe correlated changes in these representations. Finally, electrophysiological data show no evidence for temporal patterning in the coding of different stimulus durations. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Cytotoxicity of zinc oxide (ZnO) nanoparticles is influenced by cell density and culture format.

PubMed

Heng, Boon Chin; Zhao, Xinxin; Xiong, Sijing; Ng, Kee Woei; Boey, Freddy Yin-Chiang; Loo, Joachim Say-Chye

2011-06-01

A parameter that has often been overlooked in cytotoxicity assays is the density and confluency of mammalian cell monolayers utilized for toxicology screening. Hence, this study investigated how different cell seeding densities influenced their response to cytotoxic challenge with ZnO nanoparticles. Utilizing the same volume (1 ml per well) and concentration range (5-40 μg/ml) of ZnO nanoparticles, contradictory results were observed with higher-density cell monolayers (BEAS-2B cells) obtained either by increasing the number of seeded cells per well (50,000 vs. 200,000 cells per well of 12-well plate) or by seeding the same numbers of cells (50,000) within a smaller surface area (12-well vs. 48-well plate, 4.8 vs. 1.2 cm(2), respectively). Further experiments demonstrated that the data may be skewed by inconsistency in the mass/number of nanoparticles per unit area of culture surface, as well as by inconsistent nanoparticle to cell ratio. To keep these parameters constant, the same number of cells (50,000 per well) were seeded on 12-well plates, but with the cells being seeded at the edge of the well for the experimental group (by tilting the plate) to form a dense confluent monolayer, as opposed to a sparse monolayer for the control group seeded in the conventional manner. Utilizing such an experimental set-up for the comparative evaluation of four different cell lines (BEAS-2B, L-929, CRL-2922 and C2C12), it was observed that the high cell density monolayer was consistently more resistant to the cytotoxic effects of ZnO nanoparticles compared to the sparse monolayer for all four different cell types, with the greatest differences being observed above a ZnO concentration of 10 μg/ml. Hence, the results of this study demonstrate the need for the standardization of cell culture protocols utilized for toxicology screening of nanoparticles, with respect to cell density and mass/number of nanoparticles per unit area of culture surface.

Cell-type- and tissue-specific transcriptomes of the white spruce (Picea glauca) bark unmask fine-scale spatial patterns of constitutive and induced conifer defense.

PubMed

Celedon, Jose M; Yuen, Macaire M S; Chiang, Angela; Henderson, Hannah; Reid, Karen E; Bohlmann, Jörg

2017-11-01

Plant defenses often involve specialized cells and tissues. In conifers, specialized cells of the bark are important for defense against insects and pathogens. Using laser microdissection, we characterized the transcriptomes of cortical resin duct cells, phenolic cells and phloem of white spruce (Picea glauca) bark under constitutive and methyl jasmonate (MeJa)-induced conditions, and we compared these transcriptomes with the transcriptome of the bark tissue complex. Overall, ~3700 bark transcripts were differentially expressed in response to MeJa. Approximately 25% of transcripts were expressed in only one cell type, revealing cell specialization at the transcriptome level. MeJa caused cell-type-specific transcriptome responses and changed the overall patterns of cell-type-specific transcript accumulation. Comparison of transcriptomes of the conifer bark tissue complex and specialized cells resolved a masking effect inherent to transcriptome analysis of complex tissues, and showed the actual cell-type-specific transcriptome signatures. Characterization of cell-type-specific transcriptomes is critical to reveal the dynamic patterns of spatial and temporal display of constitutive and induced defense systems in a complex plant tissue or organ. This was demonstrated with the improved resolution of spatially restricted expression of sets of genes of secondary metabolism in the specialized cell types. © 2017 The Authors The Plant Journal published by John Wiley & Sons Ltd and Society for Experimental Biology.

The morphological and chemical characteristics of striatal neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the rat.

PubMed

Waldvogel, H J; Kubota, Y; Trevallyan, S C; Kawaguchi, Y; Fritschy, J M; Mohler, H; Faull, R L

1997-10-01

The distribution, morphology and chemical characteristics of neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the striatum of the basal ganglia in the rat brain were investigated at the light, confocal and electron microscope levels using single, double and triple immunohistochemical labelling techniques. The results showed that alpha1-subunit immunoreactive neurons were sparsely distributed throughout the rat striatum. Double and triple labelling results showed that all the alpha1-subunit-immunoreactive neurons were positive for glutamate decarboxylase and immunoreactive for the beta2,3 and gamma2 subunits of the GABA(A) receptor. Three types of alpha1-subunit-immunoreactive neurons were identified in the striatum on the basis of cellular morphology and chemical characteristics. The most numerous alpha1-subunit-immunoreactive neurons were medium-sized, aspiny neurons with a widely branching dendritic tree. They were parvalbumin-negative and were located mainly in the dorsolateral regions of the striatum. Electron microscopy showed that these neurons had an indented nuclear membrane, typical of striatal interneurons, and were surrounded by small numbers of axon terminals which established alpha1-subunit-immunoreactive synaptic contacts with the soma and dendrites. These cells were classified as type 1 alpha1-subunit-immunoreactive neurons and comprised 75% of the total population of alpha1-subunit-immunoreactive neurons in the striatum. The remaining alpha1-subunit-immunoreactive neurons comprised of a heterogeneous population of large-sized neurons localized in the ventral and medial regions of the striatum. The most numerous large-sized cells were parvalbumin-negative, had two to three relatively short branching dendrites and were designated type 2 alpha1-subunit-immunoreactive neurons. Electron microscopy showed that the type 2 neurons were characterized by a highly convoluted nuclear membrane and were sparsely covered with small axon terminals. The type 2 neurons comprised 20% of the total population of alpha1-subunit-immunoreactive neurons. The remaining large-sized alpha1-immunoreactive cells were designated type 3 cells; they were positive for parvalbumin and were distinguished by long branching dendrites extending dorsally for 600-800 microm into the striatum. These neurons comprised 5% of the total population of alpha1-subunit-immunoreactive neurons and were surrounded by enkephalin-immunoreactive terminals. Electron microscopy showed that the alpha1-subunit type 3 neurons had an indented nuclear membrane and were densely covered with small axon terminals which established alpha1-subunit-immunoreactive symmetrical synaptic contacts with the soma and dendrites. These results provide a detailed characterization of the distribution, morphology and chemical characteristics of the alpha1-subunit-immunoreactive neurons in the rat striatum and suggest that the type 1 and type 2 neurons comprise of separate populations of striatal interneurons while the type 3 neurons may represent the large striatonigral projection neurons described by Bolam et al. [Bolam J. P., Somogyi P., Totterdell S. and Smith A. D. (1981) Neuroscience 6, 2141-2157.].

Live Imaging of Endogenous PSD-95 Using ENABLED: A Conditional Strategy to Fluorescently Label Endogenous Proteins

PubMed Central

Fortin, Dale A.; Tillo, Shane E.; Yang, Guang; Rah, Jong-Cheol; Melander, Joshua B.; Bai, Suxia; Soler-Cedeño, Omar; Qin, Maozhen; Zemelman, Boris V.; Guo, Caiying

2014-01-01

Stoichiometric labeling of endogenous synaptic proteins for high-contrast live-cell imaging in brain tissue remains challenging. Here, we describe a conditional mouse genetic strategy termed endogenous labeling via exon duplication (ENABLED), which can be used to fluorescently label endogenous proteins with near ideal properties in all neurons, a sparse subset of neurons, or specific neuronal subtypes. We used this method to label the postsynaptic density protein PSD-95 with mVenus without overexpression side effects. We demonstrated that mVenus-tagged PSD-95 is functionally equivalent to wild-type PSD-95 and that PSD-95 is present in nearly all dendritic spines in CA1 neurons. Within spines, while PSD-95 exhibited low mobility under basal conditions, its levels could be regulated by chronic changes in neuronal activity. Notably, labeled PSD-95 also allowed us to visualize and unambiguously examine otherwise-unidentifiable excitatory shaft synapses in aspiny neurons, such as parvalbumin-positive interneurons and dopaminergic neurons. Our results demonstrate that the ENABLED strategy provides a valuable new approach to study the dynamics of endogenous synaptic proteins in vivo. PMID:25505322

Examination of drivers' cell phone use behavior at intersections by using naturalistic driving data.

PubMed

Xiong, Huimin; Bao, Shan; Sayer, James; Kato, Kazuma

2015-09-01

Many driving simulator studies have shown that cell phone use while driving greatly degraded driving performance. In terms of safety analysis, many factors including drivers, vehicles, and driving situations need to be considered. Controlled or simulated studies cannot always account for the full effects of these factors, especially situational factors such as road condition, traffic density, and weather and lighting conditions. Naturalistic driving by its nature provides a natural and realistic way to examine drivers' behaviors and associated factors for cell phone use while driving. In this study, driving speed while using a cell phone (conversation or visual/manual tasks) was compared to two baselines (baseline 1: normal driving condition, which only excludes driving while using a cell phone, baseline 2: driving-only condition, which excludes all types of secondary tasks) when traversing an intersection. The outcomes showed that drivers drove slower when using a cell for both conversation and visual/manual (VM) tasks compared to baseline conditions. With regard to cell phone conversations, drivers were more likely to drive faster during the day time compared to night time driving and drive slower under moderate traffic compared to under sparse traffic situations. With regard to VM tasks, there was a significant interaction between traffic and cell phone use conditions. The maximum speed with VM tasks was significantly lower than that with baseline conditions under sparse traffic conditions. In contrast, the maximum speed with VM tasks was slightly higher than that with baseline driving under dense traffic situations. This suggests that drivers might self-regulate their behavior based on the driving situations and demand for secondary tasks, which could provide insights on driver distraction guidelines. With the rapid development of in-vehicle technology, the findings in this research could lead the improvement of human-machine interface (HMI) design as well. Copyright © 2015 Elsevier Ltd and National Safety Council. All rights reserved.

Amesos2 and Belos: Direct and Iterative Solvers for Large Sparse Linear Systems

DOE PAGES

Bavier, Eric; Hoemmen, Mark; Rajamanickam, Sivasankaran; ...

2012-01-01

Solvers for large sparse linear systems come in two categories: direct and iterative. Amesos2, a package in the Trilinos software project, provides direct methods, and Belos, another Trilinos package, provides iterative methods. Amesos2 offers a common interface to many different sparse matrix factorization codes, and can handle any implementation of sparse matrices and vectors, via an easy-to-extend C++ traits interface. It can also factor matrices whose entries have arbitrary “Scalar” type, enabling extended-precision and mixed-precision algorithms. Belos includes many different iterative methods for solving large sparse linear systems and least-squares problems. Unlike competing iterative solver libraries, Belos completely decouples themore » algorithms from the implementations of the underlying linear algebra objects. This lets Belos exploit the latest hardware without changes to the code. Belos favors algorithms that solve higher-level problems, such as multiple simultaneous linear systems and sequences of related linear systems, faster than standard algorithms. The package also supports extended-precision and mixed-precision algorithms. Together, Amesos2 and Belos form a complete suite of sparse linear solvers.« less

Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes.

PubMed

Ackermann, Amanda M; Wang, Zhiping; Schug, Jonathan; Naji, Ali; Kaestner, Klaus H

2016-03-01

Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity. We sorted human α- and β-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to α-cells, while CHODL (chondrolectin) immunoreactivity was only present in β-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. We have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.

Assessing sensory versus optogenetic network activation by combining (o)fMRI with optical Ca2+ recordings.

PubMed

Schmid, Florian; Wachsmuth, Lydia; Schwalm, Miriam; Prouvot, Pierre-Hugues; Jubal, Eduardo Rosales; Fois, Consuelo; Pramanik, Gautam; Zimmer, Claus; Faber, Cornelius; Stroh, Albrecht

2016-11-01

Encoding of sensory inputs in the cortex is characterized by sparse neuronal network activation. Optogenetic stimulation has previously been combined with fMRI (ofMRI) to probe functional networks. However, for a quantitative optogenetic probing of sensory-driven sparse network activation, the level of similarity between sensory and optogenetic network activation needs to be explored. Here, we complement ofMRI with optic fiber-based population Ca 2+ recordings for a region-specific readout of neuronal spiking activity in rat brain. Comparing Ca 2+ responses to the blood oxygenation level-dependent signal upon sensory stimulation with increasing frequencies showed adaptation of Ca 2+ transients contrasted by an increase of blood oxygenation level-dependent responses, indicating that the optical recordings convey complementary information on neuronal network activity to the corresponding hemodynamic response. To study the similarity of optogenetic and sensory activation, we quantified the density of cells expressing channelrhodopsin-2 and modeled light propagation in the tissue. We estimated the effectively illuminated volume and numbers of optogenetically stimulated neurons, being indicative of sparse activation. At the functional level, upon either sensory or optogenetic stimulation we detected single-peak short-latency primary Ca 2+ responses with similar amplitudes and found that blood oxygenation level-dependent responses showed similar time courses. These data suggest that ofMRI can serve as a representative model for functional brain mapping. © The Author(s) 2015.

Large-scale two-photon imaging revealed super-sparse population codes in the V1 superficial layer of awake monkeys.

PubMed

Tang, Shiming; Zhang, Yimeng; Li, Zhihao; Li, Ming; Liu, Fang; Jiang, Hongfei; Lee, Tai Sing

2018-04-26

One general principle of sensory information processing is that the brain must optimize efficiency by reducing the number of neurons that process the same information. The sparseness of the sensory representations in a population of neurons reflects the efficiency of the neural code. Here, we employ large-scale two-photon calcium imaging to examine the responses of a large population of neurons within the superficial layers of area V1 with single-cell resolution, while simultaneously presenting a large set of natural visual stimuli, to provide the first direct measure of the population sparseness in awake primates. The results show that only 0.5% of neurons respond strongly to any given natural image - indicating a ten-fold increase in the inferred sparseness over previous measurements. These population activities are nevertheless necessary and sufficient to discriminate visual stimuli with high accuracy, suggesting that the neural code in the primary visual cortex is both super-sparse and highly efficient. © 2018, Tang et al.

A new evidence-based risk stratification system for cutaneous squamous cell carcinoma into low, intermediate, and high risk groups with implications for management.

PubMed

Baum, Christian L; Wright, Adam C; Martinez, Juan-Carlos; Arpey, Christopher J; Brewer, Jerry D; Roenigk, Randall K; Otley, Clark C

2018-01-01

Most primary cutaneous squamous cell carcinomas are cured with surgery. A subset, however, may develop local and nodal metastasis that may eventuate in disease-specific; death. This subset has been variably termed high risk. Herein, we review; an emerging body of data on the risks of these outcomes and propose an evidence-based; risk stratification for low-, intermediate-, and high-risk tumors that takes into; account both tumor and patient characteristics. Finally, we discuss a framework for; management of these tumors on the basis of data, when available, and our; recommendations when data are sparse. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Visual Tracking Based on Extreme Learning Machine and Sparse Representation

PubMed Central

Wang, Baoxian; Tang, Linbo; Yang, Jinglin; Zhao, Baojun; Wang, Shuigen

2015-01-01

The existing sparse representation-based visual trackers mostly suffer from both being time consuming and having poor robustness problems. To address these issues, a novel tracking method is presented via combining sparse representation and an emerging learning technique, namely extreme learning machine (ELM). Specifically, visual tracking can be divided into two consecutive processes. Firstly, ELM is utilized to find the optimal separate hyperplane between the target observations and background ones. Thus, the trained ELM classification function is able to remove most of the candidate samples related to background contents efficiently, thereby reducing the total computational cost of the following sparse representation. Secondly, to further combine ELM and sparse representation, the resultant confidence values (i.e., probabilities to be a target) of samples on the ELM classification function are used to construct a new manifold learning constraint term of the sparse representation framework, which tends to achieve robuster results. Moreover, the accelerated proximal gradient method is used for deriving the optimal solution (in matrix form) of the constrained sparse tracking model. Additionally, the matrix form solution allows the candidate samples to be calculated in parallel, thereby leading to a higher efficiency. Experiments demonstrate the effectiveness of the proposed tracker. PMID:26506359

Incorporating biological information in sparse principal component analysis with application to genomic data.

PubMed

Li, Ziyi; Safo, Sandra E; Long, Qi

2017-07-11

Sparse principal component analysis (PCA) is a popular tool for dimensionality reduction, pattern recognition, and visualization of high dimensional data. It has been recognized that complex biological mechanisms occur through concerted relationships of multiple genes working in networks that are often represented by graphs. Recent work has shown that incorporating such biological information improves feature selection and prediction performance in regression analysis, but there has been limited work on extending this approach to PCA. In this article, we propose two new sparse PCA methods called Fused and Grouped sparse PCA that enable incorporation of prior biological information in variable selection. Our simulation studies suggest that, compared to existing sparse PCA methods, the proposed methods achieve higher sensitivity and specificity when the graph structure is correctly specified, and are fairly robust to misspecified graph structures. Application to a glioblastoma gene expression dataset identified pathways that are suggested in the literature to be related with glioblastoma. The proposed sparse PCA methods Fused and Grouped sparse PCA can effectively incorporate prior biological information in variable selection, leading to improved feature selection and more interpretable principal component loadings and potentially providing insights on molecular underpinnings of complex diseases.

Hippocampal Remapping Is Constrained by Sparseness rather than Capacity

PubMed Central

Kammerer, Axel; Leibold, Christian

2014-01-01

Grid cells in the medial entorhinal cortex encode space with firing fields that are arranged on the nodes of spatial hexagonal lattices. Potential candidates to read out the space information of this grid code and to combine it with other sensory cues are hippocampal place cells. In this paper, we investigate a population of grid cells providing feed-forward input to place cells. The capacity of the underlying synaptic transformation is determined by both spatial acuity and the number of different spatial environments that can be represented. The codes for different environments arise from phase shifts of the periodical entorhinal cortex patterns that induce a global remapping of hippocampal place fields, i.e., a new random assignment of place fields for each environment. If only a single environment is encoded, the grid code can be read out at high acuity with only few place cells. A surplus in place cells can be used to store a space code for more environments via remapping. The number of stored environments can be increased even more efficiently by stronger recurrent inhibition and by partitioning the place cell population such that learning affects only a small fraction of them in each environment. We find that the spatial decoding acuity is much more resilient to multiple remappings than the sparseness of the place code. Since the hippocampal place code is sparse, we thus conclude that the projection from grid cells to the place cells is not using its full capacity to transfer space information. Both populations may encode different aspects of space. PMID:25474570

In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis.

PubMed

Kirschbaum, Klara; Sonner, Jana K; Zeller, Matthias W; Deumelandt, Katrin; Bode, Julia; Sharma, Rakesh; Krüwel, Thomas; Fischer, Manuel; Hoffmann, Angelika; Costa da Silva, Milene; Muckenthaler, Martina U; Wick, Wolfgang; Tews, Björn; Chen, John W; Heiland, Sabine; Bendszus, Martin; Platten, Michael; Breckwoldt, Michael O

2016-11-15

Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P < 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P < 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.

The influence of biomechanical properties and cannabinoids on tumor invasion

PubMed Central

Hohmann, Tim; Grabiec, Urszula; Ghadban, Chalid; Feese, Kerstin; Dehghani, Faramarz

2017-01-01

ABSTRACT Background: Cannabinoids are known to have an anti-tumorous effect, but the underlying mechanisms are only sparsely understood. Mechanical characteristics of tumor cells represent a promising marker to distinguish between tumor cells and the healthy tissue. We tested the hypothesis whether cannabinoids influence the tumor cell specific mechanical and migratory properties and if these factors are a prognostic marker for the invasiveness of tumor cells. Methods: 3 different glioblastoma cell lines were treated with cannabinoids and changes of mechanical and migratory properties of single cells were measured using atomic force microscopy and time lapse imaging. The invasiveness of cell lines was determined using a co-culture model with organotypic hippocampal slice cultures. Results: We found that cannabinoids are capable of influencing migratory and mechanical properties in a cell line specific manner. A network analysis revealed a correlation between a “generalized stiffness” and the invasiveness for all tumor cell lines after 3 and 4 d of invasion time: r3d = −0.88 [−0.52;−0.97]; r4d = −0.90 [−0.59;−0.98]. Conclusions: Here we could show that a “generalized stiffness” is a profound marker for the invasiveness of a tumor cell population in our model and thus might be of high clinical relevance for drug testing. Additionally cannabinoids were shown to be of potential use for therapeutic approaches of glioblastoma. PMID:27149140

Crystallization of bFGF-DNA Aptamer Complexes Using a Sparse Matrix Designed for Protein-Nucleic Acid Complexes

NASA Technical Reports Server (NTRS)

Cannone, Jaime J.; Barnes, Cindy L.; Achari, Aniruddha; Kundrot, Craig E.; Whitaker, Ann F. (Technical Monitor)

2001-01-01

The Sparse Matrix approach for obtaining lead crystallization conditions has proven to be very fruitful for the crystallization of proteins and nucleic acids. Here we report a Sparse Matrix developed specifically for the crystallization of protein-DNA complexes. This method is rapid and economical, typically requiring 2.5 mg of complex to test 48 conditions. The method was originally developed to crystallize basic fibroblast growth factor (bFGF) complexed with DNA sequences identified through in vitro selection, or SELEX, methods. Two DNA aptamers that bind with approximately nanomolar affinity and inhibit the angiogenic properties of bFGF were selected for co-crystallization. The Sparse Matrix produced lead crystallization conditions for both bFGF-DNA complexes.

Working with Sparse Data in Rated Language Tests: Generalizability Theory Applications

ERIC Educational Resources Information Center

Lin, Chih-Kai

2017-01-01

Sparse-rated data are common in operational performance-based language tests, as an inevitable result of assigning examinee responses to a fraction of available raters. The current study investigates the precision of two generalizability-theory methods (i.e., the rating method and the subdividing method) specifically designed to accommodate the…

Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding

PubMed Central

Lu, Rong; Neff, Norma F.; Quake, Stephen R.; Weissman, Irving L.

2011-01-01

Disentangling cellular heterogeneity is a challenge in many fields, particularly in the stem cell and cancer biology fields. Here, we demonstrate how to combine viral genetic barcoding with high-throughput sequencing to track single cells in a heterogeneous population. We use this technique to track the in vivo differentiation of unitary hematopoietic stem cells (HSCs). The results are consistent with single cell transplantation studies, but require two orders of magnitude fewer mice. In addition to its high throughput, the high sensitivity of the technique allows for a direct examination of the clonality of sparse cell populations such as HSCs. We show how these capabilities offer a clonal perspective of the HSC differentiation process. In particular, our data suggests that HSCs do not equally contribute to blood cells after irradiation-mediated transplantation, and that two distinct HSC differentiation patterns co-exist in the same recipient mouse post irradiation. This technique can be applied to any viral accessible cell type for both in vitro and in vivo processes. PMID:21964413

Assessing the effects of cocaine dependence and pathological gambling using group-wise sparse representation of natural stimulus FMRI data.

PubMed

Ren, Yudan; Fang, Jun; Lv, Jinglei; Hu, Xintao; Guo, Cong Christine; Guo, Lei; Xu, Jiansong; Potenza, Marc N; Liu, Tianming

2017-08-01

Assessing functional brain activation patterns in neuropsychiatric disorders such as cocaine dependence (CD) or pathological gambling (PG) under naturalistic stimuli has received rising interest in recent years. In this paper, we propose and apply a novel group-wise sparse representation framework to assess differences in neural responses to naturalistic stimuli across multiple groups of participants (healthy control, cocaine dependence, pathological gambling). Specifically, natural stimulus fMRI (N-fMRI) signals from all three groups of subjects are aggregated into a big data matrix, which is then decomposed into a common signal basis dictionary and associated weight coefficient matrices via an effective online dictionary learning and sparse coding method. The coefficient matrices associated with each common dictionary atom are statistically assessed for each group separately. With the inter-group comparisons based on the group-wise correspondence established by the common dictionary, our experimental results demonstrated that the group-wise sparse coding and representation strategy can effectively and specifically detect brain networks/regions affected by different pathological conditions of the brain under naturalistic stimuli.

Foxi3 deficiency compromises hair follicle stem cell specification and activation

PubMed Central

Shirokova, Vera; Biggs, Leah C.; Jussila, Maria; Ohyama, Takahiro; Groves, Andrew K.; Mikkola, Marja L.

2017-01-01

The hair follicle is an ideal system to study stem cell specification and homeostasis due to its well characterized morphogenesis and stereotypic cycles of stem cell activation upon each hair cycle to produce a new hair shaft. The adult hair follicle stem cell niche consists of two distinct populations, the bulge and the more activation-prone secondary hair germ. Hair follicle stem cells are set aside during early stages of morphogenesis. This process is known to depend on the Sox9 transcription factor, but otherwise the establishment of the hair follicle stem cell niche is poorly understood. Here we show that that mutation of Foxi3, a Forkhead family transcription factor mutated in several hairless dog breeds, compromises stem cell specification. Further, loss of Foxi3 impedes hair follicle downgrowth and progression of the hair cycle. Genome-wide profiling revealed a number of downstream effectors of Foxi3 including transcription factors with a recognized function in hair follicle stem cells such as Lhx2, Runx1, and Nfatc1, suggesting that the Foxi3 mutant phenotype results from simultaneous downregulation of several stem cell signature genes. We show that Foxi3 displays a highly dynamic expression pattern during hair morphogenesis and cycling, and identify Foxi3 as a novel secondary hair germ marker. Absence of Foxi3 results in poor hair regeneration upon hair plucking, and a sparse fur phenotype in unperturbed mice that exacerbates with age, caused by impaired secondary hair germ activation leading to progressive depletion of stem cells. Thus, Foxi3 regulates multiple aspects of hair follicle development and homeostasis. PMID:26992132

Cell-specific Labeling Enzymes for Analysis of Cell–Cell Communication in Continuous Co-culture*

PubMed Central

Tape, Christopher J.; Norrie, Ida C.; Worboys, Jonathan D.; Lim, Lindsay; Lauffenburger, Douglas A.; Jørgensen, Claus

2014-01-01

We report the orthologous screening, engineering, and optimization of amino acid conversion enzymes for cell-specific proteomic labeling. Intracellular endoplasmic-reticulum-anchored Mycobacterium tuberculosis diaminopimelate decarboxylase (DDCM.tub-KDEL) confers cell-specific meso-2,6-diaminopimelate-dependent proliferation to multiple eukaryotic cell types. Optimized lysine racemase (LyrM37-KDEL) supports D-lysine specific proliferation and efficient cell-specific isotopic labeling. When ectopically expressed in discrete cell types, these enzymes confer 90% cell-specific isotopic labeling efficiency after 10 days of co-culture. Moreover, DDCM.tub-KDEL and LyrM37-KDEL facilitate equally high cell-specific labeling fidelity without daily media exchange. Consequently, the reported novel enzyme pairing can be used to study cell-specific signaling in uninterrupted, continuous co-cultures. Demonstrating the importance of increased labeling stability for addressing novel biological questions, we compare the cell-specific phosphoproteome of fibroblasts in direct co-culture with epithelial tumor cells in both interrupted (daily media exchange) and continuous (no media exchange) co-cultures. This analysis identified multiple cell-specific phosphorylation sites specifically regulated in the continuous co-culture. Given their applicability to multiple cell types, continuous co-culture labeling fidelity, and suitability for long-term cell–cell phospho-signaling experiments, we propose DDCM.tub-KDEL and LyrM37-KDEL as excellent enzymes for cell-specific labeling with amino acid precursors. PMID:24820872

Comprehensive meta-analysis of Signal Transducers and Activators of Transcription (STAT) genomic binding patterns discerns cell-specific cis-regulatory modules

PubMed Central

2013-01-01

Background Cytokine-activated transcription factors from the STAT (Signal Transducers and Activators of Transcription) family control common and context-specific genetic programs. It is not clear to what extent cell-specific features determine the binding capacity of seven STAT members and to what degree they share genetic targets. Molecular insight into the biology of STATs was gained from a meta-analysis of 29 available ChIP-seq data sets covering genome-wide occupancy of STATs 1, 3, 4, 5A, 5B and 6 in several cell types. Results We determined that the genomic binding capacity of STATs is primarily defined by the cell type and to a lesser extent by individual family members. For example, the overlap of shared binding sites between STATs 3 and 5 in T cells is greater than that between STAT5 in T cells and non-T cells. Even for the top 1,000 highly enriched STAT binding sites, ~15% of STAT5 binding sites in mouse female liver are shared by other STATs in different cell types while in T cells ~90% of STAT5 binding sites are co-occupied by STAT3, STAT4 and STAT6. In addition, we identified 116 cis-regulatory modules (CRM), which are recognized by all STAT members across cell types defining a common JAK-STAT signature. Lastly, in liver STAT5 binding significantly coincides with binding of the cell-specific transcription factors HNF4A, FOXA1 and FOXA2 and is associated with cell-type specific gene transcription. Conclusions Our results suggest that genomic binding of STATs is primarily determined by the cell type and further specificity is achieved in part by juxtaposed binding of cell-specific transcription factors. PMID:23324445

Cell-Type-Specific Optogenetics in Monkeys.

PubMed

Namboodiri, Vijay Mohan K; Stuber, Garret D

2016-09-08

The recent advent of technologies enabling cell-type-specific recording and manipulation of neuronal activity spurred tremendous progress in neuroscience. However, they have been largely limited to mice, which lack the richness in behavior of primates. Stauffer et al. now present a generalizable method for achieving cell-type specificity in monkeys. Copyright © 2016 Elsevier Inc. All rights reserved.

Linear-scaling density-functional simulations of charged point defects in Al2O3 using hierarchical sparse matrix algebra.

PubMed

Hine, N D M; Haynes, P D; Mostofi, A A; Payne, M C

2010-09-21

We present calculations of formation energies of defects in an ionic solid (Al(2)O(3)) extrapolated to the dilute limit, corresponding to a simulation cell of infinite size. The large-scale calculations required for this extrapolation are enabled by developments in the approach to parallel sparse matrix algebra operations, which are central to linear-scaling density-functional theory calculations. The computational cost of manipulating sparse matrices, whose sizes are determined by the large number of basis functions present, is greatly improved with this new approach. We present details of the sparse algebra scheme implemented in the ONETEP code using hierarchical sparsity patterns, and demonstrate its use in calculations on a wide range of systems, involving thousands of atoms on hundreds to thousands of parallel processes.

Mammalian transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes and are predicted to act as transcriptional activator hubs.

PubMed

Joshi, Anagha

2014-12-30

Transcriptional hotspots are defined as genomic regions bound by multiple factors. They have been identified recently as cell type specific enhancers regulating developmentally essential genes in many species such as worm, fly and humans. The in-depth analysis of hotspots across multiple cell types in same species still remains to be explored and can bring new biological insights. We therefore collected 108 transcription-related factor (TF) ChIP sequencing data sets in ten murine cell types and classified the peaks in each cell type in three groups according to binding occupancy as singletons (low-occupancy), combinatorials (mid-occupancy) and hotspots (high-occupancy). The peaks in the three groups clustered largely according to the occupancy, suggesting priming of genomic loci for mid occupancy irrespective of cell type. We then characterized hotspots for diverse structural functional properties. The genes neighbouring hotspots had a small overlap with hotspot genes in other cell types and were highly enriched for cell type specific function. Hotspots were enriched for sequence motifs of key TFs in that cell type and more than 90% of hotspots were occupied by pioneering factors. Though we did not find any sequence signature in the three groups, the H3K4me1 binding profile had bimodal peaks at hotspots, distinguishing hotspots from mono-modal H3K4me1 singletons. In ES cells, differentially expressed genes after perturbation of activators were enriched for hotspot genes suggesting hotspots primarily act as transcriptional activator hubs. Finally, we proposed that ES hotspots might be under control of SetDB1 and not DNMT for silencing. Transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes. In ES cells, they are predicted to act as transcriptional activator hubs and might be under SetDB1 control for silencing.

Dense and Sparse Matrix Operations on the Cell Processor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, Samuel W.; Shalf, John; Oliker, Leonid

2005-05-01

The slowing pace of commodity microprocessor performance improvements combined with ever-increasing chip power demands has become of utmost concern to computational scientists. Therefore, the high performance computing community is examining alternative architectures that address the limitations of modern superscalar designs. In this work, we examine STI's forthcoming Cell processor: a novel, low-power architecture that combines a PowerPC core with eight independent SIMD processing units coupled with a software-controlled memory to offer high FLOP/s/Watt. Since neither Cell hardware nor cycle-accurate simulators are currently publicly available, we develop an analytic framework to predict Cell performance on dense and sparse matrix operations, usingmore » a variety of algorithmic approaches. Results demonstrate Cell's potential to deliver more than an order of magnitude better GFLOP/s per watt performance, when compared with the Intel Itanium2 and Cray X1 processors.« less

MOBE-ChIP: Probing Cell Type-Specific Binding Through Large-Scale Chromatin Immunoprecipitation.

PubMed

Wang, Shenqi; Lau, On Sun

2018-01-01

In multicellular organisms, the initiation and maintenance of specific cell types often require the activity of cell type-specific transcriptional regulators. Understanding their roles in gene regulation is crucial but probing their DNA targets in vivo, especially in a genome-wide manner, remains a technical challenge with their limited expression. To improve the sensitivity of chromatin immunoprecipitation (ChIP) for detecting the cell type-specific signals, we have developed the Maximized Objects for Better Enrichment (MOBE)-ChIP, where ChIP is performed at a substantially larger experimental scale and under low background conditions. Here, we describe the procedure in the study of transcription factors in the model plant Arabidopsis. However, with some modifications, the technique should also be implemented in other systems. Besides cell type-specific studies, MOBE-ChIP can also be used as a general strategy to improve ChIP signals.

Meningioma-like tumor of the skin. An ultrastructural and immunohistochemical study.

PubMed

Barr, R J; Yi, E S; Jensen, J L; Wuerker, R B; Liao, S Y

1993-08-01

Three unusual cutaneous tumors are described along with ultrastructural and immunohistochemical studies. All lesions were asymptomatic red-brown papulonodules. Light microscopic examination revealed a whorled configuration of spindle-shaped cells, some concentrically arranged around blood vessels. Immunohistochemical panels exhibited positive staining only with antibody to vimentin and negative staining with antibodies against S-100 protein, muscle markers, cytokeratin, epithelial membrane antigen, Leu 7, type IV collagen, and factor XIIIa, ruling out obvious nevomelanocytic, nerve sheath, meningothelial, smooth muscle, and perithelial differentiation. Electron microscopic examination demonstrated cells producing poorly formed collagen fibrils, sparse collagen fibers, and possessing occasional ill-defined intercellular junctions between their elongated cell processes. This rare tumor is considered to be either an immature fibrohistiocytic or possibly a nerve sheath neoplasm with striking similarities to so-called canine hemangiopericytoma. Because the prominent whorled pattern was reminiscent of meningioma, the lesion was referred to as meningioma-like tumor of the skin.

Cell Type-Specific Structural Organization of the Six Layers in Rat Barrel Cortex

PubMed Central

Narayanan, Rajeevan T.; Udvary, Daniel; Oberlaender, Marcel

2017-01-01

The cytoarchitectonic subdivision of the neocortex into six layers is often used to describe the organization of the cortical circuitry, sensory-evoked signal flow or cortical functions. However, each layer comprises neuronal cell types that have different genetic, functional and/or structural properties. Here, we reanalyze structural data from some of our recent work in the posterior-medial barrel-subfield of the vibrissal part of rat primary somatosensory cortex (vS1). We quantify the degree to which somata, dendrites and axons of the 10 major excitatory cell types of the cortex are distributed with respect to the cytoarchitectonic organization of vS1. We show that within each layer, somata of multiple cell types intermingle, but that each cell type displays dendrite and axon distributions that are aligned to specific cytoarchitectonic landmarks. The resultant quantification of the structural composition of each layer in terms of the cell type-specific number of somata, dendritic and axonal path lengths will aid future studies to bridge between layer- and cell type-specific analyses. PMID:29081739

Homeostatic plasticity shapes cell-type-specific wiring in the retina

PubMed Central

Tien, Nai-Wen; Soto, Florentina; Kerschensteiner, Daniel

2017-01-01

SUMMARY Convergent input from different presynaptic partners shapes the responses of postsynaptic neurons. Whether developing postsynaptic neurons establish connections with each presynaptic partner independently, or balance inputs to attain specific responses is unclear. Retinal ganglion cells (RGCs) receive convergent input from bipolar cell types with different contrast responses and temporal tuning. Here, using optogenetic activation and pharmacogenetic silencing, we found that type 6 bipolar cells (B6) dominate excitatory input to ONα-RGCs. We generated mice in which B6 cells were selectively removed from developing circuits (B6-DTA). In B6-DTA mice, ONα-RGCs adjusted connectivity with other bipolar cells in a cell-type-specific manner. They recruited new partners, increased synapses with some existing partners, and maintained constant input from others. Patch clamp recordings revealed that anatomical rewiring precisely preserved contrast- and temporal frequency response functions of ONα-RGCs, indicating that homeostatic plasticity shapes cell-type-specific wiring in the developing retina to stabilize visual information sent to the brain. PMID:28457596

Point-of-care rare cell cancer diagnostics.

PubMed

Issadore, David

2015-01-01

The sparse cells that are shed from tumors into peripheral circulation are an increasingly promising resource for noninvasive monitoring of cancer progression, early diagnosis of disease, and serve as a tool for improving our understanding of cancer metastasis. However, the extremely sparse concentration of circulating tumor cells (CTCs) in blood (~1-100 CTC in 7.5 mL of blood) as well as their heterogeneous biomarker expression has limited their detection using conventional laboratory techniques. To overcome these challenges, we have developed a microfluidic chip-based micro-Hall detector (μHD), which can directly measure single, immunomagnetically tagged cells in whole blood. The μHD can detect individual cells even in the presence of vast numbers of blood cells and unbound reactants, and does not require any washing or purification steps. Furthermore, this cost-effective, single-cell analytical technique is well suited for miniaturization into a mobile platform for low-cost point-of-care use. In this chapter, we describe the methodology used to design, fabricate, and apply these chips to cancer diagnostics.

CD4+ T-cell engagement by both wild-type and variant HCV peptides modulates the conversion of viral clearing helper T cells to Tregs

PubMed Central

Cusick, Matthew F; Libbey, Jane E; Cox Gill, Joan; Fujinami, Robert S; Eckels, David D

2013-01-01

Aim To determine whether modulation of T-cell responses by naturally occurring viral variants caused an increase in numbers of Tregs in HCV-infected patients. Patients, materials & methods Human peripheral blood mononuclear cells, having proliferative responses to a wild-type HCV-specific CD4+ T-cell epitope, were used to quantify, via proliferative assays, flow cytometry and class II tetramers, the effects of naturally occurring viral variants arising in the immunodominant epitope. Results In combination, the wild-type and variant peptides led to enhanced suppression of an anti-HCV T-cell response. The variant had a lower avidity for the wild-type-specific CD4+ T cell. Variant-stimulated CD4+ T cells had increased Foxp3, compared with wild-type-stimulated cells. Conclusion A stable viral variant from a chronic HCV subject was able to induce Tregs in multiple individuals that responded to the wild-type HCV-specific CD4+ T-cell epitope. PMID:24421862

Histological differential diagnosis between lymph node toxoplasmosis and other benign lymph node hyperplasias.

PubMed

Miettinen, M

1981-03-01

The material from 667 lymph nodes, originally suspected of toxoplasmosis, was histologically re-examined, to evaluate criteria for diagnosis and differential diagnosis. The results showed that at least 80% of benign lymph node enlargements containing small groups of epithelioid cells were associated with high titres of Toxoplasma antibodies. Furthermore, 85--95% of the lymph nodes in association with high Toxoplasma antibodies showed the typical histological appearances of toxoplasmosis. The histological diagnosis of toxoplasmosis is thus both fairly specific and sensitive. Other lymph node lesions with small groups of epithelioid cells must be considered in the differential diagnosis. Sarcoidosis and tuberculosis usually have a predominance of distinct large epithelioid cell granulomata. Lymph nodes with sinus histiocytosis showing the formation of small groups of epithelioid cells, do not demonstrate prominent hyperplasia and include sparse germinal centres and were not associated with toxoplasmosis. Lymph nodes with disturbed general structure and small groups of epithelioid cells must be carefully assessed because of the significant possibility of malignancy.

Sparse SPM: Group Sparse-dictionary learning in SPM framework for resting-state functional connectivity MRI analysis.

PubMed

Lee, Young-Beom; Lee, Jeonghyeon; Tak, Sungho; Lee, Kangjoo; Na, Duk L; Seo, Sang Won; Jeong, Yong; Ye, Jong Chul

2016-01-15

Recent studies of functional connectivity MR imaging have revealed that the default-mode network activity is disrupted in diseases such as Alzheimer's disease (AD). However, there is not yet a consensus on the preferred method for resting-state analysis. Because the brain is reported to have complex interconnected networks according to graph theoretical analysis, the independency assumption, as in the popular independent component analysis (ICA) approach, often does not hold. Here, rather than using the independency assumption, we present a new statistical parameter mapping (SPM)-type analysis method based on a sparse graph model where temporal dynamics at each voxel position are described as a sparse combination of global brain dynamics. In particular, a new concept of a spatially adaptive design matrix has been proposed to represent local connectivity that shares the same temporal dynamics. If we further assume that local network structures within a group are similar, the estimation problem of global and local dynamics can be solved using sparse dictionary learning for the concatenated temporal data across subjects. Moreover, under the homoscedasticity variance assumption across subjects and groups that is often used in SPM analysis, the aforementioned individual and group analyses using sparse dictionary learning can be accurately modeled by a mixed-effect model, which also facilitates a standard SPM-type group-level inference using summary statistics. Using an extensive resting fMRI data set obtained from normal, mild cognitive impairment (MCI), and Alzheimer's disease patient groups, we demonstrated that the changes in the default mode network extracted by the proposed method are more closely correlated with the progression of Alzheimer's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types.

PubMed

Carmona, Santiago J; Teichmann, Sarah A; Ferreira, Lauren; Macaulay, Iain C; Stubbington, Michael J T; Cvejic, Ana; Gfeller, David

2017-03-01

The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analyzed conservation of genes specific for all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans -membrane proteins in NK cells compared with other immune cell types, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA sequencing of lck:GFP cells in zebrafish and obtained the first transcriptome of specific immune cell types in a nonmammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T cells, a novel type of NK-like cells, and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immune-cell-specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed the higher gene turnover of trans -membrane proteins in NK cells compared with T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates. © 2017 Carmona et al.; Published by Cold Spring Harbor Laboratory Press.

Digital sorting of complex tissues for cell type-specific gene expression profiles.

PubMed

Zhong, Yi; Wan, Ying-Wooi; Pang, Kaifang; Chow, Lionel M L; Liu, Zhandong

2013-03-07

Cellular heterogeneity is present in almost all gene expression profiles. However, transcriptome analysis of tissue specimens often ignores the cellular heterogeneity present in these samples. Standard deconvolution algorithms require prior knowledge of the cell type frequencies within a tissue or their in vitro expression profiles. Furthermore, these algorithms tend to report biased estimations. Here, we describe a Digital Sorting Algorithm (DSA) for extracting cell-type specific gene expression profiles from mixed tissue samples that is unbiased and does not require prior knowledge of cell type frequencies. The results suggest that DSA is a specific and sensitivity algorithm in gene expression profile deconvolution and will be useful in studying individual cell types of complex tissues.

An empirical investigation of sparse distributed memory using discrete speech recognition

NASA Technical Reports Server (NTRS)

Danforth, Douglas G.

1990-01-01

Presented here is a step by step analysis of how the basic Sparse Distributed Memory (SDM) model can be modified to enhance its generalization capabilities for classification tasks. Data is taken from speech generated by a single talker. Experiments are used to investigate the theory of associative memories and the question of generalization from specific instances.

An Improved Sparse Representation over Learned Dictionary Method for Seizure Detection.

PubMed

Li, Junhui; Zhou, Weidong; Yuan, Shasha; Zhang, Yanli; Li, Chengcheng; Wu, Qi

2016-02-01

Automatic seizure detection has played an important role in the monitoring, diagnosis and treatment of epilepsy. In this paper, a patient specific method is proposed for seizure detection in the long-term intracranial electroencephalogram (EEG) recordings. This seizure detection method is based on sparse representation with online dictionary learning and elastic net constraint. The online learned dictionary could sparsely represent the testing samples more accurately, and the elastic net constraint which combines the 11-norm and 12-norm not only makes the coefficients sparse but also avoids over-fitting problem. First, the EEG signals are preprocessed using wavelet filtering and differential filtering, and the kernel function is applied to make the samples closer to linearly separable. Then the dictionaries of seizure and nonseizure are respectively learned from original ictal and interictal training samples with online dictionary optimization algorithm to compose the training dictionary. After that, the test samples are sparsely coded over the learned dictionary and the residuals associated with ictal and interictal sub-dictionary are calculated, respectively. Eventually, the test samples are classified as two distinct categories, seizure or nonseizure, by comparing the reconstructed residuals. The average segment-based sensitivity of 95.45%, specificity of 99.08%, and event-based sensitivity of 94.44% with false detection rate of 0.23/h and average latency of -5.14 s have been achieved with our proposed method.

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types

PubMed Central

Ferreira, Lauren; Macaulay, Iain C.; Stubbington, Michael J.T.

2017-01-01

The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analyzed conservation of genes specific for all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared with other immune cell types, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA sequencing of lck:GFP cells in zebrafish and obtained the first transcriptome of specific immune cell types in a nonmammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T cells, a novel type of NK-like cells, and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immune-cell–specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed the higher gene turnover of trans-membrane proteins in NK cells compared with T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates. PMID:28087841

Surface Position, Not Signaling from Surrounding Maternal Tissues, Specifies Aleurone Epidermal Cell Fate in Maize[OA

PubMed Central

Gruis, Darren (Fred); Guo, Hena; Selinger, David; Tian, Qing; Olsen, Odd-Arne

2006-01-01

Maize (Zea mays) endosperm consists of an epidermal-like surface layer of aleurone cells, an underlying body of starchy endosperm cells, and a basal layer of transfer cells. To determine whether surrounding maternal tissues perform a role in specifying endosperm cell fates, a maize endosperm organ culture technique was established whereby the developing endosperm is completely removed from surrounding maternal tissues. Using cell type-specific fluorescence markers, we show that aleurone cell fate specification occurs exclusively in response to surface position and does not require specific, continued maternal signal input. The starchy endosperm and aleurone cell fates are freely interchangeable throughout the lifespan of the endosperm, with internalized aleurone cells converting to starchy endosperm cells and with starchy endosperm cells that become positioned at the surface converting to aleurone cells. In contrast to aleurone and starchy endosperm cells, transfer cells fail to develop in in vitro-grown endosperm, supporting earlier indications that maternal tissue interaction is required to fully differentiate this cell type. Several parameters confirm that the maize endosperm organ cultures described herein retain the main developmental features of in planta endosperm, including fidelity of aleurone mutant phenotypes, temporal and spatial control of cell type-specific fluorescent markers, specificity of cell type transcripts, and control of mitotic cell divisions. PMID:16698897

beachmat: A Bioconductor C++ API for accessing high-throughput biological data from a variety of R matrix types

PubMed Central

Pagès, Hervé

2018-01-01

Biological experiments involving genomics or other high-throughput assays typically yield a data matrix that can be explored and analyzed using the R programming language with packages from the Bioconductor project. Improvements in the throughput of these assays have resulted in an explosion of data even from routine experiments, which poses a challenge to the existing computational infrastructure for statistical data analysis. For example, single-cell RNA sequencing (scRNA-seq) experiments frequently generate large matrices containing expression values for each gene in each cell, requiring sparse or file-backed representations for memory-efficient manipulation in R. These alternative representations are not easily compatible with high-performance C++ code used for computationally intensive tasks in existing R/Bioconductor packages. Here, we describe a C++ interface named beachmat, which enables agnostic data access from various matrix representations. This allows package developers to write efficient C++ code that is interoperable with dense, sparse and file-backed matrices, amongst others. We evaluated the performance of beachmat for accessing data from each matrix representation using both simulated and real scRNA-seq data, and defined a clear memory/speed trade-off to motivate the choice of an appropriate representation. We also demonstrate how beachmat can be incorporated into the code of other packages to drive analyses of a very large scRNA-seq data set. PMID:29723188

beachmat: A Bioconductor C++ API for accessing high-throughput biological data from a variety of R matrix types.

PubMed

Lun, Aaron T L; Pagès, Hervé; Smith, Mike L

2018-05-01

Biological experiments involving genomics or other high-throughput assays typically yield a data matrix that can be explored and analyzed using the R programming language with packages from the Bioconductor project. Improvements in the throughput of these assays have resulted in an explosion of data even from routine experiments, which poses a challenge to the existing computational infrastructure for statistical data analysis. For example, single-cell RNA sequencing (scRNA-seq) experiments frequently generate large matrices containing expression values for each gene in each cell, requiring sparse or file-backed representations for memory-efficient manipulation in R. These alternative representations are not easily compatible with high-performance C++ code used for computationally intensive tasks in existing R/Bioconductor packages. Here, we describe a C++ interface named beachmat, which enables agnostic data access from various matrix representations. This allows package developers to write efficient C++ code that is interoperable with dense, sparse and file-backed matrices, amongst others. We evaluated the performance of beachmat for accessing data from each matrix representation using both simulated and real scRNA-seq data, and defined a clear memory/speed trade-off to motivate the choice of an appropriate representation. We also demonstrate how beachmat can be incorporated into the code of other packages to drive analyses of a very large scRNA-seq data set.

Radiation-Induced Carcinogenesis: Mechanistically Based Differences between Gamma-Rays and Neutrons, and Interactions with DMBA

PubMed Central

Shuryak, Igor; Brenner, David J.; Ullrich, Robert L.

2011-01-01

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis. PMID:22194850

Joint analysis of multiple high-dimensional data types using sparse matrix approximations of rank-1 with applications to ovarian and liver cancer.

PubMed

Okimoto, Gordon; Zeinalzadeh, Ashkan; Wenska, Tom; Loomis, Michael; Nation, James B; Fabre, Tiphaine; Tiirikainen, Maarit; Hernandez, Brenda; Chan, Owen; Wong, Linda; Kwee, Sandi

2016-01-01

Technological advances enable the cost-effective acquisition of Multi-Modal Data Sets (MMDS) composed of measurements for multiple, high-dimensional data types obtained from a common set of bio-samples. The joint analysis of the data matrices associated with the different data types of a MMDS should provide a more focused view of the biology underlying complex diseases such as cancer that would not be apparent from the analysis of a single data type alone. As multi-modal data rapidly accumulate in research laboratories and public databases such as The Cancer Genome Atlas (TCGA), the translation of such data into clinically actionable knowledge has been slowed by the lack of computational tools capable of analyzing MMDSs. Here, we describe the Joint Analysis of Many Matrices by ITeration (JAMMIT) algorithm that jointly analyzes the data matrices of a MMDS using sparse matrix approximations of rank-1. The JAMMIT algorithm jointly approximates an arbitrary number of data matrices by rank-1 outer-products composed of "sparse" left-singular vectors (eigen-arrays) that are unique to each matrix and a right-singular vector (eigen-signal) that is common to all the matrices. The non-zero coefficients of the eigen-arrays identify small subsets of variables for each data type (i.e., signatures) that in aggregate, or individually, best explain a dominant eigen-signal defined on the columns of the data matrices. The approximation is specified by a single "sparsity" parameter that is selected based on false discovery rate estimated by permutation testing. Multiple signals of interest in a given MDDS are sequentially detected and modeled by iterating JAMMIT on "residual" data matrices that result from a given sparse approximation. We show that JAMMIT outperforms other joint analysis algorithms in the detection of multiple signatures embedded in simulated MDDS. On real multimodal data for ovarian and liver cancer we show that JAMMIT identified multi-modal signatures that were clinically informative and enriched for cancer-related biology. Sparse matrix approximations of rank-1 provide a simple yet effective means of jointly reducing multiple, big data types to a small subset of variables that characterize important clinical and/or biological attributes of the bio-samples from which the data were acquired.

Single Insulin-Specific CD8+ T Cells Show Characteristic Gene Expression Profiles in Human Type 1 Diabetes

PubMed Central

Luce, Sandrine; Lemonnier, François; Briand, Jean-Paul; Coste, Joel; Lahlou, Najiba; Muller, Sylviane; Larger, Etienne; Rocha, Benedita; Mallone, Roberto; Boitard, Christian

2011-01-01

OBJECTIVE Both the early steps and the high recurrence of autoimmunity once the disease is established are unexplained in human type 1 diabetes. Because CD8+ T cells are central and insulin is a key autoantigen in the disease process, our objective was to characterize HLA class I–restricted autoreactive CD8+ T cells specific for preproinsulin (PPI) in recent-onset and long-standing type 1 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We used HLA-A*02:01 tetramers complexed to PPI peptides to enumerate circulating PPI-specific CD8+ T cells in patients and characterize them using membrane markers and single-cell PCR. RESULTS Most autoreactive CD8+ T cells detected in recent-onset type 1 diabetic patients are specific for leader sequence peptides, notably PPI6–14, whereas CD8+ T cells in long-standing patients recognize the B-chain peptide PPI33–42 (B9–18). Both CD8+ T-cell specificities are predominantly naïve, central, and effector memory cells, and their gene expression profile differs from cytomegalovirus-specific CD8+ T cells. PPI6–14–specific CD8+ T cells detected in one healthy control displayed Il-10 mRNA expression, which was not observed in diabetic patients. CONCLUSIONS PPI-specific CD8+ T cells in type 1 diabetic patients include central memory and target different epitopes in new-onset versus long-standing disease. Our data support the hypothesis that insulin therapy may contribute to the expansion of autoreactive CD8+ T cells in the long term. PMID:21998398

Group-sparse representation with dictionary learning for medical image denoising and fusion.

PubMed

Li, Shutao; Yin, Haitao; Fang, Leyuan

2012-12-01

Recently, sparse representation has attracted a lot of interest in various areas. However, the standard sparse representation does not consider the intrinsic structure, i.e., the nonzero elements occur in clusters, called group sparsity. Furthermore, there is no dictionary learning method for group sparse representation considering the geometrical structure of space spanned by atoms. In this paper, we propose a novel dictionary learning method, called Dictionary Learning with Group Sparsity and Graph Regularization (DL-GSGR). First, the geometrical structure of atoms is modeled as the graph regularization. Then, combining group sparsity and graph regularization, the DL-GSGR is presented, which is solved by alternating the group sparse coding and dictionary updating. In this way, the group coherence of learned dictionary can be enforced small enough such that any signal can be group sparse coded effectively. Finally, group sparse representation with DL-GSGR is applied to 3-D medical image denoising and image fusion. Specifically, in 3-D medical image denoising, a 3-D processing mechanism (using the similarity among nearby slices) and temporal regularization (to perverse the correlations across nearby slices) are exploited. The experimental results on 3-D image denoising and image fusion demonstrate the superiority of our proposed denoising and fusion approaches.

Self-organized Evaluation of Dynamic Hand Gestures for Sign Language Recognition

NASA Astrophysics Data System (ADS)

Buciu, Ioan; Pitas, Ioannis

Two main theories exist with respect to face encoding and representation in the human visual system (HVS). The first one refers to the dense (holistic) representation of the face, where faces have "holon"-like appearance. The second one claims that a more appropriate face representation is given by a sparse code, where only a small fraction of the neural cells corresponding to face encoding is activated. Theoretical and experimental evidence suggest that the HVS performs face analysis (encoding, storing, face recognition, facial expression recognition) in a structured and hierarchical way, where both representations have their own contribution and goal. According to neuropsychological experiments, it seems that encoding for face recognition, relies on holistic image representation, while a sparse image representation is used for facial expression analysis and classification. From the computer vision perspective, the techniques developed for automatic face and facial expression recognition fall into the same two representation types. Like in Neuroscience, the techniques which perform better for face recognition yield a holistic image representation, while those techniques suitable for facial expression recognition use a sparse or local image representation. The proposed mathematical models of image formation and encoding try to simulate the efficient storing, organization and coding of data in the human cortex. This is equivalent with embedding constraints in the model design regarding dimensionality reduction, redundant information minimization, mutual information minimization, non-negativity constraints, class information, etc. The presented techniques are applied as a feature extraction step followed by a classification method, which also heavily influences the recognition results.

Concentrated Solutions of Single-Chain Nanoparticles: A Simple Model for Intrinsically Disordered Proteins under Crowding Conditions.

PubMed

Moreno, Angel J; Lo Verso, Federica; Arbe, Arantxa; Pomposo, José A; Colmenero, Juan

2016-03-03

By means of large-scale computer simulations and small-angle neutron scattering (SANS), we investigate solutions of single-chain nanoparticles (SCNPs), covering the whole concentration range from infinite dilution to melt density. The analysis of the conformational properties of the SCNPs reveals that these synthetic nano-objects share basic ingredients with intrinsically disordered proteins (IDPs), as topological polydispersity, generally sparse conformations, and locally compact domains. We investigate the role of the architecture of the SCNPs in their collapse behavior under macromolecular crowding. Unlike in the case of linear macromolecules, which experience the usual transition from self-avoiding to Gaussian random-walk conformations, crowding leads to collapsed conformations of SCNPs resembling those of crumpled globules. This behavior is already found at volume fractions (about 30%) that are characteristic of crowding in cellular environments. The simulation results are confirmed by the SANS experiments. Our results for SCNPs--a model system free of specific interactions--propose a general scenario for the effect of steric crowding on IDPs: collapse from sparse conformations at high dilution to crumpled globular conformations in cell environments.

Corrected confidence bands for functional data using principal components.

PubMed

Goldsmith, J; Greven, S; Crainiceanu, C

2013-03-01

Functional principal components (FPC) analysis is widely used to decompose and express functional observations. Curve estimates implicitly condition on basis functions and other quantities derived from FPC decompositions; however these objects are unknown in practice. In this article, we propose a method for obtaining correct curve estimates by accounting for uncertainty in FPC decompositions. Additionally, pointwise and simultaneous confidence intervals that account for both model- and decomposition-based variability are constructed. Standard mixed model representations of functional expansions are used to construct curve estimates and variances conditional on a specific decomposition. Iterated expectation and variance formulas combine model-based conditional estimates across the distribution of decompositions. A bootstrap procedure is implemented to understand the uncertainty in principal component decomposition quantities. Our method compares favorably to competing approaches in simulation studies that include both densely and sparsely observed functions. We apply our method to sparse observations of CD4 cell counts and to dense white-matter tract profiles. Code for the analyses and simulations is publicly available, and our method is implemented in the R package refund on CRAN. Copyright © 2013, The International Biometric Society.

Corrected Confidence Bands for Functional Data Using Principal Components

PubMed Central

Goldsmith, J.; Greven, S.; Crainiceanu, C.

2014-01-01

Functional principal components (FPC) analysis is widely used to decompose and express functional observations. Curve estimates implicitly condition on basis functions and other quantities derived from FPC decompositions; however these objects are unknown in practice. In this article, we propose a method for obtaining correct curve estimates by accounting for uncertainty in FPC decompositions. Additionally, pointwise and simultaneous confidence intervals that account for both model- and decomposition-based variability are constructed. Standard mixed model representations of functional expansions are used to construct curve estimates and variances conditional on a specific decomposition. Iterated expectation and variance formulas combine model-based conditional estimates across the distribution of decompositions. A bootstrap procedure is implemented to understand the uncertainty in principal component decomposition quantities. Our method compares favorably to competing approaches in simulation studies that include both densely and sparsely observed functions. We apply our method to sparse observations of CD4 cell counts and to dense white-matter tract profiles. Code for the analyses and simulations is publicly available, and our method is implemented in the R package refund on CRAN. PMID:23003003

Distinct interactions of Sox5 and Sox10 in fate specification of pigment cells in medaka and zebrafish

PubMed Central

Nagao, Yusuke; Takada, Hiroyuki; Miyadai, Motohiro; Adachi, Tomoko; Kamei, Yasuhiro; Hara, Ikuyo; Naruse, Kiyoshi; Hibi, Masahiko

2018-01-01

Mechanisms generating diverse cell types from multipotent progenitors are fundamental for normal development. Pigment cells are derived from multipotent neural crest cells and their diversity in teleosts provides an excellent model for studying mechanisms controlling fate specification of distinct cell types. Zebrafish have three types of pigment cells (melanocytes, iridophores and xanthophores) while medaka have four (three shared with zebrafish, plus leucophores), raising questions about how conserved mechanisms of fate specification of each pigment cell type are in these fish. We have previously shown that the Sry-related transcription factor Sox10 is crucial for fate specification of pigment cells in zebrafish, and that Sox5 promotes xanthophores and represses leucophores in a shared xanthophore/leucophore progenitor in medaka. Employing TILLING, TALEN and CRISPR/Cas9 technologies, we generated medaka and zebrafish sox5 and sox10 mutants and conducted comparative analyses of their compound mutant phenotypes. We show that specification of all pigment cells, except leucophores, is dependent on Sox10. Loss of Sox5 in Sox10-defective fish partially rescued the formation of all pigment cells in zebrafish, and melanocytes and iridophores in medaka, suggesting that Sox5 represses Sox10-dependent formation of these pigment cells, similar to their interaction in mammalian melanocyte specification. In contrast, in medaka, loss of Sox10 acts cooperatively with Sox5, enhancing both xanthophore reduction and leucophore increase in sox5 mutants. Misexpression of Sox5 in the xanthophore/leucophore progenitors increased xanthophores and reduced leucophores in medaka. Thus, the mode of Sox5 function in xanthophore specification differs between medaka (promoting) and zebrafish (repressing), which is also the case in adult fish. Our findings reveal surprising diversity in even the mode of the interactions between Sox5 and Sox10 governing specification of pigment cell types in medaka and zebrafish, and suggest that this is related to the evolution of a fourth pigment cell type. PMID:29621239

Golgi-type I and Golgi-type II neurons in the ventral anterior thalamic nucleus of the adult human: morphological features and quantitative analysis.

PubMed

Al-Hussain Bani Hani, Saleh M; El-Dwairi, Qasim A; Bataineh, Ziad M; Al-Haidari, Mohammad S; Al-Alami, Jamil

2008-05-01

The morphological and quantitative features of neurons in the adult human ventral anterior thalamic nucleus were studied in Golgi preparations. Two neuronal types were found and their quantitative features were studied. Golgi-type I neurons were medium to large cells with dense dendritic trees and dendritic protrusions and short hair-like appendages. They have somatic mean diameter of 30.8 microm (+/-9.4, n = 85). They have an average 100.3 dendritic branches, 48.97 dendritic branching points, and 58.85 dendritic tips. The mean diameters of their primary, secondary, and tertiary dendrites were 3.1 microm (+/-1, n = 80), 1.85 microm (+/-0.8, n = 145), and 1.5 microm (+/-0.4, n = 160), respectively. Golgi-type II neurons were small to medium cells with few sparsely branching dendrites and dendritic stalked appendages with or without terminal swellings. They have somatic mean diameters of 22.2 microm (+/-5.8, n = 120). They have an average 33.76 dendritic branches, 16.49 dendritic branching points, and 21.97 dendritic tips. The mean diameters of their primary, secondary, and tertiary dendrites were 1.6 microm (+/-0.86, n = 70), 1.15 microm (+/-0.55, n = 118), and 1 microm (+/-0.70, n = 95), respectively. These quantitative data may form the basis for further quantitative studies involving aging or some degenerative diseases that may affect cell bodies and/or dendritic trees of the Golgi-type I and/or Golgi-type II thalamic neurons.

Label consistent K-SVD: learning a discriminative dictionary for recognition.

PubMed

Jiang, Zhuolin; Lin, Zhe; Davis, Larry S

2013-11-01

A label consistent K-SVD (LC-KSVD) algorithm to learn a discriminative dictionary for sparse coding is presented. In addition to using class labels of training data, we also associate label information with each dictionary item (columns of the dictionary matrix) to enforce discriminability in sparse codes during the dictionary learning process. More specifically, we introduce a new label consistency constraint called "discriminative sparse-code error" and combine it with the reconstruction error and the classification error to form a unified objective function. The optimal solution is efficiently obtained using the K-SVD algorithm. Our algorithm learns a single overcomplete dictionary and an optimal linear classifier jointly. The incremental dictionary learning algorithm is presented for the situation of limited memory resources. It yields dictionaries so that feature points with the same class labels have similar sparse codes. Experimental results demonstrate that our algorithm outperforms many recently proposed sparse-coding techniques for face, action, scene, and object category recognition under the same learning conditions.

Synaptic and Network Mechanisms of Sparse and Reliable Visual Cortical Activity during Nonclassical Receptive Field Stimulation

PubMed Central

Haider, Bilal; Krause, Matthew R.; Duque, Alvaro; Yu, Yuguo; Touryan, Jonathan; Mazer, James A.; McCormick, David A.

2011-01-01

SUMMARY During natural vision, the entire visual field is stimulated by images rich in spatiotemporal structure. Although many visual system studies restrict stimuli to the classical receptive field (CRF), it is known that costimulation of the CRF and the surrounding nonclassical receptive field (nCRF) increases neuronal response sparseness. The cellular and network mechanisms underlying increased response sparseness remain largely unexplored. Here we show that combined CRF + nCRF stimulation increases the sparseness, reliability, and precision of spiking and membrane potential responses in classical regular spiking (RSC) pyramidal neurons of cat primary visual cortex. Conversely, fast-spiking interneurons exhibit increased activity and decreased selectivity during CRF + nCRF stimulation. The increased sparseness and reliability of RSC neuron spiking is associated with increased inhibitory barrages and narrower visually evoked synaptic potentials. Our experimental observations were replicated with a simple computational model, suggesting that network interactions among neuronal subtypes ultimately sharpen recurrent excitation, producing specific and reliable visual responses. PMID:20152117

Measuring the spectrum of mutation induced by nitrogen ions and protons in the human-hamster hybrid cell line A(L)C

NASA Technical Reports Server (NTRS)

Kraemer, S. M.; Kronenberg, A.; Ueno, A.; Waldren, C. A.; Chatterjee, A. (Principal Investigator)

2000-01-01

Astronauts can be exposed to charged particles, including protons, alpha particles and heavier ions, during space flights. Therefore, studying the biological effectiveness of these sparsely and densely ionizing radiations is important to understanding the potential health effects for astronauts. We evaluated the mutagenic effectiveness of sparsely ionizing 55 MeV protons and densely ionizing 32 MeV/nucleon nitrogen ions using cells of two human-hamster cell lines, A(L) and A(L)C. We have previously characterized a spectrum of mutations, including megabase deletions, in human chromosome 11, the sole human chromosome in the human-hamster hybrid cell lines A(L)C and A(L). CD59(-) mutants have lost expression of a human cell surface antigen encoded by the CD59 gene located at 11p13. Deletion of genes located on the tip of the short arm of 11 (11p15.5) is lethal to the A(L) hybrid, so that CD59 mutants that lose the entire chromosome 11 die and escape detection. In contrast, deletion of the 11p15.5 region is not lethal in the hybrid A(L)C, allowing for the detection of chromosome loss or other chromosomal mutations involving 11p15.5. The 55 MeV protons and 32 MeV/nucleon nitrogen ions were each about 10 times more mutagenic per unit dose at the CD59 locus in A(L)C cells than in A(L) cells. In the case of nitrogen ions, the mutations observed in A(L)C cells were predominantly due to chromosome loss events or 11p deletions, often containing a breakpoint in the pericentromeric region. The increase in the CD59(-) mutant fraction for A(L)C cells exposed to protons was associated with either translocation of portions of 11q onto a hamster chromosome, or discontinuous or "skipping" mutations. We demonstrate here that A(L)C cells are a powerful tool that will aid in the understanding of the mutagenic effects of different types of ionizing radiation.

Learning Low-Rank Class-Specific Dictionary and Sparse Intra-Class Variant Dictionary for Face Recognition.

PubMed

Tang, Xin; Feng, Guo-Can; Li, Xiao-Xin; Cai, Jia-Xin

2015-01-01

Face recognition is challenging especially when the images from different persons are similar to each other due to variations in illumination, expression, and occlusion. If we have sufficient training images of each person which can span the facial variations of that person under testing conditions, sparse representation based classification (SRC) achieves very promising results. However, in many applications, face recognition often encounters the small sample size problem arising from the small number of available training images for each person. In this paper, we present a novel face recognition framework by utilizing low-rank and sparse error matrix decomposition, and sparse coding techniques (LRSE+SC). Firstly, the low-rank matrix recovery technique is applied to decompose the face images per class into a low-rank matrix and a sparse error matrix. The low-rank matrix of each individual is a class-specific dictionary and it captures the discriminative feature of this individual. The sparse error matrix represents the intra-class variations, such as illumination, expression changes. Secondly, we combine the low-rank part (representative basis) of each person into a supervised dictionary and integrate all the sparse error matrix of each individual into a within-individual variant dictionary which can be applied to represent the possible variations between the testing and training images. Then these two dictionaries are used to code the query image. The within-individual variant dictionary can be shared by all the subjects and only contribute to explain the lighting conditions, expressions, and occlusions of the query image rather than discrimination. At last, a reconstruction-based scheme is adopted for face recognition. Since the within-individual dictionary is introduced, LRSE+SC can handle the problem of the corrupted training data and the situation that not all subjects have enough samples for training. Experimental results show that our method achieves the state-of-the-art results on AR, FERET, FRGC and LFW databases.

Learning Low-Rank Class-Specific Dictionary and Sparse Intra-Class Variant Dictionary for Face Recognition

PubMed Central

Tang, Xin; Feng, Guo-can; Li, Xiao-xin; Cai, Jia-xin

2015-01-01

Face recognition is challenging especially when the images from different persons are similar to each other due to variations in illumination, expression, and occlusion. If we have sufficient training images of each person which can span the facial variations of that person under testing conditions, sparse representation based classification (SRC) achieves very promising results. However, in many applications, face recognition often encounters the small sample size problem arising from the small number of available training images for each person. In this paper, we present a novel face recognition framework by utilizing low-rank and sparse error matrix decomposition, and sparse coding techniques (LRSE+SC). Firstly, the low-rank matrix recovery technique is applied to decompose the face images per class into a low-rank matrix and a sparse error matrix. The low-rank matrix of each individual is a class-specific dictionary and it captures the discriminative feature of this individual. The sparse error matrix represents the intra-class variations, such as illumination, expression changes. Secondly, we combine the low-rank part (representative basis) of each person into a supervised dictionary and integrate all the sparse error matrix of each individual into a within-individual variant dictionary which can be applied to represent the possible variations between the testing and training images. Then these two dictionaries are used to code the query image. The within-individual variant dictionary can be shared by all the subjects and only contribute to explain the lighting conditions, expressions, and occlusions of the query image rather than discrimination. At last, a reconstruction-based scheme is adopted for face recognition. Since the within-individual dictionary is introduced, LRSE+SC can handle the problem of the corrupted training data and the situation that not all subjects have enough samples for training. Experimental results show that our method achieves the state-of-the-art results on AR, FERET, FRGC and LFW databases. PMID:26571112

Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells.

PubMed

Zhao, Ming-Tao; Shao, Ning-Yi; Hu, Shijun; Ma, Ning; Srinivasan, Rajini; Jahanbani, Fereshteh; Lee, Jaecheol; Zhang, Sophia L; Snyder, Michael P; Wu, Joseph C

2017-11-10

Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type-specific gene expression in the human heart. We aimed to decipher the cell type-specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression. We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31 + CD144 + ), cardiac progenitor cells (Sca-1 + ), fibroblasts (DDR2 + ), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type-specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression. Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering the epigenetic modulation of regulatory DNA elements that fine-tune spatiotemporal gene expression in human cardiac development and diseases. © 2017 American Heart Association, Inc.

Sparse representation based biomarker selection for schizophrenia with integrated analysis of fMRI and SNPs.

PubMed

Cao, Hongbao; Duan, Junbo; Lin, Dongdong; Shugart, Yin Yao; Calhoun, Vince; Wang, Yu-Ping

2014-11-15

Integrative analysis of multiple data types can take advantage of their complementary information and therefore may provide higher power to identify potential biomarkers that would be missed using individual data analysis. Due to different natures of diverse data modality, data integration is challenging. Here we address the data integration problem by developing a generalized sparse model (GSM) using weighting factors to integrate multi-modality data for biomarker selection. As an example, we applied the GSM model to a joint analysis of two types of schizophrenia data sets: 759,075 SNPs and 153,594 functional magnetic resonance imaging (fMRI) voxels in 208 subjects (92 cases/116 controls). To solve this small-sample-large-variable problem, we developed a novel sparse representation based variable selection (SRVS) algorithm, with the primary aim to identify biomarkers associated with schizophrenia. To validate the effectiveness of the selected variables, we performed multivariate classification followed by a ten-fold cross validation. We compared our proposed SRVS algorithm with an earlier sparse model based variable selection algorithm for integrated analysis. In addition, we compared with the traditional statistics method for uni-variant data analysis (Chi-squared test for SNP data and ANOVA for fMRI data). Results showed that our proposed SRVS method can identify novel biomarkers that show stronger capability in distinguishing schizophrenia patients from healthy controls. Moreover, better classification ratios were achieved using biomarkers from both types of data, suggesting the importance of integrative analysis. Copyright © 2014 Elsevier Inc. All rights reserved.

Improved FastICA algorithm in fMRI data analysis using the sparsity property of the sources.

PubMed

Ge, Ruiyang; Wang, Yubao; Zhang, Jipeng; Yao, Li; Zhang, Hang; Long, Zhiying

2016-04-01

As a blind source separation technique, independent component analysis (ICA) has many applications in functional magnetic resonance imaging (fMRI). Although either temporal or spatial prior information has been introduced into the constrained ICA and semi-blind ICA methods to improve the performance of ICA in fMRI data analysis, certain types of additional prior information, such as the sparsity, has seldom been added to the ICA algorithms as constraints. In this study, we proposed a SparseFastICA method by adding the source sparsity as a constraint to the FastICA algorithm to improve the performance of the widely used FastICA. The source sparsity is estimated through a smoothed ℓ0 norm method. We performed experimental tests on both simulated data and real fMRI data to investigate the feasibility and robustness of SparseFastICA and made a performance comparison between SparseFastICA, FastICA and Infomax ICA. Results of the simulated and real fMRI data demonstrated the feasibility and robustness of SparseFastICA for the source separation in fMRI data. Both the simulated and real fMRI experimental results showed that SparseFastICA has better robustness to noise and better spatial detection power than FastICA. Although the spatial detection power of SparseFastICA and Infomax did not show significant difference, SparseFastICA had faster computation speed than Infomax. SparseFastICA was comparable to the Infomax algorithm with a faster computation speed. More importantly, SparseFastICA outperformed FastICA in robustness and spatial detection power and can be used to identify more accurate brain networks than FastICA algorithm. Copyright © 2016 Elsevier B.V. All rights reserved.

Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Londei, M.; Savill, C.M.; Verhoef, A.

Rheumatoid arthritis is an autoimmune disease characterized by T-cell infiltration of the synovium of joints. Analysis of the phenotype and antigen specificity of the infiltrating cells may thus provide insight into the pathogenesis of rheumatoid arthritis. T cells were cloned with interleukin 2, a procedure that selects for in vivo-activated cells. All clones had the CD4 CDW29 phenotype. Their antigen specificity was tested by using a panel of candidate joint autoantigens. Four of 17 reacted against autologous blood mononuclear cells. Two clones proliferated in response to collagen type II. After 21 months, another set of clones was derived from synovialmore » tissue of the same joint. One of eight clones tested showed a strong proliferative response against collagen type II. The uncloned synovial T cells of a third operation from another joint also responded to collagen type II. The persistence of collagen type II-specific T cells in active rheumatoid joints over a period of 3 years suggests that collagen type II could be one of the autoantigens involved in perpetuating the inflammatory process in rheumatoid arthritis.« less

Spatial distribution of osteoblast-specific transcription factor Cbfa1 and bone formation in atherosclerotic arteries.

PubMed

Bobryshev, Yuri V; Killingsworth, Murray C; Lord, Reginald S A

2008-08-01

The mechanisms of ectopic bone formation in arteries are poorly understood. Osteoblasts might originate either from stem cells that penetrate atherosclerotic plaques from the blood stream or from pluripotent mesenchymal cells that have remained in the arterial wall from embryonic stages of the development. We have examined the frequency of the expression and spatial distribution of osteoblast-specific factor-2/core binding factor-1 (Osf2/Cbfa1) in carotid and coronary arteries. Cbfa1-expressing cells were rarely observed but were found in all tissue specimens in the deep portions of atherosclerotic plaques under the necrotic cores. The deep portions of atherosclerotic plaques under the necrotic cores were characterized by the lack of capillaries of neovascularization. In contrast, plaque shoulders, which were enriched by plexuses of neovascularization, lacked Cbfa1-expressing cells. No bone formation was found in any of the 21 carotid plaques examined and ectopic bone was observed in only two of 12 coronary plaques. We speculate that the sparse invasion of sprouts of neovascularization into areas underlying the necrotic cores, where Cbfa1-expressing cells reside, might explain the rarity of events of ectopic bone formation in the arterial wall. This study has also revealed that Cbfa1-expressing cells contain alpha-smooth muscle actin and myofilaments, indicating their relationship with arterial smooth muscle cells.

X-ray computed tomography using curvelet sparse regularization.

PubMed

Wieczorek, Matthias; Frikel, Jürgen; Vogel, Jakob; Eggl, Elena; Kopp, Felix; Noël, Peter B; Pfeiffer, Franz; Demaret, Laurent; Lasser, Tobias

2015-04-01

Reconstruction of x-ray computed tomography (CT) data remains a mathematically challenging problem in medical imaging. Complementing the standard analytical reconstruction methods, sparse regularization is growing in importance, as it allows inclusion of prior knowledge. The paper presents a method for sparse regularization based on the curvelet frame for the application to iterative reconstruction in x-ray computed tomography. In this work, the authors present an iterative reconstruction approach based on the alternating direction method of multipliers using curvelet sparse regularization. Evaluation of the method is performed on a specifically crafted numerical phantom dataset to highlight the method's strengths. Additional evaluation is performed on two real datasets from commercial scanners with different noise characteristics, a clinical bone sample acquired in a micro-CT and a human abdomen scanned in a diagnostic CT. The results clearly illustrate that curvelet sparse regularization has characteristic strengths. In particular, it improves the restoration and resolution of highly directional, high contrast features with smooth contrast variations. The authors also compare this approach to the popular technique of total variation and to traditional filtered backprojection. The authors conclude that curvelet sparse regularization is able to improve reconstruction quality by reducing noise while preserving highly directional features.

Improved Estimation and Interpretation of Correlations in Neural Circuits

PubMed Central

Yatsenko, Dimitri; Josić, Krešimir; Ecker, Alexander S.; Froudarakis, Emmanouil; Cotton, R. James; Tolias, Andreas S.

2015-01-01

Ambitious projects aim to record the activity of ever larger and denser neuronal populations in vivo. Correlations in neural activity measured in such recordings can reveal important aspects of neural circuit organization. However, estimating and interpreting large correlation matrices is statistically challenging. Estimation can be improved by regularization, i.e. by imposing a structure on the estimate. The amount of improvement depends on how closely the assumed structure represents dependencies in the data. Therefore, the selection of the most efficient correlation matrix estimator for a given neural circuit must be determined empirically. Importantly, the identity and structure of the most efficient estimator informs about the types of dominant dependencies governing the system. We sought statistically efficient estimators of neural correlation matrices in recordings from large, dense groups of cortical neurons. Using fast 3D random-access laser scanning microscopy of calcium signals, we recorded the activity of nearly every neuron in volumes 200 μm wide and 100 μm deep (150–350 cells) in mouse visual cortex. We hypothesized that in these densely sampled recordings, the correlation matrix should be best modeled as the combination of a sparse graph of pairwise partial correlations representing local interactions and a low-rank component representing common fluctuations and external inputs. Indeed, in cross-validation tests, the covariance matrix estimator with this structure consistently outperformed other regularized estimators. The sparse component of the estimate defined a graph of interactions. These interactions reflected the physical distances and orientation tuning properties of cells: The density of positive ‘excitatory’ interactions decreased rapidly with geometric distances and with differences in orientation preference whereas negative ‘inhibitory’ interactions were less selective. Because of its superior performance, this ‘sparse+latent’ estimator likely provides a more physiologically relevant representation of the functional connectivity in densely sampled recordings than the sample correlation matrix. PMID:25826696

An Atypical Acidophil Cell Line Tumor Showing Focal Differentiation Toward Both Growth Hormone and Prolactin Cells.

PubMed

Naritaka, Heiji; Kameya, Toru; Sato, Yuichi; Furuhata, Shigeru; Okui, Junichi; Kamiguchi, Yuji; Otani, Mitsuhiro; Toya, Shigeo

1995-01-01

We report a case of giant pituitary adenoma in a child. Computerized tomography (CT) scan revealed a suprasellar extension tumor mass with hydrocephalus. There was no clinical evidence of acromegaly, gigantism, and other hormonal symptoms. Endocrinologic studies showed within normal value of serum growth hormone (GH: 4.2 ng/mL) and slightly increased levels of prolactin (PRL: 78 ng/mL) and other pituitary hormone values were within normal range. On suppression test by bromocryptin, both GH and PRL levels were reduced. Histopathological findings revealed that the tumor consisted of predominantly chromophobic and partly eosinophilic adenoma cells. Immunohistochemical staining detected GH and PRL in a small number of distinctly different adenoma cells, respectively. Nonradioactive in situ hybridization (ISH) also showed GH and PRL mRNA expression in identical immunopositive cells. Electron microscopy (EM) demonstrated adenoma cells with moderate or small numbers of two types of dense granules and without fibrous body which are characteristic of sparsely granulated GH-cell adenomas. The adenoma does not fit into any classification but may be an atypical acidophil cell line tumor showing focal differentiation toward both GH and PRL cells.

Exploring the cellular basis of human disease through a large-scale mapping of deleterious genes to cell types.

PubMed

Cornish, Alex J; Filippis, Ioannis; David, Alessia; Sternberg, Michael J E

2015-09-01

Each cell type found within the human body performs a diverse and unique set of functions, the disruption of which can lead to disease. However, there currently exists no systematic mapping between cell types and the diseases they can cause. In this study, we integrate protein-protein interaction data with high-quality cell-type-specific gene expression data from the FANTOM5 project to build the largest collection of cell-type-specific interactomes created to date. We develop a novel method, called gene set compactness (GSC), that contrasts the relative positions of disease-associated genes across 73 cell-type-specific interactomes to map genes associated with 196 diseases to the cell types they affect. We conduct text-mining of the PubMed database to produce an independent resource of disease-associated cell types, which we use to validate our method. The GSC method successfully identifies known disease-cell-type associations, as well as highlighting associations that warrant further study. This includes mast cells and multiple sclerosis, a cell population currently being targeted in a multiple sclerosis phase 2 clinical trial. Furthermore, we build a cell-type-based diseasome using the cell types identified as manifesting each disease, offering insight into diseases linked through etiology. The data set produced in this study represents the first large-scale mapping of diseases to the cell types in which they are manifested and will therefore be useful in the study of disease systems. Overall, we demonstrate that our approach links disease-associated genes to the phenotypes they produce, a key goal within systems medicine.

Efficient convolutional sparse coding

DOEpatents

Wohlberg, Brendt

2017-06-20

Computationally efficient algorithms may be applied for fast dictionary learning solving the convolutional sparse coding problem in the Fourier domain. More specifically, efficient convolutional sparse coding may be derived within an alternating direction method of multipliers (ADMM) framework that utilizes fast Fourier transforms (FFT) to solve the main linear system in the frequency domain. Such algorithms may enable a significant reduction in computational cost over conventional approaches by implementing a linear solver for the most critical and computationally expensive component of the conventional iterative algorithm. The theoretical computational cost of the algorithm may be reduced from O(M.sup.3N) to O(MN log N), where N is the dimensionality of the data and M is the number of elements in the dictionary. This significant improvement in efficiency may greatly increase the range of problems that can practically be addressed via convolutional sparse representations.

Analysis of the early heterocyst Cys-proteome in the multicellular cyanobacterium Nostoc punctiforme reveals novel insights into the division of labor within diazotrophic filaments.

PubMed

Sandh, Gustaf; Ramström, Margareta; Stensjö, Karin

2014-12-04

In the filamentous cyanobacterium Nostoc punctiforme ATCC 29133, removal of combined nitrogen induces the differentiation of heterocysts, a cell-type specialized in N2 fixation. The differentiation involves genomic, structural and metabolic adaptations. In cyanobacteria, changes in the availability of carbon and nitrogen have also been linked to redox regulated posttranslational modifications of protein bound thiol groups. We have here employed a thiol targeting strategy to relatively quantify the putative redox proteome in heterocysts as compared to N2-fixing filaments, 24 hours after combined nitrogen depletion. The aim of the study was to expand the coverage of the cell-type specific proteome and metabolic landscape of heterocysts. Here we report the first cell-type specific proteome of newly formed heterocysts, compared to N2-fixing filaments, using the cysteine-specific selective ICAT methodology. The data set defined a good quantitative accuracy of the ICAT reagent in complex protein samples. The relative abundance levels of 511 proteins were determined and 74% showed a cell-type specific differential abundance. The majority of the identified proteins have not previously been quantified at the cell-type specific level. We have in addition analyzed the cell-type specific differential abundance of a large section of proteins quantified in both newly formed and steady-state diazotrophic cultures in N. punctiforme. The results describe a wide distribution of members of the putative redox regulated Cys-proteome in the central metabolism of both vegetative cells and heterocysts of N. punctiforme. The data set broadens our understanding of heterocysts and describes novel proteins involved in heterocyst physiology, including signaling and regulatory proteins as well as a large number of proteins with unknown function. Significant differences in cell-type specific abundance levels were present in the cell-type specific proteomes of newly formed diazotrophic filaments as compared to steady-state cultures. Therefore we conclude that by using our approach we are able to analyze a synchronized fraction of newly formed heterocysts, which enabled a better detection of proteins involved in the heterocyst specific physiology.

Sox10+ adult stem cells contribute to biomaterial encapsulation and microvascularization

PubMed Central

Wang, Dong; Wang, Aijun; Wu, Fan; Qiu, Xuefeng; Li, Ye; Chu, Julia; Huang, Wen-Chin; Xu, Kang; Gong, Xiaohua; Li, Song

2017-01-01

Implanted biomaterials and biomedical devices generally induce foreign body reaction and end up with encapsulation by a dense avascular fibrous layer enriched in extracellular matrix. Fibroblasts/myofibroblasts are thought to be the major cell type involved in encapsulation, but it is unclear whether and how stem cells contribute to this process. Here we show, for the first time, that Sox10+ adult stem cells contribute to both encapsulation and microvessel formation. Sox10+ adult stem cells were found sparsely in the stroma of subcutaneous loose connective tissues. Upon subcutaneous biomaterial implantation, Sox10+ stem cells were activated and recruited to the biomaterial scaffold, and differentiated into fibroblasts and then myofibroblasts. This differentiation process from Sox10+ stem cells to myofibroblasts could be recapitulated in vitro. On the other hand, Sox10+ stem cells could differentiate into perivascular cells to stabilize newly formed microvessels. Sox10+ stem cells and endothelial cells in three-dimensional co-culture self-assembled into microvessels, and platelet-derived growth factor had chemotactic effect on Sox10+ stem cells. Transplanted Sox10+ stem cells differentiated into smooth muscle cells to stabilize functional microvessels. These findings demonstrate the critical role of adult stem cells in tissue remodeling and unravel the complexity of stem cell fate determination. PMID:28071739

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

PubMed Central

Chang, Chawnshang; Yeh, Shuyuan; Lee, Soo Ok; Chang, Ta-min

2013-01-01

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases. PMID:24653668

Uneven colonization of the lymphoid periphery by T cells that undergo early TCR{alpha} rearrangements.

PubMed

Hendricks, Deborah W; Fink, Pamela J

2009-04-01

A sparse population of thymocytes undergoes TCRalpha gene rearrangement early in development, before the double-positive stage. The potential of these cells to contribute to the peripheral T cell pool is unknown. To examine the peripheral T cell compartment expressing a repertoire biased to early TCR gene rearrangements, we developed a mouse model in which TCRalpha rearrangements are restricted to the double-negative stage of thymocyte development. These mice carry floxed RAG2 alleles and a Cre transgene driven by the CD4 promoter. As expected, conventional T cell development is compromised in such Cre(+) RAG2(fl/fl) mice, and the TCRalphabeta(+) T cells that develop are limited in their TCRalpha repertoire, preferentially using early rearranging Valpha genes. In the gut, the Thy-1(+)TCRalphabeta(+) intraepithelial lymphocyte (IEL) compartment is surprisingly intact, whereas the Thy-1(-)TCRalphabeta(+) subset is almost completely absent. Thus, T cells expressing a TCRalpha repertoire that is the product of early gene rearrangements can preferentially populate distinct IEL compartments. Despite this capacity, Cre(+) RAG2(fl/fl) T cell progenitors cannot compete with wild-type T cell progenitors in mixed bone marrow chimeras, suggesting that in normal mice, there is only a small contribution to the peripheral T cell pool by cells that have undergone early TCRalpha rearrangements. In the absence of wild-type competitors, aggressive homeostatic proliferation in the IEL compartment can promote a relatively normal Thy-1(+) TCRalphabeta(+) T cell pool from the limited population derived from Cre(+) RAG2(fl/fl) progenitors.

Multi-threaded Sparse Matrix-Matrix Multiplication for Many-Core and GPU Architectures.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deveci, Mehmet; Rajamanickam, Sivasankaran; Trott, Christian Robert

Sparse Matrix-Matrix multiplication is a key kernel that has applications in several domains such as scienti c computing and graph analysis. Several algorithms have been studied in the past for this foundational kernel. In this paper, we develop parallel algorithms for sparse matrix-matrix multiplication with a focus on performance portability across different high performance computing architectures. The performance of these algorithms depend on the data structures used in them. We compare different types of accumulators in these algorithms and demonstrate the performance difference between these data structures. Furthermore, we develop a meta-algorithm, kkSpGEMM, to choose the right algorithm and datamore » structure based on the characteristics of the problem. We show performance comparisons on three architectures and demonstrate the need for the community to develop two phase sparse matrix-matrix multiplication implementations for efficient reuse of the data structures involved.« less

Localization of migraine susceptibility genes in human brain by single-cell RNA sequencing.

PubMed

Renthal, William

2018-01-01

Background Migraine is a debilitating disorder characterized by severe headaches and associated neurological symptoms. A key challenge to understanding migraine has been the cellular complexity of the human brain and the multiple cell types implicated in its pathophysiology. The present study leverages recent advances in single-cell transcriptomics to localize the specific human brain cell types in which putative migraine susceptibility genes are expressed. Methods The cell-type specific expression of both familial and common migraine-associated genes was determined bioinformatically using data from 2,039 individual human brain cells across two published single-cell RNA sequencing datasets. Enrichment of migraine-associated genes was determined for each brain cell type. Results Analysis of single-brain cell RNA sequencing data from five major subtypes of cells in the human cortex (neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells) indicates that over 40% of known migraine-associated genes are enriched in the expression profiles of a specific brain cell type. Further analysis of neuronal migraine-associated genes demonstrated that approximately 70% were significantly enriched in inhibitory neurons and 30% in excitatory neurons. Conclusions This study takes the next step in understanding the human brain cell types in which putative migraine susceptibility genes are expressed. Both familial and common migraine may arise from dysfunction of discrete cell types within the neurovascular unit, and localization of the affected cell type(s) in an individual patient may provide insight into to their susceptibility to migraine.

Dynamic diamond anvil cell (dDAC): A novel device for studying the dynamic-pressure properties of materials

NASA Astrophysics Data System (ADS)

Evans, William J.; Yoo, Choong-Shik; Lee, Geun Woo; Cynn, Hyunchae; Lipp, Magnus J.; Visbeck, Ken

2007-07-01

We have developed a unique device, a dynamic diamond anvil cell (dDAC), which repetitively applies a time-dependent load/pressure profile to a sample. This capability allows studies of the kinetics of phase transitions and metastable phases at compression (strain) rates of up to 500GPa/s (˜0.16s-1 for a metal). Our approach adapts electromechanical piezoelectric actuators to a conventional diamond anvil cell design, which enables precise specification and control of a time-dependent applied load/pressure. Existing DAC instrumentation and experimental techniques are easily adapted to the dDAC to measure the properties of a sample under the varying load/pressure conditions. This capability addresses the sparsely studied regime of dynamic phenomena between static research (diamond anvil cells and large volume presses) and dynamic shock-driven experiments (gas guns, explosive, and laser shock). We present an overview of a variety of experimental measurements that can be made with this device.

Single-Molecule Tracking Photoactivated Localization Microscopy to Map Nano-Scale Structure and Dynamics in Living Spines

PubMed Central

MacGillavry, Harold D.; Blanpied, Thomas A.

2013-01-01

Super-resolution microscopy has rapidly become an indispensable tool in cell biology and neuroscience by enabling measurement in live cells of structures smaller than the classical limit imposed by diffraction. The most widely applied super-resolution method currently is localization microscopy, which takes advantage of the ability to determine the position of individual fluorescent molecules with nanometer accuracy even in cells. By iteratively measuring sparse subsets of photoactivatable fluorescent proteins, protein distribution in macromolecular structures can be accurately reconstructed. Moreover, the motion trajectories of individual molecules within cells can be measured, providing unique ability to measure transport kinetics, exchange rates, and binding affinities of even small subsets of molecules with high temporal resolution and great spatial specificity. This unit describes protocols to measure and quantify the distribution of scaffold proteins within single synapses of cultured hippocampal neurons, and to track and measure the diffusion of intracellular constituents of the neuronal plasma membrane. PMID:25429311

Compressive sensing for sparse time-frequency representation of nonstationary signals in the presence of impulsive noise

NASA Astrophysics Data System (ADS)

Orović, Irena; Stanković, Srdjan; Amin, Moeness

2013-05-01

A modified robust two-dimensional compressive sensing algorithm for reconstruction of sparse time-frequency representation (TFR) is proposed. The ambiguity function domain is assumed to be the domain of observations. The two-dimensional Fourier bases are used to linearly relate the observations to the sparse TFR, in lieu of the Wigner distribution. We assume that a set of available samples in the ambiguity domain is heavily corrupted by an impulsive type of noise. Consequently, the problem of sparse TFR reconstruction cannot be tackled using standard compressive sensing optimization algorithms. We introduce a two-dimensional L-statistics based modification into the transform domain representation. It provides suitable initial conditions that will produce efficient convergence of the reconstruction algorithm. This approach applies sorting and weighting operations to discard an expected amount of samples corrupted by noise. The remaining samples serve as observations used in sparse reconstruction of the time-frequency signal representation. The efficiency of the proposed approach is demonstrated on numerical examples that comprise both cases of monocomponent and multicomponent signals.

Can Exposure to Environmental Chemicals Increase the Risk of Diabetes Type 1 Development?

PubMed Central

Stene, Lars Christian

2015-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged. PMID:25883945

Can exposure to environmental chemicals increase the risk of diabetes type 1 development?

PubMed

Bodin, Johanna; Stene, Lars Christian; Nygaard, Unni Cecilie

2015-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, where destruction of beta-cells causes insulin deficiency. The incidence of T1DM has increased in the last decades and cannot entirely be explained by genetic predisposition. Several environmental factors are suggested to promote T1DM, like early childhood enteroviral infections and nutritional factors, but the evidence is inconclusive. Prenatal and early life exposure to environmental pollutants like phthalates, bisphenol A, perfluorinated compounds, PCBs, dioxins, toxicants, and air pollutants can have negative effects on the developing immune system, resulting in asthma-like symptoms and increased susceptibility to childhood infections. In this review the associations between environmental chemical exposure and T1DM development is summarized. Although information on environmental chemicals as possible triggers for T1DM is sparse, we conclude that it is plausible that environmental chemicals can contribute to T1DM development via impaired pancreatic beta-cell and immune-cell functions and immunomodulation. Several environmental factors and chemicals could act together to trigger T1DM development in genetically susceptible individuals, possibly via hormonal or epigenetic alterations. Further observational T1DM cohort studies and animal exposure experiments are encouraged.

Pheromone lures to monitor sparse populations of spruce budworm, Choristoneura fumiferana (Lepidoptera: Tortricidae)

Treesearch

David G. Grimble

1988-01-01

Four types of spruce budworm pheromone lures were field-tested in sparse spruce budworm populations in Maine. BioLures® with constant pheromone emission rates less than 1.0, ca. 1.0-1.5, and ca. 15.0 micrograms of pheromone per day were compared to polyvinyl chloride (PVC) lures with rapidly decreasing pheromone emission rates. Mean trap catch was roughly proportional...

Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data

PubMed Central

Toker, Lilah; Rocco, Brad; Sibille, Etienne

2017-01-01

Establishing the molecular diversity of cell types is crucial for the study of the nervous system. We compiled a cross-laboratory database of mouse brain cell type-specific transcriptomes from 36 major cell types from across the mammalian brain using rigorously curated published data from pooled cell type microarray and single-cell RNA-sequencing (RNA-seq) studies. We used these data to identify cell type-specific marker genes, discovering a substantial number of novel markers, many of which we validated using computational and experimental approaches. We further demonstrate that summarized expression of marker gene sets (MGSs) in bulk tissue data can be used to estimate the relative cell type abundance across samples. To facilitate use of this expanding resource, we provide a user-friendly web interface at www.neuroexpresso.org. PMID:29204516

NELasso: Group-Sparse Modeling for Characterizing Relations Among Named Entities in News Articles.

PubMed

Tariq, Amara; Karim, Asim; Foroosh, Hassan

2017-10-01

Named entities such as people, locations, and organizations play a vital role in characterizing online content. They often reflect information of interest and are frequently used in search queries. Although named entities can be detected reliably from textual content, extracting relations among them is more challenging, yet useful in various applications (e.g., news recommending systems). In this paper, we present a novel model and system for learning semantic relations among named entities from collections of news articles. We model each named entity occurrence with sparse structured logistic regression, and consider the words (predictors) to be grouped based on background semantics. This sparse group LASSO approach forces the weights of word groups that do not influence the prediction towards zero. The resulting sparse structure is utilized for defining the type and strength of relations. Our unsupervised system yields a named entities' network where each relation is typed, quantified, and characterized in context. These relations are the key to understanding news material over time and customizing newsfeeds for readers. Extensive evaluation of our system on articles from TIME magazine and BBC News shows that the learned relations correlate with static semantic relatedness measures like WLM, and capture the evolving relationships among named entities over time.

JiTTree: A Just-in-Time Compiled Sparse GPU Volume Data Structure.

PubMed

Labschütz, Matthias; Bruckner, Stefan; Gröller, M Eduard; Hadwiger, Markus; Rautek, Peter

2016-01-01

Sparse volume data structures enable the efficient representation of large but sparse volumes in GPU memory for computation and visualization. However, the choice of a specific data structure for a given data set depends on several factors, such as the memory budget, the sparsity of the data, and data access patterns. In general, there is no single optimal sparse data structure, but a set of several candidates with individual strengths and drawbacks. One solution to this problem are hybrid data structures which locally adapt themselves to the sparsity. However, they typically suffer from increased traversal overhead which limits their utility in many applications. This paper presents JiTTree, a novel sparse hybrid volume data structure that uses just-in-time compilation to overcome these problems. By combining multiple sparse data structures and reducing traversal overhead we leverage their individual advantages. We demonstrate that hybrid data structures adapt well to a large range of data sets. They are especially superior to other sparse data structures for data sets that locally vary in sparsity. Possible optimization criteria are memory, performance and a combination thereof. Through just-in-time (JIT) compilation, JiTTree reduces the traversal overhead of the resulting optimal data structure. As a result, our hybrid volume data structure enables efficient computations on the GPU, while being superior in terms of memory usage when compared to non-hybrid data structures.

Analysis of complex-type chromosome exchanges in astronauts' lymphocytes after space flight as a biomarker of high-LET exposure

NASA Technical Reports Server (NTRS)

George, Kerry; Wu, Honglu; Willingham, Veronica; Cucinotta, Francis A.

2002-01-01

High-LET radiation is more efficient in producing complex-type chromosome exchanges than sparsely ionizing radiation, and this can potentially be used as a biomarker of radiation quality. To investigate if complex chromosome exchanges are induced by the high-LET component of space radiation exposure, damage was assessed in astronauts' blood lymphocytes before and after long duration missions of 3-4 months. The frequency of simple translocations increased significantly for most of the crewmembers studied. However, there were few complex exchanges detected and only one crewmember had a significant increase after flight. It has been suggested that the yield of complex chromosome damage could be underestimated when analyzing metaphase cells collected at one time point after irradiation, and analysis of chemically-induced PCC may be more accurate since problems with complicated cell-cycle delays are avoided. However, in this case the yields of chromosome damage were similar for metaphase and PCC analysis of astronauts' lymphocytes. It appears that the use of complex-type exchanges as biomarker of radiation quality in vivo after low-dose chronic exposure in mixed radiation fields is hampered by statistical uncertainties.

Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus

PubMed Central

Smith, Emily M.; Lajoie, Bryan R.; Jain, Gaurav; Dekker, Job

2016-01-01

Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation. PMID:26748519

Sparse Coding for N-Gram Feature Extraction and Training for File Fragment Classification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Felix; Quach, Tu-Thach; Wheeler, Jason

File fragment classification is an important step in the task of file carving in digital forensics. In file carving, files must be reconstructed based on their content as a result of their fragmented storage on disk or in memory. Existing methods for classification of file fragments typically use hand-engineered features such as byte histograms or entropy measures. In this paper, we propose an approach using sparse coding that enables automated feature extraction. Sparse coding, or sparse dictionary learning, is an unsupervised learning algorithm, and is capable of extracting features based simply on how well those features can be used tomore » reconstruct the original data. With respect to file fragments, we learn sparse dictionaries for n-grams, continuous sequences of bytes, of different sizes. These dictionaries may then be used to estimate n-gram frequencies for a given file fragment, but for significantly larger n-gram sizes than are typically found in existing methods which suffer from combinatorial explosion. To demonstrate the capability of our sparse coding approach, we used the resulting features to train standard classifiers such as support vector machines (SVMs) over multiple file types. Experimentally, we achieved significantly better classification results with respect to existing methods, especially when the features were used in supplement to existing hand-engineered features.« less

Sparse Coding for N-Gram Feature Extraction and Training for File Fragment Classification

DOE PAGES

Wang, Felix; Quach, Tu-Thach; Wheeler, Jason; ...

2018-04-05

File fragment classification is an important step in the task of file carving in digital forensics. In file carving, files must be reconstructed based on their content as a result of their fragmented storage on disk or in memory. Existing methods for classification of file fragments typically use hand-engineered features such as byte histograms or entropy measures. In this paper, we propose an approach using sparse coding that enables automated feature extraction. Sparse coding, or sparse dictionary learning, is an unsupervised learning algorithm, and is capable of extracting features based simply on how well those features can be used tomore » reconstruct the original data. With respect to file fragments, we learn sparse dictionaries for n-grams, continuous sequences of bytes, of different sizes. These dictionaries may then be used to estimate n-gram frequencies for a given file fragment, but for significantly larger n-gram sizes than are typically found in existing methods which suffer from combinatorial explosion. To demonstrate the capability of our sparse coding approach, we used the resulting features to train standard classifiers such as support vector machines (SVMs) over multiple file types. Experimentally, we achieved significantly better classification results with respect to existing methods, especially when the features were used in supplement to existing hand-engineered features.« less

Identification of Wnt Pathway Target Genes Regulating the Division and Differentiation of Larval Seam Cells and Vulval Precursor Cells in Caenorhabditis elegans.

PubMed

Gorrepati, Lakshmi; Krause, Michael W; Chen, Weiping; Brodigan, Thomas M; Correa-Mendez, Margarita; Eisenmann, David M

2015-06-05

The evolutionarily conserved Wnt/β-catenin signaling pathway plays a fundamental role during metazoan development, regulating numerous processes including cell fate specification, cell migration, and stem cell renewal. Wnt ligand binding leads to stabilization of the transcriptional effector β-catenin and upregulation of target gene expression to mediate a cellular response. During larval development of the nematode Caenorhabditis elegans, Wnt/β-catenin pathways act in fate specification of two hypodermal cell types, the ventral vulval precursor cells (VPCs) and the lateral seam cells. Because little is known about targets of the Wnt signaling pathways acting during larval VPC and seam cell differentiation, we sought to identify genes regulated by Wnt signaling in these two hypodermal cell types. We conditionally activated Wnt signaling in larval animals and performed cell type-specific "mRNA tagging" to enrich for VPC and seam cell-specific mRNAs, and then used microarray analysis to examine gene expression compared to control animals. Two hundred thirty-nine genes activated in response to Wnt signaling were identified, and we characterized 50 genes further. The majority of these genes are expressed in seam and/or vulval lineages during normal development, and reduction of function for nine genes caused defects in the proper division, fate specification, fate execution, or differentiation of seam cells and vulval cells. Therefore, the combination of these techniques was successful at identifying potential cell type-specific Wnt pathway target genes from a small number of cells and at increasing our knowledge of the specification and behavior of these C. elegans larval hypodermal cells. Copyright © 2015 Gorrepati et al.

Automated bone segmentation from dental CBCT images using patch-based sparse representation and convex optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Li; Gao, Yaozong; Shi, Feng

Purpose: Cone-beam computed tomography (CBCT) is an increasingly utilized imaging modality for the diagnosis and treatment planning of the patients with craniomaxillofacial (CMF) deformities. Accurate segmentation of CBCT image is an essential step to generate three-dimensional (3D) models for the diagnosis and treatment planning of the patients with CMF deformities. However, due to the poor image quality, including very low signal-to-noise ratio and the widespread image artifacts such as noise, beam hardening, and inhomogeneity, it is challenging to segment the CBCT images. In this paper, the authors present a new automatic segmentation method to address these problems. Methods: To segmentmore » CBCT images, the authors propose a new method for fully automated CBCT segmentation by using patch-based sparse representation to (1) segment bony structures from the soft tissues and (2) further separate the mandible from the maxilla. Specifically, a region-specific registration strategy is first proposed to warp all the atlases to the current testing subject and then a sparse-based label propagation strategy is employed to estimate a patient-specific atlas from all aligned atlases. Finally, the patient-specific atlas is integrated into amaximum a posteriori probability-based convex segmentation framework for accurate segmentation. Results: The proposed method has been evaluated on a dataset with 15 CBCT images. The effectiveness of the proposed region-specific registration strategy and patient-specific atlas has been validated by comparing with the traditional registration strategy and population-based atlas. The experimental results show that the proposed method achieves the best segmentation accuracy by comparison with other state-of-the-art segmentation methods. Conclusions: The authors have proposed a new CBCT segmentation method by using patch-based sparse representation and convex optimization, which can achieve considerably accurate segmentation results in CBCT segmentation based on 15 patients.« less

Constraints on Fluctuations in Sparsely Characterized Biological Systems.

PubMed

Hilfinger, Andreas; Norman, Thomas M; Vinnicombe, Glenn; Paulsson, Johan

2016-02-05

Biochemical processes are inherently stochastic, creating molecular fluctuations in otherwise identical cells. Such "noise" is widespread but has proven difficult to analyze because most systems are sparsely characterized at the single cell level and because nonlinear stochastic models are analytically intractable. Here, we exactly relate average abundances, lifetimes, step sizes, and covariances for any pair of components in complex stochastic reaction systems even when the dynamics of other components are left unspecified. Using basic mathematical inequalities, we then establish bounds for whole classes of systems. These bounds highlight fundamental trade-offs that show how efficient assembly processes must invariably exhibit large fluctuations in subunit levels and how eliminating fluctuations in one cellular component requires creating heterogeneity in another.

Constraints on Fluctuations in Sparsely Characterized Biological Systems

NASA Astrophysics Data System (ADS)

Hilfinger, Andreas; Norman, Thomas M.; Vinnicombe, Glenn; Paulsson, Johan

2016-02-01

Biochemical processes are inherently stochastic, creating molecular fluctuations in otherwise identical cells. Such "noise" is widespread but has proven difficult to analyze because most systems are sparsely characterized at the single cell level and because nonlinear stochastic models are analytically intractable. Here, we exactly relate average abundances, lifetimes, step sizes, and covariances for any pair of components in complex stochastic reaction systems even when the dynamics of other components are left unspecified. Using basic mathematical inequalities, we then establish bounds for whole classes of systems. These bounds highlight fundamental trade-offs that show how efficient assembly processes must invariably exhibit large fluctuations in subunit levels and how eliminating fluctuations in one cellular component requires creating heterogeneity in another.

Role of the chromatin landscape and sequence in determining cell type-specific genomic glucocorticoid receptor binding and gene regulation

PubMed Central

Huska, Matthew R.; Jurk, Marcel; Schöpflin, Robert; Starick, Stephan R.; Schwahn, Kevin; Cooper, Samantha B.; Yamamoto, Keith R.; Thomas-Chollier, Morgane; Vingron, Martin

2017-01-01

Abstract The genomic loci bound by the glucocorticoid receptor (GR), a hormone-activated transcription factor, show little overlap between cell types. To study the role of chromatin and sequence in specifying where GR binds, we used Bayesian modeling within the universe of accessible chromatin. Taken together, our results uncovered that although GR preferentially binds accessible chromatin, its binding is biased against accessible chromatin located at promoter regions. This bias can only be explained partially by the presence of fewer GR recognition sequences, arguing for the existence of additional mechanisms that interfere with GR binding at promoters. Therefore, we tested the role of H3K9ac, the chromatin feature with the strongest negative association with GR binding, but found that this correlation does not reflect a causative link. Finally, we find a higher percentage of promoter–proximal GR binding for genes regulated by GR across cell types than for cell type-specific target genes. Given that GR almost exclusively binds accessible chromatin, we propose that cell type-specific regulation by GR preferentially occurs via distal enhancers, whose chromatin accessibility is typically cell type-specific, whereas ubiquitous target gene regulation is more likely to result from binding to promoter regions, which are often accessible regardless of cell type examined. PMID:27903902

Analysis of surface properties of fixed and live cells using derivatized agarose beads.

PubMed

Navarro, Vanessa M; Walker, Sherri L; Badali, Oliver; Abundis, Maria I; Ngo, Lylla L; Weerasinghe, Gayani; Barajas, Marcela; Zem, Gregory; Oppenheimer, Steven B

2002-01-01

A novel assay has been developed for the histochemical characterization of surface properties of cells based on their adhesion to agarose beads derivatized with more than 100 types of molecules, including sugars, lectins and other proteins, and amino acids. The assay simply involves mixing small quantities of washed cells and beads in droplets on glass microscope slides and determining to which beads various cell types adhere. Distilled water was found to be the best medium for this assay because added ions or molecules in other media inhibit adhesion in some cases. Many cells, however, cannot tolerate distilled water. Here we show that cells fixed with either of two fixatives (1% formaldehyde or Prefer fixative) displayed similar bead-binding properties as did live cells. Specificity of cell-bead binding was tested by including specific free molecules in the test suspensions in hapten-type inhibition experiments. If a hapten compound inhibited live-cell adhesion to a specific bead, it also inhibited fixed-cell adhesion to a specific bead. The results of these experiments suggest that fixed cells display authentic surface properties, opening the door for the use of this assay with many cell types that cannot tolerate distilled water.

Papillary neoplasia of the breast: immunohistochemically defined myoepithelial cells in the diagnosis of benign and malignant papillary breast neoplasms.

PubMed

Raju, U B; Lee, M W; Zarbo, R J; Crissman, J D

1989-11-01

The presence or absence of myoepithelial cells (ME) has been considered as an important feature in the differential diagnosis of benign and malignant papillary lesions of the breast. We evaluated the distribution of myoepithelial cells in formalin-fixed paraffin-embedded tissue sections of 25 papillomas and 18 papillary carcinomas by ABC immunoperoxidase technique with antibodies to muscle actin (HHF-35) and high molecular weight (HMW) keratin (clone 34BE12, cytokeratins 1, 5, 10, and 14; reacting preferentially with ME cells) and an antiserum to S-100 protein. Also included in the study were eight cases of micropapillary ductal carcinoma in situ (DCIS) having a few fibrovascular cores and five peripheral papillomas with accompanying ductal carcinoma in situ or atypical hyperplasia. The antibodies to muscle actin were sensitive and relatively specific for ME cells of the breast and uniformly labeled ME cells in all 25 papillomas. ME cells were absent or extremely sparse in papillary carcinomas. They were present focally in some of the fibrovascular cores of the micropapillary DCIS, and a mixed pattern was observed in peripheral papillomas with areas of carcinoma. HMW keratin was variably expressed in ME cells in most cases with positive internal controls and was present in several normal ductal and papilloma epithelial cells but not in epithelial cells of papillary carcinomas. HMW keratin, although less specific for ME cells, was a useful adjunct because of its reactivity with ME cells as well as hyperplastic epithelial cells in papillomas, which resulted in a combined positive reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Definition of Drosophila hemocyte subsets by cell-type specific antigens.

PubMed

Kurucz, Eva; Váczi, B; Márkus, R; Laurinyecz, Barbara; Vilmos, P; Zsámboki, J; Csorba, Kinga; Gateff, Elisabeth; Hultmark, D; Andó, I

2007-01-01

We analyzed the heterogeneity of Drosophila hemocytes on the basis of the expression of cell-type specific antigens. The antigens characterize distinct subsets which partially overlap with those defined by morphological criteria. On the basis of the expression or the lack of expression of blood cell antigens the following hemocyte populations have been defined: crystal cells, plasmatocytes, lamellocytes and precursor cells. The expression of the antigens and thus the different cell types are developmentally regulated. The hemocytes are arranged in four main compartments: the circulating blood cells, the sessile tissue, the lymph glands and the posterior hematopoietic tissue. Each hemocyte compartment has a specific and characteristic composition of the various cell types. The described markers represent the first successful attempt to define hemocyte lineages by immunological markers in Drosophila and help to define morphologically, functionally, spatially and developmentally distinct subsets of hemocytes.

Cell-Type Specific Inactivation of Hippocampal CA1 Disrupts Location-Dependent Object Recognition in the Mouse

ERIC Educational Resources Information Center

Haettig, Jakob; Sun, Yanjun; Wood, Marcelo A.; Xu, Xiangmin

2013-01-01

The allatostatin receptor (AlstR)/ligand inactivation system enables potent regulation of neuronal circuit activity. To examine how different cell types participate in memory formation, we have used this system through Cre-directed, cell-type specific expression in mouse hippocampal CA1 in vivo and examined functional effects of inactivation of…

Cell-Specific Multifunctional Processing of Heterogeneous Cell Systems in a Single Laser Pulse Treatment

PubMed Central

Lukianova-Hleb, Ekaterina Y.; Mutonga, Martin B. G.; Lapotko, Dmitri O.

2012-01-01

Current methods of cell processing for gene and cell therapies use several separate procedures for gene transfer and cell separation or elimination, because no current technology can offer simultaneous multi-functional processing of specific cell sub-sets in highly heterogeneous cell systems. Using the cell-specific generation of plasmonic nanobubbles of different sizes around cell-targeted gold nanoshells and nanospheres, we achieved simultaneous multifunctional cell-specific processing in a rapid single 70 ps laser pulse bulk treatment of heterogeneous cell suspension. This method supported the detection of cells, delivery of external molecular cargo to one type of cells and the concomitant destruction of another type of cells without damaging other cells in suspension, and real-time guidance of the two above cellular effects. PMID:23167546

Cross-Species Transcriptome Profiling Identifies New Alveolar Epithelial Type I Cell–Specific Genes

PubMed Central

Sunohara, Mitsuhiro; Pouldar, Tiffany M.; Wang, Hongjun; Liu, Yixin; Rieger, Megan E.; Tran, Evelyn; Flodby, Per; Siegmund, Kimberly D.; Crandall, Edward D.; Laird-Offringa, Ite A.

2017-01-01

Diseases involving the distal lung alveolar epithelium include chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma. Accurate labeling of specific cell types is critical for determining the contribution of each to the pathogenesis of these diseases. The distal lung alveolar epithelium is composed of two cell types, alveolar epithelial type 1 (AT1) and type 2 (AT2) cells. Although cell type–specific markers, most prominently surfactant protein C, have allowed detailed lineage tracing studies of AT2 cell differentiation and the cells’ roles in disease, studies of AT1 cells have been hampered by a lack of genes with expression unique to AT1 cells. In this study, we performed genome-wide expression profiling of multiple rat organs together with purified rat AT2, AT1, and in vitro differentiated AT1-like cells, resulting in the identification of 54 candidate AT1 cell markers. Cross-referencing with genes up-regulated in human in vitro differentiated AT1-like cells narrowed the potential list to 18 candidate genes. Testing the top four candidate genes at RNA and protein levels revealed GRAM domain 2 (GRAMD2), a protein of unknown function, as highly specific to AT1 cells. RNA sequencing (RNAseq) confirmed that GRAMD2 is transcriptionally silent in human AT2 cells. Immunofluorescence verified that GRAMD2 expression is restricted to the plasma membrane of AT1 cells and is not expressed in bronchial epithelial cells, whereas reverse transcription–polymerase chain reaction confirmed that it is not expressed in endothelial cells. Using GRAMD2 as a new AT1 cell–specific gene will enhance AT1 cell isolation, the investigation of alveolar epithelial cell differentiation potential, and the contribution of AT1 cells to distal lung diseases. PMID:27749084

Burst Firing is a Neural Code in an Insect Auditory System

PubMed Central

Eyherabide, Hugo G.; Rokem, Ariel; Herz, Andreas V. M.; Samengo, Inés

2008-01-01

Various classes of neurons alternate between high-frequency discharges and silent intervals. This phenomenon is called burst firing. To analyze burst activity in an insect system, grasshopper auditory receptor neurons were recorded in vivo for several distinct stimulus types. The experimental data show that both burst probability and burst characteristics are strongly influenced by temporal modulations of the acoustic stimulus. The tendency to burst, hence, is not only determined by cell-intrinsic processes, but also by their interaction with the stimulus time course. We study this interaction quantitatively and observe that bursts containing a certain number of spikes occur shortly after stimulus deflections of specific intensity and duration. Our findings suggest a sparse neural code where information about the stimulus is represented by the number of spikes per burst, irrespective of the detailed interspike-interval structure within a burst. This compact representation cannot be interpreted as a firing-rate code. An information-theoretical analysis reveals that the number of spikes per burst reliably conveys information about the amplitude and duration of sound transients, whereas their time of occurrence is reflected by the burst onset time. The investigated neurons encode almost half of the total transmitted information in burst activity. PMID:18946533

Live imaging of endogenous PSD-95 using ENABLED: a conditional strategy to fluorescently label endogenous proteins.

PubMed

Fortin, Dale A; Tillo, Shane E; Yang, Guang; Rah, Jong-Cheol; Melander, Joshua B; Bai, Suxia; Soler-Cedeño, Omar; Qin, Maozhen; Zemelman, Boris V; Guo, Caiying; Mao, Tianyi; Zhong, Haining

2014-12-10

Stoichiometric labeling of endogenous synaptic proteins for high-contrast live-cell imaging in brain tissue remains challenging. Here, we describe a conditional mouse genetic strategy termed endogenous labeling via exon duplication (ENABLED), which can be used to fluorescently label endogenous proteins with near ideal properties in all neurons, a sparse subset of neurons, or specific neuronal subtypes. We used this method to label the postsynaptic density protein PSD-95 with mVenus without overexpression side effects. We demonstrated that mVenus-tagged PSD-95 is functionally equivalent to wild-type PSD-95 and that PSD-95 is present in nearly all dendritic spines in CA1 neurons. Within spines, while PSD-95 exhibited low mobility under basal conditions, its levels could be regulated by chronic changes in neuronal activity. Notably, labeled PSD-95 also allowed us to visualize and unambiguously examine otherwise-unidentifiable excitatory shaft synapses in aspiny neurons, such as parvalbumin-positive interneurons and dopaminergic neurons. Our results demonstrate that the ENABLED strategy provides a valuable new approach to study the dynamics of endogenous synaptic proteins in vivo. Copyright © 2014 the authors 0270-6474/14/3416698-15$15.00/0.

Brain-specific enhancers for cell-based therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Visel, Axel; Rubenstein, John L.R.; Chen, Ying-Jiun

Herein are described a set of novel specific human enhancers for specific forebrain cell types used to study and select for human neural progenitor cells. This approach enables the ability to generate interneurons from human ES, iPS and iN cells, making them available for human transplantation and for molecular/cellular analyzes. These approaches are also directly applicable to generating other neuronal cell types, such as cortical and striatal projection neurons, which have implications for many human diseases.

Characteristics of microRNAs enriched in specific cell types and primary tissue types in solid organs.

PubMed

Kriegel, Alison J; Liu, Yong; Liu, Pengyuan; Baker, Maria Angeles; Hodges, Matthew R; Hua, Xing; Liang, Mingyu

2013-12-01

Knowledge of miRNA expression and function in specific cell types in solid organs is limited because of difficulty in obtaining appropriate specimens. We used laser capture microdissection to obtain nine tissue regions from rats, including the nucleus of the solitary tract, hypoglossal motor nucleus, ventral respiratory column/pre-Bötzinger complex, and midline raphe nucleus from the brain stem, myocardium and coronary artery from the heart, and glomerulus, proximal convoluted tubule, and medullary thick ascending limb from the kidney. Each tissue region consists of or is enriched for a specific cell type. Differential patterns of miRNA expression obtained by deep sequencing of minute amounts of laser-captured cells were highly consistent with data obtained from real-time PCR analysis. miRNA expression patterns correctly clustered the specimens by tissue regions and then by primary tissue types (neural, muscular, or epithelial). The aggregate difference in miRNA profiles between tissue regions that contained the same primary tissue type was as large as one-half of the aggregate difference between primary tissue types. miRNAs differentially expressed between primary tissue types are more likely to be abundant miRNAs, while miRNAs differentially expressed between tissue regions containing the same primary tissue type were distributed evenly across the abundance spectrum. The tissue type-enriched miRNAs were more likely to target genes enriched for specific functional categories compared with either cell type-enriched miRNAs or randomly selected miRNAs. These data indicate that the role of miRNAs in determining characteristics of primary tissue types may be different than their role in regulating cell type-specific functions in solid organs.

Deep ensemble learning of sparse regression models for brain disease diagnosis.

PubMed

Suk, Heung-Il; Lee, Seong-Whan; Shen, Dinggang

2017-04-01

Recent studies on brain imaging analysis witnessed the core roles of machine learning techniques in computer-assisted intervention for brain disease diagnosis. Of various machine-learning techniques, sparse regression models have proved their effectiveness in handling high-dimensional data but with a small number of training samples, especially in medical problems. In the meantime, deep learning methods have been making great successes by outperforming the state-of-the-art performances in various applications. In this paper, we propose a novel framework that combines the two conceptually different methods of sparse regression and deep learning for Alzheimer's disease/mild cognitive impairment diagnosis and prognosis. Specifically, we first train multiple sparse regression models, each of which is trained with different values of a regularization control parameter. Thus, our multiple sparse regression models potentially select different feature subsets from the original feature set; thereby they have different powers to predict the response values, i.e., clinical label and clinical scores in our work. By regarding the response values from our sparse regression models as target-level representations, we then build a deep convolutional neural network for clinical decision making, which thus we call 'Deep Ensemble Sparse Regression Network.' To our best knowledge, this is the first work that combines sparse regression models with deep neural network. In our experiments with the ADNI cohort, we validated the effectiveness of the proposed method by achieving the highest diagnostic accuracies in three classification tasks. We also rigorously analyzed our results and compared with the previous studies on the ADNI cohort in the literature. Copyright © 2017 Elsevier B.V. All rights reserved.

Deep ensemble learning of sparse regression models for brain disease diagnosis

PubMed Central

Suk, Heung-Il; Lee, Seong-Whan; Shen, Dinggang

2018-01-01

Recent studies on brain imaging analysis witnessed the core roles of machine learning techniques in computer-assisted intervention for brain disease diagnosis. Of various machine-learning techniques, sparse regression models have proved their effectiveness in handling high-dimensional data but with a small number of training samples, especially in medical problems. In the meantime, deep learning methods have been making great successes by outperforming the state-of-the-art performances in various applications. In this paper, we propose a novel framework that combines the two conceptually different methods of sparse regression and deep learning for Alzheimer’s disease/mild cognitive impairment diagnosis and prognosis. Specifically, we first train multiple sparse regression models, each of which is trained with different values of a regularization control parameter. Thus, our multiple sparse regression models potentially select different feature subsets from the original feature set; thereby they have different powers to predict the response values, i.e., clinical label and clinical scores in our work. By regarding the response values from our sparse regression models as target-level representations, we then build a deep convolutional neural network for clinical decision making, which thus we call ‘ Deep Ensemble Sparse Regression Network.’ To our best knowledge, this is the first work that combines sparse regression models with deep neural network. In our experiments with the ADNI cohort, we validated the effectiveness of the proposed method by achieving the highest diagnostic accuracies in three classification tasks. We also rigorously analyzed our results and compared with the previous studies on the ADNI cohort in the literature. PMID:28167394

Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.

PubMed

Henry, Rachel A; Kendall, Peggy L; Thomas, James W

2012-08-01

Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease.

Embedded sparse representation of fMRI data via group-wise dictionary optimization

NASA Astrophysics Data System (ADS)

Zhu, Dajiang; Lin, Binbin; Faskowitz, Joshua; Ye, Jieping; Thompson, Paul M.

2016-03-01

Sparse learning enables dimension reduction and efficient modeling of high dimensional signals and images, but it may need to be tailored to best suit specific applications and datasets. Here we used sparse learning to efficiently represent functional magnetic resonance imaging (fMRI) data from the human brain. We propose a novel embedded sparse representation (ESR), to identify the most consistent dictionary atoms across different brain datasets via an iterative group-wise dictionary optimization procedure. In this framework, we introduced additional criteria to make the learned dictionary atoms more consistent across different subjects. We successfully identified four common dictionary atoms that follow the external task stimuli with very high accuracy. After projecting the corresponding coefficient vectors back into the 3-D brain volume space, the spatial patterns are also consistent with traditional fMRI analysis results. Our framework reveals common features of brain activation in a population, as a new, efficient fMRI analysis method.

Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells

PubMed Central

Salopiata, Florian; Depner, Sofia; Wäsch, Marvin; Böhm, Martin E.; Mücke, Oliver; Plass, Christoph; Lehmann, Wolf D.; Kreutz, Clemens; Timmer, Jens; Klingmüller, Ursula

2016-01-01

Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid progenitor cells unaffected. Thus, the proposed modeling strategy can be employed as a general procedure to identify cell type-specific parameters and to recommend treatment strategies for the selective targeting of specific cell types. PMID:27494133

Limited-memory trust-region methods for sparse relaxation

NASA Astrophysics Data System (ADS)

Adhikari, Lasith; DeGuchy, Omar; Erway, Jennifer B.; Lockhart, Shelby; Marcia, Roummel F.

2017-08-01

In this paper, we solve the l2-l1 sparse recovery problem by transforming the objective function of this problem into an unconstrained differentiable function and applying a limited-memory trust-region method. Unlike gradient projection-type methods, which uses only the current gradient, our approach uses gradients from previous iterations to obtain a more accurate Hessian approximation. Numerical experiments show that our proposed approach eliminates spurious solutions more effectively while improving computational time.

Color opponent receptive fields self-organize in a biophysical model of visual cortex via spike-timing dependent plasticity

PubMed Central

Eguchi, Akihiro; Neymotin, Samuel A.; Stringer, Simon M.

2014-01-01

Although many computational models have been proposed to explain orientation maps in primary visual cortex (V1), it is not yet known how similar clusters of color-selective neurons in macaque V1/V2 are connected and develop. In this work, we address the problem of understanding the cortical processing of color information with a possible mechanism of the development of the patchy distribution of color selectivity via computational modeling. Each color input is decomposed into a red, green, and blue representation and transmitted to the visual cortex via a simulated optic nerve in a luminance channel and red–green and blue–yellow opponent color channels. Our model of the early visual system consists of multiple topographically-arranged layers of excitatory and inhibitory neurons, with sparse intra-layer connectivity and feed-forward connectivity between layers. Layers are arranged based on anatomy of early visual pathways, and include a retina, lateral geniculate nucleus, and layered neocortex. Each neuron in the V1 output layer makes synaptic connections to neighboring neurons and receives the three types of signals in the different channels from the corresponding photoreceptor position. Synaptic weights are randomized and learned using spike-timing-dependent plasticity (STDP). After training with natural images, the neurons display heightened sensitivity to specific colors. Information-theoretic analysis reveals mutual information between particular stimuli and responses, and that the information reaches a maximum with fewer neurons in the higher layers, indicating that estimations of the input colors can be done using the output of fewer cells in the later stages of cortical processing. In addition, cells with similar color receptive fields form clusters. Analysis of spiking activity reveals increased firing synchrony between neurons when particular color inputs are presented or removed (ON-cell/OFF-cell). PMID:24659956

Natural image sequences constrain dynamic receptive fields and imply a sparse code.

PubMed

Häusler, Chris; Susemihl, Alex; Nawrot, Martin P

2013-11-06

In their natural environment, animals experience a complex and dynamic visual scenery. Under such natural stimulus conditions, neurons in the visual cortex employ a spatially and temporally sparse code. For the input scenario of natural still images, previous work demonstrated that unsupervised feature learning combined with the constraint of sparse coding can predict physiologically measured receptive fields of simple cells in the primary visual cortex. This convincingly indicated that the mammalian visual system is adapted to the natural spatial input statistics. Here, we extend this approach to the time domain in order to predict dynamic receptive fields that can account for both spatial and temporal sparse activation in biological neurons. We rely on temporal restricted Boltzmann machines and suggest a novel temporal autoencoding training procedure. When tested on a dynamic multi-variate benchmark dataset this method outperformed existing models of this class. Learning features on a large dataset of natural movies allowed us to model spatio-temporal receptive fields for single neurons. They resemble temporally smooth transformations of previously obtained static receptive fields and are thus consistent with existing theories. A neuronal spike response model demonstrates how the dynamic receptive field facilitates temporal and population sparseness. We discuss the potential mechanisms and benefits of a spatially and temporally sparse representation of natural visual input. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Interlocked feedforward loops control cell-type-specific Rhodopsin expression in the Drosophila eye.

PubMed

Johnston, Robert J; Otake, Yoshiaki; Sood, Pranidhi; Vogt, Nina; Behnia, Rudy; Vasiliauskas, Daniel; McDonald, Elizabeth; Xie, Baotong; Koenig, Sebastian; Wolf, Reinhard; Cook, Tiffany; Gebelein, Brian; Kussell, Edo; Nakagoshi, Hideki; Desplan, Claude

2011-06-10

How complex networks of activators and repressors lead to exquisitely specific cell-type determination during development is poorly understood. In the Drosophila eye, expression patterns of Rhodopsins define at least eight functionally distinct though related subtypes of photoreceptors. Here, we describe a role for the transcription factor gene defective proventriculus (dve) as a critical node in the network regulating Rhodopsin expression. dve is a shared component of two opposing, interlocked feedforward loops (FFLs). Orthodenticle and Dve interact in an incoherent FFL to repress Rhodopsin expression throughout the eye. In R7 and R8 photoreceptors, a coherent FFL relieves repression by Dve while activating Rhodopsin expression. Therefore, this network uses repression to restrict and combinatorial activation to induce cell-type-specific expression. Furthermore, Dve levels are finely tuned to yield cell-type- and region-specific repression or activation outcomes. This interlocked FFL motif may be a general mechanism to control terminal cell-fate specification. Copyright © 2011 Elsevier Inc. All rights reserved.

Gravity and count probabilities in an expanding universe

NASA Technical Reports Server (NTRS)

Bouchet, Francois R.; Hernquist, Lars

1992-01-01

The time evolution of nonlinear clustering on large scales in cold dark matter, hot dark matter, and white noise models of the universe is investigated using N-body simulations performed with a tree code. Count probabilities in cubic cells are determined as functions of the cell size and the clustering state (redshift), and comparisons are made with various theoretical models. We isolate the features that appear to be the result of gravitational instability, those that depend on the initial conditions, and those that are likely a consequence of numerical limitations. More specifically, we study the development of skewness, kurtosis, and the fifth moment in relation to variance, the dependence of the void probability on time as well as on sparseness of sampling, and the overall shape of the count probability distribution. Implications of our results for theoretical and observational studies are discussed.

A combinatorial model for dentate gyrus sparse coding

DOE PAGES

Severa, William; Parekh, Ojas; James, Conrad D.; ...

2016-12-29

The dentate gyrus forms a critical link between the entorhinal cortex and CA3 by providing a sparse version of the signal. Concurrent with this increase in sparsity, a widely accepted theory suggests the dentate gyrus performs pattern separation—similar inputs yield decorrelated outputs. Although an active region of study and theory, few logically rigorous arguments detail the dentate gyrus’s (DG) coding. We suggest a theoretically tractable, combinatorial model for this action. The model provides formal methods for a highly redundant, arbitrarily sparse, and decorrelated output signal.To explore the value of this model framework, we assess how suitable it is for twomore » notable aspects of DG coding: how it can handle the highly structured grid cell representation in the input entorhinal cortex region and the presence of adult neurogenesis, which has been proposed to produce a heterogeneous code in the DG. We find tailoring the model to grid cell input yields expansion parameters consistent with the literature. In addition, the heterogeneous coding reflects activity gradation observed experimentally. Lastly, we connect this approach with more conventional binary threshold neural circuit models via a formal embedding.« less

Multi-channel feature dictionaries for RGB-D object recognition

NASA Astrophysics Data System (ADS)

Lan, Xiaodong; Li, Qiming; Chong, Mina; Song, Jian; Li, Jun

2018-04-01

Hierarchical matching pursuit (HMP) is a popular feature learning method for RGB-D object recognition. However, the feature representation with only one dictionary for RGB channels in HMP does not capture sufficient visual information. In this paper, we propose multi-channel feature dictionaries based feature learning method for RGB-D object recognition. The process of feature extraction in the proposed method consists of two layers. The K-SVD algorithm is used to learn dictionaries in sparse coding of these two layers. In the first-layer, we obtain features by performing max pooling on sparse codes of pixels in a cell. And the obtained features of cells in a patch are concatenated to generate patch jointly features. Then, patch jointly features in the first-layer are used to learn the dictionary and sparse codes in the second-layer. Finally, spatial pyramid pooling can be applied to the patch jointly features of any layer to generate the final object features in our method. Experimental results show that our method with first or second-layer features can obtain a comparable or better performance than some published state-of-the-art methods.

Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy

PubMed Central

Zhou, Jiehua; Rossi, John J.

2014-01-01

One hundred years ago, Dr. Paul Ehrlich popularized the “magic bullet” concept for cancer therapy in which an ideal therapeutic agent would only kill the specific tumor cells it targeted. Since then, “targeted therapy” that specifically targets the molecular defects responsible for a patient's condition has become a long-standing goal for treating human disease. However, safe and efficient drug delivery during the treatment of cancer and infectious disease remains a major challenge for clinical translation and the development of new therapies. The advent of SELEX technology has inspired many groundbreaking studies that successfully adapted cell-specific aptamers for targeted delivery of active drug substances in both in vitro and in vivo models. By covalently linking or physically functionalizing the cell-specific aptamers with therapeutic agents, such as siRNA, microRNA, chemotherapeutics or toxins, or delivery vehicles, such as organic or inorganic nanocarriers, the targeted cells and tissues can be specifically recognized and the therapeutic compounds internalized, thereby improving the local concentration of the drug and its therapeutic efficacy. Currently, many cell-type-specific aptamers have been developed that can target distinct diseases or tissues in a cell-type-specific manner. In this review, we discuss recent advances in the use of cell-specific aptamers for targeted disease therapy, as well as conjugation strategies and challenges. PMID:24936916

Single-cell transcriptomics for microbial eukaryotes.

PubMed

Kolisko, Martin; Boscaro, Vittorio; Burki, Fabien; Lynn, Denis H; Keeling, Patrick J

2014-11-17

One of the greatest hindrances to a comprehensive understanding of microbial genomics, cell biology, ecology, and evolution is that most microbial life is not in culture. Solutions to this problem have mainly focused on whole-community surveys like metagenomics, but these analyses inevitably loose information and present particular challenges for eukaryotes, which are relatively rare and possess large, gene-sparse genomes. Single-cell analyses present an alternative solution that allows for specific species to be targeted, while retaining information on cellular identity, morphology, and partitioning of activities within microbial communities. Single-cell transcriptomics, pioneered in medical research, offers particular potential advantages for uncultivated eukaryotes, but the efficiency and biases have not been tested. Here we describe a simple and reproducible method for single-cell transcriptomics using manually isolated cells from five model ciliate species; we examine impacts of amplification bias and contamination, and compare the efficacy of gene discovery to traditional culture-based transcriptomics. Gene discovery using single-cell transcriptomes was found to be comparable to mass-culture methods, suggesting single-cell transcriptomics is an efficient entry point into genomic data from the vast majority of eukaryotic biodiversity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Efficient spares matrix multiplication scheme for the CYBER 203

NASA Technical Reports Server (NTRS)

Lambiotte, J. J., Jr.

1984-01-01

This work has been directed toward the development of an efficient algorithm for performing this computation on the CYBER-203. The desire to provide software which gives the user the choice between the often conflicting goals of minimizing central processing (CPU) time or storage requirements has led to a diagonal-based algorithm in which one of three types of storage is selected for each diagonal. For each storage type, an initialization sub-routine estimates the CPU and storage requirements based upon results from previously performed numerical experimentation. These requirements are adjusted by weights provided by the user which reflect the relative importance the user places on the resources. The three storage types employed were chosen to be efficient on the CYBER-203 for diagonals which are sparse, moderately sparse, or dense; however, for many densities, no diagonal type is most efficient with respect to both resource requirements. The user-supplied weights dictate the choice.

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

PubMed Central

Bolisetty, Mohan; Kursawe, Romy; Sun, Lili; Sivakamasundari, V.; Kycia, Ina

2017-01-01

Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type–specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. PMID:27864352

Coexistence of giant blue nevus of the scalp with hair loss and alopecia areata.

PubMed

Takeichi, Sachiko; Kubo, Yoshiaki; Murao, Kazutoshi; Inoue, Natsuko; Ansai, Shin-ichi; Arase, Seiji

2011-04-01

A 43-year-old Japanese man presented with a 13-year history of a grayish macule measuring 7 cm in diameter with sparse hairs on the vertex. Histopathological examination demonstrated two types of melanocytes, spindle-shaped and ovoid cells, with abundant melanin aggregated around the upper part of the pilosebaceous apparatus. Fibrous, thick collagen bundles were also seen surrounding the upper part of the small hair follicles. There was no infiltration of melanocytes or lymphocytes in the lower dermis or adipose tissue. Based on these findings, a diagnosis of blue nevus, cellular type, was made. Giant cellular blue nevi on the scalp are rare, and 11 cases reported in the published work have shown characteristic features such as hair loss and cranial invasion of nevus cells. It should be noted that melanocytes of giant blue nevi have a high potential to damage other organs such as underlying bone and hair follicles. The patient also showed a typical lesion of alopecia areata on the left temporal which was successfully treated with topical corticosteroid. © 2010 Japanese Dermatological Association.

Constellation Pharmacology: A new paradigm for drug discovery

PubMed Central

Schmidt, Eric W.; Olivera, Baldomero M.

2015-01-01

Constellation Pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (“constellations”) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation Pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically-active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the on-going development of Constellation Pharmacology, there is a positive-feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As Constellation Pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform. PMID:25562646

Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus.

PubMed

Smith, Emily M; Lajoie, Bryan R; Jain, Gaurav; Dekker, Job

2016-01-07

Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Cell Class-Dependent Intracortical Connectivity and Output Dynamics of Layer 6 Projection Neurons of the Rat Primary Visual Cortex.

PubMed

Cotel, Florence; Fletcher, Lee N; Kalita-de Croft, Simon; Apergis-Schoute, John; Williams, Stephen R

2018-07-01

Neocortical information processing is powerfully influenced by the activity of layer 6 projection neurons through control of local intracortical and subcortical circuitry. Morphologically distinct classes of layer 6 projection neuron have been identified in the mammalian visual cortex, which exhibit contrasting receptive field properties, but little information is available on their functional specificity. To address this we combined anatomical tracing techniques with high-resolution patch-clamp recording to identify morphological and functional distinct classes of layer 6 projection neurons in the rat primary visual cortex, which innervated separable subcortical territories. Multisite whole-cell recordings in brain slices revealed that corticoclaustral and corticothalamic layer 6 projection neurons exhibited similar somatically recorded electrophysiological properties. These classes of layer 6 projection neurons were sparsely and reciprocally synaptically interconnected, but could be differentiated by cell-class, but not target-cell-dependent rules of use-dependent depression and facilitation of unitary excitatory synaptic output. Corticoclaustral and corticothalamic layer 6 projection neurons were differentially innervated by columnar excitatory circuitry, with corticoclaustral, but not corticothalamic, neurons powerfully driven by layer 4 pyramidal neurons, and long-range pathways conveyed in neocortical layer 1. Our results therefore reveal projection target-specific, functionally distinct, streams of layer 6 output in the rodent neocortex.

Generic, network schema agnostic sparse tensor factorization for single-pass clustering of heterogeneous information networks

PubMed Central

Meng, Qinggang; Deng, Su; Huang, Hongbin; Wu, Yahui; Badii, Atta

2017-01-01

Heterogeneous information networks (e.g. bibliographic networks and social media networks) that consist of multiple interconnected objects are ubiquitous. Clustering analysis is an effective method to understand the semantic information and interpretable structure of the heterogeneous information networks, and it has attracted the attention of many researchers in recent years. However, most studies assume that heterogeneous information networks usually follow some simple schemas, such as bi-typed networks or star network schema, and they can only cluster one type of object in the network each time. In this paper, a novel clustering framework is proposed based on sparse tensor factorization for heterogeneous information networks, which can cluster multiple types of objects simultaneously in a single pass without any network schema information. The types of objects and the relations between them in the heterogeneous information networks are modeled as a sparse tensor. The clustering issue is modeled as an optimization problem, which is similar to the well-known Tucker decomposition. Then, an Alternating Least Squares (ALS) algorithm and a feasible initialization method are proposed to solve the optimization problem. Based on the tensor factorization, we simultaneously partition different types of objects into different clusters. The experimental results on both synthetic and real-world datasets have demonstrated that our proposed clustering framework, STFClus, can model heterogeneous information networks efficiently and can outperform state-of-the-art clustering algorithms as a generally applicable single-pass clustering method for heterogeneous network which is network schema agnostic. PMID:28245222

Generic, network schema agnostic sparse tensor factorization for single-pass clustering of heterogeneous information networks.

PubMed

Wu, Jibing; Meng, Qinggang; Deng, Su; Huang, Hongbin; Wu, Yahui; Badii, Atta

2017-01-01

Heterogeneous information networks (e.g. bibliographic networks and social media networks) that consist of multiple interconnected objects are ubiquitous. Clustering analysis is an effective method to understand the semantic information and interpretable structure of the heterogeneous information networks, and it has attracted the attention of many researchers in recent years. However, most studies assume that heterogeneous information networks usually follow some simple schemas, such as bi-typed networks or star network schema, and they can only cluster one type of object in the network each time. In this paper, a novel clustering framework is proposed based on sparse tensor factorization for heterogeneous information networks, which can cluster multiple types of objects simultaneously in a single pass without any network schema information. The types of objects and the relations between them in the heterogeneous information networks are modeled as a sparse tensor. The clustering issue is modeled as an optimization problem, which is similar to the well-known Tucker decomposition. Then, an Alternating Least Squares (ALS) algorithm and a feasible initialization method are proposed to solve the optimization problem. Based on the tensor factorization, we simultaneously partition different types of objects into different clusters. The experimental results on both synthetic and real-world datasets have demonstrated that our proposed clustering framework, STFClus, can model heterogeneous information networks efficiently and can outperform state-of-the-art clustering algorithms as a generally applicable single-pass clustering method for heterogeneous network which is network schema agnostic.

The Arabidopsis translatome cell-specific mRNA atlas: Mining suberin and cutin lipid monomer biosynthesis genes as an example for data application.

PubMed

Mustroph, Angelika; Bailey-Serres, Julia

2010-03-01

Plants consist of distinct cell types distinguished by position, morphological features and metabolic activities. We recently developed a method to extract cell-type specific mRNA populations by immunopurification of ribosome-associated mRNAs. Microarray profiles of 21 cell-specific mRNA populations from seedling roots and shoots comprise the Arabidopsis Translatome dataset. This gene expression atlas provides a new tool for the study of cell-specific processes. Here we provide an example of how genes involved in a pathway limited to one or few cell-types can be further characterized and new candidate genes can be predicted. Cells of the root endodermis produce suberin as an inner barrier between the cortex and stele, whereas the shoot epidermal cells form cutin as a barrier to the external environment. Both polymers consist of fatty acid derivates, and share biosynthetic origins. We use the Arabidopsis Translatome dataset to demonstrate the significant cell-specific expression patterns of genes involved in those biosynthetic processes and suggest new candidate genes in the biosynthesis of suberin and cutin.

Face Aging Effect Simulation Using Hidden Factor Analysis Joint Sparse Representation.

PubMed

Yang, Hongyu; Huang, Di; Wang, Yunhong; Wang, Heng; Tang, Yuanyan

2016-06-01

Face aging simulation has received rising investigations nowadays, whereas it still remains a challenge to generate convincing and natural age-progressed face images. In this paper, we present a novel approach to such an issue using hidden factor analysis joint sparse representation. In contrast to the majority of tasks in the literature that integrally handle the facial texture, the proposed aging approach separately models the person-specific facial properties that tend to be stable in a relatively long period and the age-specific clues that gradually change over time. It then transforms the age component to a target age group via sparse reconstruction, yielding aging effects, which is finally combined with the identity component to achieve the aged face. Experiments are carried out on three face aging databases, and the results achieved clearly demonstrate the effectiveness and robustness of the proposed method in rendering a face with aging effects. In addition, a series of evaluations prove its validity with respect to identity preservation and aging effect generation.

Objective sea level pressure analysis for sparse data areas

NASA Technical Reports Server (NTRS)

Druyan, L. M.

1972-01-01

A computer procedure was used to analyze the pressure distribution over the North Pacific Ocean for eleven synoptic times in February, 1967. Independent knowledge of the central pressures of lows is shown to reduce the analysis errors for very sparse data coverage. The application of planned remote sensing of sea-level wind speeds is shown to make a significant contribution to the quality of the analysis especially in the high gradient mid-latitudes and for sparse coverage of conventional observations (such as over Southern Hemisphere oceans). Uniform distribution of the available observations of sea-level pressure and wind velocity yields results far superior to those derived from a random distribution. A generalization of the results indicates that the average lower limit for analysis errors is between 2 and 2.5 mb based on the perfect specification of the magnitude of the sea-level pressure gradient from a known verification analysis. A less than perfect specification will derive from wind-pressure relationships applied to satellite observed wind speeds.

Identification of tissue-specific cell death using methylation patterns of circulating DNA

PubMed Central

Lehmann-Werman, Roni; Neiman, Daniel; Zemmour, Hai; Moss, Joshua; Magenheim, Judith; Vaknin-Dembinsky, Adi; Rubertsson, Sten; Nellgård, Bengt; Blennow, Kaj; Zetterberg, Henrik; Spalding, Kirsty; Haller, Michael J.; Wasserfall, Clive H.; Schatz, Desmond A.; Greenbaum, Carla J.; Dorrell, Craig; Grompe, Markus; Zick, Aviad; Hubert, Ayala; Maoz, Myriam; Fendrich, Volker; Bartsch, Detlef K.; Golan, Talia; Ben Sasson, Shmuel A.; Zamir, Gideon; Razin, Aharon; Cedar, Howard; Shapiro, A. M. James; Glaser, Benjamin; Shemer, Ruth; Dor, Yuval

2016-01-01

Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics. PMID:26976580

SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs.

PubMed

Hagey, Daniel W; Klum, Susanne; Kurtsdotter, Idha; Zaouter, Cecile; Topcic, Danijal; Andersson, Olov; Bergsland, Maria; Muhr, Jonas

2018-02-01

Stem cells are defined by their capacities to self-renew and generate progeny of multiple lineages. The transcription factor SOX2 has key roles in the regulation of stem cell characteristics, but whether SOX2 achieves these functions through similar mechanisms in distinct stem cell populations is not known. To address this question, we performed RNA-seq and SOX2 ChIP-seq on embryonic mouse cortex, spinal cord, stomach and lung/esophagus. We demonstrate that, although SOX2 binds a similar motif in the different cell types, its target regions are primarily cell-type-specific and enriched for the distinct binding motifs of appropriately expressed interacting co-factors. Furthermore, cell-type-specific SOX2 binding in endodermal and neural cells is most often found around genes specifically expressed in the corresponding tissue. Consistent with this, we demonstrate that SOX2 target regions can act as cis-regulatory modules capable of directing reporter expression to appropriate tissues in a zebrafish reporter assay. In contrast, SOX2 binding sites found in both endodermal and neural tissues are associated with genes regulating general stem cell features, such as proliferation. Notably, we provide evidence that SOX2 regulates proliferation through conserved mechanisms and target genes in both germ layers examined. Together, these findings demonstrate how SOX2 simultaneously regulates cell-type-specific, as well as core transcriptional programs in neural and endodermal stem cells.

Autoreactive T effector memory differentiation mirrors β-cell function in type 1 diabetes.

PubMed

Yeo, Lorraine; Woodwyk, Alyssa; Sood, Sanjana; Lorenc, Anna; Eichmann, Martin; Pujol-Autonell, Irma; Melchiotti, Rossella; Skowera, Ania; Fidanis, Efthymios; Dolton, Garry M; Tungatt, Katie; Sewell, Andrew K; Heck, Susanne; Saxena, Alka; Beam, Craig A; Peakman, Mark

2018-05-31

In type 1 diabetes, cytotoxic CD8 T cells with specificity for β-cell autoantigens are found in the pancreatic islets where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β-cell-reactive CD8 T cells that are detectable in the circulation, and their relationship to β-cell function, are not known. Here, we tracked multiple, circulating β-cell-reactive CD8 T cell subsets and measured β-cell function longitudinally for two years, starting immediately after diagnosis of type 1 diabetes. We found that change in β-cell-specific effector memory CD8 T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8 T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer specific protein 37 and CD16, and reduced expression of CD28) compared with their CD57-negative counterparts, and network association modelling indicated that the dynamics of β-cell-reactive CD57+ effector memory CD8 T cell subsets were strongly linked. Thus, coordinated changes in circulating β-cell-specific CD8 T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

Metabolic profiling of Arabidopsis thaliana epidermal cells

PubMed Central

Ebert, Berit; Zöller, Daniela; Erban, Alexander; Fehrle, Ines; Hartmann, Jürgen; Niehl, Annette; Kopka, Joachim; Fisahn, Joachim

2010-01-01

Metabolic phenotyping at cellular resolution may be considered one of the challenges in current plant physiology. A method is described which enables the cell type-specific metabolic analysis of epidermal cell types in Arabidopsis thaliana pavement, basal, and trichome cells. To achieve the required high spatial resolution, single cell sampling using microcapillaries was combined with routine gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) based metabolite profiling. The identification and relative quantification of 117 mostly primary metabolites has been demonstrated. The majority, namely 90 compounds, were accessible without analytical background correction. Analyses were performed using cell type-specific pools of 200 microsampled individual cells. Moreover, among these identified metabolites, 38 exhibited differential pool sizes in trichomes, basal or pavement cells. The application of an independent component analysis confirmed the cell type-specific metabolic phenotypes. Significant pool size changes between individual cells were detectable within several classes of metabolites, namely amino acids, fatty acids and alcohols, alkanes, lipids, N-compounds, organic acids and polyhydroxy acids, polyols, sugars, sugar conjugates and phenylpropanoids. It is demonstrated here that the combination of microsampling and GC-MS based metabolite profiling provides a method to investigate the cellular metabolism of fully differentiated plant cell types in vivo. PMID:20150518

Vignettes from the field of mathematical biology: the application of mathematics to biology and medicine.

PubMed

Murray, J D

2012-08-06

The application of mathematical models in biology and medicine has a long history. From the sparse number of papers in the first half of the twentieth century with a few scientists working in the field it has become vast with thousands of active researchers. We give a brief, and far from definitive history, of how some parts of the field have developed and how the type of research has changed. We describe in more detail just two examples of specific models which are directly related to real biological problems, namely animal coat patterns and the growth and image enhancement of glioblastoma brain tumours.

Larval habitats of anopheline mosquitoes in the Upper Orinoco, Venezuela.

PubMed

Rejmánková, E; Rubio-Palis, Y; Villegas, L

1999-12-01

Survey of larval habitats of anopheline mosquitoes was conducted in Ocamo in the State of Amazonas, southern Venezuela. The sampled habitats belonged to three different hydrological types: lagoons (26 habitats), forest pools including flooded forest (16 habitats), and forest streams (4 habitats). Out of 46 habitats surveyed, 31 contained anopheline larvae. Six species were found: Anopheles darlingi, Anopheles triannulatus, Anopheles oswaldoi, Anopheles peryassui, Anopheles punctimacula, and Anopheles mediopunctatus. Anopheles triannulatus was the most abundant species. Significantly higher numbers of anopheline larvae, in general, and of An. triannulatus specifically were found in lagoons with submersed macrophytes and sparse emergent graminoids than in forest pools with detritus.

WE-H-BRA-08: A Monte Carlo Cell Nucleus Model for Assessing Cell Survival Probability Based On Particle Track Structure Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, B; Georgia Institute of Technology, Atlanta, GA; Wang, C

Purpose: To correlate the damage produced by particles of different types and qualities to cell survival on the basis of nanodosimetric analysis and advanced DNA structures in the cell nucleus. Methods: A Monte Carlo code was developed to simulate subnuclear DNA chromatin fibers (CFs) of 30nm utilizing a mean-free-path approach common to radiation transport. The cell nucleus was modeled as a spherical region containing 6000 chromatin-dense domains (CDs) of 400nm diameter, with additional CFs modeled in a sparser interchromatin region. The Geant4-DNA code was utilized to produce a particle track database representing various particles at different energies and dose quantities.more » These tracks were used to stochastically position the DNA structures based on their mean free path to interaction with CFs. Excitation and ionization events intersecting CFs were analyzed using the DBSCAN clustering algorithm for assessment of the likelihood of producing DSBs. Simulated DSBs were then assessed based on their proximity to one another for a probability of inducing cell death. Results: Variations in energy deposition to chromatin fibers match expectations based on differences in particle track structure. The quality of damage to CFs based on different particle types indicate more severe damage by high-LET radiation than low-LET radiation of identical particles. In addition, the model indicates more severe damage by protons than of alpha particles of same LET, which is consistent with differences in their track structure. Cell survival curves have been produced showing the L-Q behavior of sparsely ionizing radiation. Conclusion: Initial results indicate the feasibility of producing cell survival curves based on the Monte Carlo cell nucleus method. Accurate correlation between simulated DNA damage to cell survival on the basis of nanodosimetric analysis can provide insight into the biological responses to various radiation types. Current efforts are directed at producing cell survival curves for high-LET radiation.« less

Role of the chromatin landscape and sequence in determining cell type-specific genomic glucocorticoid receptor binding and gene regulation.

PubMed

Love, Michael I; Huska, Matthew R; Jurk, Marcel; Schöpflin, Robert; Starick, Stephan R; Schwahn, Kevin; Cooper, Samantha B; Yamamoto, Keith R; Thomas-Chollier, Morgane; Vingron, Martin; Meijsing, Sebastiaan H

2017-02-28

The genomic loci bound by the glucocorticoid receptor (GR), a hormone-activated transcription factor, show little overlap between cell types. To study the role of chromatin and sequence in specifying where GR binds, we used Bayesian modeling within the universe of accessible chromatin. Taken together, our results uncovered that although GR preferentially binds accessible chromatin, its binding is biased against accessible chromatin located at promoter regions. This bias can only be explained partially by the presence of fewer GR recognition sequences, arguing for the existence of additional mechanisms that interfere with GR binding at promoters. Therefore, we tested the role of H3K9ac, the chromatin feature with the strongest negative association with GR binding, but found that this correlation does not reflect a causative link. Finally, we find a higher percentage of promoter-proximal GR binding for genes regulated by GR across cell types than for cell type-specific target genes. Given that GR almost exclusively binds accessible chromatin, we propose that cell type-specific regulation by GR preferentially occurs via distal enhancers, whose chromatin accessibility is typically cell type-specific, whereas ubiquitous target gene regulation is more likely to result from binding to promoter regions, which are often accessible regardless of cell type examined. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Gene selection for the reconstruction of stem cell differentiation trees: a linear programming approach.

PubMed

Ghadie, Mohamed A; Japkowicz, Nathalie; Perkins, Theodore J

2015-08-15

Stem cell differentiation is largely guided by master transcriptional regulators, but it also depends on the expression of other types of genes, such as cell cycle genes, signaling genes, metabolic genes, trafficking genes, etc. Traditional approaches to understanding gene expression patterns across multiple conditions, such as principal components analysis or K-means clustering, can group cell types based on gene expression, but they do so without knowledge of the differentiation hierarchy. Hierarchical clustering can organize cell types into a tree, but in general this tree is different from the differentiation hierarchy itself. Given the differentiation hierarchy and gene expression data at each node, we construct a weighted Euclidean distance metric such that the minimum spanning tree with respect to that metric is precisely the given differentiation hierarchy. We provide a set of linear constraints that are provably sufficient for the desired construction and a linear programming approach to identify sparse sets of weights, effectively identifying genes that are most relevant for discriminating different parts of the tree. We apply our method to microarray gene expression data describing 38 cell types in the hematopoiesis hierarchy, constructing a weighted Euclidean metric that uses just 175 genes. However, we find that there are many alternative sets of weights that satisfy the linear constraints. Thus, in the style of random-forest training, we also construct metrics based on random subsets of the genes and compare them to the metric of 175 genes. We then report on the selected genes and their biological functions. Our approach offers a new way to identify genes that may have important roles in stem cell differentiation. tperkins@ohri.ca Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Spatio-temporal Event Classification using Time-series Kernel based Structured Sparsity

PubMed Central

Jeni, László A.; Lőrincz, András; Szabó, Zoltán; Cohn, Jeffrey F.; Kanade, Takeo

2016-01-01

In many behavioral domains, such as facial expression and gesture, sparse structure is prevalent. This sparsity would be well suited for event detection but for one problem. Features typically are confounded by alignment error in space and time. As a consequence, high-dimensional representations such as SIFT and Gabor features have been favored despite their much greater computational cost and potential loss of information. We propose a Kernel Structured Sparsity (KSS) method that can handle both the temporal alignment problem and the structured sparse reconstruction within a common framework, and it can rely on simple features. We characterize spatio-temporal events as time-series of motion patterns and by utilizing time-series kernels we apply standard structured-sparse coding techniques to tackle this important problem. We evaluated the KSS method using both gesture and facial expression datasets that include spontaneous behavior and differ in degree of difficulty and type of ground truth coding. KSS outperformed both sparse and non-sparse methods that utilize complex image features and their temporal extensions. In the case of early facial event classification KSS had 10% higher accuracy as measured by F1 score over kernel SVM methods1. PMID:27830214

Sequentially switching cell assemblies in random inhibitory networks of spiking neurons in the striatum.

PubMed

Ponzi, Adam; Wickens, Jeff

2010-04-28

The striatum is composed of GABAergic medium spiny neurons with inhibitory collaterals forming a sparse random asymmetric network and receiving an excitatory glutamatergic cortical projection. Because the inhibitory collaterals are sparse and weak, their role in striatal network dynamics is puzzling. However, here we show by simulation of a striatal inhibitory network model composed of spiking neurons that cells form assemblies that fire in sequential coherent episodes and display complex identity-temporal spiking patterns even when cortical excitation is simply constant or fluctuating noisily. Strongly correlated large-scale firing rate fluctuations on slow behaviorally relevant timescales of hundreds of milliseconds are shown by members of the same assembly whereas members of different assemblies show strong negative correlation, and we show how randomly connected spiking networks can generate this activity. Cells display highly irregular spiking with high coefficients of variation, broadly distributed low firing rates, and interspike interval distributions that are consistent with exponentially tailed power laws. Although firing rates vary coherently on slow timescales, precise spiking synchronization is absent in general. Our model only requires the minimal but striatally realistic assumptions of sparse to intermediate random connectivity, weak inhibitory synapses, and sufficient cortical excitation so that some cells are depolarized above the firing threshold during up states. Our results are in good qualitative agreement with experimental studies, consistent with recently determined striatal anatomy and physiology, and support a new view of endogenously generated metastable state switching dynamics of the striatal network underlying its information processing operations.

Cell Type–Specific Three-Dimensional Structure of Thalamocortical Circuits in a Column of Rat Vibrissal Cortex

PubMed Central

de Kock, Christiaan P. J.; Bruno, Randy M.; Ramirez, Alejandro; Meyer, Hanno S.; Dercksen, Vincent J.; Helmstaedter, Moritz; Sakmann, Bert

2012-01-01

Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type–specific lemniscal synaptic wiring diagram and elucidates structure–function relationships of this physiologically relevant pathway at single-cell resolution. PMID:22089425

Image fusion via nonlocal sparse K-SVD dictionary learning.

PubMed

Li, Ying; Li, Fangyi; Bai, Bendu; Shen, Qiang

2016-03-01

Image fusion aims to merge two or more images captured via various sensors of the same scene to construct a more informative image by integrating their details. Generally, such integration is achieved through the manipulation of the representations of the images concerned. Sparse representation plays an important role in the effective description of images, offering a great potential in a variety of image processing tasks, including image fusion. Supported by sparse representation, in this paper, an approach for image fusion by the use of a novel dictionary learning scheme is proposed. The nonlocal self-similarity property of the images is exploited, not only at the stage of learning the underlying description dictionary but during the process of image fusion. In particular, the property of nonlocal self-similarity is combined with the traditional sparse dictionary. This results in an improved learned dictionary, hereafter referred to as the nonlocal sparse K-SVD dictionary (where K-SVD stands for the K times singular value decomposition that is commonly used in the literature), and abbreviated to NL_SK_SVD. The performance of the NL_SK_SVD dictionary is applied for image fusion using simultaneous orthogonal matching pursuit. The proposed approach is evaluated with different types of images, and compared with a number of alternative image fusion techniques. The resultant superior fused images using the present approach demonstrates the efficacy of the NL_SK_SVD dictionary in sparse image representation.

A mixture of sparse coding models explaining properties of face neurons related to holistic and parts-based processing

PubMed Central

2017-01-01

Experimental studies have revealed evidence of both parts-based and holistic representations of objects and faces in the primate visual system. However, it is still a mystery how such seemingly contradictory types of processing can coexist within a single system. Here, we propose a novel theory called mixture of sparse coding models, inspired by the formation of category-specific subregions in the inferotemporal (IT) cortex. We developed a hierarchical network that constructed a mixture of two sparse coding submodels on top of a simple Gabor analysis. The submodels were each trained with face or non-face object images, which resulted in separate representations of facial parts and object parts. Importantly, evoked neural activities were modeled by Bayesian inference, which had a top-down explaining-away effect that enabled recognition of an individual part to depend strongly on the category of the whole input. We show that this explaining-away effect was indeed crucial for the units in the face submodel to exhibit significant selectivity to face images over object images in a similar way to actual face-selective neurons in the macaque IT cortex. Furthermore, the model explained, qualitatively and quantitatively, several tuning properties to facial features found in the middle patch of face processing in IT as documented by Freiwald, Tsao, and Livingstone (2009). These included, in particular, tuning to only a small number of facial features that were often related to geometrically large parts like face outline and hair, preference and anti-preference of extreme facial features (e.g., very large/small inter-eye distance), and reduction of the gain of feature tuning for partial face stimuli compared to whole face stimuli. Thus, we hypothesize that the coding principle of facial features in the middle patch of face processing in the macaque IT cortex may be closely related to mixture of sparse coding models. PMID:28742816

A mixture of sparse coding models explaining properties of face neurons related to holistic and parts-based processing.

PubMed

Hosoya, Haruo; Hyvärinen, Aapo

2017-07-01

Experimental studies have revealed evidence of both parts-based and holistic representations of objects and faces in the primate visual system. However, it is still a mystery how such seemingly contradictory types of processing can coexist within a single system. Here, we propose a novel theory called mixture of sparse coding models, inspired by the formation of category-specific subregions in the inferotemporal (IT) cortex. We developed a hierarchical network that constructed a mixture of two sparse coding submodels on top of a simple Gabor analysis. The submodels were each trained with face or non-face object images, which resulted in separate representations of facial parts and object parts. Importantly, evoked neural activities were modeled by Bayesian inference, which had a top-down explaining-away effect that enabled recognition of an individual part to depend strongly on the category of the whole input. We show that this explaining-away effect was indeed crucial for the units in the face submodel to exhibit significant selectivity to face images over object images in a similar way to actual face-selective neurons in the macaque IT cortex. Furthermore, the model explained, qualitatively and quantitatively, several tuning properties to facial features found in the middle patch of face processing in IT as documented by Freiwald, Tsao, and Livingstone (2009). These included, in particular, tuning to only a small number of facial features that were often related to geometrically large parts like face outline and hair, preference and anti-preference of extreme facial features (e.g., very large/small inter-eye distance), and reduction of the gain of feature tuning for partial face stimuli compared to whole face stimuli. Thus, we hypothesize that the coding principle of facial features in the middle patch of face processing in the macaque IT cortex may be closely related to mixture of sparse coding models.

Open-target sparse sensing of biological agents using DNA microarray

PubMed Central

2011-01-01

Background Current biosensors are designed to target and react to specific nucleic acid sequences or structural epitopes. These 'target-specific' platforms require creation of new physical capture reagents when new organisms are targeted. An 'open-target' approach to DNA microarray biosensing is proposed and substantiated using laboratory generated data. The microarray consisted of 12,900 25 bp oligonucleotide capture probes derived from a statistical model trained on randomly selected genomic segments of pathogenic prokaryotic organisms. Open-target detection of organisms was accomplished using a reference library of hybridization patterns for three test organisms whose DNA sequences were not included in the design of the microarray probes. Results A multivariate mathematical model based on the partial least squares regression (PLSR) was developed to detect the presence of three test organisms in mixed samples. When all 12,900 probes were used, the model correctly detected the signature of three test organisms in all mixed samples (mean(R2)) = 0.76, CI = 0.95), with a 6% false positive rate. A sampling algorithm was then developed to sparsely sample the probe space for a minimal number of probes required to capture the hybridization imprints of the test organisms. The PLSR detection model was capable of correctly identifying the presence of the three test organisms in all mixed samples using only 47 probes (mean(R2)) = 0.77, CI = 0.95) with nearly 100% specificity. Conclusions We conceived an 'open-target' approach to biosensing, and hypothesized that a relatively small, non-specifically designed, DNA microarray is capable of identifying the presence of multiple organisms in mixed samples. Coupled with a mathematical model applied to laboratory generated data, and sparse sampling of capture probes, the prototype microarray platform was able to capture the signature of each organism in all mixed samples with high sensitivity and specificity. It was demonstrated that this new approach to biosensing closely follows the principles of sparse sensing. PMID:21801424

Experiments with osteoblasts cultured under hypergravity conditions

NASA Technical Reports Server (NTRS)

Kacena, Melissa A.; Todd, Paul; Gerstenfeld, Louis C.; Landis, William J.

2004-01-01

To understand further the role of gravity in osteoblast attachment, osteoblasts were subjected to hypergravity conditions in vitro. Scanning electron microscopy of all confluent coverslips from FPA units show that the number of attached osteoblasts was similar among gravitational levels and growth durations (90 cells/microscopic field). Specifically, confluent 1.0 G control cultures contained an average of 91 +/- 8 cells/field, 3.3 G samples had 88 +/- 8 cells/field, and 4.0 G cultures averaged 90 +/- 7 cells/field. The sparsely plated cultures assessed by immunohistochemistry also had similar numbers of cells at each time point (l.0 G was similar to 3.3 and 4.0 G), but cell number changed from one time point to the next as those cells proliferated. Immunohistochemistry of centrifuged samples showed an increase in number (up to 160% increase) and thickness (up to 49% increase) of actin fibers, a decrease in intensity of fibronectin fluorescence (18-23% decrease) and an increase in number of vinculin bulbs (202-374% increase in number of vinculin bulbs/area). While hypergravity exposure did not alter the number of attached osteoblasts, it did result in altered actin, fibronectin, and vinculin elements, changing some aspects of osteoblast- substrate adhesion.

Integrating and mining the chromatin landscape of cell-type specificity using self-organizing maps.

PubMed

Mortazavi, Ali; Pepke, Shirley; Jansen, Camden; Marinov, Georgi K; Ernst, Jason; Kellis, Manolis; Hardison, Ross C; Myers, Richard M; Wold, Barbara J

2013-12-01

We tested whether self-organizing maps (SOMs) could be used to effectively integrate, visualize, and mine diverse genomics data types, including complex chromatin signatures. A fine-grained SOM was trained on 72 ChIP-seq histone modifications and DNase-seq data sets from six biologically diverse cell lines studied by The ENCODE Project Consortium. We mined the resulting SOM to identify chromatin signatures related to sequence-specific transcription factor occupancy, sequence motif enrichment, and biological functions. To highlight clusters enriched for specific functions such as transcriptional promoters or enhancers, we overlaid onto the map additional data sets not used during training, such as ChIP-seq, RNA-seq, CAGE, and information on cis-acting regulatory modules from the literature. We used the SOM to parse known transcriptional enhancers according to the cell-type-specific chromatin signature, and we further corroborated this pattern on the map by EP300 (also known as p300) occupancy. New candidate cell-type-specific enhancers were identified for multiple ENCODE cell types in this way, along with new candidates for ubiquitous enhancer activity. An interactive web interface was developed to allow users to visualize and custom-mine the ENCODE SOM. We conclude that large SOMs trained on chromatin data from multiple cell types provide a powerful way to identify complex relationships in genomic data at user-selected levels of granularity.

Integrating and mining the chromatin landscape of cell-type specificity using self-organizing maps

PubMed Central

Mortazavi, Ali; Pepke, Shirley; Jansen, Camden; Marinov, Georgi K.; Ernst, Jason; Kellis, Manolis; Hardison, Ross C.; Myers, Richard M.; Wold, Barbara J.

2013-01-01

We tested whether self-organizing maps (SOMs) could be used to effectively integrate, visualize, and mine diverse genomics data types, including complex chromatin signatures. A fine-grained SOM was trained on 72 ChIP-seq histone modifications and DNase-seq data sets from six biologically diverse cell lines studied by The ENCODE Project Consortium. We mined the resulting SOM to identify chromatin signatures related to sequence-specific transcription factor occupancy, sequence motif enrichment, and biological functions. To highlight clusters enriched for specific functions such as transcriptional promoters or enhancers, we overlaid onto the map additional data sets not used during training, such as ChIP-seq, RNA-seq, CAGE, and information on cis-acting regulatory modules from the literature. We used the SOM to parse known transcriptional enhancers according to the cell-type-specific chromatin signature, and we further corroborated this pattern on the map by EP300 (also known as p300) occupancy. New candidate cell-type-specific enhancers were identified for multiple ENCODE cell types in this way, along with new candidates for ubiquitous enhancer activity. An interactive web interface was developed to allow users to visualize and custom-mine the ENCODE SOM. We conclude that large SOMs trained on chromatin data from multiple cell types provide a powerful way to identify complex relationships in genomic data at user-selected levels of granularity. PMID:24170599

Signal mingle: Micropatterns of BMP-2 and fibronectin on soft biopolymeric films regulate myoblast shape and SMAD signaling.

PubMed

Fitzpatrick, Vincent; Fourel, Laure; Destaing, Olivier; Gilde, Flora; Albigès-Rizo, Corinne; Picart, Catherine; Boudou, Thomas

2017-01-30

In vivo, bone morphogenetic protein 2 (BMP-2) exists both in solution and bound to the extracellular matrix (ECM). While these two modes of presentation are known to influence cell behavior distinctly, their role in the niche microenvironment and their functional relevance in the genesis of a biological response has sparsely been investigated at a cellular level. Here we used the natural affinity of BMP-2 for fibronectin (FN) to engineer cell-sized micropatterns of BMP-2. This technique allowed the simultaneous control of the spatial presentation of fibronectin-bound BMP-2 and cell spreading. These micropatterns induced a specific actin and adhesion organization around the nucleus, and triggered the phosphorylation and nuclear translocation of SMAD1/5/8 in C2C12 myoblasts and mesenchymal stem cells, an early indicator of their osteoblastic trans-differentiation. We found that cell spreading itself potentiated a BMP-2-dependent phosphorylation of SMAD1/5/8. Finally, we demonstrated that FN/BMP-2-mediated early SMAD signaling depended on LIM kinase 2 and ROCK, rather than myosin II activation. Altogether, our results show that FN/BMP-2 micropatterns are a useful tool to study the mechanisms underlying BMP-2-mediated mechanotransduction. More broadly, our approach could be adapted to other combinations of ECM proteins and growth factors, opening an exciting avenue to recreate tissue-specific niches in vitro.

Signal mingle: Micropatterns of BMP-2 and fibronectin on soft biopolymeric films regulate myoblast shape and SMAD signaling

NASA Astrophysics Data System (ADS)

Fitzpatrick, Vincent; Fourel, Laure; Destaing, Olivier; Gilde, Flora; Albigès-Rizo, Corinne; Picart, Catherine; Boudou, Thomas

2017-01-01

In vivo, bone morphogenetic protein 2 (BMP-2) exists both in solution and bound to the extracellular matrix (ECM). While these two modes of presentation are known to influence cell behavior distinctly, their role in the niche microenvironment and their functional relevance in the genesis of a biological response has sparsely been investigated at a cellular level. Here we used the natural affinity of BMP-2 for fibronectin (FN) to engineer cell-sized micropatterns of BMP-2. This technique allowed the simultaneous control of the spatial presentation of fibronectin-bound BMP-2 and cell spreading. These micropatterns induced a specific actin and adhesion organization around the nucleus, and triggered the phosphorylation and nuclear translocation of SMAD1/5/8 in C2C12 myoblasts and mesenchymal stem cells, an early indicator of their osteoblastic trans-differentiation. We found that cell spreading itself potentiated a BMP-2-dependent phosphorylation of SMAD1/5/8. Finally, we demonstrated that FN/BMP-2-mediated early SMAD signaling depended on LIM kinase 2 and ROCK, rather than myosin II activation. Altogether, our results show that FN/BMP-2 micropatterns are a useful tool to study the mechanisms underlying BMP-2-mediated mechanotransduction. More broadly, our approach could be adapted to other combinations of ECM proteins and growth factors, opening an exciting avenue to recreate tissue-specific niches in vitro.

Mesoscopic in vivo 3-D tracking of sparse cell populations using angular multiplexed optical projection tomography

PubMed Central

Chen, Lingling; Alexandrov, Yuriy; Kumar, Sunil; Andrews, Natalie; Dallman, Margaret J.; French, Paul M. W.; McGinty, James

2015-01-01

We describe an angular multiplexed imaging technique for 3-D in vivo cell tracking of sparse cell distributions and optical projection tomography (OPT) with superior time-lapse resolution and a significantly reduced light dose compared to volumetric time-lapse techniques. We demonstrate that using dual axis OPT, where two images are acquired simultaneously at different projection angles, can enable localization and tracking of features in 3-D with a time resolution equal to the camera frame rate. This is achieved with a 200x reduction in light dose compared to an equivalent volumetric time-lapse single camera OPT acquisition with 200 projection angles. We demonstrate the application of this technique to mapping the 3-D neutrophil migration pattern observed over ~25.5 minutes in a live 2 day post-fertilisation transgenic LysC:GFP zebrafish embryo following a tail wound. PMID:25909009

Mesoscopic in vivo 3-D tracking of sparse cell populations using angular multiplexed optical projection tomography.

PubMed

Chen, Lingling; Alexandrov, Yuriy; Kumar, Sunil; Andrews, Natalie; Dallman, Margaret J; French, Paul M W; McGinty, James

2015-04-01

We describe an angular multiplexed imaging technique for 3-D in vivo cell tracking of sparse cell distributions and optical projection tomography (OPT) with superior time-lapse resolution and a significantly reduced light dose compared to volumetric time-lapse techniques. We demonstrate that using dual axis OPT, where two images are acquired simultaneously at different projection angles, can enable localization and tracking of features in 3-D with a time resolution equal to the camera frame rate. This is achieved with a 200x reduction in light dose compared to an equivalent volumetric time-lapse single camera OPT acquisition with 200 projection angles. We demonstrate the application of this technique to mapping the 3-D neutrophil migration pattern observed over ~25.5 minutes in a live 2 day post-fertilisation transgenic LysC:GFP zebrafish embryo following a tail wound.

Dimension-Factorized Range Migration Algorithm for Regularly Distributed Array Imaging

PubMed Central

Guo, Qijia; Wang, Jie; Chang, Tianying

2017-01-01

The two-dimensional planar MIMO array is a popular approach for millimeter wave imaging applications. As a promising practical alternative, sparse MIMO arrays have been devised to reduce the number of antenna elements and transmitting/receiving channels with predictable and acceptable loss in image quality. In this paper, a high precision three-dimensional imaging algorithm is proposed for MIMO arrays of the regularly distributed type, especially the sparse varieties. Termed the Dimension-Factorized Range Migration Algorithm, the new imaging approach factorizes the conventional MIMO Range Migration Algorithm into multiple operations across the sparse dimensions. The thinner the sparse dimensions of the array, the more efficient the new algorithm will be. Advantages of the proposed approach are demonstrated by comparison with the conventional MIMO Range Migration Algorithm and its non-uniform fast Fourier transform based variant in terms of all the important characteristics of the approaches, especially the anti-noise capability. The computation cost is analyzed as well to evaluate the efficiency quantitatively. PMID:29113083

Biology as population dynamics: heuristics for transmission risk.

PubMed

Keebler, Daniel; Walwyn, David; Welte, Alex

2013-02-01

Population-type models, accounting for phenomena such as population lifetimes, mixing patterns, recruitment patterns, genetic evolution and environmental conditions, can be usefully applied to the biology of HIV infection and viral replication. A simple dynamic model can explore the effect of a vaccine-like stimulus on the mortality and infectiousness, which formally looks like fertility, of invading virions; the mortality of freshly infected cells; and the availability of target cells, all of which impact on the probability of infection. Variations on this model could capture the importance of the timing and duration of different key events in viral transmission, and hence be applied to questions of mucosal immunology. The dynamical insights and assumptions of such models are compatible with the continuum of between- and within-individual risks in sexual violence and may be helpful in making sense of the sparse data available on the association between HIV transmission and sexual violence. © 2012 John Wiley & Sons A/S.

In-situ recording of ionic currents in projection neurons and Kenyon cells in the olfactory pathway of the honeybee

PubMed Central

Rössler, Wolfgang

2018-01-01

The honeybee olfactory pathway comprises an intriguing pattern of convergence and divergence: ~60.000 olfactory sensory neurons (OSN) convey olfactory information on ~900 projection neurons (PN) in the antennal lobe (AL). To transmit this information reliably, PNs employ relatively high spiking frequencies with complex patterns. PNs project via a dual olfactory pathway to the mushroom bodies (MB). This pathway comprises the medial (m-ALT) and the lateral antennal lobe tract (l-ALT). PNs from both tracts transmit information from a wide range of similar odors, but with distinct differences in coding properties. In the MBs, PNs form synapses with many Kenyon cells (KC) that encode odors in a spatially and temporally sparse way. The transformation from complex information coding to sparse coding is a well-known phenomenon in insect olfactory coding. Intrinsic neuronal properties as well as GABAergic inhibition are thought to contribute to this change in odor representation. In the present study, we identified intrinsic neuronal properties promoting coding differences between PNs and KCs using in-situ patch-clamp recordings in the intact brain. We found very prominent K+ currents in KCs clearly differing from the PN currents. This suggests that odor coding differences between PNs and KCs may be caused by differences in their specific ion channel properties. Comparison of ionic currents of m- and l-ALT PNs did not reveal any differences at a qualitative level. PMID:29351552

Decipher the Molecular Response of Plant Single Cell Types to Environmental Stresses

DOE PAGES

Nourbakhsh-Rey, Mehrnoush; Libault, Marc

2016-01-01

The analysis of the molecular response of entire plants or organs to environmental stresses suffers from the cellular complexity of the samples used. Specifically, this cellular complexity masks cell-specific responses to environmental stresses and logically leads to the dilution of the molecular changes occurring in each cell type composing the tissue/organ/plant in response to the stress. Therefore, to generate a more accurate picture of these responses, scientists are focusing on plant single cell type approaches. Several cell types are now considered as models such as the pollen, the trichomes, the cotton fiber, various root cell types including the root hairmore » cell, and the guard cell of stomata. Among them, several have been used to characterize plant response to abiotic and biotic stresses. Lastly, in this review, we are describing the various -omic studies performed on these different plant single cell type models to better understand plant cell response to biotic and abiotic stresses.« less

Decipher the Molecular Response of Plant Single Cell Types to Environmental Stresses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nourbakhsh-Rey, Mehrnoush; Libault, Marc

The analysis of the molecular response of entire plants or organs to environmental stresses suffers from the cellular complexity of the samples used. Specifically, this cellular complexity masks cell-specific responses to environmental stresses and logically leads to the dilution of the molecular changes occurring in each cell type composing the tissue/organ/plant in response to the stress. Therefore, to generate a more accurate picture of these responses, scientists are focusing on plant single cell type approaches. Several cell types are now considered as models such as the pollen, the trichomes, the cotton fiber, various root cell types including the root hairmore » cell, and the guard cell of stomata. Among them, several have been used to characterize plant response to abiotic and biotic stresses. Lastly, in this review, we are describing the various -omic studies performed on these different plant single cell type models to better understand plant cell response to biotic and abiotic stresses.« less

Amino acid Alphabet Size in Protein Evolution Experiments: Better to Search a Small library Thoroughly or a Large Library Sparsely?

PubMed Central

Muñoz, Enrique

2015-01-01

We compare the results obtained from searching a smaller library thoroughly versus searching a more diverse, larger library sparsely. We study protein evolution with reduced amino acid alphabets, by simulating directed evolution experiments at three different alphabet sizes: 20, 5 and 2. We employ a physical model for evolution, the generalized NK model, that has proved successful in modeling protein evolution, antibody evolution, and T cell selection. We find that antibodies with higher affinity are found by searching a library with a larger alphabet sparsely than by searching a smaller library thoroughly, even with well-designed reduced libraries. We find ranked amino acid usage frequencies in agreement with observations of the CDR-H3 variable region of human antibodies. PMID:18375453

An atlas of active enhancers across human cell types and tissues

NASA Astrophysics Data System (ADS)

Andersson, Robin; Gebhard, Claudia; Miguel-Escalada, Irene; Hoof, Ilka; Bornholdt, Jette; Boyd, Mette; Chen, Yun; Zhao, Xiaobei; Schmidl, Christian; Suzuki, Takahiro; Ntini, Evgenia; Arner, Erik; Valen, Eivind; Li, Kang; Schwarzfischer, Lucia; Glatz, Dagmar; Raithel, Johanna; Lilje, Berit; Rapin, Nicolas; Bagger, Frederik Otzen; Jørgensen, Mette; Andersen, Peter Refsing; Bertin, Nicolas; Rackham, Owen; Burroughs, A. Maxwell; Baillie, J. Kenneth; Ishizu, Yuri; Shimizu, Yuri; Furuhata, Erina; Maeda, Shiori; Negishi, Yutaka; Mungall, Christopher J.; Meehan, Terrence F.; Lassmann, Timo; Itoh, Masayoshi; Kawaji, Hideya; Kondo, Naoto; Kawai, Jun; Lennartsson, Andreas; Daub, Carsten O.; Heutink, Peter; Hume, David A.; Jensen, Torben Heick; Suzuki, Harukazu; Hayashizaki, Yoshihide; Müller, Ferenc; Consortium, The Fantom; Forrest, Alistair R. R.; Carninci, Piero; Rehli, Michael; Sandelin, Albin

2014-03-01

Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.

Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation.

PubMed

Preissl, Sebastian; Fang, Rongxin; Huang, Hui; Zhao, Yuan; Raviram, Ramya; Gorkin, David U; Zhang, Yanxiao; Sos, Brandon C; Afzal, Veena; Dickel, Diane E; Kuan, Samantha; Visel, Axel; Pennacchio, Len A; Zhang, Kun; Ren, Bing

2018-03-01

Analysis of chromatin accessibility can reveal transcriptional regulatory sequences, but heterogeneity of primary tissues poses a significant challenge in mapping the precise chromatin landscape in specific cell types. Here we report single-nucleus ATAC-seq, a combinatorial barcoding-assisted single-cell assay for transposase-accessible chromatin that is optimized for use on flash-frozen primary tissue samples. We apply this technique to the mouse forebrain through eight developmental stages. Through analysis of more than 15,000 nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell types. We further define cell-type-specific transcriptional regulatory sequences, infer potential master transcriptional regulators and delineate developmental changes in forebrain cellular composition. Our results provide insight into the molecular and cellular dynamics that underlie forebrain development in the mouse and establish technical and analytical frameworks that are broadly applicable to other heterogeneous tissues.

Labelling and targeted ablation of specific bipolar cell types in the zebrafish retina

PubMed Central

2009-01-01

Background Development of a functional retina depends on regulated differentiation of several types of neurons and generation of a highly complex network between the different types of neurons. In addition, each type of retinal neuron includes several distinct morphological types. Very little is known about the mechanisms responsible for generating this diversity of retinal neurons, which may also display specific patterns of regional distribution. Results In a screen in zebrafish, using a trapping vector carrying an engineered yeast Gal4 transcription activator and a UAS:eGFP reporter cassette, we have identified two transgenic lines of zebrafish co-expressing eGFP and Gal4 in specific subsets of retinal bipolar cells. The eGFP-labelling facilitated analysis of axon terminals within the inner plexiform layer of the adult retina and showed that the fluorescent bipolar cells correspond to previously defined morphological types. Strong regional restriction of eGFP-positive bipolar cells to the central part of the retina surrounding the optic nerve was observed in adult zebrafish. Furthermore, we achieved specific ablation of the labelled bipolar cells in 5 days old larvae, using a bacterial nitroreductase gene under Gal4-UAS control in combination with the prodrug metronidazole. Following prodrug treatment, nitroreductase expressing bipolar cells were efficiently ablated without affecting surrounding retina architecture, and recovery occurred within a few days due to increased generation of new bipolar cells. Conclusion This report shows that enhancer trapping can be applied to label distinct morphological types of bipolar cells in the zebrafish retina. The genetic labelling of these cells yielded co-expression of a modified Gal4 transcription activator and the fluorescent marker eGFP. Our work also demonstrates the potential utility of the Gal4-UAS system for induction of other transgenes, including a bacterial nitroreductase fusion gene, which can facilitate analysis of bipolar cell differentiation and how the retina recovers from specific ablation of these cells. PMID:19712466

Common themes and cell type specific variations of higher order chromatin arrangements in the mouse

PubMed Central

Mayer, Robert; Brero, Alessandro; von Hase, Johann; Schroeder, Timm; Cremer, Thomas; Dietzel, Steffen

2005-01-01

Background Similarities as well as differences in higher order chromatin arrangements of human cell types were previously reported. For an evolutionary comparison, we now studied the arrangements of chromosome territories and centromere regions in six mouse cell types (lymphocytes, embryonic stem cells, macrophages, fibroblasts, myoblasts and myotubes) with fluorescence in situ hybridization and confocal laser scanning microscopy. Both species evolved pronounced differences in karyotypes after their last common ancestors lived about 87 million years ago and thus seem particularly suited to elucidate common and cell type specific themes of higher order chromatin arrangements in mammals. Results All mouse cell types showed non-random correlations of radial chromosome territory positions with gene density as well as with chromosome size. The distribution of chromosome territories and pericentromeric heterochromatin changed during differentiation, leading to distinct cell type specific distribution patterns. We exclude a strict dependence of these differences on nuclear shape. Positional differences in mouse cell nuclei were less pronounced compared to human cell nuclei in agreement with smaller differences in chromosome size and gene density. Notably, the position of chromosome territories relative to each other was very variable. Conclusion Chromosome territory arrangements according to chromosome size and gene density provide common, evolutionary conserved themes in both, human and mouse cell types. Our findings are incompatible with a previously reported model of parental genome separation. PMID:16336643

Statin use and mortality among ovarian cancer patients: A population-based cohort study.

PubMed

Verdoodt, Freija; Kjaer Hansen, Merete; Kjaer, Susanne K; Pottegård, Anton; Friis, Søren; Dehlendorff, Christian

2017-07-15

Statin use has been suggested to improve prognosis in cancer patients, however, for ovarian cancer, the evidence is sparse. From the Danish Cancer Registry, we identified patients aged 30-84 years with a histologically verified first diagnosis of epithelial ovarian cancer between 2000 and 2013. Data on filled prescriptions, death, and potential confounding factors were obtained from nationwide registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnostic statin use and all-cause or ovarian cancer-specific mortality. Among 4,419 patients with epithelial ovarian cancer, post-diagnostic statin use was not statistically significantly associated with all-cause (HR: 0.90, 95% CI: 0.78-1.04) or ovarian cancer-specific mortality (HR: 0.90, 95% CI: 0.76-1.08). There was little evidence of a dose-response relationship and the neutral associations persisted in sensitivity analyses. In women with endometrioid or clear cell tumour histology, cancer-specific mortality was reduced by 30-40% among statin users compared to non-users, however the analyses were limited by small numbers. Significantly reduced mortality with statin use was observed in subcohorts of new users of statins and of patients not using low-dose aspirin. In conclusion, we found no strong evidence of an association between post-diagnostic statin use and reduced mortality in ovarian cancer patients. However, our finding of potential differential susceptibility to statins among patients with different histologic types of ovarian cancer warrants further evaluation. © 2017 UICC.

Allelic exchange of pheromones and their receptors reprograms sexual identity in Cryptococcus neoformans.

PubMed

Stanton, Brynne C; Giles, Steven S; Staudt, Mark W; Kruzel, Emilia K; Hull, Christina M

2010-02-26

Cell type specification is a fundamental process that all cells must carry out to ensure appropriate behaviors in response to environmental stimuli. In fungi, cell identity is critical for defining "sexes" known as mating types and is controlled by components of mating type (MAT) loci. MAT-encoded genes function to define sexes via two distinct paradigms: 1) by controlling transcription of components common to both sexes, or 2) by expressing specially encoded factors (pheromones and their receptors) that differ between mating types. The human fungal pathogen Cryptococcus neoformans has two mating types (a and alpha) that are specified by an extremely unusual MAT locus. The complex architecture of this locus makes it impossible to predict which paradigm governs mating type. To identify the mechanism by which the C. neoformans sexes are determined, we created strains in which the pheromone and pheromone receptor from one mating type (a) replaced the pheromone and pheromone receptor of the other (alpha). We discovered that these "alpha(a)" cells effectively adopt a new mating type (that of a cells); they sense and respond to alpha factor, they elicit a mating response from alpha cells, and they fuse with alpha cells. In addition, alpha(a) cells lose the alpha cell type-specific response to pheromone and do not form germ tubes, instead remaining spherical like a cells. Finally, we discovered that exogenous expression of the diploid/dikaryon-specific transcription factor Sxi2a could then promote complete sexual development in crosses between alpha and alpha(a) strains. These data reveal that cell identity in C. neoformans is controlled fully by three kinds of MAT-encoded proteins: pheromones, pheromone receptors, and homeodomain proteins. Our findings establish the mechanisms for maintenance of distinct cell types and subsequent developmental behaviors in this unusual human fungal pathogen.

Novel insights into embryonic stem cell self-renewal revealed through comparative human and mouse systems biology networks.

PubMed

Dowell, Karen G; Simons, Allen K; Bai, Hao; Kell, Braden; Wang, Zack Z; Yun, Kyuson; Hibbs, Matthew A

2014-05-01

Embryonic stem cells (ESCs), characterized by their ability to both self-renew and differentiate into multiple cell lineages, are a powerful model for biomedical research and developmental biology. Human and mouse ESCs share many features, yet have distinctive aspects, including fundamental differences in the signaling pathways and cell cycle controls that support self-renewal. Here, we explore the molecular basis of human ESC self-renewal using Bayesian network machine learning to integrate cell-type-specific, high-throughput data for gene function discovery. We integrated high-throughput ESC data from 83 human studies (~1.8 million data points collected under 1,100 conditions) and 62 mouse studies (~2.4 million data points collected under 1,085 conditions) into separate human and mouse predictive networks focused on ESC self-renewal to analyze shared and distinct functional relationships among protein-coding gene orthologs. Computational evaluations show that these networks are highly accurate, literature validation confirms their biological relevance, and reverse transcriptase polymerase chain reaction (RT-PCR) validation supports our predictions. Our results reflect the importance of key regulatory genes known to be strongly associated with self-renewal and pluripotency in both species (e.g., POU5F1, SOX2, and NANOG), identify metabolic differences between species (e.g., threonine metabolism), clarify differences between human and mouse ESC developmental signaling pathways (e.g., leukemia inhibitory factor (LIF)-activated JAK/STAT in mouse; NODAL/ACTIVIN-A-activated fibroblast growth factor in human), and reveal many novel genes and pathways predicted to be functionally associated with self-renewal in each species. These interactive networks are available online at www.StemSight.org for stem cell researchers to develop new hypotheses, discover potential mechanisms involving sparsely annotated genes, and prioritize genes of interest for experimental validation. © 2013 AlphaMed Press.

MODFLOW–USG version 1: An unstructured grid version of MODFLOW for simulating groundwater flow and tightly coupled processes using a control volume finite-difference formulation

USGS Publications Warehouse

Panday, Sorab; Langevin, Christian D.; Niswonger, Richard G.; Ibaraki, Motomu; Hughes, Joseph D.

2013-01-01

A new version of MODFLOW, called MODFLOW–USG (for UnStructured Grid), was developed to support a wide variety of structured and unstructured grid types, including nested grids and grids based on prismatic triangles, rectangles, hexagons, and other cell shapes. Flexibility in grid design can be used to focus resolution along rivers and around wells, for example, or to subdiscretize individual layers to better represent hydrostratigraphic units. MODFLOW–USG is based on an underlying control volume finite difference (CVFD) formulation in which a cell can be connected to an arbitrary number of adjacent cells. To improve accuracy of the CVFD formulation for irregular grid-cell geometries or nested grids, a generalized Ghost Node Correction (GNC) Package was developed, which uses interpolated heads in the flow calculation between adjacent connected cells. MODFLOW–USG includes a Groundwater Flow (GWF) Process, based on the GWF Process in MODFLOW–2005, as well as a new Connected Linear Network (CLN) Process to simulate the effects of multi-node wells, karst conduits, and tile drains, for example. The CLN Process is tightly coupled with the GWF Process in that the equations from both processes are formulated into one matrix equation and solved simultaneously. This robustness results from using an unstructured grid with unstructured matrix storage and solution schemes. MODFLOW–USG also contains an optional Newton-Raphson formulation, based on the formulation in MODFLOW–NWT, for improving solution convergence and avoiding problems with the drying and rewetting of cells. Because the existing MODFLOW solvers were developed for structured and symmetric matrices, they were replaced with a new Sparse Matrix Solver (SMS) Package developed specifically for MODFLOW–USG. The SMS Package provides several methods for resolving nonlinearities and multiple symmetric and asymmetric linear solution schemes to solve the matrix arising from the flow equations and the Newton-Raphson formulation, respectively.

The number of satellite cells in slow and fast fibres from human vastus lateralis muscle.

PubMed

Kadi, Fawzi; Charifi, Nadia; Henriksson, Jan

2006-07-01

The aim of this investigation was to study the distribution of satellite cells in slow (type I fibres) and fast (type II fibres) fibres from human vastus lateralis muscle. This muscle is characterised by a mixed fibre type composition and is considered as the site of choice for biopsies in research work and for clinical diagnosis. Biopsy samples were obtained from five healthy young volunteers and a total of 1,747 type I fibres and 1,760 type II fibres were assessed. Satellite cells and fibre type composition were studied on serial muscle cross-sections stained with specific monoclonal antibodies. From a total of 218 satellite cells, 116 satellite cells were found in contact with type I fibres (53.6+/-8% of the satellite cells associated to type I fibres) and 102 satellite cells in contact with type II fibres (46.4+/-8% of the satellite cells associated to type II fibres). There was no significant difference (P=0.4) between the percentages of satellite cells in contact with type I and with type II fibres. Additionally, there was no relationship between the mean number of satellite cells per fibre and the mean cross-sectional area of muscle fibres. In conclusion, our results show that there is no fibre type-specific distribution of satellite cells in a human skeletal muscle with mixed fibre type composition.

Junctional Epidermolysis Bullosa (Non-Herlitz Type).

PubMed

Bhinder, Munir Ahmad; Arshad, Muhammad Waqar; Zahoor, Muhammad Yasir; Shehzad, Wasim; Tariq, Muhammad; Shabbir, Muhammad Imran

2017-05-01

Junctional epidermolysis bullosa (JEB) is a recessively inherited skin blistering disease and is caused due to abnormalities in proteins that hold layers of the skin. Herlitz JEB is the severe form and non-Herlitz JEB is the milder form. This report describes a case of congenitally affected male child aged 5 years, with skin blistering. He has mitten-like hands and soft skin blistering on hands, legs and knees. Symptoms almost disappeared at the age of 3 years but reappeared with increased severity after 6 months. Histopathological examination showed epidermal detachment with intact basal cell layer and sparse infiltrate of lymphocytes with few eosinophils in the dermis. There was no blistering on the moist lining of the mouth and digestive tract. Localized symptoms with less lethality and histopathological examination indicated the presence of non-Herlitz type of JEB. This is the first report which confirms the presence of non-Herlitz junctional epidermolysis bullosa in Pakistan.

Performance of mid infrared spectroscopy in skin cancer cell type identification

NASA Astrophysics Data System (ADS)

Kastl, Lena; Kemper, Björn; Lloyd, Gavin R.; Nallala, Jayakrupakar; Stone, Nick; Naranjo, Valery; Penaranda, Francisco; Schnekenburger, Jürgen

2017-02-01

Marker free optical spectroscopy is a powerful tool for the rapid inspection of pathologically suspicious skin lesions and the non-invasive detection of early skin tumors. This goal can be reached by the combination of signal localization and the spectroscopical detection of chemical cell signatures. We here present the development and application of mid infrared spectroscopy (midIR) for the analysis of skin tumor cell types and three dimensional tissue phantoms towards the application of midIR spectroscopy for fast and reliable skin diagnostics. We developed standardized in vitro skin systems with increasing complexity, from single skin cell types as fibroblasts, keratinocytes and melanoma cells, to mixtures of these and finally three dimensional skin cancer phantoms. The cell systems were characterized with different systems in the midIR range up to 12 μm. The analysis of the spectra by novel data processing algorithms demonstrated the clear separation of all cell types, especially melanoma cells. Special attention and algorithm training was required for closely related mesenchymal cell types as dedifferentiated melanoma cells and fibroblasts. Proof of concept experiments with mixtures of in vivo fluorescence labelled skin cell types allowed the test of the new algorithms performance for the identification of specific cell types. The intense training of the software systems with various samples resulted in a increased sensitivity and specificity of the combined midIR and software system. These data highlight the potential of midIR spectroscopy as sensitive and specific future optical biopsy technology.

Resonant Interneurons Can Increase Robustness of Gamma Oscillations.

PubMed

Tikidji-Hamburyan, Ruben A; Martínez, Joan José; White, John A; Canavier, Carmen C

2015-11-25

Gamma oscillations are believed to play a critical role in in information processing, encoding, and retrieval. Inhibitory interneuronal network gamma (ING) oscillations may arise from a coupled oscillator mechanism in which individual neurons oscillate or from a population oscillator in which individual neurons fire sparsely and stochastically. All ING mechanisms, including the one proposed herein, rely on alternating waves of inhibition and windows of opportunity for spiking. The coupled oscillator model implemented with Wang-Buzsáki model neurons is not sufficiently robust to heterogeneity in excitatory drive, and therefore intrinsic frequency, to account for in vitro models of ING. Similarly, in a tightly synchronized regime, the stochastic population oscillator model is often characterized by sparse firing, whereas interneurons both in vivo and in vitro do not fire sparsely during gamma, but rather on average every other cycle. We substituted so-called resonator neural models, which exhibit class 2 excitability and postinhibitory rebound (PIR), for the integrators that are typically used. This results in much greater robustness to heterogeneity that actually increases as the average participation in spikes per cycle approximates physiological levels. Moreover, dynamic clamp experiments that show autapse-induced firing in entorhinal cortical interneurons support the idea that PIR can serve as a network gamma mechanism. Furthermore, parvalbumin-positive (PV(+)) cells were much more likely to display both PIR and autapse-induced firing than GAD2(+) cells, supporting the view that PV(+) fast-firing basket cells are more likely to exhibit class 2 excitability than other types of inhibitory interneurons. Gamma oscillations are believed to play a critical role in information processing, encoding, and retrieval. Networks of inhibitory interneurons are thought to be essential for these oscillations. We show that one class of interneurons with an abrupt onset of firing at a threshold frequency may allow more robust synchronization in the presence of noise and heterogeneity. The mechanism for this robustness depends on the intrinsic resonance at this threshold frequency. Moreover, we show experimentally the feasibility of the proposed mechanism and suggest a way to distinguish between this mechanism and another proposed mechanism: that of a stochastic population oscillator independent of the dynamics of individual neurons. Copyright © 2015 the authors 0270-6474/15/3515682-14$15.00/0.

Ribosome Profiling Reveals a Cell-Type-Specific Translational Landscape in Brain Tumors

PubMed Central

Gonzalez, Christian; Sims, Jennifer S.; Hornstein, Nicholas; Mela, Angeliki; Garcia, Franklin; Lei, Liang; Gass, David A.; Amendolara, Benjamin; Bruce, Jeffrey N.

2014-01-01

Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5′-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation. PMID:25122893

Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers

PubMed Central

2011-01-01

Background Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a small percentage of infected individuals. ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC) already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8+ T-cells in various clinical status of HTLV-1 infection. Results By using tetramers consisting of HLA-A*0201, -A*2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8+ T-cells in the peripheral blood from 87.0% of ACs (n = 20/23) and 100% of HAM/TSP patients (n = 18/18) tested. We also detected Tax-specific CD8+ T-cells in 38.1% of chronic type ATL (cATL) patients (n = 8/21), although its frequencies in peripheral blood CD8+ T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8+ T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8+ T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8+ T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8+ T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69) and degranulation (CD107a) markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV) pp65-specific CD8+ T-cells that possessed functions upon CMV pp65 peptide stimulation. We further examined additional samples of two smoldering type ATL patients and found that they also showed dysfunctions of Tax-specific but not CMV-specific CD8+ T-cells. Conclusions These findings indicated that Tax-specific CD8+ T-cells were scarce and dysfunctional not only in ATL patients but also in a limited AC population, and that the dysfunction was selective for HTLV-1-specifc CD8+ T-cells in early stages. PMID:22151736

Response of selected binomial coefficients to varying degrees of matrix sparseness and to matrices with known data interrelationships

USGS Publications Warehouse

Archer, A.W.; Maples, C.G.

1989-01-01

Numerous departures from ideal relationships are revealed by Monte Carlo simulations of widely accepted binomial coefficients. For example, simulations incorporating varying levels of matrix sparseness (presence of zeros indicating lack of data) and computation of expected values reveal that not only are all common coefficients influenced by zero data, but also that some coefficients do not discriminate between sparse or dense matrices (few zero data). Such coefficients computationally merge mutually shared and mutually absent information and do not exploit all the information incorporated within the standard 2 ?? 2 contingency table; therefore, the commonly used formulae for such coefficients are more complicated than the actual range of values produced. Other coefficients do differentiate between mutual presences and absences; however, a number of these coefficients do not demonstrate a linear relationship to matrix sparseness. Finally, simulations using nonrandom matrices with known degrees of row-by-row similarities signify that several coefficients either do not display a reasonable range of values or are nonlinear with respect to known relationships within the data. Analyses with nonrandom matrices yield clues as to the utility of certain coefficients for specific applications. For example, coefficients such as Jaccard, Dice, and Baroni-Urbani and Buser are useful if correction of sparseness is desired, whereas the Russell-Rao coefficient is useful when sparseness correction is not desired. ?? 1989 International Association for Mathematical Geology.

Functional brain networks reconstruction using group sparsity-regularized learning.

PubMed

Zhao, Qinghua; Li, Will X Y; Jiang, Xi; Lv, Jinglei; Lu, Jianfeng; Liu, Tianming

2018-06-01

Investigating functional brain networks and patterns using sparse representation of fMRI data has received significant interests in the neuroimaging community. It has been reported that sparse representation is effective in reconstructing concurrent and interactive functional brain networks. To date, most of data-driven network reconstruction approaches rarely take consideration of anatomical structures, which are the substrate of brain function. Furthermore, it has been rarely explored whether structured sparse representation with anatomical guidance could facilitate functional networks reconstruction. To address this problem, in this paper, we propose to reconstruct brain networks utilizing the structure guided group sparse regression (S2GSR) in which 116 anatomical regions from the AAL template, as prior knowledge, are employed to guide the network reconstruction when performing sparse representation of whole-brain fMRI data. Specifically, we extract fMRI signals from standard space aligned with the AAL template. Then by learning a global over-complete dictionary, with the learned dictionary as a set of features (regressors), the group structured regression employs anatomical structures as group information to regress whole brain signals. Finally, the decomposition coefficients matrix is mapped back to the brain volume to represent functional brain networks and patterns. We use the publicly available Human Connectome Project (HCP) Q1 dataset as the test bed, and the experimental results indicate that the proposed anatomically guided structure sparse representation is effective in reconstructing concurrent functional brain networks.

Linear viral load increase of a single HPV-type in women with multiple HPV infections predicts progression to cervical cancer.

PubMed

Depuydt, Christophe E; Thys, Sofie; Beert, Johan; Jonckheere, Jef; Salembier, Geert; Bogers, Johannes J

2016-11-01

Persistent high-risk human papillomavirus (HPV) infection is strongly associated with development of high-grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type-specific viral-load measurements predict the natural history of the infection. In infections with multiple HPV-types, the individual type-specific viral-load profile could distinguish progressing HPV-infections from regressing infections. A case-cohort natural history study was established using samples from untreated women with multiple HPV-infections who developed CIN3+ (n = 57) or cleared infections (n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real-time qPCR-assay (18 HPV-types). Using serial type-specific viral-load measurements (≥3) we calculated HPV-specific slopes and coefficient of determination (R(2) ) by linear regression. For each woman slopes and R(2) were used to calculate which HPV-induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV-types, each single HPV-type generated similar increasing (0.27copies/cell/day) and decreasing (-0.27copies/cell/day) viral-load slopes. In CIN3+, at least one of the HPV-types had a clonal progressive course (R(2)  ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases (n = 6), immunostaining detecting type-specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion-producing infections the RNA-staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly-formed virions. RNA-hybridization patterns matched the calculated ongoing processes measured by R(2) and slope in serial type-specific viral-load measurements preceding the biopsy. In women with multiple HPV-types, serial type-specific viral-load measurements predict the natural history of the different HPV-types and elucidates HPV-genotype attribution. © 2016 UICC.

Tactical 3D Model Generation using Structure-From-Motion on Video from Unmanned Systems

DTIC Science & Technology

2015-04-01

available SfM application known as VisualSFM .6,7 VisualSFM is an end-user, “off-the-shelf” implementation of SfM that is easy to configure and used for...most 3D model generation applications from imagery. While the usual interface with VisualSFM is through their graphical user interface (GUI), we will be...of our system.5 There are two types of 3D model generation available within VisualSFM ; sparse and dense reconstruction. Sparse reconstruction begins

Fast sparsely synchronized brain rhythms in a scale-free neural network

NASA Astrophysics Data System (ADS)

Kim, Sang-Yoon; Lim, Woochang

2015-08-01

We consider a directed version of the Barabási-Albert scale-free network model with symmetric preferential attachment with the same in- and out-degrees and study the emergence of sparsely synchronized rhythms for a fixed attachment degree in an inhibitory population of fast-spiking Izhikevich interneurons. Fast sparsely synchronized rhythms with stochastic and intermittent neuronal discharges are found to appear for large values of J (synaptic inhibition strength) and D (noise intensity). For an intensive study we fix J at a sufficiently large value and investigate the population states by increasing D . For small D , full synchronization with the same population-rhythm frequency fp and mean firing rate (MFR) fi of individual neurons occurs, while for large D partial synchronization with fp> ( : ensemble-averaged MFR) appears due to intermittent discharge of individual neurons; in particular, the case of fp>4 is referred to as sparse synchronization. For the case of partial and sparse synchronization, MFRs of individual neurons vary depending on their degrees. As D passes a critical value D* (which is determined by employing an order parameter), a transition to unsynchronization occurs due to the destructive role of noise to spoil the pacing between sparse spikes. For D

Chemical compound-based direct reprogramming for future clinical applications

PubMed Central

Takeda, Yukimasa; Harada, Yoshinori; Yoshikawa, Toshikazu; Dai, Ping

2018-01-01

Recent studies have revealed that a combination of chemical compounds enables direct reprogramming from one somatic cell type into another without the use of transgenes by regulating cellular signaling pathways and epigenetic modifications. The generation of induced pluripotent stem (iPS) cells generally requires virus vector-mediated expression of multiple transcription factors, which might disrupt genomic integrity and proper cell functions. The direct reprogramming is a promising alternative to rapidly prepare different cell types by bypassing the pluripotent state. Because the strategy also depends on forced expression of exogenous lineage-specific transcription factors, the direct reprogramming in a chemical compound-based manner is an ideal approach to further reduce the risk for tumorigenesis. So far, a number of reported research efforts have revealed that combinations of chemical compounds and cell-type specific medium transdifferentiate somatic cells into desired cell types including neuronal cells, glial cells, neural stem cells, brown adipocytes, cardiomyocytes, somatic progenitor cells, and pluripotent stem cells. These desired cells rapidly converted from patient-derived autologous fibroblasts can be applied for their own transplantation therapy to avoid immune rejection. However, complete chemical compound-induced conversions remain challenging particularly in adult human-derived fibroblasts compared with mouse embryonic fibroblasts (MEFs). This review summarizes up-to-date progress in each specific cell type and discusses prospects for future clinical application toward cell transplantation therapy. PMID:29739872

Differential 3’ processing of specific transcripts expands regulatory and protein diversity across neuronal cell types

PubMed Central

Jereb, Saša; Hwang, Hun-Way; Van Otterloo, Eric; Govek, Eve-Ellen; Fak, John J; Yuan, Yuan; Hatten, Mary E

2018-01-01

Alternative polyadenylation (APA) regulates mRNA translation, stability, and protein localization. However, it is unclear to what extent APA regulates these processes uniquely in specific cell types. Using a new technique, cTag-PAPERCLIP, we discovered significant differences in APA between the principal types of mouse cerebellar neurons, the Purkinje and granule cells, as well as between proliferating and differentiated granule cells. Transcripts that differed in APA in these comparisons were enriched in key neuronal functions and many differed in coding sequence in addition to 3’UTR length. We characterize Memo1, a transcript that shifted from expressing a short 3’UTR isoform to a longer one during granule cell differentiation. We show that Memo1 regulates granule cell precursor proliferation and that its long 3’UTR isoform is targeted by miR-124, contributing to its downregulation during development. Our findings provide insight into roles for APA in specific cell types and establish a platform for further functional studies. PMID:29578408

The cell biology of lignification in higher plants

PubMed Central

Barros, Jaime; Serk, Henrik; Granlund, Irene; Pesquet, Edouard

2015-01-01

Background Lignin is a polyphenolic polymer that strengthens and waterproofs the cell wall of specialized plant cell types. Lignification is part of the normal differentiation programme and functioning of specific cell types, but can also be triggered as a response to various biotic and abiotic stresses in cells that would not otherwise be lignifying. Scope Cell wall lignification exhibits specific characteristics depending on the cell type being considered. These characteristics include the timing of lignification during cell differentiation, the palette of associated enzymes and substrates, the sub-cellular deposition sites, the monomeric composition and the cellular autonomy for lignin monomer production. This review provides an overview of the current understanding of lignin biosynthesis and polymerization at the cell biology level. Conclusions The lignification process ranges from full autonomy to complete co-operation depending on the cell type. The different roles of lignin for the function of each specific plant cell type are clearly illustrated by the multiple phenotypic defects exhibited by knock-out mutants in lignin synthesis, which may explain why no general mechanism for lignification has yet been defined. The range of phenotypic effects observed include altered xylem sap transport, loss of mechanical support, reduced seed protection and dispersion, and/or increased pest and disease susceptibility. PMID:25878140

Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and glutaric aciduria type 3.

PubMed

La Serna-Infantes, Jorge; Pastor, Miguel Chávez; Trubnykova, Milana; Velásquez, Félix Chavesta; Sotomayor, Flor Vásquez; Barriga, Hugo Abarca

2018-07-01

Trichothiodystrophy type 4 is a rare autosomal recessive and ectodermal disorder, characterized by dry, brittle, sparse and sulfur-deficient hair and other features like intellectual disability, ichthyotic skin and short stature, caused by a homozygous mutation in MPLKIP gene. Glutaric aciduria type 3 is caused by a homozygous mutation in SUGCT gene with no distinctive phenotype. Both genes are localized on chromosome 7 (7p14). We report an 8-year-old female with short stature, microcephaly, development delay, intellectual disability and hair characterized for dark, short, coarse, sparse and brittle associated to classical trichorrhexis microscopy pattern. Chromosome microarray analysis showed a 125 kb homozygous pathogenic deletion, which includes genes MPLKIP and SUGCT, not described before. This is the first case described in Peru of a novel contiguous gene deletion of Trichothiodystrophy type 4 and Glutaric aciduria type 3 performed by chromosome microarray analysis, highlighting the contribution and importance of molecular technologies on diagnosis of rare genetic conditions. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Temporally-Constrained Group Sparse Learning for Longitudinal Data Analysis in Alzheimer’s Disease

PubMed Central

Jie, Biao; Liu, Mingxia; Liu, Jun

2016-01-01

Sparse learning has been widely investigated for analysis of brain images to assist the diagnosis of Alzheimer’s disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). However, most existing sparse learning-based studies only adopt cross-sectional analysis methods, where the sparse model is learned using data from a single time-point. Actually, multiple time-points of data are often available in brain imaging applications, which can be used in some longitudinal analysis methods to better uncover the disease progression patterns. Accordingly, in this paper we propose a novel temporally-constrained group sparse learning method aiming for longitudinal analysis with multiple time-points of data. Specifically, we learn a sparse linear regression model by using the imaging data from multiple time-points, where a group regularization term is first employed to group the weights for the same brain region across different time-points together. Furthermore, to reflect the smooth changes between data derived from adjacent time-points, we incorporate two smoothness regularization terms into the objective function, i.e., one fused smoothness term which requires that the differences between two successive weight vectors from adjacent time-points should be small, and another output smoothness term which requires the differences between outputs of two successive models from adjacent time-points should also be small. We develop an efficient optimization algorithm to solve the proposed objective function. Experimental results on ADNI database demonstrate that, compared with conventional sparse learning-based methods, our proposed method can achieve improved regression performance and also help in discovering disease-related biomarkers. PMID:27093313

Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

PubMed Central

Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

2013-01-01

Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune function. PMID:24278029

Pathways-driven sparse regression identifies pathways and genes associated with high-density lipoprotein cholesterol in two Asian cohorts.

PubMed

Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

2013-11-01

Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune function.

Cell envelope stress response in cell wall-deficient L-forms of Bacillus subtilis.

PubMed

Wolf, Diana; Domínguez-Cuevas, Patricia; Daniel, Richard A; Mascher, Thorsten

2012-11-01

L-forms are cell wall-deficient bacteria that can grow and proliferate in osmotically stabilizing media. Recently, a strain of the Gram-positive model bacterium Bacillus subtilis was constructed that allowed controlled switching between rod-shaped wild-type cells and corresponding L-forms. Both states can be stably maintained under suitable culture conditions. Because of the absence of a cell wall, L-forms are known to be insensitive to β-lactam antibiotics, but reports on the susceptibility of L-forms to other antibiotics that interfere with membrane-anchored steps of cell wall biosynthesis are sparse, conflicting, and strongly influenced by strain background and method of L-form generation. Here we investigated the response of B. subtilis to the presence of cell envelope antibiotics, with regard to both antibiotic resistance and the induction of the known LiaRS- and BceRS-dependent cell envelope stress biosensors. Our results show that B. subtilis L-forms are resistant to antibiotics that interfere with the bactoprenol cycle, such as bacitracin, vancomycin, and mersacidin, but are hypersensitive to nisin and daptomycin, which both affect membrane integrity. Moreover, we established a lacZ-based reporter gene assay for L-forms and provide evidence that LiaRS senses its inducers indirectly (damage sensing), while the Bce module detects its inducers directly (drug sensing).

Cell Envelope Stress Response in Cell Wall-Deficient L-Forms of Bacillus subtilis

PubMed Central

Wolf, Diana; Domínguez-Cuevas, Patricia; Daniel, Richard A.

2012-01-01

L-forms are cell wall-deficient bacteria that can grow and proliferate in osmotically stabilizing media. Recently, a strain of the Gram-positive model bacterium Bacillus subtilis was constructed that allowed controlled switching between rod-shaped wild-type cells and corresponding L-forms. Both states can be stably maintained under suitable culture conditions. Because of the absence of a cell wall, L-forms are known to be insensitive to β-lactam antibiotics, but reports on the susceptibility of L-forms to other antibiotics that interfere with membrane-anchored steps of cell wall biosynthesis are sparse, conflicting, and strongly influenced by strain background and method of L-form generation. Here we investigated the response of B. subtilis to the presence of cell envelope antibiotics, with regard to both antibiotic resistance and the induction of the known LiaRS- and BceRS-dependent cell envelope stress biosensors. Our results show that B. subtilis L-forms are resistant to antibiotics that interfere with the bactoprenol cycle, such as bacitracin, vancomycin, and mersacidin, but are hypersensitive to nisin and daptomycin, which both affect membrane integrity. Moreover, we established a lacZ-based reporter gene assay for L-forms and provide evidence that LiaRS senses its inducers indirectly (damage sensing), while the Bce module detects its inducers directly (drug sensing). PMID:22964256

Nonconvex Sparse Logistic Regression With Weakly Convex Regularization

NASA Astrophysics Data System (ADS)

Shen, Xinyue; Gu, Yuantao

2018-06-01

In this work we propose to fit a sparse logistic regression model by a weakly convex regularized nonconvex optimization problem. The idea is based on the finding that a weakly convex function as an approximation of the $\\ell_0$ pseudo norm is able to better induce sparsity than the commonly used $\\ell_1$ norm. For a class of weakly convex sparsity inducing functions, we prove the nonconvexity of the corresponding sparse logistic regression problem, and study its local optimality conditions and the choice of the regularization parameter to exclude trivial solutions. Despite the nonconvexity, a method based on proximal gradient descent is used to solve the general weakly convex sparse logistic regression, and its convergence behavior is studied theoretically. Then the general framework is applied to a specific weakly convex function, and a necessary and sufficient local optimality condition is provided. The solution method is instantiated in this case as an iterative firm-shrinkage algorithm, and its effectiveness is demonstrated in numerical experiments by both randomly generated and real datasets.

Full-reference quality assessment of stereoscopic images by learning binocular receptive field properties.

PubMed

Shao, Feng; Li, Kemeng; Lin, Weisi; Jiang, Gangyi; Yu, Mei; Dai, Qionghai

2015-10-01

Quality assessment of 3D images encounters more challenges than its 2D counterparts. Directly applying 2D image quality metrics is not the solution. In this paper, we propose a new full-reference quality assessment for stereoscopic images by learning binocular receptive field properties to be more in line with human visual perception. To be more specific, in the training phase, we learn a multiscale dictionary from the training database, so that the latent structure of images can be represented as a set of basis vectors. In the quality estimation phase, we compute sparse feature similarity index based on the estimated sparse coefficient vectors by considering their phase difference and amplitude difference, and compute global luminance similarity index by considering luminance changes. The final quality score is obtained by incorporating binocular combination based on sparse energy and sparse complexity. Experimental results on five public 3D image quality assessment databases demonstrate that in comparison with the most related existing methods, the devised algorithm achieves high consistency with subjective assessment.

Recruitment of Mediator Complex by Cell Type and Stage-Specific Factors Required for Tissue-Specific TAF Dependent Gene Activation in an Adult Stem Cell Lineage.

PubMed

Lu, Chenggang; Fuller, Margaret T

2015-12-01

Onset of terminal differentiation in adult stem cell lineages is commonly marked by robust activation of new transcriptional programs required to make the appropriate differentiated cell type(s). In the Drosophila male germ line stem cell lineage, the switch from proliferating spermatogonia to spermatocyte is accompanied by one of the most dramatic transcriptional changes in the fly, as over 1000 new transcripts turn on in preparation for meiosis and spermatid differentiation. Here we show that function of the coactivator complex Mediator is required for activation of hundreds of new transcripts in the spermatocyte program. Mediator appears to act in a sequential hierarchy, with the testis activating Complex (tMAC), a cell type specific form of the Mip/dREAM general repressor, required to recruit Mediator subunits to the chromatin, and Mediator function required to recruit the testis TAFs (tTAFs), spermatocyte specific homologs of subunits of TFIID. Mediator, tMAC and the tTAFs co-regulate expression of a major set of spermatid differentiation genes. The Mediator subunit Med22 binds the tMAC component Topi when the two are coexpressed in S2 cells, suggesting direct recruitment. Loss of Med22 function in spermatocytes causes meiosis I maturation arrest male infertility, similar to loss of function of the tMAC subunits or the tTAFs. Our results illuminate how cell type specific versions of the Mip/dREAM complex and the general transcription machinery cooperate to drive selective gene activation during differentiation in stem cell lineages.

Myelin-reactive “type B” T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice

PubMed Central

Kawamura, Kazuyuki; McLaughlin, Katherine A.; Weissert, Robert; Forsthuber, Thomas G.

2009-01-01

Genes of the major histocompatibility complex (MHC) show the strongest genetic association with multiple sclerosis (MS) but the underlying mechanisms have remained unresolved. Here, we asked whether the MS-associated MHC class II molecules, HLA-DRB1*1501, HLA-DRB5*0101, and HLA-DRB1*0401 contribute to autoimmune central nervous system (CNS) demyelination by promoting pathogenic T cell responses to human myelin basic protein (hMBP), using three transgenic (Tg) mouse lines expressing these MHC molecules. Unexpectedly, profound T cell tolerance to the high-affinity MHC-binding hMBP82-100 epitope was observed in all Tg mouse lines. T cell tolerance to hMBP82-100 was abolished upon backcrossing the HLA-DR Tg mice to MBP-deficient mice. In contrast, T cell tolerance was incomplete for low-affinity MHC-binding hMBP epitopes. Furthermore, hMBP82-100-specific “type B” T cells escaped tolerance in HLA-DRB5*0101 Tg mice. Importantly, T cells specific for low-affinity MHC-binding hMBP epitopes and hMBP82-100-specific “type B” T cells were highly encephalitogenic. Collectively, the results show that MS-associated MHC class II molecules are highly efficient at inducing T cell tolerance to high-affinity MHC-binding epitope, whereas autoreactive T cells specific for the low-affinity MHC-binding epitopes and “type B” T cells can escape the induction of T cell tolerance and may promote MS. PMID:18713991

Probing the closed-loop model of mRNA translation in living cells

PubMed Central

Archer, Stuart K; Shirokikh, Nikolay E; Hallwirth, Claus V; Beilharz, Traude H; Preiss, Thomas

2015-01-01

The mRNA closed-loop, formed through interactions between the cap structure, poly(A) tail, eIF4E, eIF4G and PAB, features centrally in models of eukaryotic translation initiation, although direct support for its existence in vivo is not well established. Here, we investigated the closed-loop using a combination of mRNP isolation from rapidly cross-linked cells and high-throughput qPCR. Using the interaction between these factors and the opposing ends of mRNAs as a proxy for the closed-loop, we provide evidence that it is prevalent for eIF4E/4G-bound but unexpectedly sparse for PAB1-bound mRNAs, suggesting it primarily occurs during a distinct phase of polysome assembly. We observed mRNA-specific variation in the extent of closed-loop formation, consistent with a role for polysome topology in the control of gene expression. PMID:25826658

Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion.

PubMed

Gage, P J; Roller, M L; Saunders, T L; Scarlett, L M; Camper, S A

1996-01-01

The Ames dwarf mouse transmits a recessive mutation (df) resulting in a profound anterior pituitary hypocellularity due to a general lack of thyrotropes, somatotropes and lactotropes. These cell types are also dependent on the pituitary-specific transcription factor, Pit-1. We present evidence that expression of Pit-1 and limited commitment to these cells lineages occurs in df/df pituitaries. Thus, the crucial role of df may be in lineage-specific proliferation, rather than cytodifferentiation. The presence of all three Pit-1-dependent cell types in clonally derived clusters provides compelling evidence that these three lineages share a common, pluripotent precursor cell. Clusters containing different combinations of Pit-1-dependent cell types suggests that the Pit-1+ precursor cells choose from multiple developmental options during ontogeny. Characterization of df/df<-->+/+ chimeric mice demonstrated that df functions by a cell-autonomous mechanism. Therefore, df and Pit-1 are both cell-autonomous factors required for thyrotrope, somatotrope and lactotrope ontogeny, but their relative roles are different.

CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

PubMed

Ramberger, Melanie; Högl, Birgit; Stefani, Ambra; Mitterling, Thomas; Reindl, Markus; Lutterotti, Andreas

2017-03-01

Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. © Sleep Research Society 2016. Published by Oxford University Press [on behalf of the Sleep Research Society].

Measuring Sparseness in the Brain: Comment on Bowers (2009)

ERIC Educational Resources Information Center

Quian Quiroga, Rodrigo; Kreiman, Gabriel

2010-01-01

Bowers challenged the common view in favor of distributed representations in psychological modeling and the main arguments given against localist and grandmother cell coding schemes. He revisited the results of several single-cell studies, arguing that they do not support distributed representations. We praise the contribution of Bowers (2009) for…

Replicating receptive fields of simple and complex cells in primary visual cortex in a neuronal network model with temporal and population sparseness and reliability.

PubMed

Tanaka, Takuma; Aoyagi, Toshio; Kaneko, Takeshi

2012-10-01

We propose a new principle for replicating receptive field properties of neurons in the primary visual cortex. We derive a learning rule for a feedforward network, which maintains a low firing rate for the output neurons (resulting in temporal sparseness) and allows only a small subset of the neurons in the network to fire at any given time (resulting in population sparseness). Our learning rule also sets the firing rates of the output neurons at each time step to near-maximum or near-minimum levels, resulting in neuronal reliability. The learning rule is simple enough to be written in spatially and temporally local forms. After the learning stage is performed using input image patches of natural scenes, output neurons in the model network are found to exhibit simple-cell-like receptive field properties. When the output of these simple-cell-like neurons are input to another model layer using the same learning rule, the second-layer output neurons after learning become less sensitive to the phase of gratings than the simple-cell-like input neurons. In particular, some of the second-layer output neurons become completely phase invariant, owing to the convergence of the connections from first-layer neurons with similar orientation selectivity to second-layer neurons in the model network. We examine the parameter dependencies of the receptive field properties of the model neurons after learning and discuss their biological implications. We also show that the localized learning rule is consistent with experimental results concerning neuronal plasticity and can replicate the receptive fields of simple and complex cells.

Computational neuroanatomy: mapping cell-type densities in the mouse brain, simulations from the Allen Brain Atlas

NASA Astrophysics Data System (ADS)

Grange, Pascal

2015-09-01

The Allen Brain Atlas of the adult mouse (ABA) consists of digitized expression profiles of thousands of genes in the mouse brain, co-registered to a common three-dimensional template (the Allen Reference Atlas).This brain-wide, genome-wide data set has triggered a renaissance in neuroanatomy. Its voxelized version (with cubic voxels of side 200 microns) is available for desktop computation in MATLAB. On the other hand, brain cells exhibit a great phenotypic diversity (in terms of size, shape and electrophysiological activity), which has inspired the names of some well-studied cell types, such as granule cells and medium spiny neurons. However, no exhaustive taxonomy of brain cell is available. A genetic classification of brain cells is being undertaken, and some cell types have been chraracterized by their transcriptome profiles. However, given a cell type characterized by its transcriptome, it is not clear where else in the brain similar cells can be found. The ABA can been used to solve this region-specificity problem in a data-driven way: rewriting the brain-wide expression profiles of all genes in the atlas as a sum of cell-type-specific transcriptome profiles is equivalent to solving a quadratic optimization problem at each voxel in the brain. However, the estimated brain-wide densities of 64 cell types published recently were based on one series of co-registered coronal in situ hybridization (ISH) images per gene, whereas the online ABA contains several image series per gene, including sagittal ones. In the presented work, we simulate the variability of cell-type densities in a Monte Carlo way by repeatedly drawing a random image series for each gene and solving the optimization problem. This yields error bars on the region-specificity of cell types.

Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system

PubMed Central

Vandenbon, Alexis; Dinh, Viet H.; Mikami, Norihisa; Kitagawa, Yohko; Teraguchi, Shunsuke; Ohkura, Naganari; Sakaguchi, Shimon

2016-01-01

High-throughput gene expression data are one of the primary resources for exploring complex intracellular dynamics in modern biology. The integration of large amounts of public data may allow us to examine general dynamical relationships between regulators and target genes. However, obstacles for such analyses are study-specific biases or batch effects in the original data. Here we present Immuno-Navigator, a batch-corrected gene expression and coexpression database for 24 cell types of the mouse immune system. We systematically removed batch effects from the underlying gene expression data and showed that this removal considerably improved the consistency between inferred correlations and prior knowledge. The data revealed widespread cell type-specific correlation of expression. Integrated analysis tools allow users to use this correlation of expression for the generation of hypotheses about biological networks and candidate regulators in specific cell types. We show several applications of Immuno-Navigator as examples. In one application we successfully predicted known regulators of importance in naturally occurring Treg cells from their expression correlation with a set of Treg-specific genes. For one high-scoring gene, integrin β8 (Itgb8), we confirmed an association between Itgb8 expression in forkhead box P3 (Foxp3)-positive T cells and Treg-specific epigenetic remodeling. Our results also suggest that the regulation of Treg-specific genes within Treg cells is relatively independent of Foxp3 expression, supporting recent results pointing to a Foxp3-independent component in the development of Treg cells. PMID:27078110

Birthdating Studies Reshape Models for Pituitary Gland Cell Specification

PubMed Central

Davis, Shannon W.; Mortensen, Amanda H.; Camper, Sally A.

2011-01-01

The intermediate and anterior lobes of the pituitary gland are derived from an invagination of oral ectoderm that forms Rathke’s pouch. During gestation proliferating cells are enriched around the pouch lumen, and they appear to delaminate as they exit the cell cycle and differentiate. During late mouse gestation and the post-natal period, anterior lobe progenitors re-enter the cell cycle and expand the populations of specialized, hormone-producing cells. At birth, all cell types are present, and their localization appears stratified based on cell type. We conducted a birth dating study of Rathke’s pouch derivatives to determine whether the location of specialized cells at birth is correlated with the timing of cell cycle exit. We find that all of the anterior lobe cell types initiate differentiation concurrently with a peak between e11.5 and e13.5. Differentiation of intermediate lobe melanotropes is delayed relative to anterior lobe cell types. We discovered that specialized cell types are not grouped together based on birth date and are dispersed throughout the anterior lobe. Thus, the apparent stratification of specialized cells at birth is not correlated with cell cycle exit. Thus, the currently popular model of cell specification, dependent upon timing of extrinsic, directional gradients of signaling molecules, needs revision. We propose that signals intrinsic to Rathke’s pouch are necessary for cell specification between e11.5 and e13.5 and that cell-cell communication likely plays an important role in regulating this process. PMID:21262217

Birthdating studies reshape models for pituitary gland cell specification.

PubMed

Davis, Shannon W; Mortensen, Amanda H; Camper, Sally A

2011-04-15

The intermediate and anterior lobes of the pituitary gland are derived from an invagination of oral ectoderm that forms Rathke's pouch. During gestation proliferating cells are enriched around the pouch lumen, and they appear to delaminate as they exit the cell cycle and differentiate. During late mouse gestation and the postnatal period, anterior lobe progenitors re-enter the cell cycle and expand the populations of specialized, hormone-producing cells. At birth, all cell types are present, and their localization appears stratified based on cell type. We conducted a birth dating study of Rathke's pouch derivatives to determine whether the location of specialized cells at birth is correlated with the timing of cell cycle exit. We find that all of the anterior lobe cell types initiate differentiation concurrently with a peak between e11.5 and e13.5. Differentiation of intermediate lobe melanotropes is delayed relative to anterior lobe cell types. We discovered that specialized cell types are not grouped together based on birth date and are dispersed throughout the anterior lobe. Thus, the apparent stratification of specialized cells at birth is not correlated with cell cycle exit. Thus, the currently popular model of cell specification, dependent upon timing of extrinsic, directional gradients of signaling molecules, needs revision. We propose that signals intrinsic to Rathke's pouch are necessary for cell specification between e11.5 and e13.5 and that cell-cell communication likely plays an important role in regulating this process. Copyright © 2011 Elsevier Inc. All rights reserved.

Influence of the Cell Wall on Intracellular Delivery to Algal Cells by Electroporation and Sonication

PubMed Central

Azencott, Harold R.; Peter, Gary F.; Prausnitz, Mark R.

2007-01-01

To assess the cell wall’s role as a barrier to intracellular delivery, wild-type Chlamydomonas reinhardtii algal cells and mutant cells lacking a cell wall were exposed to electroporation or sonication. Flow cytometry determined intracellular uptake of calcein and bovine serum albumin (BSA) and loss of cell viability as functions of electroporation transmembrane potential and acoustic energy. Electroporation of wild-type cells increased calcein uptake with increasing transmembrane potential, but delivered much less BSA. Electroporation of wall-deficient cells had similar effects on calcein uptake, but increased BSA uptake as much as 7.5-fold relative to wild-type cells, which indicated that the cell wall was a significant barrier to BSA delivery during electroporation. Sonication of wild-type cells caused calcein and BSA uptake at similar levels. This suggests that the cell wall barrier to BSA delivery can be overcome by sonication. Increased electroporation transmembrane potential or acoustic energy also caused increased loss of cell viability, where wall-deficient cells were especially susceptible to lysis. Overall, we believe this is the first study to compare the effects of electroporation and sonication in a direct fashion in any cell type. Specifically, these findings suggest that electroporation primarily transports molecules across the plasma membrane, because its mechanism is specific to lipid bilayer disruption, whereas sonication transports molecules across both the plasma membrane and cell wall, because it non-specifically disrupts cell-surface barriers. PMID:17602827

Capacity for patterns and sequences in Kanerva's SDM as compared to other associative memory models. [Sparse, Distributed Memory

NASA Technical Reports Server (NTRS)

Keeler, James D.

1988-01-01

The information capacity of Kanerva's Sparse Distributed Memory (SDM) and Hopfield-type neural networks is investigated. Under the approximations used here, it is shown that the total information stored in these systems is proportional to the number connections in the network. The proportionality constant is the same for the SDM and Hopfield-type models independent of the particular model, or the order of the model. The approximations are checked numerically. This same analysis can be used to show that the SDM can store sequences of spatiotemporal patterns, and the addition of time-delayed connections allows the retrieval of context dependent temporal patterns. A minor modification of the SDM can be used to store correlated patterns.

Sustained transcription of the immediate early gene Arc in the dentate gyrus after spatial exploration.

PubMed

Ramirez-Amaya, Victor; Angulo-Perkins, Arafat; Chawla, Monica K; Barnes, Carol A; Rosi, Susanna

2013-01-23

After spatial exploration in rats, Arc mRNA is expressed in ∼2% of dentate gyrus (DG) granule cells, and this proportion of Arc-positive neurons remains stable for ∼8 h. This long-term presence of Arc mRNA following behavior is not observed in hippocampal CA1 pyramidal cells. We report here that in rats ∼50% of granule cells with cytoplasmic Arc mRNA, induced some hours previously during exploration, also show Arc expression in the nucleus. This suggests that recent transcription can occur long after the exploration behavior that elicited it. To confirm that the delayed nuclear Arc expression was indeed recent transcription, Actinomycin D was administered immediately after exploration. This treatment resulted in inhibition of recent Arc expression both when evaluated shortly after exploratory behavior as well as after longer time intervals. Together, these data demonstrate a unique kinetic profile for Arc transcription in hippocampal granule neurons following behavior that is not observed in other cell types. Among a number of possibilities, this sustained transcription may provide a mechanism that ensures that the synaptic connection weights in the sparse population of granule cells recruited during a given behavioral event are able to be modified.

Neuronal cell fate specification in Drosophila.

PubMed

Jan, Y N; Jan, L Y

1994-02-01

Recent work indicates that the Drosophila nervous system develops in a progressive process of cell fate specification. Expression of specific proneural genes in clusters of cells (the proneural clusters) in the cellular blastoderm endows these cells with the potential to form certain types of neural precursors. Intercellular interactions that involve both proneural genes and neurogenic genes then allow the neural precursors to be singled out from the proneural clusters. Expression of neural precursor genes in all neural precursors is likely to account for the universal aspects of neuronal differentiation, such as axonal outgrowth. Selective expression of certain neuronal-type selector genes further specifies the type of neuron(s) that a neural precursor will produce.

Abnormal Functional Lateralization and Activity of Language Brain Areas in Typical Specific Language Impairment (Developmental Dysphasia)

ERIC Educational Resources Information Center

de Guibert, Clement; Maumet, Camille; Jannin, Pierre; Ferre, Jean-Christophe; Treguier, Catherine; Barillot, Christian; Le Rumeur, Elisabeth; Allaire, Catherine; Biraben, Arnaud

2011-01-01

Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting…

High-performance sparse matrix-matrix products on Intel KNL and multicore architectures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagasaka, Y; Matsuoka, S; Azad, A

Sparse matrix-matrix multiplication (SpGEMM) is a computational primitive that is widely used in areas ranging from traditional numerical applications to recent big data analysis and machine learning. Although many SpGEMM algorithms have been proposed, hardware specific optimizations for multi- and many-core processors are lacking and a detailed analysis of their performance under various use cases and matrices is not available. We firstly identify and mitigate multiple bottlenecks with memory management and thread scheduling on Intel Xeon Phi (Knights Landing or KNL). Specifically targeting multi- and many-core processors, we develop a hash-table-based algorithm and optimize a heap-based shared-memory SpGEMM algorithm. Wemore » examine their performance together with other publicly available codes. Different from the literature, our evaluation also includes use cases that are representative of real graph algorithms, such as multi-source breadth-first search or triangle counting. Our hash-table and heap-based algorithms are showing significant speedups from libraries in the majority of the cases while different algorithms dominate the other scenarios with different matrix size, sparsity, compression factor and operation type. We wrap up in-depth evaluation results and make a recipe to give the best SpGEMM algorithm for target scenario. A critical finding is that hash-table-based SpGEMM gets a significant performance boost if the nonzeros are not required to be sorted within each row of the output matrix.« less

Microfluidic differential immunocapture biochip for specific leukocyte counting

PubMed Central

Hassan, Umer; Watkins, Nicholas N; Reddy, Bobby; Damhorst, Gregory; Bashir, Rashid

2016-01-01

Enumerating specific cell types from whole blood can be very useful for research and diagnostic purposes—e.g., for counting of cD4 and cD8 t cells in HIV/aIDs diagnostics. We have developed a biosensor based on a differential immunocapture technology to enumerate specific cells in 30 min using 10 µl of blood. this paper provides a comprehensive stepwise protocol to replicate our biosensor for cD4 and cD8 cell counts. the biochip can also be adapted to enumerate other specific cell types such as somatic cells or cells from tissue or liquid biopsies. capture of other specific cells requires immobilization of their corresponding antibodies within the capture chamber. therefore, this protocol is useful for research into areas surrounding immunocapture-based biosensor development. the biosensor production requires 24 h, a one-time cell capture optimization takes 6–9 h, and the final cell counting experiment in a laboratory environment requires 30 min to complete. PMID:26963632

Magnetic resonance brain tissue segmentation based on sparse representations

NASA Astrophysics Data System (ADS)

Rueda, Andrea

2015-12-01

Segmentation or delineation of specific organs and structures in medical images is an important task in the clinical diagnosis and treatment, since it allows to characterize pathologies through imaging measures (biomarkers). In brain imaging, segmentation of main tissues or specific structures is challenging, due to the anatomic variability and complexity, and the presence of image artifacts (noise, intensity inhomogeneities, partial volume effect). In this paper, an automatic segmentation strategy is proposed, based on sparse representations and coupled dictionaries. Image intensity patterns are singly related to tissue labels at the level of small patches, gathering this information in coupled intensity/segmentation dictionaries. This dictionaries are used within a sparse representation framework to find the projection of a new intensity image onto the intensity dictionary, and the same projection can be used with the segmentation dictionary to estimate the corresponding segmentation. Preliminary results obtained with two publicly available datasets suggest that the proposal is capable of estimating adequate segmentations for gray matter (GM) and white matter (WM) tissues, with an average overlapping of 0:79 for GM and 0:71 for WM (with respect to original segmentations).

Piano Transcription with Convolutional Sparse Lateral Inhibition

DOE PAGES

Cogliati, Andrea; Duan, Zhiyao; Wohlberg, Brendt Egon

2017-02-08

This paper extends our prior work on contextdependent piano transcription to estimate the length of the notes in addition to their pitch and onset. This approach employs convolutional sparse coding along with lateral inhibition constraints to approximate a musical signal as the sum of piano note waveforms (dictionary elements) convolved with their temporal activations. The waveforms are pre-recorded for the specific piano to be transcribed in the specific environment. A dictionary containing multiple waveforms per pitch is generated by truncating a long waveform for each pitch to different lengths. During transcription, the dictionary elements are fixed and their temporal activationsmore » are estimated and post-processed to obtain the pitch, onset and note length estimation. A sparsity penalty promotes globally sparse activations of the dictionary elements, and a lateral inhibition term penalizes concurrent activations of different waveforms corresponding to the same pitch within a temporal neighborhood, to achieve note length estimation. Experiments on the MAPS dataset show that the proposed approach significantly outperforms a state-of-the-art music transcription method trained in the same context-dependent setting in transcription accuracy.« less

Piano Transcription with Convolutional Sparse Lateral Inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cogliati, Andrea; Duan, Zhiyao; Wohlberg, Brendt Egon

This paper extends our prior work on contextdependent piano transcription to estimate the length of the notes in addition to their pitch and onset. This approach employs convolutional sparse coding along with lateral inhibition constraints to approximate a musical signal as the sum of piano note waveforms (dictionary elements) convolved with their temporal activations. The waveforms are pre-recorded for the specific piano to be transcribed in the specific environment. A dictionary containing multiple waveforms per pitch is generated by truncating a long waveform for each pitch to different lengths. During transcription, the dictionary elements are fixed and their temporal activationsmore » are estimated and post-processed to obtain the pitch, onset and note length estimation. A sparsity penalty promotes globally sparse activations of the dictionary elements, and a lateral inhibition term penalizes concurrent activations of different waveforms corresponding to the same pitch within a temporal neighborhood, to achieve note length estimation. Experiments on the MAPS dataset show that the proposed approach significantly outperforms a state-of-the-art music transcription method trained in the same context-dependent setting in transcription accuracy.« less

Two-Stage, In Silico Deconvolution of the Lymphocyte Compartment of the Peripheral Whole Blood Transcriptome in the Context of Acute Kidney Allograft Rejection

PubMed Central

Shannon, Casey P.; Balshaw, Robert; Ng, Raymond T.; Wilson-McManus, Janet E.; Keown, Paul; McMaster, Robert; McManus, Bruce M.; Landsberg, David; Isbel, Nicole M.; Knoll, Greg; Tebbutt, Scott J.

2014-01-01

Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially expressed probe-set lists is consistent with the originating tissue and their functional enrichment consistent with allograft rejection. Finally, we demonstrate that the strategy described here can be used to derive useful hypotheses by validating a cell type-specific ratio in an independent cohort using the nanoString nCounter assay. PMID:24733377

Expression of gamma-aminobutyric acid rho 1 and rho 1 Delta 450 as gene fusions with the green fluorescent protein.

PubMed

Martinez-Torres, A; Miledi, R

2001-02-13

The functional characteristics and cellular localization of the gamma aminobutyric acid (GABA) rho 1 receptor and its nonfunctional isoform rho 1 Delta 450 were investigated by expressing them as gene fusions with the enhanced version of the green fluorescent protein (GFP). Oocytes injected with rho 1-GFP had receptors that gated chloride channels when activated by GABA. The functional characteristics of these receptors were the same as for those of wild-type rho 1 receptors. Fluorescence, because of the chimeric receptors expressed, was over the whole oocyte but was more intense near the cell surface and more abundant in the animal hemisphere. Similar to the wild type, rho 1 Delta 450-GFP did not lead to the expression of functional GABA receptors, and injected oocytes failed to generate currents even after exposure to high concentrations of GABA. Nonetheless, the fluorescence displayed by oocytes expressing rho 1 Delta 450-GFP was distributed similarly to that of rho 1-GFP. Mammalian cells transfected with the rho 1-GFP or rho 1 Delta 450-GFP constructs showed mostly intracellularly distributed fluorescence in confocal microscope images. A sparse localization of fluorescence was observed in the plasma membrane regardless of the cell line used. We conclude that rho 1 Delta 450 is expressed and transported close to, and perhaps incorporated into, the plasma membrane. Thus, rho 1- and rho 1 Delta 450-GFP fusions provide a powerful tool to visualize the traffic of GABA type C receptors.

Parallel iterative methods for sparse linear and nonlinear equations

NASA Technical Reports Server (NTRS)

Saad, Youcef

1989-01-01

As three-dimensional models are gaining importance, iterative methods will become almost mandatory. Among these, preconditioned Krylov subspace methods have been viewed as the most efficient and reliable, when solving linear as well as nonlinear systems of equations. There has been several different approaches taken to adapt iterative methods for supercomputers. Some of these approaches are discussed and the methods that deal more specifically with general unstructured sparse matrices, such as those arising from finite element methods, are emphasized.

The Global Positioning System (GPS) and attitude determination: Applications and activities in the Flight Dynamics Division

NASA Technical Reports Server (NTRS)

Ketchum, Eleanor; Garrick, Joe

1995-01-01

The application of GPS to spacecraft attitude determination is a new and growing field. Although the theoretical literature is extensive, space flight testing is currently sparse and inadequate. As an operations organization, the Flight Dynamics Division (FDD) has the responsibility to investigate this new technology, and determine how best to implement the innovation to provide adequate support for future missions. This paper presents some of the current efforts within FDD with regard to GPS attitude determination. This effort specifically addresses institutional capabilities to accommodate a new type of sensor, critically evaluating the literature for recent advancements, and in examining some available -albeit crude- flight data.

Vignettes from the field of mathematical biology: the application of mathematics to biology and medicine

PubMed Central

Murray, J. D.

2012-01-01

The application of mathematical models in biology and medicine has a long history. From the sparse number of papers in the first half of the twentieth century with a few scientists working in the field it has become vast with thousands of active researchers. We give a brief, and far from definitive history, of how some parts of the field have developed and how the type of research has changed. We describe in more detail just two examples of specific models which are directly related to real biological problems, namely animal coat patterns and the growth and image enhancement of glioblastoma brain tumours. PMID:23919124

Sparse-sampling with time-encoded (TICO) stimulated Raman scattering for fast image acquisition

NASA Astrophysics Data System (ADS)

Hakert, Hubertus; Eibl, Matthias; Karpf, Sebastian; Huber, Robert

2017-07-01

Modern biomedical imaging modalities aim to provide researchers a multimodal contrast for a deeper insight into a specimen under investigation. A very promising technique is stimulated Raman scattering (SRS) microscopy, which can unveil the chemical composition of a sample with a very high specificity. Although the signal intensities are enhanced manifold to achieve a faster acquisition of images if compared to standard Raman microscopy, there is a trade-off between specificity and acquisition speed. Commonly used SRS concepts either probe only very few Raman transitions as the tuning of the applied laser sources is complicated or record whole spectra with a spectrometer based setup. While the first approach is fast, it reduces the specificity and the spectrometer approach records whole spectra -with energy differences where no Raman information is present-, which limits the acquisition speed. Therefore, we present a new approach based on the TICO-Raman concept, which we call sparse-sampling. The TICO-sparse-sampling setup is fully electronically controllable and allows probing of only the characteristic peaks of a Raman spectrum instead of always acquiring a whole spectrum. By reducing the spectral points to the relevant peaks, the acquisition time can be greatly reduced compared to a uniformly, equidistantly sampled Raman spectrum while the specificity and the signal to noise ratio (SNR) are maintained. Furthermore, all laser sources are completely fiber based. The synchronized detection enables a full resolution of the Raman signal, whereas the analogue and digital balancing allows shot noise limited detection. First imaging results with polystyrene (PS) and polymethylmethacrylate (PMMA) beads confirm the advantages of TICO sparse-sampling. We achieved a pixel dwell time as low as 35 μs for an image differentiating both species. The mechanical properties of the applied voice coil stage for scanning the sample currently limits even faster acquisition.

Oxygen vacancies: The origin of n -type conductivity in ZnO

NASA Astrophysics Data System (ADS)

Liu, Lishu; Mei, Zengxia; Tang, Aihua; Azarov, Alexander; Kuznetsov, Andrej; Xue, Qi-Kun; Du, Xiaolong

2016-06-01

Oxygen vacancy (VO) is a common native point defect that plays crucial roles in determining the physical and chemical properties of metal oxides such as ZnO. However, fundamental understanding of VO is still very sparse. Specifically, whether VO is mainly responsible for the n -type conductivity in ZnO has been still unsettled in the past 50 years. Here, we report on a study of oxygen self-diffusion by conceiving and growing oxygen-isotope ZnO heterostructures with delicately controlled chemical potential and Fermi level. The diffusion process is found to be predominantly mediated by VO. We further demonstrate that, in contrast to the general belief of their neutral attribute, the oxygen vacancies in ZnO are actually +2 charged and thus responsible for the unintentional n -type conductivity as well as the nonstoichiometry of ZnO. The methodology can be extended to study oxygen-related point defects and their energetics in other technologically important oxide materials.

Cell-type-specific profiling of protein-DNA interactions without cell isolation using targeted DamID with next-generation sequencing.

PubMed

Marshall, Owen J; Southall, Tony D; Cheetham, Seth W; Brand, Andrea H

2016-09-01

This protocol is an extension to: Nat. Protoc. 2, 1467-1478 (2007); doi:10.1038/nprot.2007.148; published online 7 June 2007The ability to profile transcription and chromatin binding in a cell-type-specific manner is a powerful aid to understanding cell-fate specification and cellular function in multicellular organisms. We recently developed targeted DamID (TaDa) to enable genome-wide, cell-type-specific profiling of DNA- and chromatin-binding proteins in vivo without cell isolation. As a protocol extension, this article describes substantial modifications to an existing protocol, and it offers additional applications. TaDa builds upon DamID, a technique for detecting genome-wide DNA-binding profiles of proteins, by coupling it with the GAL4 system in Drosophila to enable both temporal and spatial resolution. TaDa ensures that Dam-fusion proteins are expressed at very low levels, thus avoiding toxicity and potential artifacts from overexpression. The modifications to the core DamID technique presented here also increase the speed of sample processing and throughput, and adapt the method to next-generation sequencing technology. TaDa is robust, reproducible and highly sensitive. Compared with other methods for cell-type-specific profiling, the technique requires no cell-sorting, cross-linking or antisera, and binding profiles can be generated from as few as 10,000 total induced cells. By profiling the genome-wide binding of RNA polymerase II (Pol II), TaDa can also identify transcribed genes in a cell-type-specific manner. Here we describe a detailed protocol for carrying out TaDa experiments and preparing the material for next-generation sequencing. Although we developed TaDa in Drosophila, it should be easily adapted to other organisms with an inducible expression system. Once transgenic animals are obtained, the entire experimental procedure-from collecting tissue samples to generating sequencing libraries-can be accomplished within 5 d.

ERE environment- and cell type-specific transcriptional effects of estrogen in normal endometrial cells.

PubMed

Lascombe, I; Sallot, M; Vuillermoz, C; Weisz, A; Adessi, G L; Jouvenot, M

1998-04-30

Our previous results have suggested a repression of E2 (17beta-estradiol) effect on the c-fos gene of cultured guinea-pig endometrial cells. To investigate this repression, the expression of three human c-fos gene recombinants, pFC1-BL (-2250/+41), pFC2-BL (-1400/+41) and pFC2E (-1300/-1050 and -230/+41), known to be E2-responsive in Hela cells, was studied in stromal (SC) and glandular epithelial cells (GEC). In both cellular types, pFC1-BL was not induced by E2, even in the presence of growth factors or co-transfected estrogen receptor. The pattern of pFC2-BL and pFC2E expression was strikingly different and depended on the cellular type: pFC2-BL and pFC2E induction was restricted to the glandular epithelial cells and did not occur in the SCs. We argue for a repression of E2 action which is dependent on the estrogen-responsive cis-acting element (ERE) environment and also cell type-specific involving DNA/protein and/or protein/protein interactions with cellular type-specific factors.

Use of Autoantigen-Loaded Phosphatidylserine-Liposomes to Arrest Autoimmunity in Type 1 Diabetes

PubMed Central

Pujol-Autonell, Irma; Serracant-Prat, Arnau; Cano-Sarabia, Mary; Ampudia, Rosa M.; Rodriguez-Fernandez, Silvia; Sanchez, Alex; Izquierdo, Cristina; Stratmann, Thomas; Puig-Domingo, Manuel; Maspoch, Daniel; Verdaguer, Joan; Vives-Pi, Marta

2015-01-01

Introduction The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. Objective To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes. Methods A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. Results We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. Conclusions We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases. PMID:26039878

Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes.

PubMed

Pujol-Autonell, Irma; Serracant-Prat, Arnau; Cano-Sarabia, Mary; Ampudia, Rosa M; Rodriguez-Fernandez, Silvia; Sanchez, Alex; Izquierdo, Cristina; Stratmann, Thomas; Puig-Domingo, Manuel; Maspoch, Daniel; Verdaguer, Joan; Vives-Pi, Marta

2015-01-01

The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes. A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases.

Molecular beacon-enabled purification of living cells by targeting cell type-specific mRNAs.

PubMed

Wile, Brian M; Ban, Kiwon; Yoon, Young-Sup; Bao, Gang

2014-10-01

Molecular beacons (MBs) are dual-labeled oligonucleotides that fluoresce only in the presence of complementary mRNA. The use of MBs to target specific mRNAs allows sorting of specific cells from a mixed cell population. In contrast to existing approaches that are limited by available surface markers or selectable metabolic characteristics, the MB-based method enables the isolation of a wide variety of cells. For example, the ability to purify specific cell types derived from pluripotent stem cells (PSCs) is important for basic research and therapeutics. In addition to providing a general protocol for MB design, validation and nucleofection into cells, we describe how to isolate a specific cell population from differentiating PSCs. By using this protocol, we have successfully isolated cardiomyocytes differentiated from mouse or human PSCs (hPSCs) with ∼ 97% purity, as confirmed by electrophysiology and immunocytochemistry. After designing MBs, their ordering and validation requires 2 weeks, and the isolation process requires 3 h.

Targeted Deletion and Lipidomic Analysis Identify Epithelial Cell COX-2 as a Major Driver of Chemically-induced Skin Cancer

PubMed Central

Jiao, Jing; Ishikawa, Tomo-o; Dumlao, Darren S.; Norris, Paul C.; Magyar, Clara E.; Mikulec, Carol; Catapang, Art; Dennis, Edward A.; Fischer, Susan M.; Herschman, Harvey R.

2014-01-01

Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX2) plays a critical role in DMBA/TPA-induced skin tumor induction. While many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell-type specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared to littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2 expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell-type specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biological responses. PMID:25063587

Differential Sox10 Genomic Occupancy in Myelinating Glia

PubMed Central

Lopez-Anido, Camila; Sun, Guannan; Koenning, Matthias; Srinivasan, Rajini; Hung, Holly A.; Emery, Ben; Keles, Sunduz; Svaren, John

2015-01-01

Myelin is formed by specialized myelinating glia: oligodendrocytes and Schwann cells in the central and peripheral nervous systems, respectively. While there are distinct developmental aspects and regulatory pathways in these two cell types, myelination in both systems requires the transcriptional activator Sox10. Sox10 interacts with cell type-specific transcription factors at some loci to induce myelin gene expression, but it is largely unknown how Sox10 transcriptional networks globally compare between oligodendrocytes and Schwann cells. We used in vivo ChIP-Seq analysis of spinal cord and peripheral nerve (sciatic nerve) to identify unique and shared Sox10 binding sites and assess their correlation with active enhancers and transcriptional profiles in oligodendrocytes and Schwann cells. Sox10 binding sites overlap with active enhancers and critical cell type-specific regulators of myelination, such as Olig2 and Myrf in oligodendrocytes, and Egr2/Krox20 in Schwann cells. Sox10 sites also associate with genes critical for myelination in both oligodendrocytes and Schwann cells, and are found within super-enhancers previously defined in brain. In Schwann cells, Sox10 sites contain binding motifs of putative partners in the Sp/Klf, Tead, and nuclear receptor protein families. Specifically, siRNA analysis of nuclear receptors Nr2f1 and Nr2f2 revealed downregulation of myelin genes Mbp and Ndrg1 in primary Schwann cells. Our analysis highlights different mechanisms that establish cell type-specific genomic occupancy of Sox10, which reflects the unique characteristics of oligodendrocyte and Schwann cell differentiation. PMID:25974668

Genomic Knockout of Endogenous Canine P-Glycoprotein in Wild-Type, Human P-Glycoprotein and Human BCRP Transfected MDCKII Cell Lines by Zinc Finger Nucleases.

PubMed

Gartzke, Dominik; Delzer, Jürgen; Laplanche, Loic; Uchida, Yasuo; Hoshi, Yutaro; Tachikawa, Masanori; Terasaki, Tetsuya; Sydor, Jens; Fricker, Gert

2015-06-01

To investigate whether it is possible to specifically suppress the expression and function of endogenous canine P-glycoprotein (cPgp) in Madin-Darby canine kidney type II cells (MDCKII) transfected with hPGP and breast cancer resistance protein (hBCRP) by zinc finger nuclease (ZFN) producing sequence specific DNA double strand breaks. Wild-type, hPGP-transfected, and hBCRP-transfected MDCKII cells were transfected with ZFN targeting for cPgp. Net efflux ratios (NER) of Pgp and Bcrp substrates were determined by dividing efflux ratios (basal-to-apical / apical-to-basal) in over-expressing cell monolayers by those in wild-type ones. From ZFN-transfected cells, cell populations (ko-cells) showing knockout of cPgp were selected based on genotyping by PCR. qRT-PCR analysis showed the significant knock-downs of cPgp and interestingly also cMrp2 expressions. Specific knock-downs of protein expression for cPgp were shown by western blotting and quantitative targeted absolute proteomics. Endogenous canine Bcrp proteins were not detected. For PGP-transfected cells, NERs of 5 Pgp substrates in ko-cells were significantly greater than those in parental cells not transfected with ZFN. Similar result was obtained for BCRP-transfected cells with a dual Pgp and Bcrp substrate. Specific efflux mediated by hPGP or hBCRP can be determined with MDCKII cells where cPgp has been knocked out by ZFN.

Bridging the Gap: Towards a Cell-Type Specific Understanding of Neural Circuits Underlying Fear Behaviors

PubMed Central

McCullough, KM; Morrison, FG; Ressler, KJ

2016-01-01

Fear and anxiety-related disorders are remarkably common and debilitating, and are often characterized by dysregulated fear responses. Rodent models of fear learning and memory have taken great strides towards elucidating the specific neuronal circuitries underlying the learning of fear responses. The present review addresses recent research utilizing optogenetic approaches to parse circuitries underlying fear behaviors. It also highlights the powerful advances made when optogenetic techniques are utilized in a genetically defined, cell-type specific, manner. The application of next-generation genetic and sequencing approaches in a cell-type specific context will be essential for a mechanistic understanding of the neural circuitry underlying fear behavior and for the rational design of targeted, circuit specific, pharmacologic interventions for the treatment and prevention of fear-related disorders. PMID:27470092

Evaluation of pharmacokinetic and pharmacodynamic profiles of liposomes for the cell type-specific delivery of small molecule drugs.

PubMed

Dasa, Siva Sai Krishna; Suzuki, Ryo; Mugler, Emily; Chen, Lanlin; Jansson-Löfmark, Rasmus; Michaëlsson, Erik; Lindfors, Lennart; Klibanov, Alexander L; French, Brent A; Kelly, Kimberly A

2017-11-01

Liposome-based drug formulations represent an exciting avenue of research as they increase efficacy to toxicity ratios. Current formulations rely on passive accumulation to the disease site where drug is taken up by the cells. Ligand mediated targeting increases the net accumulation of liposomes, however, an unexplored benefit is to potentially refine pharmacodynamics (PD) of a drug specifically to different cell types within diseased tissue. As a model system, we engineered cardiomyocyte- (I-1) and endothelial-targeted (B-40) liposomes to carry a VEGFR2 inhibitor (PTK787), and examined the effect of cell type-specific delivery on both pharmacokinetics (PK) and PD. Neovascularization in post-myocardial infarction was significantly reduced by B-40 liposomes loaded with PTK787 as compared to animals injected with I-1 liposomes, and profoundly more as compared to free PTK787. This study thus shows that the intraorgan targeting of drugs through cell type-specific delivery holds substantial promise towards lowering the minimal efficacious dose administered systemically. Published by Elsevier Inc.

Comparative photodynamic therapy cytotoxicity of mannose-conjugated chlorin and talaporfin sodium in cultured human and rat cells.

PubMed

Shinoda, Yo; Takahashi, Tsutomu; Akimoto, Jiro; Ichikawa, Megumi; Yamazaki, Hiromi; Narumi, Atsushi; Yano, Shigenobu; Fujiwara, Yasuyuki

2017-01-01

Photodynamic therapy (PDT) is a Food and Drug Administration authorized method for cancer treatment, which uses photosensitizer and laser photo-irradiation to generate reactive oxygen species to induce cell death in tumors. Photosensitizers have been progressively developed, from first to third generation, with improvements in cell specificity, reduced side effects and toxicity, increased sensitivity for irradiation and reduced persistence of photosensitizer in healthy cells. These improvements have been achieved by basic comparative experiments between current and novel photosensitizers using cell lines; however, photosensitizers should be carefully evaluated because they may have cell type specificity. In the present study, we compared a third-generation photosensitizer, β-mannose-conjugated chlorin (β-M-chlorin), with the second generation, talaporfin sodium (NPe6), using seven different rat and human cell lines and a neuronal/glial primary culture prepared from rat embryos. NPe6 was more effective than β-M-chlorin in human-derived cell lines, and β-M-chlorin was more effective than NPe6 in rat primary cultures and rat-derived cell lines, except for the rat pheochromocytoma cell line, PC12. These differences of phototoxicity in different cell types are not because of differences in photosensitivity between the photosensitizers, but rather are associated with different distribution and accumulation rates in the different cell types. These data suggest that evaluation of photosensitizers for PDT should be carried out using as large a variety of cell types as possible because each photosensitizer may have cell type specificity.

Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum.

PubMed

Kim, Steve M; Ganguli, Surya; Frank, Loren M

2012-08-22

Hippocampal place cells convey spatial information through a combination of spatially selective firing and theta phase precession. The way in which this information influences regions like the subiculum that receive input from the hippocampus remains unclear. The subiculum receives direct inputs from area CA1 of the hippocampus and sends divergent output projections to many other parts of the brain, so we examined the firing patterns of rat subicular neurons. We found a substantial transformation in the subicular code for space from sparse to dense firing rate representations along a proximal-distal anatomical gradient: neurons in the proximal subiculum are more similar to canonical, sparsely firing hippocampal place cells, whereas neurons in the distal subiculum have higher firing rates and more distributed spatial firing patterns. Using information theory, we found that the more distributed spatial representation in the subiculum carries, on average, more information about spatial location and context than the sparse spatial representation in CA1. Remarkably, despite the disparate firing rate properties of subicular neurons, we found that neurons at all proximal-distal locations exhibit robust theta phase precession, with similar spiking oscillation frequencies as neurons in area CA1. Our findings suggest that the subiculum is specialized to compress sparse hippocampal spatial codes into highly informative distributed codes suitable for efficient communication to other brain regions. Moreover, despite this substantial compression, the subiculum maintains finer scale temporal properties that may allow it to participate in oscillatory phase coding and spike timing-dependent plasticity in coordination with other regions of the hippocampal circuit.

SU-D-201-03: Imaging Cellular Pharmacokinetics of 18F-FDG in Inflammatory/Stem Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zaman, R; Tuerkcan, S; Mahmoudi, M

Purpose: Atherosclerosis is a progressive inflammatory condition that underlies coronary artery disease (CAD)—the leading cause of death in the USA. Thus, understating the metabolism of inflammatory cells can be a valuable tool for investigating CAD. To the best of our knowledge, we are the first to successfully investigate the pharmacokinetics of [18F]fluoro-deoxyglucose (18F-FDG) uptake in a single macrophages and compared with induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) with a novel imaging technique, radioluminescence microscopy, initially developed for cancer imaging. Methods: Live cells were cultured sparsely on Matrigel in a glass-bottom dish and starved for 1 hourmore » before incubation with 250 microCi of 18F-FDG for 45 minutes. Excess radiotracer was removed using DMEM medium without glucose. Before imaging, DMEM (1 mL) was added to the cell culture and a 100 microm-thin CdWO4 scintillator plate was placed on top of the cells. Light produced following beta decay was imaged with a highly sensitive inverted microscope (LV200, Olympus) fitted with a 40x/1.3 high-NA oil objective, and an EM-CCD camera. The images were collected over 18,000 frames with 4×4 binning (1200 MHz EM Gain, 300ms exposure). Custom-written software was developed in MATLAB for image processing (Figure 1). For statistical analysis 10 different region-of-interests (ROIs) were selected for each cell type. Results: Figures 2A–2B show bright-field/fusion images for all three different cell types. The relationship between cell-to-cell comparisons was found to be linear for macrophages unlike iPSCs and MSCs, which were best fitted with moving or rolling average (Figure 2C). The average observed decay of 18F-FDG in a single cell of MSCs per second (0.067) was 20% and 36% higher compared to iPSCs (0.054) and macrophages (0.043), respectively (Figure 2D). Conclusion: MSCs was found to be 2–3x more sensitive to glucose molecule despite constant parameters for each cell type examined.« less

Multiple Sparse Representations Classification

PubMed Central

Plenge, Esben; Klein, Stefan S.; Niessen, Wiro J.; Meijering, Erik

2015-01-01

Sparse representations classification (SRC) is a powerful technique for pixelwise classification of images and it is increasingly being used for a wide variety of image analysis tasks. The method uses sparse representation and learned redundant dictionaries to classify image pixels. In this empirical study we propose to further leverage the redundancy of the learned dictionaries to achieve a more accurate classifier. In conventional SRC, each image pixel is associated with a small patch surrounding it. Using these patches, a dictionary is trained for each class in a supervised fashion. Commonly, redundant/overcomplete dictionaries are trained and image patches are sparsely represented by a linear combination of only a few of the dictionary elements. Given a set of trained dictionaries, a new patch is sparse coded using each of them, and subsequently assigned to the class whose dictionary yields the minimum residual energy. We propose a generalization of this scheme. The method, which we call multiple sparse representations classification (mSRC), is based on the observation that an overcomplete, class specific dictionary is capable of generating multiple accurate and independent estimates of a patch belonging to the class. So instead of finding a single sparse representation of a patch for each dictionary, we find multiple, and the corresponding residual energies provides an enhanced statistic which is used to improve classification. We demonstrate the efficacy of mSRC for three example applications: pixelwise classification of texture images, lumen segmentation in carotid artery magnetic resonance imaging (MRI), and bifurcation point detection in carotid artery MRI. We compare our method with conventional SRC, K-nearest neighbor, and support vector machine classifiers. The results show that mSRC outperforms SRC and the other reference methods. In addition, we present an extensive evaluation of the effect of the main mSRC parameters: patch size, dictionary size, and sparsity level. PMID:26177106

Pulmonary Langerhans cell histiocytosis and diabetes insipidus in pregnant women: our experience.

PubMed

Fuks, Leonardo; Kramer, Mordechai R; Shitrit, David; Raviv, Yael

2014-04-01

Pulmonary Langerhans cell histiocytosis (PLCH) occurs predominantly in young adult smokers. Diabetes insipidus occurs in up to 15 % patients with PLCH. Information on PLCH in pregnancy is sparse, especially associated with diabetes insipidus. We report three patients with these conditions and describe the disease history and pregnancy outcomes.

Toward the human cellular microRNAome.

PubMed

McCall, Matthew N; Kim, Min-Sik; Adil, Mohammed; Patil, Arun H; Lu, Yin; Mitchell, Christopher J; Leal-Rojas, Pamela; Xu, Jinchong; Kumar, Manoj; Dawson, Valina L; Dawson, Ted M; Baras, Alexander S; Rosenberg, Avi Z; Arking, Dan E; Burns, Kathleen H; Pandey, Akhilesh; Halushka, Marc K

2017-10-01

MicroRNAs are short RNAs that serve as regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell-autonomously, and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data have caused considerable confusion, and comprehensive cell-level data do not yet exist. Here, we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues. It identified both specific and ubiquitous patterns of expression that strongly correlate with adjacent superenhancer activity. Analysis of unaligned RNA reads uncovered 207 unknown minor strand (passenger) microRNAs of known microRNA loci and 495 novel putative microRNA loci. Although cancer cell lines generally recapitulated the expression patterns of matched primary cells, their isomiR sequence families exhibited increased disorder, suggesting DROSHA- and DICER1-dependent microRNA processing variability. Cell-specific patterns of microRNA expression were used to de-convolute variable cellular composition of colon and adipose tissue samples, highlighting one use of these cell-specific microRNA expression data. Characterization of cellular microRNA expression across a wide variety of cell types provides a new understanding of this critical regulatory RNA species. © 2017 McCall et al.; Published by Cold Spring Harbor Laboratory Press.

Pig but not Human Interferon-γ Initiates Human Cell-Mediated Rejection of Pig Tissue in vivo

NASA Astrophysics Data System (ADS)

Sultan, Parvez; Murray, Allan G.; McNiff, Jennifer M.; Lorber, Marc I.; Askenase, Philip W.; Bothwell, Alfred L. M.; Pober, Jordan S.

1997-08-01

Split-thickness pig skin was transplanted on severe combined immunodeficient mice so that pig dermal microvessels spontaneously inosculated with mouse microvessels and functioned to perfuse the grafts. Pig endothelial cells in the healed grafts constitutively expressed class I and class II major histocompatibility complex molecules. Major histocompatibility complex molecule expression could be further increased by intradermal injection of pig interferon-γ (IFN-γ ) but not human IFN-γ or tumor necrosis factor. Grafts injected with pig IFN-γ also developed a sparse infiltrate of mouse neutrophils and eosinophils without evidence of injury. Introduction of human peripheral blood mononuclear cells into the animals by intraperitoneal inoculation resulted in sparse perivascular mononuclear cell infiltrates in the grafts confined to the pig dermis. Injection of pig skin grafts on mice that received human peripheral blood mononuclear cells with pig IFN-γ (but not human IFN-γ or heat-inactivated pig IFN-γ ) induced human CD4+ and CD8+ T cells and macrophages to more extensively infiltrate the pig skin grafts and injure pig dermal microvessels. These findings suggest that human T cell-mediated rejection of xenotransplanted pig organs may be prevented if cellular sources of pig interferon (e.g., passenger lymphocytes) are eliminated from the graft.

Maternal T-Cell Engraftment Interferes With Human Leukocyte Antigen Typing in Severe Combined Immunodeficiency.

PubMed

Liu, Chang; Duffy, Brian; Bednarski, Jeffrey J; Calhoun, Cecelia; Lay, Lindsay; Rundblad, Barrett; Payton, Jacqueline E; Mohanakumar, Thalachallour

2016-02-01

To report the laboratory investigation of a case of severe combined immunodeficiency (SCID) with maternal T-cell engraftment, focusing on the interference of human leukocyte antigen (HLA) typing by blood chimerism. HLA typing was performed with three different methods, including sequence-specific primer (SSP), sequence-specific oligonucleotide, and Sanger sequencing on peripheral blood leukocytes and buccal cells, from a 3-month-old boy and peripheral blood leukocytes from his parents. Short tandem repeat (STR) testing was performed in parallel. HLA typing of the patient's peripheral blood leukocytes using the SSP method demonstrated three different alleles for each of the HLA-B and HLA-C loci, with both maternal alleles present at each locus. Typing results from the patient's buccal cells showed a normal pattern of inheritance for paternal and maternal haplotypes. STR enrichment testing of the patient's CD3+ T lymphocytes and CD15+ myeloid cells confirmed maternal T-cell engraftment, while the myeloid cell profile matched the patient's buccal cells. Maternal T-cell engraftment may interfere with HLA typing in patients with SCID. Selection of the appropriate typing methods and specimens is critical for accurate HLA typing and immunologic assessment before allogeneic hematopoietic stem cell transplantation. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Practices in public health finance: an investigation of jurisdiction funding patterns and performance.

PubMed

Honoré, Peggy A; Simoes, Eduardo J; Jones, Walter J; Moonesinghe, Ramal

2004-01-01

A field of study for public health finance has never been adequately developed. Consequently, very little is known about the relationships, types, and amount of finances that fund the public health system in America. This research was undertaken to build on the sparse knowledge of public health finance by examining the value of performance measurement systems to financial analysis. A correlational study was conducted to examine the associations between public health system performance of the 10 essential public health services and funding patterns of 50 local health departments in a large state. The specific objectives were to investigate if different levels and types of revenues, expenditures, and other demographic variables in a jurisdiction are correlated to performance. Pearson correlation analysis did not conclusively show strong associations; however, statistically significant positive associations primarily between higher levels of performance and jurisdiction taxes per capita were found.

Object-Place Recognition Learning Triggers Rapid Induction of Plasticity-Related Immediate Early Genes and Synaptic Proteins in the Rat Dentate Gyrus

PubMed Central

Soulé, Jonathan; Penke, Zsuzsa; Kanhema, Tambudzai; Alme, Maria Nordheim; Laroche, Serge; Bramham, Clive R.

2008-01-01

Long-term recognition memory requires protein synthesis, but little is known about the coordinate regulation of specific genes. Here, we examined expression of the plasticity-associated immediate early genes (Arc, Zif268, and Narp) in the dentate gyrus following long-term object-place recognition learning in rats. RT-PCR analysis from dentate gyrus tissue collected shortly after training did not reveal learning-specific changes in Arc mRNA expression. In situ hybridization and immunohistochemistry were therefore used to assess possible sparse effects on gene expression. Learning about objects increased the density of granule cells expressing Arc, and to a lesser extent Narp, specifically in the dorsal blade of the dentate gyrus, while Zif268 expression was elevated across both blades. Thus, object-place recognition triggers rapid, blade-specific upregulation of plasticity-associated immediate early genes. Furthermore, Western blot analysis of dentate gyrus homogenates demonstrated concomitant upregulation of three postsynaptic density proteins (Arc, PSD-95, and α-CaMKII) with key roles in long-term synaptic plasticity and long-term memory. PMID:19190776

PNA lectin for purifying mouse acinar cells from the inflamed pancreas.

PubMed

Xiao, Xiangwei; Fischbach, Shane; Fusco, Joseph; Zimmerman, Ray; Song, Zewen; Nebres, Philip; Ricks, David Matthew; Prasadan, Krishna; Shiota, Chiyo; Husain, Sohail Z; Gittes, George K

2016-02-17

Better methods for purifying human or mouse acinar cells without the need for genetic modification are needed. Such techniques would be advantageous for the specific study of certain mechanisms, such as acinar-to-beta-cell reprogramming and pancreatitis. Ulex Europaeus Agglutinin I (UEA-I) lectin has been used to label and isolate acinar cells from the pancreas. However, the purity of the UEA-I-positive cell fraction has not been fully evaluated. Here, we screened 20 widely used lectins for their binding specificity for major pancreatic cell types, and found that UEA-I and Peanut agglutinin (PNA) have a specific affinity for acinar cells in the mouse pancreas, with minimal affinity for other major pancreatic cell types including endocrine cells, duct cells and endothelial cells. Moreover, PNA-purified acinar cells were less contaminated with mesenchymal and inflammatory cells, compared to UEA-I purified acinar cells. Thus, UEA-I and PNA appear to be excellent lectins for pancreatic acinar cell purification. PNA may be a better choice in situations where mesenchymal cells or inflammatory cells are significantly increased in the pancreas, such as type 1 diabetes, pancreatitis and pancreatic cancer.

PNA lectin for purifying mouse acinar cells from the inflamed pancreas

PubMed Central

Xiao, Xiangwei; Fischbach, Shane; Fusco, Joseph; Zimmerman, Ray; Song, Zewen; Nebres, Philip; Ricks, David Matthew; Prasadan, Krishna; Shiota, Chiyo; Husain, Sohail Z.; Gittes, George K.

2016-01-01

Better methods for purifying human or mouse acinar cells without the need for genetic modification are needed. Such techniques would be advantageous for the specific study of certain mechanisms, such as acinar-to-beta-cell reprogramming and pancreatitis. Ulex Europaeus Agglutinin I (UEA-I) lectin has been used to label and isolate acinar cells from the pancreas. However, the purity of the UEA-I-positive cell fraction has not been fully evaluated. Here, we screened 20 widely used lectins for their binding specificity for major pancreatic cell types, and found that UEA-I and Peanut agglutinin (PNA) have a specific affinity for acinar cells in the mouse pancreas, with minimal affinity for other major pancreatic cell types including endocrine cells, duct cells and endothelial cells. Moreover, PNA-purified acinar cells were less contaminated with mesenchymal and inflammatory cells, compared to UEA-I purified acinar cells. Thus, UEA-I and PNA appear to be excellent lectins for pancreatic acinar cell purification. PNA may be a better choice in situations where mesenchymal cells or inflammatory cells are significantly increased in the pancreas, such as type 1 diabetes, pancreatitis and pancreatic cancer. PMID:26884345

Improving M-SBL for Joint Sparse Recovery Using a Subspace Penalty

NASA Astrophysics Data System (ADS)

Ye, Jong Chul; Kim, Jong Min; Bresler, Yoram

2015-12-01

The multiple measurement vector problem (MMV) is a generalization of the compressed sensing problem that addresses the recovery of a set of jointly sparse signal vectors. One of the important contributions of this paper is to reveal that the seemingly least related state-of-art MMV joint sparse recovery algorithms - M-SBL (multiple sparse Bayesian learning) and subspace-based hybrid greedy algorithms - have a very important link. More specifically, we show that replacing the $\\log\\det(\\cdot)$ term in M-SBL by a rank proxy that exploits the spark reduction property discovered in subspace-based joint sparse recovery algorithms, provides significant improvements. In particular, if we use the Schatten-$p$ quasi-norm as the corresponding rank proxy, the global minimiser of the proposed algorithm becomes identical to the true solution as $p \\rightarrow 0$. Furthermore, under the same regularity conditions, we show that the convergence to a local minimiser is guaranteed using an alternating minimization algorithm that has closed form expressions for each of the minimization steps, which are convex. Numerical simulations under a variety of scenarios in terms of SNR, and condition number of the signal amplitude matrix demonstrate that the proposed algorithm consistently outperforms M-SBL and other state-of-the art algorithms.

Living on the Edge: A Geometric Theory of Phase Transitions in Convex Optimization

DTIC Science & Technology

2013-03-24

framework for constructing a regularizer f that promotes a specified type of structure, as well as many additional examples. We say that the...Rd that promote the structures we expect to find in x0 8 D. AMELUNXEN, M. LOTZ, M. B. MCCOY, AND J. A. TROPP and y0. Then we can frame the convex...signal x0 is sparse in the standard basis, and the second signal U y0 is sparse in a known basis U . In this case, we can use `1 norms to promote

Interaction of phospholipid vesicles with cultured mammalial cells. I. Characteristics of uptake

PubMed Central

1975-01-01

The interaction of monolayer cultures of Chinese hamster V79 cells with artificially generated, unilamellar lipid vesicles (approximately 500 A diameter) was examined. Vesicles prepared from a variety of natural and synthetic radiolabeled phosphatidyl cholines (lecithins) were incubated with V79 cells bathed in a simple balanced salt solution. After incubation, the cells were analyzed for exogenous lipid incorporation. Large quantities (approximately 10(8) molecules/cell/h) of lecithin became cell associated without affecting cell viability. The effects of pH, charged lipids, and the influence of the vesicle lipid phase transition on the uptake process were examined. Glutaraldehyde fixation of cells before vesicle treatment, or incubation in the presence of metabolic inhibitors, failed to reduce the lecithin uptake by more than 25-50%, suggesting that the lipid uptake is largely energy independent. Cells in sparse culture took up about ten times more lipid than dense cultures. Prolonged incubation (greater than 15 h) of sparse cell cultures with lecithin vesicles resulted in significant cell death while no deleterious effect was found in dense cultures, or with 1:1 lecithin/cholesterol vesicles. When vesicle-treated cells were homogenized and fractionated, about 20-30% of the exogenous lipid was found in the plasma membrane fraction, with the remainder being distributed into intracellular fractions. Electron microscope radioautography further demonstrated that most of the internalized lipid was present in the cytoplasm, with little in the nucleus. These results are discussed in terms of possible modification of cell behavior by lipid vesicle treatment. PMID:240860

Fast sparsely synchronized brain rhythms in a scale-free neural network.

PubMed

Kim, Sang-Yoon; Lim, Woochang

2015-08-01

We consider a directed version of the Barabási-Albert scale-free network model with symmetric preferential attachment with the same in- and out-degrees and study the emergence of sparsely synchronized rhythms for a fixed attachment degree in an inhibitory population of fast-spiking Izhikevich interneurons. Fast sparsely synchronized rhythms with stochastic and intermittent neuronal discharges are found to appear for large values of J (synaptic inhibition strength) and D (noise intensity). For an intensive study we fix J at a sufficiently large value and investigate the population states by increasing D. For small D, full synchronization with the same population-rhythm frequency fp and mean firing rate (MFR) fi of individual neurons occurs, while for large D partial synchronization with fp>〈fi〉 (〈fi〉: ensemble-averaged MFR) appears due to intermittent discharge of individual neurons; in particular, the case of fp>4〈fi〉 is referred to as sparse synchronization. For the case of partial and sparse synchronization, MFRs of individual neurons vary depending on their degrees. As D passes a critical value D* (which is determined by employing an order parameter), a transition to unsynchronization occurs due to the destructive role of noise to spoil the pacing between sparse spikes. For D

Drug Transporter Protein Quantification of Immortalized Human Lung Cell Lines Derived from Tracheobronchial Epithelial Cells (Calu-3 and BEAS2-B), Bronchiolar-Alveolar Cells (NCI-H292 and NCI-H441), and Alveolar Type II-like Cells (A549) by Liquid Chromatography-Tandem Mass Spectrometry.

PubMed

Sakamoto, Atsushi; Matsumaru, Takehisa; Yamamura, Norio; Suzuki, Shinobu; Uchida, Yasuo; Tachikawa, Masanori; Terasaki, Tetsuya

2015-09-01

Understanding the mechanisms of drug transport in the human lung is an important issue in pulmonary drug discovery and development. For this purpose, there is an increasing interest in immortalized lung cell lines as alternatives to primary cultured lung cells. We recently reported the protein expression in human lung tissues and pulmonary epithelial cells in primary culture, (Sakamoto A, Matsumaru T, Yamamura N, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T. 2013. J Pharm Sci 102(9):3395-3406) whereas comprehensive quantification of protein expressions in immortalized lung cell lines is sparse. Therefore, the aim of the present study was to clarify the drug transporter protein expression of five commercially available immortalized lung cell lines derived from tracheobronchial cells (Calu-3 and BEAS2-B), bronchiolar-alveolar cells (NCI-H292 and NCI-H441), and alveolar type II cells (A549), by liquid chromatography-tandem mass spectrometry-based approaches. Among transporters detected, breast cancer-resistance protein in Calu-3, NCI-H292, NCI-H441, and A549 and OCTN2 in BEAS2-B showed the highest protein expression. Compared with data from our previous study,(Sakamoto A, Matsumaru T, Yamamura N, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T. 2013. J Pharm Sci 102(9):3395-3406) NCI-H441 was the most similar with primary lung cells from all regions in terms of protein expression of organic cation/carnitine transporter 1 (OCTN1). In conclusion, the protein expression profiles of transporters in five immortalized lung cell lines were determined, and these findings may contribute to a better understanding of drug transport in immortalized lung cell lines. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

In vitro Neurons in Mammalian Cortical Layer 4 Exhibit Intrinsic Oscillatory Activity in the 10- to 50-Hz Frequency Range

NASA Astrophysics Data System (ADS)

Llinas, Rodolfo R.; Grace, Anthony A.; Yarom, Yosef

1991-02-01

We report here the presence of fast subthreshold oscillatory potentials recorded in vitro from neurons within layer 4 of the guinea pig frontal cortex. Two types of oscillatory neurons were recorded: (i) One type exhibited subthreshold oscillations whose frequency increased with membrane depolarization and encompassed a range of 10-45 Hz. Action potentials in this type of neuron demonstrated clear after-hyperpolarizations. (ii) The second type of neuron was characterized by narrow-frequency oscillations near 35-50 Hz. These oscillations often outlasted the initiating depolarizing stimulus. No calcium component could be identified in their action potential. In both types of cell the subthreshold oscillations were tetrodotoxin-sensitive, indicating that the depolarizing phase of the oscillation was generated by a voltage-dependent sodium conductance. The initial depolarizing phase was followed by a potassium conductance responsible for the falling phase of the oscillatory wave. In both types of cell, the subthreshold oscillation could trigger spikes at the oscillatory frequency, if the membrane was sufficiently depolarized. Combining intracellular recordings with Lucifer yellow staining showed that the narrow-frequency oscillatory activity was produced by a sparsely spinous interneuron located in layer 4 of the cortex. This neuron has extensive local axonal collaterals that ramify in layers 3 and 4 such that they may contribute to the columnar synchronization of activity in the 40- to 50-Hz range. Cortical activity in this frequency range has been proposed as the basis for the "conjunctive properties" of central nervous system networks.

Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression

PubMed Central

Ruijtenberg, Suzan; van den Heuvel, Sander

2016-01-01

ABSTRACT Cell proliferation and differentiation show a remarkable inverse relationship. Precursor cells continue division before acquiring a fully differentiated state, while terminal differentiation usually coincides with proliferation arrest and permanent exit from the division cycle. Mechanistic insight in the temporal coordination between cell cycle exit and differentiation has come from studies of cells in culture and genetic animal models. As initially described for skeletal muscle differentiation, temporal coordination involves mutual antagonism between cyclin-dependent kinases that promote cell cycle entry and transcription factors that induce tissue-specific gene expression. Recent insights highlight the contribution of chromatin-regulating complexes that act in conjunction with the transcription factors and determine their activity. In particular SWI/SNF chromatin remodelers contribute to dual regulation of cell cycle and tissue-specific gene expression during terminal differentiation. We review the concerted regulation of the cell cycle and cell type-specific transcription, and discuss common mutations in human cancer that emphasize the clinical importance of proliferation versus differentiation control. PMID:26825227

Characterizing and differentiating task-based and resting state fMRI signals via two-stage sparse representations.

PubMed

Zhang, Shu; Li, Xiang; Lv, Jinglei; Jiang, Xi; Guo, Lei; Liu, Tianming

2016-03-01

A relatively underexplored question in fMRI is whether there are intrinsic differences in terms of signal composition patterns that can effectively characterize and differentiate task-based or resting state fMRI (tfMRI or rsfMRI) signals. In this paper, we propose a novel two-stage sparse representation framework to examine the fundamental difference between tfMRI and rsfMRI signals. Specifically, in the first stage, the whole-brain tfMRI or rsfMRI signals of each subject were composed into a big data matrix, which was then factorized into a subject-specific dictionary matrix and a weight coefficient matrix for sparse representation. In the second stage, all of the dictionary matrices from both tfMRI/rsfMRI data across multiple subjects were composed into another big data-matrix, which was further sparsely represented by a cross-subjects common dictionary and a weight matrix. This framework has been applied on the recently publicly released Human Connectome Project (HCP) fMRI data and experimental results revealed that there are distinctive and descriptive atoms in the cross-subjects common dictionary that can effectively characterize and differentiate tfMRI and rsfMRI signals, achieving 100% classification accuracy. Moreover, our methods and results can be meaningfully interpreted, e.g., the well-known default mode network (DMN) activities can be recovered from the very noisy and heterogeneous aggregated big-data of tfMRI and rsfMRI signals across all subjects in HCP Q1 release.

Espin cytoskeletal proteins in the sensory cells of rodent taste buds

PubMed Central

Sekerková, Gabriella; Freeman, David; Mugnaini, Enrico; Bartles, James R.

2010-01-01

Espins are multifunctional actin-bundling proteins that are highly enriched in the microvilli of certain chemosensory and mechanosensory cells, where they are believed to regulate the integrity and/or dimensions of the parallel-actin-bundle cytoskeletal scaffold. We have determined that, in rats and mice, affinity purified espin antibody intensely labels the lingual and palatal taste buds of the oral cavity and taste buds in the pharyngo-laryngeal region. Intense immunolabeling was observed in the apical, microvillar region of taste buds, while the level of cytoplasmic labeling in taste bud cells was considerably lower. Taste bud cells contain tightly packed collections of sensory cells (light, or type II plus type III) and supporting cells (dark, or type I), which can be distinguished by microscopic features and cell type-specific markers. On the basis of results obtained using an antigen-retrieval method in conjunction with double immunofluorescence for espin and sensory taste cell-specific markers, we propose that espins are expressed predominantly in the sensory cells of rat circumvallate taste buds. In confocal images, we counted 21.5±0.3 espin-positive cells/taste bud, in agreement with a previous report showing 20.7±1.3 light cells/taste bud when counted at the ultrastructural level. The espin antibody labeled spindle-shaped cells with round nuclei and showed 100% colocalization with cell-specific markers recognizing all type II [inositol 1,4,5-trisphosphate receptor type III (IP3R3),α-gustducin, protein-specific gene product 9.5 (PGP9.5)] and a subpopulation of type III (IP3R3, PGP9.5) taste cells. On average, 72%, 50%, and 32% of the espin-positive taste cells were labeled with antibodies to IP3R3, α-gustducin, and PGP9.5, respectively. Upon sectional analysis, the taste buds of rat circumvallate papillae commonly revealed a multi-tiered, espin-positive apical cytoskeletal apparatus. One espin-positive zone, a collection of ~3 μm-long microvilli occupying the taste pore, was separated by an espin-depleted zone from a second espin-positive zone situated lower within the taste pit. This latter zone included espin-positive rod-like structures that occasionally extended basally to a depth of 10-12 μm into the cytoplasm of taste cells. We propose that the espin-positive zone in the taste pit coincides with actin bundles in association with the microvilli of type II taste cells, whereas the espin-positive microvilli in the taste pore are the single microvilli of type III taste cells. PMID:16841162

Epigenetic regulation of normal human mammary cell type-specific miRNAs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vrba, Lukas; Garbe, James C.; Stampfer, Martha R.

2011-08-26

Epigenetic mechanisms are important regulators of cell type–specific genes, including miRNAs. In order to identify cell type-specific miRNAs regulated by epigenetic mechanisms, we undertook a global analysis of miRNA expression and epigenetic states in three isogenic pairs of human mammary epithelial cells (HMEC) and human mammary fibroblasts (HMF), which represent two differentiated cell types typically present within a given organ, each with a distinct phenotype and a distinct epigenotype. While miRNA expression and epigenetic states showed strong interindividual concordance within a given cell type, almost 10% of the expressed miRNA showed a cell type–specific pattern of expression that was linkedmore » to the epigenetic state of their promoter. The tissue-specific miRNA genes were epigenetically repressed in nonexpressing cells by DNA methylation (38%) and H3K27me3 (58%), with only a small set of miRNAs (21%) showing a dual epigenetic repression where both DNA methylation and H3K27me3 were present at their promoters, such as MIR10A and MIR10B. Individual miRNA clusters of closely related miRNA gene families can each display cell type–specific repression by the same or complementary epigenetic mechanisms, such as the MIR200 family, and MIR205, where fibroblasts repress MIR200C/141 by DNA methylation, MIR200A/200B/429 by H3K27me3, and MIR205 by both DNA methylation and H3K27me3. Since deregulation of many of the epigenetically regulated miRNAs that we identified have been linked to disease processes such as cancer, it is predicted that compromise of the epigenetic control mechanisms is important for this process. Overall, these results highlight the importance of epigenetic regulation in the control of normal cell type–specific miRNA expression.« less

Immunomicrospheres - Reagents for cell labeling and separation

NASA Technical Reports Server (NTRS)

Rembaum, A.; Dreyer, W. J.

1980-01-01

Immunomicrospheres are specially designed microscopic particles that have antibodies or similar molecules chemically bound to their surfaces. The antibody-coated microspheres react in a highly specific way with target cells, viruses, or other antigenic agents. Immunomicrospheres may be synthesized so that they incorporate compounds that are highly radioactive, intensely fluorescent, magnetic, electron opaque, highly colored, or pharmacologically active. These various types of microspheres may be coated with pure, highly specific monoclonal antibodies obtained by the new hybridoma cell cloning techniques or with conventional antibody preparations. Some of the many present and potential applications for these new reagents are (1) new types of radioimmune or immunofluorescent assays, (2) improved fluorescence microscopy, (3) separation of cells on the basis of the fluorescent, electrophoretic, or magnetic properties of bound immunomicrospheres, (4) markers for use in several types of electron or standard light microscopy, and (5) delivery of lethal compouds to specific undesirable living cells. The combination of the various new types of synthetic microspheres and the newly available homogeneous antibodies offers new opportunities in research, diagnosis, and therapy.

Human stem cells and drug screening: opportunities and challenges.

PubMed

Ebert, Allison D; Svendsen, Clive N

2010-05-01

High-throughput screening technologies are widely used in the early stages of drug discovery to rapidly evaluate the properties of thousands of compounds. However, they generally rely on testing compound libraries on highly proliferative immortalized or cancerous cell lines, which do not necessarily provide an accurate indication of the effects of compounds in normal human cells or the specific cell type under study. Recent advances in stem cell technology have the potential to allow production of a virtually limitless supply of normal human cells that can be differentiated into any specific cell type. Moreover, using induced pluripotent stem cell technology, they can also be generated from patients with specific disease traits, enabling more relevant modelling and drug screens. This article discusses the opportunities and challenges for the use of stem cells in drug screening with a focus on induced pluripotent stem cells.

Changes in Appetitive Associative Strength Modulates Nucleus Accumbens, But Not Orbitofrontal Cortex Neuronal Ensemble Excitability.

PubMed

Ziminski, Joseph J; Hessler, Sabine; Margetts-Smith, Gabriella; Sieburg, Meike C; Crombag, Hans S; Koya, Eisuke

2017-03-22

Cues that predict the availability of food rewards influence motivational states and elicit food-seeking behaviors. If a cue no longer predicts food availability, then animals may adapt accordingly by inhibiting food-seeking responses. Sparsely activated sets of neurons, coined "neuronal ensembles," have been shown to encode the strength of reward-cue associations. Although alterations in intrinsic excitability have been shown to underlie many learning and memory processes, little is known about these properties specifically on cue-activated neuronal ensembles. We examined the activation patterns of cue-activated orbitofrontal cortex (OFC) and nucleus accumbens (NAc) shell ensembles using wild-type and Fos-GFP mice, which express green fluorescent protein (GFP) in activated neurons, after appetitive conditioning with sucrose and extinction learning. We also investigated the neuronal excitability of recently activated, GFP+ neurons in these brain areas using whole-cell electrophysiology in brain slices. Exposure to a sucrose cue elicited activation of neurons in both the NAc shell and OFC. In the NAc shell, but not the OFC, these activated GFP+ neurons were more excitable than surrounding GFP- neurons. After extinction, the number of neurons activated in both areas was reduced and activated ensembles in neither area exhibited altered excitability. These data suggest that learning-induced alterations in the intrinsic excitability of neuronal ensembles is regulated dynamically across different brain areas. Furthermore, we show that changes in associative strength modulate the excitability profile of activated ensembles in the NAc shell. SIGNIFICANCE STATEMENT Sparsely distributed sets of neurons called "neuronal ensembles" encode learned associations about food and cues predictive of its availability. Widespread changes in neuronal excitability have been observed in limbic brain areas after associative learning, but little is known about the excitability changes that occur specifically on neuronal ensembles that encode appetitive associations. Here, we reveal that sucrose cue exposure recruited a more excitable ensemble in the nucleus accumbens, but not orbitofrontal cortex, compared with their surrounding neurons. This excitability difference was not observed when the cue's salience was diminished after extinction learning. These novel data provide evidence that the intrinsic excitability of appetitive memory-encoding ensembles is regulated differentially across brain areas and adapts dynamically to changes in associative strength. Copyright © 2017 the authors 0270-6474/17/373160-11$15.00/0.

The protein expression landscape of the Arabidopsis root

PubMed Central

Petricka, Jalean J.; Schauer, Monica A.; Megraw, Molly; Breakfield, Natalie W.; Thompson, J. Will; Georgiev, Stoyan; Soderblom, Erik J.; Ohler, Uwe; Moseley, Martin Arthur; Grossniklaus, Ueli; Benfey, Philip N.

2012-01-01

Because proteins are the major functional components of cells, knowledge of their cellular localization is crucial to gaining an understanding of the biology of multicellular organisms. We have generated a protein expression map of the Arabidopsis root providing the identity and cell type-specific localization of nearly 2,000 proteins. Grouping proteins into functional categories revealed unique cellular functions and identified cell type-specific biomarkers. Cellular colocalization provided support for numerous protein–protein interactions. With a binary comparison, we found that RNA and protein expression profiles are weakly correlated. We then performed peak integration at cell type-specific resolution and found an improved correlation with transcriptome data using continuous values. We performed GeLC-MS/MS (in-gel tryptic digestion followed by liquid chromatography-tandem mass spectrometry) proteomic experiments on mutants with ectopic and no root hairs, providing complementary proteomic data. Finally, among our root hair-specific proteins we identified two unique regulators of root hair development. PMID:22447775

A structured sparse regression method for estimating isoform expression level from multi-sample RNA-seq data.

PubMed

Zhang, L; Liu, X J

2016-06-03

With the rapid development of next-generation high-throughput sequencing technology, RNA-seq has become a standard and important technique for transcriptome analysis. For multi-sample RNA-seq data, the existing expression estimation methods usually deal with each single-RNA-seq sample, and ignore that the read distributions are consistent across multiple samples. In the current study, we propose a structured sparse regression method, SSRSeq, to estimate isoform expression using multi-sample RNA-seq data. SSRSeq uses a non-parameter model to capture the general tendency of non-uniformity read distribution for all genes across multiple samples. Additionally, our method adds a structured sparse regularization, which not only incorporates the sparse specificity between a gene and its corresponding isoform expression levels, but also reduces the effects of noisy reads, especially for lowly expressed genes and isoforms. Four real datasets were used to evaluate our method on isoform expression estimation. Compared with other popular methods, SSRSeq reduced the variance between multiple samples, and produced more accurate isoform expression estimations, and thus more meaningful biological interpretations.

Perceptually controlled doping for audio source separation

NASA Astrophysics Data System (ADS)

Mahé, Gaël; Nadalin, Everton Z.; Suyama, Ricardo; Romano, João MT

2014-12-01

The separation of an underdetermined audio mixture can be performed through sparse component analysis (SCA) that relies however on the strong hypothesis that source signals are sparse in some domain. To overcome this difficulty in the case where the original sources are available before the mixing process, the informed source separation (ISS) embeds in the mixture a watermark, which information can help a further separation. Though powerful, this technique is generally specific to a particular mixing setup and may be compromised by an additional bitrate compression stage. Thus, instead of watermarking, we propose a `doping' method that makes the time-frequency representation of each source more sparse, while preserving its audio quality. This method is based on an iterative decrease of the distance between the distribution of the signal and a target sparse distribution, under a perceptual constraint. We aim to show that the proposed approach is robust to audio coding and that the use of the sparsified signals improves the source separation, in comparison with the original sources. In this work, the analysis is made only in instantaneous mixtures and focused on voice sources.

Two-dimensional sparse wavenumber recovery for guided wavefields

NASA Astrophysics Data System (ADS)

Sabeti, Soroosh; Harley, Joel B.

2018-04-01

The multi-modal and dispersive behavior of guided waves is often characterized by their dispersion curves, which describe their frequency-wavenumber behavior. In prior work, compressive sensing based techniques, such as sparse wavenumber analysis (SWA), have been capable of recovering dispersion curves from limited data samples. A major limitation of SWA, however, is the assumption that the structure is isotropic. As a result, SWA fails when applied to composites and other anisotropic structures. There have been efforts to address this issue in the literature, but they either are not easily generalizable or do not sufficiently express the data. In this paper, we enhance the existing approaches by employing a two-dimensional wavenumber model to account for direction-dependent velocities in anisotropic media. We integrate this model with tools from compressive sensing to reconstruct a wavefield from incomplete data. Specifically, we create a modified two-dimensional orthogonal matching pursuit algorithm that takes an undersampled wavefield image, with specified unknown elements, and determines its sparse wavenumber characteristics. We then recover the entire wavefield from the sparse representations obtained with our small number of data samples.

On-Chip Neural Data Compression Based On Compressed Sensing With Sparse Sensing Matrices.

PubMed

Zhao, Wenfeng; Sun, Biao; Wu, Tong; Yang, Zhi

2018-02-01

On-chip neural data compression is an enabling technique for wireless neural interfaces that suffer from insufficient bandwidth and power budgets to transmit the raw data. The data compression algorithm and its implementation should be power and area efficient and functionally reliable over different datasets. Compressed sensing is an emerging technique that has been applied to compress various neurophysiological data. However, the state-of-the-art compressed sensing (CS) encoders leverage random but dense binary measurement matrices, which incur substantial implementation costs on both power and area that could offset the benefits from the reduced wireless data rate. In this paper, we propose two CS encoder designs based on sparse measurement matrices that could lead to efficient hardware implementation. Specifically, two different approaches for the construction of sparse measurement matrices, i.e., the deterministic quasi-cyclic array code (QCAC) matrix and -sparse random binary matrix [-SRBM] are exploited. We demonstrate that the proposed CS encoders lead to comparable recovery performance. And efficient VLSI architecture designs are proposed for QCAC-CS and -SRBM encoders with reduced area and total power consumption.

SPReM: Sparse Projection Regression Model For High-dimensional Linear Regression *

PubMed Central

Sun, Qiang; Zhu, Hongtu; Liu, Yufeng; Ibrahim, Joseph G.

2014-01-01

The aim of this paper is to develop a sparse projection regression modeling (SPReM) framework to perform multivariate regression modeling with a large number of responses and a multivariate covariate of interest. We propose two novel heritability ratios to simultaneously perform dimension reduction, response selection, estimation, and testing, while explicitly accounting for correlations among multivariate responses. Our SPReM is devised to specifically address the low statistical power issue of many standard statistical approaches, such as the Hotelling’s T2 test statistic or a mass univariate analysis, for high-dimensional data. We formulate the estimation problem of SPREM as a novel sparse unit rank projection (SURP) problem and propose a fast optimization algorithm for SURP. Furthermore, we extend SURP to the sparse multi-rank projection (SMURP) by adopting a sequential SURP approximation. Theoretically, we have systematically investigated the convergence properties of SURP and the convergence rate of SURP estimates. Our simulation results and real data analysis have shown that SPReM out-performs other state-of-the-art methods. PMID:26527844

Beyond generalized hair cells: Molecular cues for hair cell types

PubMed Central

Jahan, Israt; Pan, Ning; Kersigo, Jennifer; Fritzsch, Bernd

2012-01-01

Basic helix-loop-helix (bHLH) transcription factors (TFs) are crucial for inner ear neurosensory development. The proneural TF Atoh1 regulates the differentiation of hair cells (HCs) whereas Neurog1 and Neurod1 regulate specification and differentiation of neurons, respectively, but also affect HC development. Expression of Delta and Jagged ligands in nascent HCs and Notch receptors in supporting cells induce supporting cell differentiation through the regulation of neurogenic bHLH TFs (such as Hes1, Hes5) and suppression of limited Atoh1 expression. In sensorineural hearing loss, HCs are lost followed by supporting cells and progressive degeneration of neurons, at least in rodents. Regaining complete hearing may require reconstituting the organ of Corti (OC) from scratch, including the two types of HCs, inner (IHC) and outer (OHC) hair cells with the precise sorting of two types of afferent (type I and II) and efferent (lateral, LOC and medial, MOC olivo-cochlear) innervation. We review effects of bHLH TF dosage and their cross-regulation to differentiate HC types in the OC. We categorize findings of specific gene expressions in HCs: 1. as markers without meaning for the regeneration task, 2. as stabilizers who are needed to maintain or complete differentiation, and 3. as decision making genes, expressed and acting early enough to be useful in this process. Only one TF has been characterized that fits the last aspect: Atoh1. We propose that temporal and intensity variations of Atoh1 are naturally modulated to differentiate specific types of HCs. Importantly, the molecular means to modify the Atoh1 expression are at least partially understood and can be readily implemented in the attempts to regenerate specific types of HCs. PMID:23201032

[Polyamines and cell growth: specific aspects in Amoeba proteus and in certain cancer cell lines].

PubMed

Dubois, J; Schenkel, E; Hanocq, M

1995-01-01

The differences between the metabolic schemes of polyamines can be the starting point to investigate the discovery of new antiparasitic or anticancer drugs which would be cell type specific. The studies, which were undertaken with the P388 cancer cells and Amoeba proteus, have shown that the pool of polyamine was very different in both cell types. Moreover, the cytotoxicity of putrescine, spermidine, spermine and 1-3 diaminopropane was found to be dependent of the activity of cell enzymes which could play a role to control cell proliferation by producing toxic metabolites.

Differentiation of human umbilical cord mesenchymal stem cells into dermal fibroblasts in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Yanfu; Chai, Jiake, E-mail: cjk304@126.com; Sun, Tianjun

2011-10-07

Highlights: {yields} Mesenchymal stem cells (MSCs) are potential seed cells for tissue-engineered skin. {yields} Tissue-derived umbilical cord MSCs (UCMSCs) can readily be isolated in vitro. {yields} We induce UCMSCs to differentiate into dermal fibroblasts via conditioned medium. {yields} Collagen type I and collagen type III mRNA level was higher in differentiated cells. {yields} UCMSCs-derived fibroblast-like cells strongly express fibroblast-specific protein. -- Abstract: Tissue-derived umbilical cord mesenchymal stem cells (UCMSCs) can be readily obtained, avoid ethical or moral constraints, and show excellent pluripotency and proliferation potential. UCMSCs are considered to be a promising source of stem cells in regenerative medicine. Inmore » this study, we collected newborn umbilical cord tissue under sterile conditions and isolated UCMSCs through a tissue attachment method. UCMSC cell surface markers were examined using flow cytometry. On the third passage, UCMSCs were induced to differentiate into dermal fibroblasts in conditioned induction media. The induction results were detected using immunofluorescence with a fibroblast-specific monoclonal antibody and real time PCR for type I and type III collagen. UCMSCs exhibited a fibroblast-like morphology and reached 90% confluency 14 to 18 days after primary culture. Cultured UCMSCs showed strong positive staining for CD73, CD29, CD44, CD105, and HLA-I, but not CD34, CD45, CD31, or HLA-DR. After differentiation, immunostaining for collagen type I, type III, fibroblast-specific protein, vimentin, and desmin were all strongly positive in induced cells, and staining was weak or negative in non-induced cells; total transcript production of collagen type I and collagen type III mRNA was higher in induced cells than in non-induced cells. These results demonstrate that UCMSCs can be induced to differentiate into fibroblasts with conditioned induction media and, in turn, could be used as seed cells for tissue-engineered dermis.« less

Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

PubMed Central

Garg, Abhishek D.; De Ruysscher, Dirk; Agostinis, Patrizia

2016-01-01

ABSTRACT The emerging role of the cancer cell-immune cell interface in shaping tumorigenesis/anticancer immunotherapy has increased the need to identify prognostic biomarkers. Henceforth, our primary aim was to identify the immunogenic cell death (ICD)-derived metagene signatures in breast, lung and ovarian cancer that associate with improved patient survival. To this end, we analyzed the prognostic impact of differential gene-expression of 33 pre-clinically-validated ICD-parameters through a large-scale meta-analysis involving 3,983 patients (‘discovery’ dataset) across lung (1,432), breast (1,115) and ovarian (1,436) malignancies. The main results were also substantiated in ‘validation’ datasets consisting of 818 patients of same cancer-types (i.e. 285 breast/274 lung/259 ovarian). The ICD-associated parameters exhibited a highly-clustered and largely cancer type-specific prognostic impact. Interestingly, we delineated ICD-derived consensus-metagene signatures that exhibited a positive prognostic impact that was either cancer type-independent or specific. Importantly, most of these ICD-derived consensus-metagenes (acted as attractor-metagenes and thereby) ‘attracted’ highly co-expressing sets of genes or convergent-metagenes. These convergent-metagenes also exhibited positive prognostic impact in respective cancer types. Remarkably, we found that the cancer type-independent consensus-metagene acted as an ‘attractor’ for cancer-specific convergent-metagenes. This reaffirms that the immunological prognostic landscape of cancer tends to segregate between cancer-independent and cancer-type specific gene signatures. Moreover, this prognostic landscape was largely dominated by the classical T cell activity/infiltration/function-related biomarkers. Interestingly, each cancer type tended to associate with biomarkers representing a specific T cell activity or function rather than pan-T cell biomarkers. Thus, our analysis confirms that ICD can serve as a platform for discovery of novel prognostic metagenes. PMID:27057433

Who actually receives cell phone use while driving citations and how much are these laws enforced among states? A descriptive, cross-sectional study.

PubMed

Rudisill, Toni M; Zhu, Motao

2016-06-14

While numerous cell phone use while driving laws have been passed among states, little information exists regarding who gets cited for these traffic infractions and how much these laws are enforced at the state-level within the USA. Cross-sectional, descriptive study. 14 states and the District of Columbia. Those receiving cell phone use while driving citations within included states from 2007 to 2013. Demographic characteristics of cited drivers were assessed. Rates of infractions per 100 000 licensed in-state drivers per year for various cell phone use while driving violations were calculated. Drivers were cited for hand-held use violations (n=2.5 million) more than texting (n=14 682) or young driver all cell phone bans (n=342). Among states that provided data for all traffic violations, cell phone use while driving citations comprised 1% of all written citations. Regardless of ban type, males (68.2%) were cited more frequently than females. Drivers 25-64 years of age (90.8%) were more likely to be cited for hand-held phone use. The average yearly rate of infractions per 100 000 licensed in-state drivers from 2010-2013 was 5.8 for texting bans, 2607 for hand-held bans, and 9954 for any traffic violation. Among cited drivers, age and sex differences existed by the type of ban violated. State-level enforcement appeared sparse. Due to the potential serious consequences of cell phone use while driving in the USA, more enforcement and targeted public safety campaigns are likely needed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Who actually receives cell phone use while driving citations and how much are these laws enforced among states? A descriptive, cross-sectional study

PubMed Central

Rudisill, Toni M; Zhu, Motao

2016-01-01

Objectives While numerous cell phone use while driving laws have been passed among states, little information exists regarding who gets cited for these traffic infractions and how much these laws are enforced at the state-level within the USA. Design Cross-sectional, descriptive study. Setting 14 states and the District of Columbia. Participants Those receiving cell phone use while driving citations within included states from 2007 to 2013. Primary outcome Demographic characteristics of cited drivers were assessed. Rates of infractions per 100 000 licensed in-state drivers per year for various cell phone use while driving violations were calculated. Results Drivers were cited for hand-held use violations (n=2.5 million) more than texting (n=14 682) or young driver all cell phone bans (n=342). Among states that provided data for all traffic violations, cell phone use while driving citations comprised 1% of all written citations. Regardless of ban type, males (68.2%) were cited more frequently than females. Drivers 25–64 years of age (90.8%) were more likely to be cited for hand-held phone use. The average yearly rate of infractions per 100 000 licensed in-state drivers from 2010–2013 was 5.8 for texting bans, 2607 for hand-held bans, and 9954 for any traffic violation. Conclusions Among cited drivers, age and sex differences existed by the type of ban violated. State-level enforcement appeared sparse. Due to the potential serious consequences of cell phone use while driving in the USA, more enforcement and targeted public safety campaigns are likely needed. PMID:27301485

Differential co-localization with choline acetyltransferase in nervus terminalis suggests functional differences for GnRH isoforms in bonnethead sharks (Sphyrna tiburo)

PubMed Central

Moeller, John F.; Meredith, Michael

2010-01-01

The nervus terminalis (NT) is a vertebrate cranial nerve whose function in adults is unknown. In bonnethead sharks the nerve is anatomically independent of the olfactory system, with two major cell populations within one or more ganglia along its exposed length. Most cells are immunoreactive for either gonadotropin-releasing hormone (GnRH) or RFamide-like peptides. To define further the cell populations and connectivity, we used double-label immuno-cytochemistry with antisera to different isoforms of GnRH and to choline acetyltransferase (ChAT). The labeling patterns of two GnRH antisera revealed different populations of GnRH immunoreactive (ir) cell-profiles in the NT ganglion. One antiserum labeled a large group of cells and fibers, which likely contain mammalian GnRH (GnRH-I) as described in previous studies, and which were ChAT immunoreactive. The other antiserum labeled large club-like structures, which were anuclear, and a sparse number of fibers, but with no clear labeling of cell bodies in the ganglion. These club structures were choline acetyltrasferase (ChAT) negative, and preabsorption control tests suggest they may contain chicken-GnRH-II (GnRH-II) or dogfish GnRH. The second major NT ganglion cell-type was immunoreactive for RF-amides, which regulate GnRH release in other vertebrates, and may provide an intraganglionic influence on GnRH release. The immunocytochemical and anatomical differences between the two GnRH immunoreactive profile types indicate possible functional differences for these isoforms in the NT. The club-like structures may be sites of GnRH release into the general circulation since these structures were observed near blood vessels and resembled structures seen in the median eminence of rats. PMID:20950589

Differential co-localization with choline acetyltransferase in nervus terminalis suggests functional differences for GnRH isoforms in bonnethead sharks (Sphyrna tiburo).

PubMed

Moeller, John F; Meredith, Michael

2010-12-17

The nervus terminalis (NT) is a vertebrate cranial nerve whose function in adults is unknown. In bonnethead sharks, the nerve is anatomically independent of the olfactory system, with two major cell populations within one or more ganglia along its exposed length. Most cells are immunoreactive for either gonadotropin-releasing hormone (GnRH) or RF-amide-like peptides. To define further the cell populations and connectivity, we used double-label immunocytochemistry with antisera to different isoforms of GnRH and to choline acetyltransferase (ChAT). The labeling patterns of two GnRH antisera revealed different populations of GnRH-immunoreactive (ir) cell profiles in the NT ganglion. One antiserum labeled a large group of cells and fibers, which likely contain mammalian GnRH (GnRH-I) as described in previous studies and which were ChAT immunoreactive. The other antiserum labeled large club-like structures, which were anuclear, and a sparse number of fibers, but with no clear labeling of cell bodies in the ganglion. These club structures were choline acetyltrasferase (ChAT)-negative, and preabsorption control tests suggest they may contain chicken-GnRH-II (GnRH-II) or dogfish GnRH. The second major NT ganglion cell-type was immunoreactive for RF-amides, which regulate GnRH release in other vertebrates, and may provide an intraganglionic influence on GnRH release. The immunocytochemical and anatomical differences between the two GnRH-immunoreactive profile types indicate possible functional differences for these isoforms in the NT. The club-like structures may be sites of GnRH release into the general circulation since these structures were observed near blood vessels and resembled structures seen in the median eminence of rats. Copyright © 2010 Elsevier B.V. All rights reserved.

IFNγ Signaling Endows DCs with the Capacity to Control Type I Inflammation during Parasitic Infection through Promoting T-bet+ Regulatory T Cells

PubMed Central

Lee, Hyang-Mi; Fleige, Anne; Forman, Ruth; Cho, Sunglim; Khan, Aly Azeem; Lin, Ling-Li; Nguyen, Duc T.; O'Hara-Hall, Aisling; Yin, Zhinan; Hunter, Christopher A.; Muller, Werner; Lu, Li-Fan

2015-01-01

IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population. PMID:25658840

Properties of Cells Carrying the Herpes Simplex Virus Type 2 Thymidine Kinase Gene: Mechanisms of Reversion to a Thymidine Kinase-Negative Phenotype

PubMed Central

Bastow, K. F.; Darby, G.; Wildy, P.; Minson, A. C.

1980-01-01

We have isolated cells with a thymidine kinase-negative (tk−) phenotype from cells which carry the herpes simplex virus type 2 tk gene by selection in 5-bromodeoxyuridine or 9-(2-hydroxyethoxymethyl)guanine. Both selection routines generated revertants with a frequency of 10−3 to 10−4, and resistance to either compound conferred simultaneous resistance to the other. tk− revertants fell into three classes: (i) cells that arose by deletion of all virus sequences, (ii) cells that had lost the virus tk gene but retained a nonselected virus-specific function and arose by deletion of part of the virus-specific sequence, and (iii) cells that retained the potential to express all of the virus-specific functions of the parental cells and retained all of the virus-specific DNA sequences. Images PMID:16789205

Terminal sialic acid linkages determine different cell infectivities of human parainfluenza virus type 1 and type 3.

PubMed

Fukushima, Keijo; Takahashi, Tadanobu; Ito, Seigo; Takaguchi, Masahiro; Takano, Maiko; Kurebayashi, Yuuki; Oishi, Kenta; Minami, Akira; Kato, Tatsuya; Park, Enoch Y; Nishimura, Hidekazu; Takimoto, Toru; Suzuki, Takashi

2014-09-01

Human parainfluenza virus type 1 (hPIV1) and type 3 (hPIV3) initiate infection by sialic acid binding. Here, we investigated sialic acid linkage specificities for binding and infection of hPIV1 and hPIV3 by using sialic acid linkage-modified cells treated with sialidases or sialyltransferases. The hPIV1 is bound to only α2,3-linked sialic acid residues, whereas hPIV3 is bound to α2,6-linked sialic acid residues in addition to α2,3-linked sialic acid residues in human red blood cells. α2,3 linkage-specific sialidase treatment of LLC-MK2 cells and A549 cells decreased the infectivity of hPIV1 but not that of hPIV3. Treatment of A549 cells with α2,3 linkage-specific sialyltransferase increased infectivities of both hPIV1 and hPIV3, whereas α2,6 linkage-specific sialyltransferase treatment increased only hPIV3 infectivity. Clinical isolates also showed similar sialic acid linkage specificities. We concluded that hPIV1 utilizes only α2,3 sialic acid linkages and that hPIV3 makes use of α2,6 sialic acid linkages in addition to α2,3 sialic acid linkages as viral receptors. Copyright © 2014. Published by Elsevier Inc.

Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.

PubMed

Coetzee, Simon G; Shen, Howard C; Hazelett, Dennis J; Lawrenson, Kate; Kuchenbaecker, Karoline; Tyrer, Jonathan; Rhie, Suhn K; Levanon, Keren; Karst, Alison; Drapkin, Ronny; Ramus, Susan J; Couch, Fergus J; Offit, Kenneth; Chenevix-Trench, Georgia; Monteiro, Alvaro N A; Antoniou, Antonis; Freedman, Matthew; Coetzee, Gerhard A; Pharoah, Paul D P; Noushmehr, Houtan; Gayther, Simon A

2015-07-01

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Isolation of major pancreatic cell types and long-term culture-initiating cells using novel human surface markers.

PubMed

Dorrell, Craig; Abraham, Stephanie L; Lanxon-Cookson, Kelsea M; Canaday, Pamela S; Streeter, Philip R; Grompe, Markus

2008-09-01

We have developed a novel panel of cell-surface markers for the isolation and study of all major cell types of the human pancreas. Hybridomas were selected after subtractive immunization of Balb/C mice with intact or dissociated human islets and assessed for cell-type specificity and cell-surface reactivity by immunohistochemistry and flow cytometry. Antibodies were identified by specific binding of surface antigens on islet (panendocrine or alpha-specific) and nonislet pancreatic cell subsets (exocrine and duct). These antibodies were used individually or in combination to isolate populations of alpha, beta, exocrine, or duct cells from primary human pancreas by FACS and to characterize the detailed cell composition of human islet preparations. They were also employed to show that human islet expansion cultures originated from nonendocrine cells and that insulin expression levels could be increased to up to 1% of normal islet cells by subpopulation sorting and overexpression of the transcription factors Pdx-1 and ngn3, an improvement over previous results with this culture system. These methods permit the analysis and isolation of functionally distinct pancreatic cell populations with potential for cell therapy.

SARS-CoV replicates in primary human alveolar type II cell cultures but not in type I-like cells

PubMed Central

Mossel, Eric C.; Wang, Jieru; Jeffers, Scott; Edeen, Karen E.; Wang, Shuanglin; Cosgrove, Gregory P.; Funk, C. Joel; Manzer, Rizwan; Miura, Tanya A.; Pearson, Leonard D.; Holmes, Kathryn V.; Mason, Robert J.

2008-01-01

Severe acute respiratory syndrome (SARS) is a disease characterized by diffuse alveolar damage. We isolated alveolar type II cells and maintained them in a highly differentiated state. Type II cell cultures supported SARS-CoV replication as evidenced by RT-PCR detection of viral subgenomic RNA and an increase in virus titer. Virus titers were maximal by 24 hours and peaked at approximately 105 pfu/mL. Two cell types within the cultures were infected. One cell type was type II cells, which were positive for SP-A, SP-C, cytokeratin, a type II cell-specific monoclonal antibody, and Ep-CAM. The other cell type was composed of spindle-shaped cells that were positive for vimentin and collagen III and likely fibroblasts. Viral replication was not detected in type I-like cells or macrophages. Hence, differentiated adult human alveolar type II cells were infectible but alveolar type I-like cells and alveolar macrophages did not support productive infection. PMID:18022664

Subcellular distribution of glutathione and its dynamic changes under oxidative stress in the yeast Saccharomyces cerevisiae

PubMed Central

Zechmann, Bernd; Liou, Liang-Chun; Koffler, Barbara E; Horvat, Lucija; Tomašić, Ana; Fulgosi, Hrvoje; Zhang, Zhaojie

2011-01-01

Glutathione is an important antioxidant in most prokaryotes and eukaryotes. It detoxifies reactive oxygen species and is also involved in the modulation of gene expression, in redox signaling, and in the regulation of enzymatic activities. In this study, the subcellular distribution of glutathione was studied in Saccharomyces cerevisiae by quantitative immunoelectron microscopy. Highest glutathione contents were detected in mitochondria and subsequently in the cytosol, nuclei, cell walls, and vacuoles. The induction of oxidative stress by hydrogen peroxide (H2O2) led to changes in glutathione-specific labeling. Three cell types were identified. Cell types I and II contained more glutathione than control cells. Cell type II differed from cell type I in showing a decrease in glutathione-specific labeling solely in mitochondria. Cell type III contained much less glutathione contents than the control and showed the strongest decrease in mitochondria, suggesting that high and stable levels of glutathione in mitochondria are important for the protection and survival of the cells during oxidative stress. Additionally, large amounts of glutathione were relocated and stored in vacuoles in cell type III, suggesting the importance of the sequestration of glutathione in vacuoles under oxidative stress. PMID:22093747

Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and β-cell regeneration in mice.

PubMed

Criscimanna, Angela; Coudriet, Gina M; Gittes, George K; Piganelli, Jon D; Esni, Farzad

2014-11-01

Although the cells that contribute to pancreatic regeneration have been widely studied, little is known about the mediators of this process. During tissue regeneration, infiltrating macrophages debride the site of injury and coordinate the repair response. We investigated the role of macrophages in pancreatic regeneration in mice. We used a saporin-conjugated antibody against CD11b to reduce the number of macrophages in mice following diphtheria toxin receptor-mediated cell ablation of pancreatic cells, and evaluated the effects on pancreatic regeneration. We analyzed expression patterns of infiltrating macrophages after cell-specific injury or from the pancreas of nonobese diabetic mice. We developed an in vitro culture system to study the ability of macrophages to induce cell-specific regeneration. Depletion of macrophages impaired pancreatic regeneration. Macrophage polarization, as assessed by expression of tumor necrosis factor-α, interleukin 6, interleukin 10, and CD206, depended on the type of injury. The signals provided by polarized macrophages promoted lineage-specific generation of acinar or endocrine cells. Macrophage from nonobese diabetic mice failed to provide signals necessary for β-cell generation. Macrophages produce cell type-specific signals required for pancreatic regeneration in mice. Additional study of these processes and signals might lead to new approaches for treating type 1 diabetes or pancreatitis. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease.

PubMed

Kim, Juhyun; Hughes, Ethan G; Shetty, Ashwin S; Arlotta, Paola; Goff, Loyal A; Bergles, Dwight E; Brown, Solange P

2017-09-13

Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of hSOD1 G93A mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and in vivo calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS. SIGNIFICANCE STATEMENT It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase monotonically with disease progression. Moreover, although all neuronal cell types tested exhibited abnormal functional properties, analysis of their gene expression demonstrated cell type-specific responses to the ALS-causing mutation. These findings suggest that therapies for ALS may need to be tailored for different cell types and stages of disease. Copyright © 2017 the authors 0270-6474/17/379038-17$15.00/0.

Indexing amyloid peptide diffraction from serial femtosecond crystallography: new algorithms for sparse patterns

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brewster, Aaron S.; Sawaya, Michael R.; University of California, Los Angeles, CA 90095-1570

2015-02-01

Special methods are required to interpret sparse diffraction patterns collected from peptide crystals at X-ray free-electron lasers. Bragg spots can be indexed from composite-image powder rings, with crystal orientations then deduced from a very limited number of spot positions. Still diffraction patterns from peptide nanocrystals with small unit cells are challenging to index using conventional methods owing to the limited number of spots and the lack of crystal orientation information for individual images. New indexing algorithms have been developed as part of the Computational Crystallography Toolbox (cctbx) to overcome these challenges. Accurate unit-cell information derived from an aggregate data setmore » from thousands of diffraction patterns can be used to determine a crystal orientation matrix for individual images with as few as five reflections. These algorithms are potentially applicable not only to amyloid peptides but also to any set of diffraction patterns with sparse properties, such as low-resolution virus structures or high-throughput screening of still images captured by raster-scanning at synchrotron sources. As a proof of concept for this technique, successful integration of X-ray free-electron laser (XFEL) data to 2.5 Å resolution for the amyloid segment GNNQQNY from the Sup35 yeast prion is presented.« less

Regulation of epidermal cell fate in Arabidopsis roots: the importance of multiple feedback loops

PubMed Central

Schiefelbein, John; Huang, Ling; Zheng, Xiaohua

2014-01-01

The specification of distinct cell types in multicellular organisms is accomplished via establishment of differential gene expression. A major question is the nature of the mechanisms that establish this differential expression in time and space. In plants, the formation of the hair and non-hair cell types in the root epidermis has been used as a model to understand regulation of cell specification. Recent findings show surprising complexity in the number and the types of regulatory interactions between the multiple transcription factor genes/proteins influencing root epidermis cell fate. Here, we describe this regulatory network and the importance of the multiple feedback loops for its establishment and maintenance. PMID:24596575

Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo.

PubMed

Ulges, Alexander; Klein, Matthias; Reuter, Sebastian; Gerlitzki, Bastian; Hoffmann, Markus; Grebe, Nadine; Staudt, Valérie; Stergiou, Natascha; Bohn, Toszka; Brühl, Till-Julius; Muth, Sabine; Yurugi, Hajime; Rajalingam, Krishnaraj; Bellinghausen, Iris; Tuettenberg, Andrea; Hahn, Susanne; Reißig, Sonja; Haben, Irma; Zipp, Frauke; Waisman, Ari; Probst, Hans-Christian; Beilhack, Andreas; Buchou, Thierry; Filhol-Cochet, Odile; Boldyreff, Brigitte; Breloer, Minka; Jonuleit, Helmut; Schild, Hansjörg; Schmitt, Edgar; Bopp, Tobias

2015-03-01

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3(+) Treg cell subpopulation that was unable to control the maturation of IRF4(+)PD-L2(+) dendritic cells required for the development of TH2 responses in vivo.

Selective effect of irradiation on responses to thymus-independent antigen.

PubMed

Lee, S K; Woodland, R T

1985-02-01

Low doses of ionizing radiation have a selective immunosuppressive effect on in vivo B cell responses to thymus-independent (TI) antigens. The B cell response, assayed as direct anti-trinitrophenyl (TNP)-specific plaque-forming cells (PFC), induced by type 2, TI antigens (TNP-Ficoll or TNP-Dextran), was reduced, on the average, by 10-fold in animals exposed to 200 rad of ionizing radiation 24 hr before antigen challenge. In contrast, PFC responses to type 1, TI antigens (TNP-lipopolysaccharide or TNP-Brucella abortus) are unaffected in mice exposed to the same dose of radiation. Adoptive transfers showed that this selective immunosuppression is a result of the specific inactivation of the B cell subpopulation responding to type 2, TI antigens. These experiments suggest that physiologic differences exist in the B cell subpopulations of normal mice which respond to type 1, or type 2, TI antigens.

The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages.

PubMed

Guo, Jian-Kan; Shi, Hongmei; Koraishy, Farrukh; Marlier, Arnaud; Ding, Zhaowei; Shan, Alan; Cantley, Lloyd G

2013-11-01

Biomedical research often requires primary cultures of specific cell types, which are challenging to obtain at high purity in a reproducible manner. Here we engineered the murine Rosa26 locus by introducing the diphtheria toxin receptor flanked by loxP sites. The resultant strain was nicknamed the Terminator mouse. This approach results in diphtheria toxin-receptor expression in all non-Cre expressing cell types, making these cells susceptible to diphtheria toxin exposure. In primary cultures of kidney cells derived from the Terminator mouse, over 99.99% of cells were dead within 72 h of diphtheria toxin treatment. After crossing the Terminator with the podocin-Cre (podocyte specific) mouse or the Ggt-Cre (proximal tubule specific) mouse, diphtheria toxin treatment killed non-Cre expressing cells but spared podocytes and proximal tubule cells, respectively, enriching the primary cultures to over 99% purity, based on both western blotting and immunostaining of marker proteins. Thus, the Terminator mouse can be a useful tool to selectively and reproducibly obtain even low-abundant cell types at high quantity and purity.

Cell Context Dependent p53 Genome-Wide Binding Patterns and Enrichment at Repeats

DOE PAGES

Botcheva, Krassimira; McCorkle, Sean R.

2014-11-21

The p53 ability to elicit stress specific and cell type specific responses is well recognized, but how that specificity is established remains to be defined. Whether upon activation p53 binds to its genomic targets in a cell type and stress type dependent manner is still an open question. Here we show that the p53 binding to the human genome is selective and cell context-dependent. We mapped the genomic binding sites for the endogenous wild type p53 protein in the human cancer cell line HCT116 and compared them to those we previously determined in the normal cell line IMR90. We reportmore » distinct p53 genome-wide binding landscapes in two different cell lines, analyzed under the same treatment and experimental conditions, using the same ChIP-seq approach. This is evidence for cell context dependent p53 genomic binding. The observed differences affect the p53 binding sites distribution with respect to major genomic and epigenomic elements (promoter regions, CpG islands and repeats). We correlated the high-confidence p53 ChIP-seq peaks positions with the annotated human repeats (UCSC Human Genome Browser) and observed both common and cell line specific trends. In HCT116, the p53 binding was specifically enriched at LINE repeats, compared to IMR90 cells. The p53 genome-wide binding patterns in HCT116 and IMR90 likely reflect the different epigenetic landscapes in these two cell lines, resulting from cancer-associated changes (accumulated in HCT116) superimposed on tissue specific differences (HCT116 has epithelial, while IMR90 has mesenchymal origin). In conclusion, our data support the model for p53 binding to the human genome in a highly selective manner, mobilizing distinct sets of genes, contributing to distinct pathways.« less

Potential of mid IR spectroscopy in the rapid label free identification of skin malignancies

NASA Astrophysics Data System (ADS)

Kastl, Lena; Kemper, Björn; Lloyd, Gavin R.; Nallala, Jayakrupakar; Stone, Nick; Naranjo, Valery; Penaranda, Francisco; Schnekenburger, Jürgen

2016-03-01

The rapid inspection of suspicious skin lesions for pathological cell types is the objective of optical point of care diagnostics technologies. A marker free fast diagnosis of skin malignancies would overcome the limitations of the current gold standard surgical biopsy. The time consuming and costly biopsy procedure requires the inspection of each sample by a trained pathologist, which limits the analysis of potentially malignant lesions. Optical technologies like RAMAN or infrared spectroscopy, which provide both, localization and chemical information, can be used to differentiate malignant from healthy tissue by the analysis of multi cell structures and cell type specific spectra. We here report the application of midIR spectroscopy towards fast and reliable skin diagnostics. Within the European research project MINERVA we developed standardized in vitro skin systems with increasing complexity, from single skin cell types as fibroblasts, keratinocytes and melanoma cells, to mixtures of these and finally three dimensional human skin equivalents. The standards were characterized in the established midIR range and also with newly developed systems for fast imaging up to 12 μm. The analysis of the spectra by novel data processing algorithms demonstrated the clear separation of all cell types, especially the tumor cells. The signals from single cell layers were sufficient for cell type differentiation. We have compared different midIR systems and found all of them suitable for specific cell type identification. Our data demonstrate the potential of midIR spectroscopy for fast image acquisition and an improved data processing as sensitive and specific optical biopsy technology.

Sox5 Functions as a Fate Switch in Medaka Pigment Cell Development

PubMed Central

Nagao, Yusuke; Suzuki, Takao; Shimizu, Atsushi; Kimura, Tetsuaki; Seki, Ryoko; Adachi, Tomoko; Inoue, Chikako; Omae, Yoshihiro; Kamei, Yasuhiro; Hara, Ikuyo; Taniguchi, Yoshihito; Naruse, Kiyoshi; Wakamatsu, Yuko; Kelsh, Robert N.; Hibi, Masahiko; Hashimoto, Hisashi

2014-01-01

Mechanisms generating diverse cell types from multipotent progenitors are crucial for normal development. Neural crest cells (NCCs) are multipotent stem cells that give rise to numerous cell-types, including pigment cells. Medaka has four types of NCC-derived pigment cells (xanthophores, leucophores, melanophores and iridophores), making medaka pigment cell development an excellent model for studying the mechanisms controlling specification of distinct cell types from a multipotent progenitor. Medaka many leucophores-3 (ml-3) mutant embryos exhibit a unique phenotype characterized by excessive formation of leucophores and absence of xanthophores. We show that ml-3 encodes sox5, which is expressed in premigratory NCCs and differentiating xanthophores. Cell transplantation studies reveal a cell-autonomous role of sox5 in the xanthophore lineage. pax7a is expressed in NCCs and required for both xanthophore and leucophore lineages; we demonstrate that Sox5 functions downstream of Pax7a. We propose a model in which multipotent NCCs first give rise to pax7a-positive partially fate-restricted intermediate progenitors for xanthophores and leucophores; some of these progenitors then express sox5, and as a result of Sox5 action develop into xanthophores. Our results provide the first demonstration that Sox5 can function as a molecular switch driving specification of a specific cell-fate (xanthophore) from a partially-restricted, but still multipotent, progenitor (the shared xanthophore-leucophore progenitor). PMID:24699463

Multiplex polymerase chain reaction on FTA cards vs. flow cytometry for B-lymphocyte clonality.

PubMed

Dictor, Michael; Skogvall, Ingela; Warenholt, Janina; Rambech, Eva

2007-01-01

Two-colour flow cytometry was compared with multiplex PCR with capillary electrophoresis for clonality determination in specific categories of B-cell lymphoma. FTA cards were evaluated for preserving DNA from node imprints and expediting molecular analysis. A single-tube multiplex PCR targeted IGH and lymphoma-specific translocations in DNA extracted from 180 frozen lymphoid tissues and DNA bound to FTA cards from 192 fresh tissues and 137 aspirates. PCR results were compared with flow cytometry in the extracted and aspirated samples. Overall, single-tube multiplex PCR sensitivity was equivalent in the sample groups (intergroup range 79%-91%). False negatives were associated with tumour origin in the follicle centre. Multiplex PCR and flow cytometry were equally sensitive and together detected 98% of B-cell lymphomas. Additional two-tube targeting of IGK suggested an overall molecular sensitivity >90%. False positive (pseudoclonal) single-tube multiplex PCR was associated with necrosis and sparse lymphocytes. Multiplex PCR using template DNA bound to an FTA card effectively detects B-lymphocyte clonality, obviates DNA extraction and refrigeration, and can be used without diminished sensitivity in fine needle aspirates or node imprints as a replacement for or complement to flow cytometry at any point in the diagnostic work-up.

Jacalin and peanut agglutinin (PNA) bindings in the taste bud cells of the rat: new reliable markers for type IV cells of the rat taste buds.

PubMed

Taniguchi, Ryo; Shi, Lei; Fujii, Masae; Ueda, Katsura; Honma, Shiho; Wakisaka, Satoshi

2005-12-01

Lectin histochemistry of Jacalin (Artocarpus integrifolia) and peanut agglutinin (PNA), specific lectins for galactosyl (beta-1, 3) N-acetylgalactosamine (galactosyl (beta-1, 3) GalNAc), was applied to the gustatory epithelium of the adult rat. In the ordinary lingual epithelium, Jacalin and PNA labeled the cell membrane from the basal to granular cell layer. They also bound membranes of rounded-cells at the basal portion of taste buds, but the number of PNA labeled cells was smaller than that of Jacalin labeled cells. There was no apparent difference in the binding patterns of Jacalin and PNA among the taste buds of the lingual papillae and those of the palatal epithelium. Occasionally, a few spindle-shaped cells were labeled with Jacalin, but not with PNA. Double labeling of Jacalin and alpha-gustducin, a specific marker for type II cells, revealed that Jacalin-labeled spindle-shaped taste cells were immunonegative for alpha-gustducin. Spindle-shaped cells expressing protein gene product 9.5 (PGP 9.5) immunoreactivity lacked Jacalin labeling. During the development of taste buds in circumvallate papillae, the binding pattern of Jacalin became almost identical from postnatal day 5. The present results indicate that rounded cells at the basal portion of the taste buds cells (type IV cells) bind to Jacalin and PNA, and these lectins are specific markers for type IV cells of the rat taste cells.

Sparse models for correlative and integrative analysis of imaging and genetic data

PubMed Central

Lin, Dongdong; Cao, Hongbao; Calhoun, Vince D.

2014-01-01

The development of advanced medical imaging technologies and high-throughput genomic measurements has enhanced our ability to understand their interplay as well as their relationship with human behavior by integrating these two types of datasets. However, the high dimensionality and heterogeneity of these datasets presents a challenge to conventional statistical methods; there is a high demand for the development of both correlative and integrative analysis approaches. Here, we review our recent work on developing sparse representation based approaches to address this challenge. We show how sparse models are applied to the correlation and integration of imaging and genetic data for biomarker identification. We present examples on how these approaches are used for the detection of risk genes and classification of complex diseases such as schizophrenia. Finally, we discuss future directions on the integration of multiple imaging and genomic datasets including their interactions such as epistasis. PMID:25218561

A high-capacity model for one shot association learning in the brain

PubMed Central

Einarsson, Hafsteinn; Lengler, Johannes; Steger, Angelika

2014-01-01

We present a high-capacity model for one-shot association learning (hetero-associative memory) in sparse networks. We assume that basic patterns are pre-learned in networks and associations between two patterns are presented only once and have to be learned immediately. The model is a combination of an Amit-Fusi like network sparsely connected to a Willshaw type network. The learning procedure is palimpsest and comes from earlier work on one-shot pattern learning. However, in our setup we can enhance the capacity of the network by iterative retrieval. This yields a model for sparse brain-like networks in which populations of a few thousand neurons are capable of learning hundreds of associations even if they are presented only once. The analysis of the model is based on a novel result by Janson et al. on bootstrap percolation in random graphs. PMID:25426060

Analysis, tuning and comparison of two general sparse solvers for distributed memory computers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amestoy, P.R.; Duff, I.S.; L'Excellent, J.-Y.

2000-06-30

We describe the work performed in the context of a Franco-Berkeley funded project between NERSC-LBNL located in Berkeley (USA) and CERFACS-ENSEEIHT located in Toulouse (France). We discuss both the tuning and performance analysis of two distributed memory sparse solvers (superlu from Berkeley and mumps from Toulouse) on the 512 processor Cray T3E from NERSC (Lawrence Berkeley National Laboratory). This project gave us the opportunity to improve the algorithms and add new features to the codes. We then quite extensively analyze and compare the two approaches on a set of large problems from real applications. We further explain the main differencesmore » in the behavior of the approaches on artificial regular grid problems. As a conclusion to this activity report, we mention a set of parallel sparse solvers on which this type of study should be extended.« less

A high-capacity model for one shot association learning in the brain.

PubMed

Einarsson, Hafsteinn; Lengler, Johannes; Steger, Angelika

2014-01-01

We present a high-capacity model for one-shot association learning (hetero-associative memory) in sparse networks. We assume that basic patterns are pre-learned in networks and associations between two patterns are presented only once and have to be learned immediately. The model is a combination of an Amit-Fusi like network sparsely connected to a Willshaw type network. The learning procedure is palimpsest and comes from earlier work on one-shot pattern learning. However, in our setup we can enhance the capacity of the network by iterative retrieval. This yields a model for sparse brain-like networks in which populations of a few thousand neurons are capable of learning hundreds of associations even if they are presented only once. The analysis of the model is based on a novel result by Janson et al. on bootstrap percolation in random graphs.

Single-cell Hi-C for genome-wide detection of chromatin interactions that occur simultaneously in a single cell.

PubMed

Nagano, Takashi; Lubling, Yaniv; Yaffe, Eitan; Wingett, Steven W; Dean, Wendy; Tanay, Amos; Fraser, Peter

2015-12-01

Hi-C is a powerful method that provides pairwise information on genomic regions in spatial proximity in the nucleus. Hi-C requires millions of cells as input and, as genome organization varies from cell to cell, a limitation of Hi-C is that it only provides a population average of genome conformations. We developed single-cell Hi-C to create snapshots of thousands of chromatin interactions that occur simultaneously in a single cell. To adapt Hi-C to single-cell analysis, we modified the protocol to include in-nucleus ligation. This enables the isolation of single nuclei carrying Hi-C-ligated DNA into separate tubes, followed by reversal of cross-links, capture of biotinylated ligation junctions on streptavidin-coated magnetic beads and PCR amplification of single-cell Hi-C libraries. The entire laboratory protocol can be carried out in 1 week, and although we have demonstrated its use in mouse T helper (TH1) cells, it should be applicable to any cell type or species for which standard Hi-C has been successful. We also developed an analysis pipeline to filter noise and assess the quality of data sets in a few hours. Although the interactome maps produced by single-cell Hi-C are sparse, the data provide useful information to understand cellular variability in nuclear genome organization and chromosome structure. Standard wet and dry laboratory skills in molecular biology and computational analysis are required.

Human T-Cell Clones from Autoimmune Thyroid Glands: Specific Recognition of Autologous Thyroid Cells

NASA Astrophysics Data System (ADS)

Londei, Marco; Bottazzo, G. Franco; Feldmann, Marc

1985-04-01

The thyroid glands of patients with autoimmune diseases such as Graves' disease and certain forms of goiter contain infiltrating activated T lymphocytes and, unlike cells of normal glands, the epithelial follicular cells strongly express histocompatability antigens of the HLA-DR type. In a study of such autoimmune disorders, the infiltrating T cells from the thyroid glands of two patients with Graves' disease were cloned in mitogen-free interleukin-2 (T-cell growth factor). The clones were expanded and their specificity was tested. Three types of clones were found. One group, of T4 phenotype, specifically recognized autologous thyroid cells. Another, also of T4 phenotype, recognized autologous thyroid or blood cells and thus responded positively in the autologous mixed lymphocyte reaction. Other clones derived from cells that were activated in vivo were of no known specificity. These clones provide a model of a human autoimmune disease and their analysis should clarify mechanisms of pathogenesis and provide clues to abrogating these undesirable immune responses.

Improved specific energy Ni-H2 cell

NASA Astrophysics Data System (ADS)

Miller, L.

1985-07-01

Design optimization activities which have evolved and validated the necessary technology to produce Ni-H2 battery cells exhibiting a specific energy of 75-80 Whr/Kg (energy density approximately 73 Whr/L are summarized. Final design validation is currently underway with the production of battery cells for qualification and life testing. The INTELSAT type Ni-H2 battery cell design has been chosen for expository purposes. However, it should be recognized portions of the improved technology could be applied to the Air Force type Ni-H2 battery cell design with equal benefit.

Improved Specific Energy Ni-h2 Cell

NASA Technical Reports Server (NTRS)

Miller, L.

1985-01-01

Design optimization activities which have evolved and validated the necessary technology to produce Ni-H2 battery cells exhibiting a specific energy of 75-80 Whr/Kg (energy density approximately 73 Whr/L are summarized. Final design validation is currently underway with the production of battery cells for qualification and life testing. The INTELSAT type Ni-H2 battery cell design has been chosen for expository purposes. However, it should be recognized portions of the improved technology could be applied to the Air Force type Ni-H2 battery cell design with equal benefit.

The MYB23 Gene Provides a Positive Feedback Loop for Cell Fate Specification in the Arabidopsis Root Epidermis[C][W

PubMed Central

Kang, Yeon Hee; Kirik, Victor; Hulskamp, Martin; Nam, Kyoung Hee; Hagely, Katherine; Lee, Myeong Min; Schiefelbein, John

2009-01-01

The specification of cell fates during development requires precise regulatory mechanisms to ensure robust cell type patterns. Theoretical models of pattern formation suggest that a combination of negative and positive feedback mechanisms are necessary for efficient specification of distinct fates in a field of differentiating cells. Here, we examine the role of the R2R3-MYB transcription factor gene, AtMYB23 (MYB23), in the establishment of the root epidermal cell type pattern in Arabidopsis thaliana. MYB23 is closely related to, and is positively regulated by, the WEREWOLF (WER) MYB gene during root epidermis development. Furthermore, MYB23 is able to substitute for the function of WER and to induce its own expression when controlled by WER regulatory sequences. We also show that the MYB23 protein binds to its own promoter, suggesting a MYB23 positive feedback loop. The localization of MYB23 transcripts and MYB23-green fluorescent protein (GFP) fusion protein, as well as the effect of a chimeric MYB23-SRDX repressor construct, links MYB23 function to the developing non-hair cell type. Using mutational analyses, we find that MYB23 is necessary for precise establishment of the root epidermal pattern, particularly under conditions that compromise the cell specification process. These results suggest that MYB23 participates in a positive feedback loop to reinforce cell fate decisions and ensure robust establishment of the cell type pattern in the Arabidopsis root epidermis. PMID:19395683

The MYB23 gene provides a positive feedback loop for cell fate specification in the Arabidopsis root epidermis.

PubMed

Kang, Yeon Hee; Kirik, Victor; Hulskamp, Martin; Nam, Kyoung Hee; Hagely, Katherine; Lee, Myeong Min; Schiefelbein, John

2009-04-01

The specification of cell fates during development requires precise regulatory mechanisms to ensure robust cell type patterns. Theoretical models of pattern formation suggest that a combination of negative and positive feedback mechanisms are necessary for efficient specification of distinct fates in a field of differentiating cells. Here, we examine the role of the R2R3-MYB transcription factor gene, AtMYB23 (MYB23), in the establishment of the root epidermal cell type pattern in Arabidopsis thaliana. MYB23 is closely related to, and is positively regulated by, the WEREWOLF (WER) MYB gene during root epidermis development. Furthermore, MYB23 is able to substitute for the function of WER and to induce its own expression when controlled by WER regulatory sequences. We also show that the MYB23 protein binds to its own promoter, suggesting a MYB23 positive feedback loop. The localization of MYB23 transcripts and MYB23-green fluorescent protein (GFP) fusion protein, as well as the effect of a chimeric MYB23-SRDX repressor construct, links MYB23 function to the developing non-hair cell type. Using mutational analyses, we find that MYB23 is necessary for precise establishment of the root epidermal pattern, particularly under conditions that compromise the cell specification process. These results suggest that MYB23 participates in a positive feedback loop to reinforce cell fate decisions and ensure robust establishment of the cell type pattern in the Arabidopsis root epidermis.

Strain-Specific Changes in Locomotor Behavior in Larval Zebrafish Elicited by Cholinergic Challenge

EPA Science Inventory

Some studies have compared the baseline behavior of different strains of larval zebrafish (Danio rerio), but there is sparse information on strain-specific responses to chemical challenges. The following study examines both the basal activity and response to a pharmacological cha...

Specific Accumulation of Tumor-Derived Adhesion Factor in Tumor Blood Vessels and in Capillary Tube-Like Structures of Cultured Vascular Endothelial Cells

NASA Astrophysics Data System (ADS)

Akaogi, Kotaro; Okabe, Yukie; Sato, Junji; Nagashima, Yoji; Yasumitsu, Hidetaro; Sugahara, Kazuyuki; Miyazaki, Kaoru

1996-08-01

Tumor-derived adhesion factor (TAF) was previously identified as a cell adhesion molecule secreted by human bladder carcinoma cell line EJ-1. To elucidate the physiological function of TAF, we examined its distribution in human normal and tumor tissues. Immunochemical staining with an anti-TAF monoclonal antibody showed that TAF was specifically accumulated in small blood vessels and capillaries within and adjacent to tumor nests, but not in those in normal tissues. Tumor blood vessel-specific staining of TAF was observed in various human cancers, such as esophagus, brain, lung, and stomach cancers. Double immunofluorescent staining showed apparent colocalization of TAF and type IV collagen in the vascular basement membrane. In vitro experiments demonstrated that TAF preferentially bound to type IV collagen among various extracellular matrix components tested. In cell culture experiments, TAF promoted adhesion of human umbilical vein endothelial cells to type IV collagen substrate and induced their morphological change. Furthermore, when the endothelial cells were induced to form capillary tube-like structures by type I collagen, TAF and type IV collagen were exclusively detected on the tubular structures. The capillary tube formation in vitro was prevented by heparin, which inhibited the binding of TAF to the endothelial cells. These results strongly suggest that TAF contributes to the organization of new capillary vessels in tumor tissues by modulating the interaction of endothelial cells with type IV collagen.

Cell-specific prediction and application of drug-induced gene expression profiles.

PubMed

Hodos, Rachel; Zhang, Ping; Lee, Hao-Chih; Duan, Qiaonan; Wang, Zichen; Clark, Neil R; Ma'ayan, Avi; Wang, Fei; Kidd, Brian; Hu, Jianying; Sontag, David; Dudley, Joel

2018-01-01

Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes.

Cell-specific prediction and application of drug-induced gene expression profiles

PubMed Central

Hodos, Rachel; Zhang, Ping; Lee, Hao-Chih; Duan, Qiaonan; Wang, Zichen; Clark, Neil R.; Ma'ayan, Avi; Wang, Fei; Kidd, Brian; Hu, Jianying; Sontag, David

2017-01-01

Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes. PMID:29218867

Subject-Specific Sparse Dictionary Learning for Atlas-Based Brain MRI Segmentation.

PubMed

Roy, Snehashis; He, Qing; Sweeney, Elizabeth; Carass, Aaron; Reich, Daniel S; Prince, Jerry L; Pham, Dzung L

2015-09-01

Quantitative measurements from segmentations of human brain magnetic resonance (MR) images provide important biomarkers for normal aging and disease progression. In this paper, we propose a patch-based tissue classification method from MR images that uses a sparse dictionary learning approach and atlas priors. Training data for the method consists of an atlas MR image, prior information maps depicting where different tissues are expected to be located, and a hard segmentation. Unlike most atlas-based classification methods that require deformable registration of the atlas priors to the subject, only affine registration is required between the subject and training atlas. A subject-specific patch dictionary is created by learning relevant patches from the atlas. Then the subject patches are modeled as sparse combinations of learned atlas patches leading to tissue memberships at each voxel. The combination of prior information in an example-based framework enables us to distinguish tissues having similar intensities but different spatial locations. We demonstrate the efficacy of the approach on the application of whole-brain tissue segmentation in subjects with healthy anatomy and normal pressure hydrocephalus, as well as lesion segmentation in multiple sclerosis patients. For each application, quantitative comparisons are made against publicly available state-of-the art approaches.

TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts.

PubMed

Bernstein, Diana L; Le Lay, John E; Ruano, Elena G; Kaestner, Klaus H

2015-05-01

Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator-like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics.

TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts

PubMed Central

Bernstein, Diana L.; Le Lay, John E.; Ruano, Elena G.; Kaestner, Klaus H.

2015-01-01

Current strategies to alter disease-associated epigenetic modifications target ubiquitously expressed epigenetic regulators. This approach does not allow specific genes to be controlled in specific cell types; therefore, tools to selectively target epigenetic modifications in the desired cell type and strategies to more efficiently correct aberrant gene expression in disease are needed. Here, we have developed a method for directing DNA methylation to specific gene loci by conjugating catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator–like effectors (TALEs). We demonstrated that these TALE-DNMTs direct DNA methylation specifically to the targeted gene locus in human cells. Further, we determined that minimizing direct nucleotide sequence repeats within the TALE moiety permits efficient lentivirus transduction, allowing easy targeting of primary cell types. Finally, we demonstrated that directed DNA methylation with a TALE-DNMT targeting the CDKN2A locus, which encodes the cyclin-dependent kinase inhibitor p16, decreased CDKN2A expression and increased replication of primary human fibroblasts, as intended. Moreover, overexpression of p16 in these cells reversed the proliferative phenotype, demonstrating the specificity of our epigenetic targeting. Together, our results demonstrate that TALE-DNMTs can selectively target specific genes and suggest that this strategy has potential application for the development of locus-specific epigenetic therapeutics. PMID:25866970

Clostridium perfringens Type E Virulence Traits Involved in Gut Colonization

PubMed Central

Redondo, Leandro M.; Carrasco, Juan M. Díaz; Redondo, Enzo A.; Delgado, Fernando; Miyakawa, Mariano E. Fernández

2015-01-01

Clostridium perfringens type E disease in ruminants has been characterized by hemorrhagic enteritis or sudden death. Although type E isolates are defined by the production of alpha and iota toxin, little is known about the pathogenesis of C. perfringens type E infections. Thus far, the role of iota toxin as a virulence factor is unknown. In this report, iota toxin showed positive effects on adherence and colonization of C. perfringens type E while having negative effect on the adherence of type A cells. In-vitro and in-vivo models suggest that toxinotype E would be particularly adapted to exploit the changes induced by iota toxin in the surface of epithelial cells. In addition, type E strains produce metabolites that affected the growth of potential intra-specific competitors. These results suggest that the alteration of the enterocyte morphology induced by iota toxin concomitantly with the specific increase of type E cell adhesion and the strong intra-specific growth inhibition of other strains could be competitive traits inherent to type E isolates that improve its fitness within the bovine gut environment. PMID:25799452

Immunity to herpes simplex virus type 2. Suppression of virus-induced immune responses in ultraviolet B-irradiated mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yasumoto, S.; Hayashi, Y.; Aurelian, L.

1987-10-15

Ultraviolet B irradiation (280 to 320 nm) of mice at the site of intradermal infection with herpes simplex virus type 2 increased the severity of the herpes simplex virus type 2 disease and decreased delayed-type hypersensitivity (DTH) responses to viral antigen. Decrease in DTH resulted from the induction of suppressor T cells, as evidenced by the ability of spleen cells from UV-irradiated mice to inhibit DTH and proliferative responses after adoptive transfer. Lymph node cells from UV-irradiated animals did not transfer suppression. DTH was suppressed at the induction but not the expression phase. Suppressor T cells were Lyt-1+, L3T4+, andmore » their activity was antigen-specific. However, after in vitro culture of spleen cells from UV-irradiated mice with herpes simplex virus type 2 antigen, suppressor activity was mediated by Lyt-2+ cells. Culture supernatants contained soluble nonantigen-specific suppressive factors.« less

Functional respiratory morphology in the newborn quokka wallaby (Setonix brachyurus)

PubMed Central

Makanya, A N; Tschanz, S A; Haenni, B; Burri, P H

2007-01-01

A morphological and morphometric study of the lung of the newborn quokka wallaby (Setonix brachyurus) was undertaken to assess its morphofunctional status at birth. Additionally, skin structure and morphometry were investigated to assess the possibility of cutaneous gas exchange. The lung was at canalicular stage and comprised a few conducting airways and a parenchyma of thick-walled tubules lined by stretches of cuboidal pneumocytes alternating with squamous epithelium, with occasional portions of thin blood–gas barrier. The tubules were separated by abundant intertubular mesenchyme, aggregations of developing capillaries and mesenchymal cells. Conversion of the cuboidal pneumocytes to type I cells occurred through cell broadening and lamellar body extrusion. Superfluous cuboidal cells were lost through apoptosis and subsequent clearance by alveolar macrophages. The establishment of the thin blood–gas barrier was established through apposition of the incipient capillaries to the formative thin squamous epithelium. The absolute volume of the lung was 0.02 ± 0.001 cm3 with an air space surface area of 4.85 ± 0.43 cm2. Differentiated type I pneumocytes covered 78% of the tubular surface, the rest 22% going to long stretches of type II cells, their precursors or low cuboidal transitory cells with sparse lamellar bodies. The body weight-related diffusion capacity was 2.52 ± 0.56 mL O2 min−1 kg−1. The epidermis was poorly developed, and measured 29.97 ± 4.88 µm in thickness, 13% of which was taken by a thin layer of stratum corneum, measuring 4.87 ± 0.98 µm thick. Superficial capillaries were closely associated with the epidermis, showing the possibility that the skin also participated in some gaseous exchange. Qualitatively, the neonate quokka lung had the basic constituents for gas exchange but was quantitatively inadequate, implying the significance of percutaneous gas exchange. PMID:17553103

Distinct roles of neuroepithelial-like and radial glia-like progenitor cells in cerebellar regeneration.

PubMed

Kaslin, Jan; Kroehne, Volker; Ganz, Julia; Hans, Stefan; Brand, Michael

2017-04-15

Zebrafish can regenerate after brain injury, and the regenerative process is driven by resident stem cells. Stem cells are heterogeneous in the vertebrate brain, but the significance of having heterogeneous stem cells in regeneration is not understood. Limited availability of specific stem cells might impair the regeneration of particular cell lineages. We studied regeneration of the adult zebrafish cerebellum, which contains two major stem and progenitor cell types: ventricular zone and neuroepithelial cells. Using conditional lineage tracing we demonstrate that cerebellar regeneration depends on the availability of specific stem cells. Radial glia-like cells are thought to be the predominant stem cell type in homeostasis and after injury. However, we find that radial glia-like cells play a minor role in adult cerebellar neurogenesis and in recovery after injury. Instead, we find that neuroepithelial cells are the predominant stem cell type supporting cerebellar regeneration after injury. Zebrafish are able to regenerate many, but not all, cell types in the cerebellum, which emphasizes the need to understand the contribution of different adult neural stem and progenitor cell subtypes in the vertebrate central nervous system. © 2017. Published by The Company of Biologists Ltd.

Folded concave penalized sparse linear regression: sparsity, statistical performance, and algorithmic theory for local solutions.

PubMed

Liu, Hongcheng; Yao, Tao; Li, Runze; Ye, Yinyu

2017-11-01

This paper concerns the folded concave penalized sparse linear regression (FCPSLR), a class of popular sparse recovery methods. Although FCPSLR yields desirable recovery performance when solved globally, computing a global solution is NP-complete. Despite some existing statistical performance analyses on local minimizers or on specific FCPSLR-based learning algorithms, it still remains open questions whether local solutions that are known to admit fully polynomial-time approximation schemes (FPTAS) may already be sufficient to ensure the statistical performance, and whether that statistical performance can be non-contingent on the specific designs of computing procedures. To address the questions, this paper presents the following threefold results: (i) Any local solution (stationary point) is a sparse estimator, under some conditions on the parameters of the folded concave penalties. (ii) Perhaps more importantly, any local solution satisfying a significant subspace second-order necessary condition (S 3 ONC), which is weaker than the second-order KKT condition, yields a bounded error in approximating the true parameter with high probability. In addition, if the minimal signal strength is sufficient, the S 3 ONC solution likely recovers the oracle solution. This result also explicates that the goal of improving the statistical performance is consistent with the optimization criteria of minimizing the suboptimality gap in solving the non-convex programming formulation of FCPSLR. (iii) We apply (ii) to the special case of FCPSLR with minimax concave penalty (MCP) and show that under the restricted eigenvalue condition, any S 3 ONC solution with a better objective value than the Lasso solution entails the strong oracle property. In addition, such a solution generates a model error (ME) comparable to the optimal but exponential-time sparse estimator given a sufficient sample size, while the worst-case ME is comparable to the Lasso in general. Furthermore, to guarantee the S 3 ONC admits FPTAS.

Regulation of DNA Replication Timing on Human Chromosome by a Cell-Type Specific DNA Binding Protein SATB1

PubMed Central

Oda, Masako; Kanoh, Yutaka; Watanabe, Yoshihisa; Masai, Hisao

2012-01-01

Background Replication timing of metazoan DNA during S-phase may be determined by many factors including chromosome structures, nuclear positioning, patterns of histone modifications, and transcriptional activity. It may be determined by Mb-domain structures, termed as “replication domains”, and recent findings indicate that replication timing is under developmental and cell type-specific regulation. Methodology/Principal Findings We examined replication timing on the human 5q23/31 3.5-Mb segment in T cells and non-T cells. We used two independent methods to determine replication timing. One is quantification of nascent replicating DNA in cell cycle-fractionated stage-specific S phase populations. The other is FISH analyses of replication foci. Although the locations of early- and late-replicating domains were common between the two cell lines, the timing transition region (TTR) between early and late domains were offset by 200-kb. We show that Special AT-rich sequence Binding protein 1 (SATB1), specifically expressed in T-cells, binds to the early domain immediately adjacent to TTR and delays the replication timing of the TTR. Measurement of the chromosome copy number along the TTR during synchronized S phase suggests that the fork movement may be slowed down by SATB1. Conclusions Our results reveal a novel role of SATB1 in cell type-specific regulation of replication timing along the chromosome. PMID:22879953

Regulation of DNA replication timing on human chromosome by a cell-type specific DNA binding protein SATB1.

PubMed

Oda, Masako; Kanoh, Yutaka; Watanabe, Yoshihisa; Masai, Hisao

2012-01-01

Replication timing of metazoan DNA during S-phase may be determined by many factors including chromosome structures, nuclear positioning, patterns of histone modifications, and transcriptional activity. It may be determined by Mb-domain structures, termed as "replication domains", and recent findings indicate that replication timing is under developmental and cell type-specific regulation. We examined replication timing on the human 5q23/31 3.5-Mb segment in T cells and non-T cells. We used two independent methods to determine replication timing. One is quantification of nascent replicating DNA in cell cycle-fractionated stage-specific S phase populations. The other is FISH analyses of replication foci. Although the locations of early- and late-replicating domains were common between the two cell lines, the timing transition region (TTR) between early and late domains were offset by 200-kb. We show that Special AT-rich sequence Binding protein 1 (SATB1), specifically expressed in T-cells, binds to the early domain immediately adjacent to TTR and delays the replication timing of the TTR. Measurement of the chromosome copy number along the TTR during synchronized S phase suggests that the fork movement may be slowed down by SATB1. Our results reveal a novel role of SATB1 in cell type-specific regulation of replication timing along the chromosome.

Signal processing using sparse derivatives with applications to chromatograms and ECG

NASA Astrophysics Data System (ADS)

Ning, Xiaoran

In this thesis, we investigate the sparsity exist in the derivative domain. Particularly, we focus on the type of signals which posses up to Mth (M > 0) order sparse derivatives. Efforts are put on formulating proper penalty functions and optimization problems to capture properties related to sparse derivatives, searching for fast, computationally efficient solvers. Also the effectiveness of these algorithms are applied to two real world applications. In the first application, we provide an algorithm which jointly addresses the problems of chromatogram baseline correction and noise reduction. The series of chromatogram peaks are modeled as sparse with sparse derivatives, and the baseline is modeled as a low-pass signal. A convex optimization problem is formulated so as to encapsulate these non-parametric models. To account for the positivity of chromatogram peaks, an asymmetric penalty function is also utilized with symmetric penalty functions. A robust, computationally efficient, iterative algorithm is developed that is guaranteed to converge to the unique optimal solution. The approach, termed Baseline Estimation And Denoising with Sparsity (BEADS), is evaluated and compared with two state-of-the-art methods using both simulated and real chromatogram data. Promising result is obtained. In the second application, a novel Electrocardiography (ECG) enhancement algorithm is designed also based on sparse derivatives. In the real medical environment, ECG signals are often contaminated by various kinds of noise or artifacts, for example, morphological changes due to motion artifact, non-stationary noise due to muscular contraction (EMG), etc. Some of these contaminations severely affect the usefulness of ECG signals, especially when computer aided algorithms are utilized. By solving the proposed convex l1 optimization problem, artifacts are reduced by modeling the clean ECG signal as a sum of two signals whose second and third-order derivatives (differences) are sparse respectively. At the end, the algorithm is applied to a QRS detection system and validated using the MIT-BIH Arrhythmia database (109452 anotations), resulting a sensitivity of Se = 99.87%$ and a positive prediction of +P = 99.88%.

Kinetic Simulations of Type II Radio Burst Emission Processes

NASA Astrophysics Data System (ADS)

Ganse, U.; Spanier, F. A.; Vainio, R. O.

2011-12-01

The fundamental emission process of Type II Radio Bursts has been under discussion for many decades. While analytic deliberations point to three wave interaction as the source for fundamental and harmonic radio emissions, sparse in-situ observational data and high computational demands for kinetic simulations have not allowed for a definite conclusion to be reached. A popular model puts the radio emission into the foreshock region of a coronal mass ejection's shock front, where shock drift acceleration can create eletrcon beam populations in the otherwise quiescent foreshock plasma. Beam-driven instabilities are then assumed to create waves, forming the starting point of three wave interaction processes. Using our kinetic particle-in-cell code, we have studied a number of emission scenarios based on electron beam populations in a CME foreshock, with focus on wave-interaction microphysics on kinetic scales. The self-consistent, fully kinetic simulations with completely physical mass-ratio show fundamental and harmonic emission of transverse electromagnetic waves and allow for detailled statistical analysis of all contributing wavemodes and their couplings.

Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome previously diagnosed as Seckel syndrome: report of a novel mutation of the PCNT gene.

PubMed

Piane, Maria; Della Monica, Matteo; Piatelli, Gianluca; Lulli, Patrizia; Lonardo, Fortunato; Chessa, Luciana; Scarano, Gioacchino

2009-11-01

We report on a 3-year-old boy with prenatal onset of proportionate dwarfism, postnatal severe microcephaly, high forehead with receded hairline, sparse scalp hair, beaked nose, mild retrognathia and hypotonia diagnosed at birth as Seckel syndrome. At age 3 years, he became paralyzed due to a cerebrovascular malformation. Based on the clinical and radiological features showing evidence of skeletal dysplasia, the diagnosis was revised to Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome. Western blot analysis of the patient's lymphoblastoid cell line lysate showed the absence of the protein pericentrin. Subsequent molecular analysis identified a novel homozygous single base insertion (c.1527_1528insA) in exon 10 of the PCNT gene, which leads to a frameshift (Treo510fs) and to premature protein truncation. PCNT mutations must be considered diagnostic of MOPD II syndrome. A possible role of pericentrin in the development of cerebral vessels is suggested. Copyright 2009 Wiley-Liss, Inc.

Comparison between sparsely distributed memory and Hopfield-type neural network models

NASA Technical Reports Server (NTRS)

Keeler, James D.

1986-01-01

The Sparsely Distributed Memory (SDM) model (Kanerva, 1984) is compared to Hopfield-type neural-network models. A mathematical framework for comparing the two is developed, and the capacity of each model is investigated. The capacity of the SDM can be increased independently of the dimension of the stored vectors, whereas the Hopfield capacity is limited to a fraction of this dimension. However, the total number of stored bits per matrix element is the same in the two models, as well as for extended models with higher order interactions. The models are also compared in their ability to store sequences of patterns. The SDM is extended to include time delays so that contextual information can be used to cover sequences. Finally, it is shown how a generalization of the SDM allows storage of correlated input pattern vectors.

Genetic identification of brain cell types underlying schizophrenia.

PubMed

Skene, Nathan G; Bryois, Julien; Bakken, Trygve E; Breen, Gerome; Crowley, James J; Gaspar, Héléna A; Giusti-Rodriguez, Paola; Hodge, Rebecca D; Miller, Jeremy A; Muñoz-Manchado, Ana B; O'Donovan, Michael C; Owen, Michael J; Pardiñas, Antonio F; Ryge, Jesper; Walters, James T R; Linnarsson, Sten; Lein, Ed S; Sullivan, Patrick F; Hjerling-Leffler, Jens

2018-06-01

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.

The mathematical cell model reconstructed from interference microscopy data

NASA Astrophysics Data System (ADS)

Rogotnev, A. A.; Nikitiuk, A. S.; Naimark, O. B.; Nebogatikov, V. O.; Grishko, V. V.

2017-09-01

The mathematical model of cell dynamics is developed to link the dynamics of the phase cell thickness with the signs of the oncological pathology. The measurements of irregular oscillations of cancer cells phase thickness were made with laser interference microscope MIM-340 in order to substantiate this model. These data related to the dynamics of phase thickness for different cross-sections of cells (nuclei, nucleolus, and cytoplasm) allow the reconstruction of the attractor of dynamic system. The attractor can be associated with specific types of collective modes of phase thickness responsible for the normal and cancerous cell dynamics. Specific type of evolution operator was determined using an algorithm of designing of the mathematical cell model and temporal phase thickness data for cancerous and normal cells. Qualitative correspondence of attractor types to the cell states was analyzed in terms of morphological signs associated with maximum value of mean square irregular oscillations of phase thickness dynamics.

Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity

PubMed Central

Krönig, Malte; Walter, Max; Drendel, Vanessa; Werner, Martin; Jilg, Cordula A.; Richter, Andreas S.; Backofen, Rolf; McGarry, David; Follo, Marie; Schultze-Seemann, Wolfgang; Schüle, Roland

2015-01-01

A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer. PMID:25514598

Classification of Clouds in Satellite Imagery Using Adaptive Fuzzy Sparse Representation.

PubMed

Jin, Wei; Gong, Fei; Zeng, Xingbin; Fu, Randi

2016-12-16

Automatic cloud detection and classification using satellite cloud imagery have various meteorological applications such as weather forecasting and climate monitoring. Cloud pattern analysis is one of the research hotspots recently. Since satellites sense the clouds remotely from space, and different cloud types often overlap and convert into each other, there must be some fuzziness and uncertainty in satellite cloud imagery. Satellite observation is susceptible to noises, while traditional cloud classification methods are sensitive to noises and outliers; it is hard for traditional cloud classification methods to achieve reliable results. To deal with these problems, a satellite cloud classification method using adaptive fuzzy sparse representation-based classification (AFSRC) is proposed. Firstly, by defining adaptive parameters related to attenuation rate and critical membership, an improved fuzzy membership is introduced to accommodate the fuzziness and uncertainty of satellite cloud imagery; secondly, by effective combination of the improved fuzzy membership function and sparse representation-based classification (SRC), atoms in training dictionary are optimized; finally, an adaptive fuzzy sparse representation classifier for cloud classification is proposed. Experiment results on FY-2G satellite cloud image show that, the proposed method not only improves the accuracy of cloud classification, but also has strong stability and adaptability with high computational efficiency.

Energy Balanced Strategies for Maximizing the Lifetime of Sparsely Deployed Underwater Acoustic Sensor Networks

PubMed Central

Luo, Hanjiang; Guo, Zhongwen; Wu, Kaishun; Hong, Feng; Feng, Yuan

2009-01-01

Underwater acoustic sensor networks (UWA-SNs) are envisioned to perform monitoring tasks over the large portion of the world covered by oceans. Due to economics and the large area of the ocean, UWA-SNs are mainly sparsely deployed networks nowadays. The limited battery resources is a big challenge for the deployment of such long-term sensor networks. Unbalanced battery energy consumption will lead to early energy depletion of nodes, which partitions the whole networks and impairs the integrity of the monitoring datasets or even results in the collapse of the entire networks. On the contrary, balanced energy dissipation of nodes can prolong the lifetime of such networks. In this paper, we focus on the energy balance dissipation problem of two types of sparsely deployed UWA-SNs: underwater moored monitoring systems and sparsely deployed two-dimensional UWA-SNs. We first analyze the reasons of unbalanced energy consumption in such networks, then we propose two energy balanced strategies to maximize the lifetime of networks both in shallow and deep water. Finally, we evaluate our methods by simulations and the results show that the two strategies can achieve balanced energy consumption per node while at the same time prolong the networks lifetime. PMID:22399970

Adoptive Transfer of Tumor-Specific Th2 Cells Eradicates Tumors by Triggering an In Situ Inflammatory Immune Response.

PubMed

Lorvik, Kristina Berg; Hammarström, Clara; Fauskanger, Marte; Haabeth, Ole Audun Werner; Zangani, Michael; Haraldsen, Guttorm; Bogen, Bjarne; Corthay, Alexandre

2016-12-01

Adoptive cell therapy (ACT) trials to date have focused on transfer of autologous tumor-specific cytotoxic CD8 + T cells; however, the potential of CD4 + T helper (Th) cells for ACT is gaining interest. While encouraging results have been reported with IFNγ-producing Th1 cells, tumor-specific Th2 cells have been largely neglected for ACT due to their reported tumor-promoting properties. In this study, we tested the efficacy of idiotype-specific Th2 cells for the treatment of mice with MHC class II-negative myeloma. Th2 ACT efficiently eradicated subcutaneous myeloma in an antigen-specific fashion. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Cancer eradication mediated by tumor-specific Th2 cells did not require B cells, natural killer T cells, CD8 + T cells, or IFNγ. Th2 ACT was also curative against B-cell lymphoma. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. In vivo blockade of arginase strongly inhibited Th2 ACT, consistent with a key role of arginase and M2 macrophages in myeloma elimination by Th2 cells. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, ACT with tumor-specific Th2 cells may represent a highly efficient immunotherapy protocol against cancer. Cancer Res; 76(23); 6864-76. ©2016 AACR. ©2016 American Association for Cancer Research.

GAD-specific T cells are induced by GAD-alum treatment in Type-1 diabetes patients.

PubMed

Pihl, Mikael; Barcenilla, Hugo; Axelsson, Stina; Chéramy, Mikael; Åkerman, Linda; Johansson, Ingela; Ludvigsson, Johnny; Casas, Rosaura

2017-03-01

Administration of Glutamic Acid Decarboxylase (GAD) 65 formulated in aluminium hydroxide preserved insulin secretion in a phase II trial in recent onset Type 1 Diabetes. A subsequent European phase III trial was closed at 15months after failing to reach primary endpoint, but the majority of the Swedish patients completed the 21months follow-up. We studied the frequencies and phenotype of T cells, suppressive capacity of Tregs, GAD 65 -induced proliferation, and frequencies of T cells with a GAD 65 -specific TCR in Swedes participating in the trial. Stimulation with GAD 65 induced activated T cells and also cells with a suppressive phenotype. Activated GAD 65 -specific effector T cells were detected by tetramer staining while the frequency of GAD 65 -specific Treg was not affected by the treatment. Additional doses of GAD-alum increased frequencies of CD25 + CD127 + , but had no effect on CD25 hi CD127 lo . Our findings indicate that GAD-alum treatment primarily induced activated T cells. GAD 65 -specific cells were mainly of activated phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic tracing of the gustatory neural pathway originating from Pkd1l3-expressing type III taste cells in circumvallate and foliate papillae

PubMed Central

Yamamoto, Kurumi; Ishimaru, Yoshiro; Ohmoto, Makoto; Matsumoto, Ichiro; Asakura, Tomiko; Abe, Keiko

2011-01-01

Polycystic kidney disease 1-like 3 (Pkd1l3) is expressed specifically in sour-sensing type III taste cells that have synaptic contacts with afferent nerve fibers in circumvallate and foliate papillae located in the posterior region of the tongue, though not in fungiform papillae or the palate. To visualize the gustatory neural pathways that originate from type III taste cells in circumvallate and foliate papillae, we established transgenic mouse lines that express the transneuronal tracer wheat germ agglutinin (WGA) under the control of the mouse Pkd1l3 gene promoter/enhancer. The WGA transgene was accurately expressed in Pkd1l3-expressing type III taste cells in circumvallate and foliate papillae. Punctate WGA protein signals appeared to be detected specifically in type III taste cells but not in other types of taste cells. WGA protein was transferred primarily to a subset of neurons located in close proximity to the glossopharyngeal nerve bundles in the nodose/petrosal ganglion. WGA signals were also observed in a small population of neurons in the geniculate ganglion. This result demonstrates the anatomical connection between taste receptor cells in the foliate papillae and the chorda tympani nerves. WGA protein was further conveyed to neurons in a rostro-central subdivision of the nucleus of the solitary tract. These findings demonstrate that the approximately 10 kb 5’-flanking region of the mouse Pkd1l3 gene functions as a type III taste cell-specific promoter/enhancer. In addition, experiments using the pkd1l3-WGA transgenic mice reveal a sour gustatory pathway that originates from taste receptor cells in the posterior region of the tongue. PMID:21883212

Computing sparse derivatives and consecutive zeros problem

NASA Astrophysics Data System (ADS)

Chandra, B. V. Ravi; Hossain, Shahadat

2013-02-01

We describe a substitution based sparse Jacobian matrix determination method using algorithmic differentiation. Utilizing the a priori known sparsity pattern, a compression scheme is determined using graph coloring. The "compressed pattern" of the Jacobian matrix is then reordered into a form suitable for computation by substitution. We show that the column reordering of the compressed pattern matrix (so as to align the zero entries into consecutive locations in each row) can be viewed as a variant of traveling salesman problem. Preliminary computational results show that on the test problems the performance of nearest-neighbor type heuristic algorithms is highly encouraging.

Satellite cell response to concurrent resistance exercise and high-intensity interval training in sedentary, overweight/obese, middle-aged individuals.

PubMed

Pugh, Jamie K; Faulkner, Steve H; Turner, Mark C; Nimmo, Myra A

2018-02-01

Sarcopenia can begin from the 4-5th decade of life and is exacerbated by obesity and inactivity. A combination of resistance exercise (RE) and endurance exercise is recommended to combat rising obesity and inactivity levels. However, work continues to elucidate whether interference in adaptive outcomes occur when RE and endurance exercise are performed concurrently. This study examined whether a single bout of concurrent RE and high-intensity interval training (HIIT) alters the satellite cell response following exercise compared to RE alone. Eight sedentary, overweight/obese, middle-aged individuals performed RE only (8 × 8 leg extensions at 70% 1RM), or RE + HIIT (10 × 1 min at 90% HR max on a cycle ergometer). Muscle biopsies were collected from the vastus lateralis before and 96 h after the RE component to determine muscle fiber type-specific total (Pax7 + cells) and active (MyoD + cells) satellite cell number using immunofluorescence microscopy. Type-I-specific Pax7 + (P = 0.001) cell number increased after both exercise trials. Type-I-specific MyoD + (P = 0.001) cell number increased after RE only. However, an elevated baseline value in RE + HIIT compared to RE (P = 0.046) was observed, with no differences between exercise trials at 96 h (P = 0.21). Type-II-specific Pax7 + and MyoD + cell number remained unchanged after both exercise trials (all P ≥ 0.13). Combining a HIIT session after a single bout of RE does not interfere with the increase in type-I-specific total, and possibly active, satellite cell number, compared to RE only. Concurrent RE + HIIT may offer a time-efficient way to maximise the physiological benefits from a single bout of exercise in sedentary, overweight/obese, middle-aged individuals.

Differences in overland flow, hydrophobicity and soil moisture dynamics between Mediterranean woodland types in a peri-urban catchment in Portugal

NASA Astrophysics Data System (ADS)

Ferreira, C. S. S.; Walsh, R. P. D.; Shakesby, R. A.; Keizer, J. J.; Soares, D.; González-Pelayo, O.; Coelho, C. O. A.; Ferreira, A. J. D.

2016-02-01

Forest hydrology has been widely investigated, but the impacts of different woodland types on hydrological processes within a peri-urban catchment mosaic are poorly understood. This paper investigates overland flow generation processes in three different types of woodland in a small (6.2 km2) catchment in central Portugal that has undergone strong urban development over the past 50 years. A semi-natural oak stand and a sparse eucalyptus stand on partly abandoned peri-urban land and a dense eucalyptus plantation were each instrumented with three 16 m2 runoff plots and 15 throughfall gauges, which were monitored at c. 1- to 2-week intervals over two hydrological years. In addition, surface soil moisture content (0-5 cm) and hydrophobicity (0-2 cm, 2-5 cm and 5-7 cm) were measured at the same time as overland flow and throughfall. Although all three woodland types produced relatively little overland flow (<3% of the incident rainfall overall), the dense eucalypt stand produced twice as much overland flow as the sparse eucalypt and oak woodland types. This contrast in overland flow can be attributed to infiltration-excess processes operating in storms following dry antecedent weather when severe hydrophobicity was widespread in the dense eucalypt plantation, whereas it was of moderate and low severity and less widespread in the sparse eucalypt and oak woodlands, respectively. In contrast, under wet conditions greater (albeit still small) percentages of overland flow were produced in oak woodland than in the two eucalypt plantations; this was probably linked to saturation-excess overland flow being generated more readily at the oak site as a result of its shallower soil. Differences in water retention in surface depressions affected overland flow generation and downslope flow transport. Implications of the seasonal differentials in overland flow generation between the three distinct woodland types for the hydrological response of peri-urban catchments are addressed.

Molecular fingerprinting of principal neurons in the rodent hippocampus: A neuroinformatics approach.

PubMed

Hamilton, D J; White, C M; Rees, C L; Wheeler, D W; Ascoli, G A

2017-09-10

Neurons are often classified by their morphological and molecular properties. The online knowledge base Hippocampome.org primarily defines neuron types from the rodent hippocampal formation based on their main neurotransmitter (glutamate or GABA) and the spatial distributions of their axons and dendrites. For each neuron type, this open-access resource reports any and all published information regarding the presence or absence of known molecular markers, including calcium-binding proteins, neuropeptides, receptors, channels, transcription factors, and other molecules of biomedical relevance. The resulting chemical profile is relatively sparse: even for the best studied neuron types, the expression or lack thereof of fewer than 70 molecules has been firmly established to date. The mouse genome-wide in situ hybridization mapping of the Allen Brain Atlas provides a wealth of data that, when appropriately analyzed, can substantially augment the molecular marker knowledge in Hippocampome.org. Here we focus on the principal cell layers of dentate gyrus (DG), CA3, CA2, and CA1, which together contain approximately 90% of hippocampal neurons. These four anatomical parcels are densely packed with somata of mostly excitatory projection neurons. Thus, gene expression data for those layers can be justifiably linked to the respective principal neuron types: granule cells in DG and pyramidal cells in CA3, CA2, and CA1. In order to enable consistent interpretation across genes and regions, we screened the whole-genome dataset against known molecular markers of those neuron types. The resulting threshold values allow over 6000 very-high confidence (>99.5%) expressed/not-expressed assignments, expanding the biochemical information content of Hippocampome.org more than five-fold. Many of these newly identified molecular markers are potential pharmacological targets for major neurological and psychiatric conditions. Furthermore, our approach yields reasonable expression/non-expression estimates for every single gene in each of these four neuron types with >90% average confidence, providing a considerably complete genetic characterization of hippocampal principal neurons. Copyright © 2017 Elsevier B.V. All rights reserved.

Single-cell-type Proteomics: Toward a Holistic Understanding of Plant Function*

PubMed Central

Dai, Shaojun; Chen, Sixue

2012-01-01

Multicellular organisms such as plants contain different types of cells with specialized functions. Analyzing the protein characteristics of each type of cell will not only reveal specific cell functions, but also enhance understanding of how an organism works. Most plant proteomics studies have focused on using tissues and organs containing a mixture of different cells. Recent single-cell-type proteomics efforts on pollen grains, guard cells, mesophyll cells, root hairs, and trichomes have shown utility. We expect that high resolution proteomic analyses will reveal novel functions in single cells. This review provides an overview of recent developments in plant single-cell-type proteomics. We discuss application of the approach for understanding important cell functions, and we consider the technical challenges of extending the approach to all plant cell types. Finally, we consider the integration of single-cell-type proteomics with transcriptomics and metabolomics with the goal of providing a holistic understanding of plant function. PMID:22982375

Expression of γ-aminobutyric acid ρ1 and ρ1Δ450 as gene fusions with the green fluorescent protein

PubMed Central

Martínez-Torres, Ataúlfo; Miledi, Ricardo

2001-01-01

The functional characteristics and cellular localization of the γaminobutyric acid (GABA) ρ1 receptor and its nonfunctional isoform ρ1Δ450 were investigated by expressing them as gene fusions with the enhanced version of the green fluorescent protein (GFP). Oocytes injected with ρ1-GFP had receptors that gated chloride channels when activated by GABA. The functional characteristics of these receptors were the same as for those of wild-type ρ1 receptors. Fluorescence, because of the chimeric receptors expressed, was over the whole oocyte but was more intense near the cell surface and more abundant in the animal hemisphere. Similar to the wild type, ρ1Δ450-GFP did not lead to the expression of functional GABA receptors, and injected oocytes failed to generate currents even after exposure to high concentrations of GABA. Nonetheless, the fluorescence displayed by oocytes expressing ρ1Δ450-GFP was distributed similarly to that of ρ1-GFP. Mammalian cells transfected with the ρ1-GFP or ρ1Δ450-GFP constructs showed mostly intracellularly distributed fluorescence in confocal microscope images. A sparse localization of fluorescence was observed in the plasma membrane regardless of the cell line used. We conclude that ρ1Δ450 is expressed and transported close to, and perhaps incorporated into, the plasma membrane. Thus, ρ1- and ρ1Δ450-GFP fusions provide a powerful tool to visualize the traffic of GABA type C receptors. PMID:11172056

Disarmed by density: A glycolytic break for immunostimulatory dendritic cells?

PubMed

Nasi, Aikaterini; Rethi, Bence

2013-12-01

We observed a cell concentration-dependent differentiation switch among cultured dendritic cells (DCs) triggered by lactic acid, a product of glycolytic metabolism. In particular, while interleukin (IL)-12, IL-23, and tumor necrosis factor α (TNFα)-producing, migratory DCs developed in sparse cultures, IL-10-producing, non-migratory DCs differentiated in dense cultures. This points to a novel opportunity for tailoring DC-based anticancer therapies through metabolism modulation in developing DCs.

Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis

PubMed Central

Capurro, Alberto; Bodea, Liviu-Gabriel; Schaefer, Patrick; Luthi-Carter, Ruth; Perreau, Victoria M.

2015-01-01

The characterization of molecular changes in diseased tissues gives insight into pathophysiological mechanisms and is important for therapeutic development. Genome-wide gene expression analysis has proven valuable for identifying biological processes in neurodegenerative diseases using post mortem human brain tissue and numerous datasets are publically available. However, many studies utilize heterogeneous tissue samples consisting of multiple cell types, all of which contribute to global gene expression values, confounding biological interpretation of the data. In particular, changes in numbers of neuronal and glial cells occurring in neurodegeneration confound transcriptomic analyses, particularly in human brain tissues where sample availability and controls are limited. To identify cell specific gene expression changes in neurodegenerative disease, we have applied our recently published computational deconvolution method, population specific expression analysis (PSEA). PSEA estimates cell-type-specific expression values using reference expression measures, which in the case of brain tissue comprises mRNAs with cell-type-specific expression in neurons, astrocytes, oligodendrocytes and microglia. As an exercise in PSEA implementation and hypothesis development regarding neurodegenerative diseases, we applied PSEA to Parkinson's and Huntington's disease (PD, HD) datasets. Genes identified as differentially expressed in substantia nigra pars compacta neurons by PSEA were validated using external laser capture microdissection data. Network analysis and Annotation Clustering (DAVID) identified molecular processes implicated by differential gene expression in specific cell types. The results of these analyses provided new insights into the implementation of PSEA in brain tissues and additional refinement of molecular signatures in human HD and PD. PMID:25620908

Targeted deletion and lipidomic analysis identify epithelial cell COX-2 as a major driver of chemically induced skin cancer.

PubMed

Jiao, Jing; Ishikawa, Tomo-O; Dumlao, Darren S; Norris, Paul C; Magyar, Clara E; Mikulec, Carol; Catapang, Art; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey R

2014-11-01

Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA-induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type-specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2-expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type-specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses. Cox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors. ©2014 American Association for Cancer Research.

Fiber/collagen composites for ligament tissue engineering: influence of elastic moduli of sparse aligned fibers on mesenchymal stem cells.

PubMed

Thayer, Patrick S; Verbridge, Scott S; Dahlgren, Linda A; Kakar, Sanjeev; Guelcher, Scott A; Goldstein, Aaron S

2016-08-01

Electrospun microfibers are attractive for the engineering of oriented tissues because they present instructive topographic and mechanical cues to cells. However, high-density microfiber networks are too cell-impermeable for most tissue applications. Alternatively, the distribution of sparse microfibers within a three-dimensional hydrogel could present instructive cues to guide cell organization while not inhibiting cell behavior. In this study, thin (∼5 fibers thick) layers of aligned microfibers (0.7 μm) were embedded within collagen hydrogels containing mesenchymal stem cells (MSCs), cultured for up to 14 days, and assayed for expression of ligament markers and imaged for cell organization. These microfibers were generated through the electrospinning of polycaprolactone (PCL), poly(ester-urethane) (PEUR), or a 75/25 PEUR/PCL blend to produce microfiber networks with elastic moduli of 31, 15, and 5.6 MPa, respectively. MSCs in composites containing 5.6 MPa fibers exhibited increased expression of the ligament marker scleraxis and the contractile phenotype marker α-smooth muscle actin versus the stiffer fiber composites. Additionally, cells within the 5.6 MPa microfiber composites were more oriented compared to cells within the 15 and 31 MPa microfiber composites. Together, these data indicate that the mechanical properties of microfiber/collagen composites can be tuned for the engineering of ligament and other target tissues. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1894-1901, 2016. © 2016 Wiley Periodicals, Inc.

Prediction of siRNA potency using sparse logistic regression.

PubMed

Hu, Wei; Hu, John

2014-06-01

RNA interference (RNAi) can modulate gene expression at post-transcriptional as well as transcriptional levels. Short interfering RNA (siRNA) serves as a trigger for the RNAi gene inhibition mechanism, and therefore is a crucial intermediate step in RNAi. There have been extensive studies to identify the sequence characteristics of potent siRNAs. One such study built a linear model using LASSO (Least Absolute Shrinkage and Selection Operator) to measure the contribution of each siRNA sequence feature. This model is simple and interpretable, but it requires a large number of nonzero weights. We have introduced a novel technique, sparse logistic regression, to build a linear model using single-position specific nucleotide compositions which has the same prediction accuracy of the linear model based on LASSO. The weights in our new model share the same general trend as those in the previous model, but have only 25 nonzero weights out of a total 84 weights, a 54% reduction compared to the previous model. Contrary to the linear model based on LASSO, our model suggests that only a few positions are influential on the efficacy of the siRNA, which are the 5' and 3' ends and the seed region of siRNA sequences. We also employed sparse logistic regression to build a linear model using dual-position specific nucleotide compositions, a task LASSO is not able to accomplish well due to its high dimensional nature. Our results demonstrate the superiority of sparse logistic regression as a technique for both feature selection and regression over LASSO in the context of siRNA design.

Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm.

PubMed

Zaret, K S; Watts, J; Xu, J; Wandzioch, E; Smale, S T; Sekiya, T

2008-01-01

The endoderm is a multipotent progenitor cell population in the embryo that gives rise to the liver, pancreas, and other cell types and provides paradigms for understanding cell-type specification. Studies of isolated embryo tissue cells and genetic approaches in vivo have defined fibroblast growth factor/mitogen-activated protein kinase (FGF/MAPK) and bone morphogenetic protein (BMP) signaling pathways that induce liver and pancreatic fates in the endoderm. In undifferentiated endoderm cells, the FoxA and GATA transcription factors are among the first to engage silent genes, helping to endow competence for cell-type specification. FoxA proteins can bind their target sites in highly compacted chromatin and open up the local region for other factors to bind; hence, they have been termed "pioneer factors." We recently found that FoxA proteins remain bound to chromatin in mitosis, as an epigenetic mark. In embryonic stem cells, which lack FoxA, FoxA target sites can be occupied by FoxD3, which in turn helps to maintain a local demethylation of chromatin. By these means, a cascade of Fox factors helps to endow progenitor cells with the competence to activate genes in response to tissue-inductive signals. Understanding such epigenetic mechanisms for transcriptional competence coupled with knowledge of the relevant signals for cell-type specification should greatly facilitate efforts to predictably differentiate stem cells to liver and pancreatic fates.

Local and Long-Range Circuit Connections to Hilar Mossy Cells in the Dentate Gyrus

PubMed Central

Sun, Yanjun; Grieco, Steven F.; Holmes, Todd C.

2017-01-01

Abstract Hilar mossy cells are the prominent glutamatergic cell type in the dentate hilus of the dentate gyrus (DG); they have been proposed to have critical roles in the DG network. To better understand how mossy cells contribute to DG function, we have applied new viral genetic and functional circuit mapping approaches to quantitatively map and compare local and long-range circuit connections of mossy cells and dentate granule cells in the mouse. The great majority of inputs to mossy cells consist of two parallel inputs from within the DG: an excitatory input pathway from dentate granule cells and an inhibitory input pathway from local DG inhibitory neurons. Mossy cells also receive a moderate degree of excitatory and inhibitory CA3 input from proximal CA3 subfields. Long range inputs to mossy cells are numerically sparse, and they are only identified readily from the medial septum and the septofimbrial nucleus. In comparison, dentate granule cells receive most of their inputs from the entorhinal cortex. The granule cells receive significant synaptic inputs from the hilus and the medial septum, and they also receive direct inputs from both distal and proximal CA3 subfields, which has been underdescribed in the existing literature. Our slice-based physiological mapping studies further supported the identified circuit connections of mossy cells and granule cells. Together, our data suggest that hilar mossy cells are major local circuit integrators and they exert modulation of the activity of dentate granule cells as well as the CA3 region through “back-projection” pathways. PMID:28451637

Link between DNA damage and centriole disengagement/reduplication in untransformed human cells.

PubMed

Douthwright, Stephen; Sluder, Greenfield

2014-10-01

The radiation and radiomimetic drugs used to treat human tumors damage DNA in both cancer cells and normal proliferating cells. Centrosome amplification after DNA damage is well established for transformed cell types but is sparsely reported and not fully understood in untransformed cells. We characterize centriole behavior after DNA damage in synchronized untransformed human cells. One hour treatment of S phase cells with the radiomimetic drug, Doxorubicin, prolongs G2 by at least 72 h, though 14% of the cells eventually go through mitosis in that time. By 72 h after DNA damage we observe a 52% incidence of centriole disengagement plus a 10% incidence of extra centrioles. We find that either APC/C or Plk activities can disengage centrioles after DNA damage, though they normally work in concert. All disengaged centrioles are associated with γ-tubulin and maturation markers and thus, should in principle be capable of reduplicating and organizing spindle poles. The low incidence of reduplication of disengaged centrioles during G2 is due to the p53-dependent expression of p21 and the consequent loss of Cdk2 activity. We find that 26% of the cells going through mitosis after DNA damage contain disengaged or extra centrioles. This could produce genomic instability through transient or persistent spindle multipolarity. Thus, for cancer patients the use of DNA damaging therapies raises the chances of genomic instability and evolution of transformed characteristics in proliferating normal cell populations. © 2014 Wiley Periodicals, Inc.

A Contractile Network of Interstitial Cells of Cajal in the Supratarsal Mueller's Smooth Muscle Fibers With Sparse Sympathetic Innervation

PubMed Central

Yuzuriha, Shunsuke; Matsuo, Kiyoshi; Ban, Ryokuya; Yano, Shiharu; Moriizumi, Tetsuji

2012-01-01

Background: We previously reported that the supratarsal Mueller's muscle is innervated by both sympathetic efferent fibers and trigeminal proprioceptive afferent fibers, which function as mechanoreceptors-inducing reflexive contractions of both the levator and frontalis muscles. Controversy still persists regarding the role of the mechanoreceptors in Mueller's muscle; therefore, we clinically and histologically investigated Mueller's muscle. Methods: We evaluated the role of phenylephrine administration into the upper fornix in contraction of Mueller's smooth muscle fibers and how intraoperative stretching of Mueller's muscle alters the degree of eyelid retraction in 20 patients with aponeurotic blepharoptosis. In addition, we stained Mueller's muscle in 7 cadavers with antibodies against α-smooth muscle actin, S100, tyrosine hydroxylase, c-kit, and connexin 43. Results: Maximal eyelid retraction occurred approximately 3.8 minutes after administration of phenylephrine and prolonged eyelid retraction for at least 20 minutes after administration. Intraoperative stretching of Mueller's muscle increased eyelid retraction due to its reflexive contraction. The tyrosine hydroxylase antibody sparsely stained postganglionic sympathetic nerve fibers, whereas the S100 and c-kit antibodies densely stained the interstitial cells of Cajal (ICCs) among Mueller's smooth muscle fibers. A connexin 43 antibody failed to stain Mueller's muscle. Conclusions: A contractile network of ICCs may mediate neurotransmission within Mueller's multiunit smooth muscle fibers that are sparsely innervated by postganglionic sympathetic fibers. Interstitial cells of Cajal may also serve as mechanoreceptors that reflexively contract Mueller's smooth muscle fibers, forming intimate associations with intramuscular trigeminal proprioceptive fibers to induce reflexive contraction of the levator and frontalis muscles. PMID:22359687

The phosphorylated C-terminus of cAR1 plays a role in cell-type-specific gene expression and STATa tyrosine phosphorylation.

PubMed

Briscoe, C; Moniakis, J; Kim, J Y; Brown, J M; Hereld, D; Devreotes, P N; Firtel, R A

2001-05-01

cAMP receptors mediate some signaling pathways via coupled heterotrimeric G proteins, while others are G-protein-independent. This latter class includes the activation of the transcription factors GBF and STATa. Within the cellular mounds formed by aggregation of Dictyostelium, micromolar levels of cAMP activate GBF function, thereby inducing the transcription of postaggregative genes and initiating multicellular differentiation. Activation of STATa, a regulator of culmination and ecmB expression, results from cAMP receptor-dependent tyrosine phosphorylation and nuclear localization, also in mound-stage cells. During mound development, the cAMP receptor cAR1 is in a low-affinity state and is phosphorylated on multiple serine residues in its C-terminus. This paper addresses possible roles of cAMP receptor phosphorylation in the cAMP-mediated stimulation of GBF activity, STATa tyrosine phosphorylation, and cell-type-specific gene expression. To accomplish this, we have expressed cAR1 mutants in a strain in which the endogenous cAMP receptors that mediate postaggregative gene expression in vivo are deleted. We then examined the ability of these cells to undergo morphogenesis and induce postaggregative and cell-type-specific gene expression and STATa tyrosine phosphorylation. Analysis of cAR1 mutants in which the C-terminal tail is deleted or the ligand-mediated phosphorylation sites are mutated suggests that the cAR1 C-terminus is not essential for GBF-mediated postaggregative gene expression or STATa tyrosine phosphorylation, but may play a role in regulating cell-type-specific gene expression and morphogenesis. A mutant receptor, in which the C-terminal tail is constitutively phosphorylated, exhibits constitutive activation of STATa tyrosine phosphorylation in pulsed cells in suspension and a significantly impaired ability to induce cell-type-specific gene expression. The constitutively phosphorylated receptor also exerts a partial dominant negative effect on multicellular development when expressed in wild-type cells. These findings suggest that the phosphorylated C-terminus of cAR1 may be involved in regulating aspects of receptor-mediated processes, is not essential for GBF function, and may play a role in mediating subsequent development. Copyright 2001 Academic Press.

Cell fate control in the developing central nervous system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guérout, Nicolas; Li, Xiaofei; Barnabé-Heider, Fanie, E-mail: Fanie.Barnabe-Heider@ki.se

The principal neural cell types forming the mature central nervous system (CNS) are now understood to be diverse. This cellular subtype diversity originates to a large extent from the specification of the earlier proliferating progenitor populations during development. Here, we review the processes governing the differentiation of a common neuroepithelial cell progenitor pool into mature neurons, astrocytes, oligodendrocytes, ependymal cells and adult stem cells. We focus on studies performed in mice and involving two distinct CNS structures: the spinal cord and the cerebral cortex. Understanding the origin, specification and developmental regulators of neural cells will ultimately impact comprehension and treatmentsmore » of neurological disorders and diseases. - Highlights: • Similar mechanisms regulate cell fate in different CNS cell types and structures. • Cell fate regulators operate in a spatial–temporal manner. • Different neural cell types rely on the generation of a diversity of progenitor cells. • Cell fate decision is dictated by the integration of intrinsic and extrinsic signals.« less

Noise-aware dictionary-learning-based sparse representation framework for detection and removal of single and combined noises from ECG signal

PubMed Central

Ramkumar, Barathram; Sabarimalai Manikandan, M.

2017-01-01

Automatic electrocardiogram (ECG) signal enhancement has become a crucial pre-processing step in most ECG signal analysis applications. In this Letter, the authors propose an automated noise-aware dictionary learning-based generalised ECG signal enhancement framework which can automatically learn the dictionaries based on the ECG noise type for effective representation of ECG signal and noises, and can reduce the computational load of sparse representation-based ECG enhancement system. The proposed framework consists of noise detection and identification, noise-aware dictionary learning, sparse signal decomposition and reconstruction. The noise detection and identification is performed based on the moving average filter, first-order difference, and temporal features such as number of turning points, maximum absolute amplitude, zerocrossings, and autocorrelation features. The representation dictionary is learned based on the type of noise identified in the previous stage. The proposed framework is evaluated using noise-free and noisy ECG signals. Results demonstrate that the proposed method can significantly reduce computational load as compared with conventional dictionary learning-based ECG denoising approaches. Further, comparative results show that the method outperforms existing methods in automatically removing noises such as baseline wanders, power-line interference, muscle artefacts and their combinations without distorting the morphological content of local waves of ECG signal. PMID:28529758

Noise-aware dictionary-learning-based sparse representation framework for detection and removal of single and combined noises from ECG signal.

PubMed

Satija, Udit; Ramkumar, Barathram; Sabarimalai Manikandan, M

2017-02-01

Automatic electrocardiogram (ECG) signal enhancement has become a crucial pre-processing step in most ECG signal analysis applications. In this Letter, the authors propose an automated noise-aware dictionary learning-based generalised ECG signal enhancement framework which can automatically learn the dictionaries based on the ECG noise type for effective representation of ECG signal and noises, and can reduce the computational load of sparse representation-based ECG enhancement system. The proposed framework consists of noise detection and identification, noise-aware dictionary learning, sparse signal decomposition and reconstruction. The noise detection and identification is performed based on the moving average filter, first-order difference, and temporal features such as number of turning points, maximum absolute amplitude, zerocrossings, and autocorrelation features. The representation dictionary is learned based on the type of noise identified in the previous stage. The proposed framework is evaluated using noise-free and noisy ECG signals. Results demonstrate that the proposed method can significantly reduce computational load as compared with conventional dictionary learning-based ECG denoising approaches. Further, comparative results show that the method outperforms existing methods in automatically removing noises such as baseline wanders, power-line interference, muscle artefacts and their combinations without distorting the morphological content of local waves of ECG signal.

Accelerated High-Dimensional MR Imaging with Sparse Sampling Using Low-Rank Tensors

PubMed Central

He, Jingfei; Liu, Qiegen; Christodoulou, Anthony G.; Ma, Chao; Lam, Fan

2017-01-01

High-dimensional MR imaging often requires long data acquisition time, thereby limiting its practical applications. This paper presents a low-rank tensor based method for accelerated high-dimensional MR imaging using sparse sampling. This method represents high-dimensional images as low-rank tensors (or partially separable functions) and uses this mathematical structure for sparse sampling of the data space and for image reconstruction from highly undersampled data. More specifically, the proposed method acquires two datasets with complementary sampling patterns, one for subspace estimation and the other for image reconstruction; image reconstruction from highly undersampled data is accomplished by fitting the measured data with a sparsity constraint on the core tensor and a group sparsity constraint on the spatial coefficients jointly using the alternating direction method of multipliers. The usefulness of the proposed method is demonstrated in MRI applications; it may also have applications beyond MRI. PMID:27093543

DOLPHIn—Dictionary Learning for Phase Retrieval

NASA Astrophysics Data System (ADS)

Tillmann, Andreas M.; Eldar, Yonina C.; Mairal, Julien

2016-12-01

We propose a new algorithm to learn a dictionary for reconstructing and sparsely encoding signals from measurements without phase. Specifically, we consider the task of estimating a two-dimensional image from squared-magnitude measurements of a complex-valued linear transformation of the original image. Several recent phase retrieval algorithms exploit underlying sparsity of the unknown signal in order to improve recovery performance. In this work, we consider such a sparse signal prior in the context of phase retrieval, when the sparsifying dictionary is not known in advance. Our algorithm jointly reconstructs the unknown signal - possibly corrupted by noise - and learns a dictionary such that each patch of the estimated image can be sparsely represented. Numerical experiments demonstrate that our approach can obtain significantly better reconstructions for phase retrieval problems with noise than methods that cannot exploit such "hidden" sparsity. Moreover, on the theoretical side, we provide a convergence result for our method.

Glass promotes the differentiation of neuronal and non-neuronal cell types in the Drosophila eye

PubMed Central

Morrison, Carolyn A.; Chen, Hao; Cook, Tiffany; Brown, Stuart

2018-01-01

Transcriptional regulators can specify different cell types from a pool of equivalent progenitors by activating distinct developmental programs. The Glass transcription factor is expressed in all progenitors in the developing Drosophila eye, and is maintained in both neuronal and non-neuronal cell types. Glass is required for neuronal progenitors to differentiate as photoreceptors, but its role in non-neuronal cone and pigment cells is unknown. To determine whether Glass activity is limited to neuronal lineages, we compared the effects of misexpressing it in neuroblasts of the larval brain and in epithelial cells of the wing disc. Glass activated overlapping but distinct sets of genes in these neuronal and non-neuronal contexts, including markers of photoreceptors, cone cells and pigment cells. Coexpression of other transcription factors such as Pax2, Eyes absent, Lozenge and Escargot enabled Glass to induce additional genes characteristic of the non-neuronal cell types. Cell type-specific glass mutations generated in cone or pigment cells using somatic CRISPR revealed autonomous developmental defects, and expressing Glass specifically in these cells partially rescued glass mutant phenotypes. These results indicate that Glass is a determinant of organ identity that acts in both neuronal and non-neuronal cells to promote their differentiation into functional components of the eye. PMID:29324767

A Learning Model for L/M Specificity in Ganglion Cells

NASA Technical Reports Server (NTRS)

Ahumada, Albert J.

2016-01-01

An unsupervised learning model for developing LM specific wiring at the ganglion cell level would support the research indicating LM specific wiring at the ganglion cell level (Reid and Shapley, 2002). Removing the contributions to the surround from cells of the same cone type improves the signal-to-noise ratio of the chromatic signals. The unsupervised learning model used is Hebbian associative learning, which strengthens the surround input connections according to the correlation of the output with the input. Since the surround units of the same cone type as the center are redundant with the center, their weights end up disappearing. This process can be thought of as a general mechanism for eliminating unnecessary cells in the nervous system.

GiniClust: detecting rare cell types from single-cell gene expression data with Gini index.

PubMed

Jiang, Lan; Chen, Huidong; Pinello, Luca; Yuan, Guo-Cheng

2016-07-01

High-throughput single-cell technologies have great potential to discover new cell types; however, it remains challenging to detect rare cell types that are distinct from a large population. We present a novel computational method, called GiniClust, to overcome this challenge. Validation against a benchmark dataset indicates that GiniClust achieves high sensitivity and specificity. Application of GiniClust to public single-cell RNA-seq datasets uncovers previously unrecognized rare cell types, including Zscan4-expressing cells within mouse embryonic stem cells and hemoglobin-expressing cells in the mouse cortex and hippocampus. GiniClust also correctly detects a small number of normal cells that are mixed in a cancer cell population.

A Large Sparse Aperture Densified Pupil Hypertelescope Concept for Ground Based Detection of Extra-Solar Earth-Like Planets

NASA Technical Reports Server (NTRS)

Gezari, D.; Lyon, R.; Woodruff, R.; Labeyrie, A.; Oegerle, William (Technical Monitor)

2002-01-01

A concept is presented for a large (10 - 30 meter) sparse aperture hyper telescope to image extrasolar earth-like planets from the ground in the presence of atmospheric seeing. The telescope achieves high dynamic range very close to bright stellar sources with good image quality using pupil densification techniques. Active correction of the perturbed wavefront is simplified by using 36 small flat mirrors arranged in a parabolic steerable array structure, eliminating the need for large delat lines and operating at near-infrared (1 - 3 Micron) wavelengths with flats comparable in size to the seeing cells.

Transplantation of subalpine wood-pasture turfs along a natural climatic gradient reveals lower resistance of unwooded pastures to climate change compared to wooded ones.

PubMed

Gavazov, Konstantin; Spiegelberger, Thomas; Buttler, Alexandre

2014-04-01

Climate change could impact strongly on cold-adapted mountain ecosystems, but little is known about its interaction with traditional land-use practices. We used an altitudinal gradient to simulate a year-round warmer and drier climate for semi-natural subalpine grasslands across a landscape of contrasting land-use management. Turf mesocosms from three pasture-woodland land-use types-unwooded pasture, sparsely wooded pasture, and densely wooded pasture-spanning a gradient from high to low management intensity were transplanted downslope to test their resistance to two intensities of climate change. We found strong overall effects of intensive (+4 K) experimental climate change (i.e., warming and reduced precipitation) on plant community structure and function, while moderate (+2 K) climate change did not substantially affect the studied land-use types, thus indicating an ecosystem response threshold to moderate climate perturbation. The individual land-use types were affected differently under the +4 K scenario, with a 60% decrease in aboveground biomass (AGB) in unwooded pasture turfs, a 40% decrease in sparsely wooded pasture turfs, and none in densely wooded ones. Similarly, unwooded pasture turfs experienced a 30% loss of species, advanced (by 30 days) phenological development, and a mid-season senescence due to drought stress, while no such effects were recorded for the other land-use types. The observed contrasting effects of climate change across the pasture-woodland landscape have important implications for future decades. The reduced impact of climate change on wooded pastures as compared to unwooded ones should promote the sustainable land use of wooded pastures by maintaining low management intensity and a sparse forest canopy, which buffer the immediate impacts of climate change on herbaceous vegetation.

Targeted interactomics reveals a complex core cell cycle machinery in Arabidopsis thaliana.

PubMed

Van Leene, Jelle; Hollunder, Jens; Eeckhout, Dominique; Persiau, Geert; Van De Slijke, Eveline; Stals, Hilde; Van Isterdael, Gert; Verkest, Aurine; Neirynck, Sandy; Buffel, Yelle; De Bodt, Stefanie; Maere, Steven; Laukens, Kris; Pharazyn, Anne; Ferreira, Paulo C G; Eloy, Nubia; Renne, Charlotte; Meyer, Christian; Faure, Jean-Denis; Steinbrenner, Jens; Beynon, Jim; Larkin, John C; Van de Peer, Yves; Hilson, Pierre; Kuiper, Martin; De Veylder, Lieven; Van Onckelen, Harry; Inzé, Dirk; Witters, Erwin; De Jaeger, Geert

2010-08-10

Cell proliferation is the main driving force for plant growth. Although genome sequence analysis revealed a high number of cell cycle genes in plants, little is known about the molecular complexes steering cell division. In a targeted proteomics approach, we mapped the core complex machinery at the heart of the Arabidopsis thaliana cell cycle control. Besides a central regulatory network of core complexes, we distinguished a peripheral network that links the core machinery to up- and downstream pathways. Over 100 new candidate cell cycle proteins were predicted and an in-depth biological interpretation demonstrated the hypothesis-generating power of the interaction data. The data set provided a comprehensive view on heterodimeric cyclin-dependent kinase (CDK)-cyclin complexes in plants. For the first time, inhibitory proteins of plant-specific B-type CDKs were discovered and the anaphase-promoting complex was characterized and extended. Important conclusions were that mitotic A- and B-type cyclins form complexes with the plant-specific B-type CDKs and not with CDKA;1, and that D-type cyclins and S-phase-specific A-type cyclins seem to be associated exclusively with CDKA;1. Furthermore, we could show that plants have evolved a combinatorial toolkit consisting of at least 92 different CDK-cyclin complex variants, which strongly underscores the functional diversification among the large family of cyclins and reflects the pivotal role of cell cycle regulation in the developmental plasticity of plants.

Mechanical Detection of a Long-Range Actin Network Emanating from a Biomimetic Cortex

PubMed Central

Bussonnier, Matthias; Carvalho, Kevin; Lemière, Joël; Joanny, Jean-François; Sykes, Cécile; Betz, Timo

2014-01-01

Actin is ubiquitous globular protein that polymerizes into filaments and forms networks that participate in the force generation of eukaryotic cells. Such forces are used for cell motility, cytokinesis, and tissue remodeling. Among those actin networks, we focus on the actin cortex, a dense branched network beneath the plasma membrane that is of particular importance for the mechanical properties of the cell. Here we reproduce the cellular cortex by activating actin filament growth on a solid surface. We unveil the existence of a sparse actin network that emanates from the surface and extends over a distance that is at least 10 times larger than the cortex itself. We call this sparse actin network the “actin cloud” and characterize its mechanical properties with optical tweezers. We show, both experimentally and theoretically, that the actin cloud is mechanically relevant and that it should be taken into account because it can sustain forces as high as several picoNewtons (pN). In particular, it is known that in plant cells, actin networks similar to the actin cloud have a role in positioning the nucleus; in large oocytes, they play a role in driving chromosome movement. Recent evidence shows that such networks even prevent granule condensation in large cells. PMID:25140420

Carotenoids in Adipose Tissue Biology and Obesity.

PubMed

Bonet, M Luisa; Canas, Jose A; Ribot, Joan; Palou, Andreu

2016-01-01

Cell, animal and human studies dealing with carotenoids and carotenoid derivatives as nutritional regulators of adipose tissue biology with implications for the etiology and management of obesity and obesity-related metabolic diseases are reviewed. Most studied carotenoids in this context are β-carotene, cryptoxanthin, astaxanthin and fucoxanthin, together with β-carotene-derived retinoids and some other apocarotenoids. Studies indicate an impact of these compounds on essential aspects of adipose tissue biology including the control of adipocyte differentiation (adipogenesis), adipocyte metabolism, oxidative stress and the production of adipose tissue-derived regulatory signals and inflammatory mediators. Specific carotenoids and carotenoid derivatives restrain adipogenesis and adipocyte hypertrophy while enhancing fat oxidation and energy dissipation in brown and white adipocytes, and counteract obesity in animal models. Intake, blood levels and adipocyte content of carotenoids are reduced in human obesity. Specifically designed human intervention studies in the field, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. In summary, studies support a role of specific carotenoids and carotenoid derivatives in the prevention of excess adiposity, and suggest that carotenoid requirements may be dependent on body composition.

Microarray Detection Call Methodology as a Means to Identify and Compare Transcripts Expressed within Syncytial Cells from Soybean (Glycine max) Roots Undergoing Resistant and Susceptible Reactions to the Soybean Cyst Nematode (Heterodera glycines)

PubMed Central

Klink, Vincent P.; Overall, Christopher C.; Alkharouf, Nadim W.; MacDonald, Margaret H.; Matthews, Benjamin F.

2010-01-01

Background. A comparative microarray investigation was done using detection call methodology (DCM) and differential expression analyses. The goal was to identify genes found in specific cell populations that were eliminated by differential expression analysis due to the nature of differential expression methods. Laser capture microdissection (LCM) was used to isolate nearly homogeneous populations of plant root cells. Results. The analyses identified the presence of 13,291 transcripts between the 4 different sample types. The transcripts filtered down into a total of 6,267 that were detected as being present in one or more sample types. A comparative analysis of DCM and differential expression methods showed a group of genes that were not differentially expressed, but were expressed at detectable amounts within specific cell types. Conclusion. The DCM has identified patterns of gene expression not shown by differential expression analyses. DCM has identified genes that are possibly cell-type specific and/or involved in important aspects of plant nematode interactions during the resistance response, revealing the uniqueness of a particular cell population at a particular point during its differentiation process. PMID:20508855

Direct comparison of progenitor cells derived from adipose, muscle, and bone marrow from wild-type or craniosynostotic rabbits

PubMed Central

GM, Cooper; EL, Lensie; JJ, Cray; MR, Bykowski; GE, DeCesare; MA, Smalley; MP, Mooney; PG, Campbell; JE, Losee

2010-01-01

Background Reports have identified cells capable of osteogenic differentiation in bone marrow, muscle, and adipose tissues, but there are few direct comparisons of these different cell-types. Also, few have investigated the potential connection between a tissue-specific pathology and cells derived from seemingly unrelated tissues. Here, we compare cells isolated from wild-type rabbits or rabbits with nonsyndromic craniosynostosis, defined as the premature fusion of one or more of the cranial sutures. Methods Cells were derived from bone marrow, adipose, and muscle of 10 day-old wild-type rabbits (WT; n=17) or from age-matched rabbits with familial nonsyndromic craniosynostosis (CS; n=18). Cells were stimulated with bone morphogenetic protein 4 (BMP4) and alkaline phosphatase expression and cell proliferation were assessed. Results In WT rabbits, cells derived from muscle had more alkaline phosphatase activity than cells derived from either adipose or bone marrow. The cells derived from CS rabbit bone marrow and muscle were significantly more osteogenic than WT. Adipose-derived cells demonstrated no significant differences. While muscle-derived cells were most osteogenic in WT rabbits, bone marrow-derived cells were most osteogenic in CS rabbits. Conclusions Results suggest that cells from different tissues have different potentials for differentiation. Furthermore, cells derived from rabbits with craniosynostosis were different from wild-type derived cells. Interestingly, cells derived from the craniosynostotic rabbits were not uniformly more responsive compared with wild-type cells, suggesting that specific tissue-derived cells may react differently in individuals with craniosynostosis. PMID:20871482

TOPICAL REVIEW: Artificial extracellular matrix for embryonic stem cell cultures: a new frontier of nanobiomaterials

NASA Astrophysics Data System (ADS)

Amranul Haque, Md; Nagaoka, Masato; Hexig, Bayar; Akaike, Toshihiro

2010-02-01

Nanobiomaterials can play a central role in regenerative medicine and tissue engineering by facilitating cellular behavior and function, such as those where extracellular matrices (ECMs) direct embryonic stem (ES) cell morphogenesis, proliferation, differentiation and apoptosis. However, controlling ES cell proliferation and differentiation using matrices from natural sources is still challenging due to complex and heterogeneous culture conditions. Moreover, the systemic investigation of the regulation of self-renewal and differentiation to lineage specific cells depends on the use of defined and stress-free culture conditions. Both goals can be achieved by the development of biomaterial design targeting ECM or growth factors for ES cell culture. This targeted application will benefit from expansion of ES cells for transplantation, as well as the production of a specific differentiated cell type either by controlling the differentiation in a very specific pathway or by elimination of undesirable cell types.

Root Type-Specific Reprogramming of Maize Pericycle Transcriptomes by Local High Nitrate Results in Disparate Lateral Root Branching Patterns1[OPEN

PubMed Central

Lithio, Andrew

2016-01-01

The adaptability of root system architecture to unevenly distributed mineral nutrients in soil is a key determinant of plant performance. The molecular mechanisms underlying nitrate dependent plasticity of lateral root branching across the different root types of maize are only poorly understood. In this study, detailed morphological and anatomical analyses together with cell type-specific transcriptome profiling experiments combining laser capture microdissection with RNA-seq were performed to unravel the molecular signatures of lateral root formation in primary, seminal, crown, and brace roots of maize (Zea mays) upon local high nitrate stimulation. The four maize root types displayed divergent branching patterns of lateral roots upon local high nitrate stimulation. In particular, brace roots displayed an exceptional architectural plasticity compared to other root types. Transcriptome profiling revealed root type-specific transcriptomic reprogramming of pericycle cells upon local high nitrate stimulation. The alteration of the transcriptomic landscape of brace root pericycle cells in response to local high nitrate stimulation was most significant. Root type-specific transcriptome diversity in response to local high nitrate highlighted differences in the functional adaptability and systemic shoot nitrogen starvation response during development. Integration of morphological, anatomical, and transcriptomic data resulted in a framework underscoring similarity and diversity among root types grown in heterogeneous nitrate environments. PMID:26811190

Properties of Dental Pulp-derived Mesenchymal Stem Cells and the Effects of Culture Conditions.

PubMed

Kawashima, Nobuyuki; Noda, Sonoko; Yamamoto, Mioko; Okiji, Takashi

2017-09-01

Dental pulp mesenchymal stem cells (DPMSCs) highly express mesenchymal stem cell markers and possess the potential to differentiate into neural cells, osteoblasts, adipocytes, and chondrocytes. Thus, DPMSCs are considered suitable for tissue regeneration. The colony isolation method has commonly been used to collect relatively large amounts of heterogeneous DPMSCs. Homogenous DPMSCs can be isolated by fluorescence-activated cell sorting using antibodies against mesenchymal stem cell markers, although this method yields a limited number of cells. Both quality and quantity of DPMSCs are critical to regenerative therapy, and cell culture methods need to be improved. We thus investigated the properties of DPMSCs cultured with different methods. DPMSCs in a three-dimensional spheroid culture system, which is similar to the hanging drop culture for differentiation of embryonic stem cells, showed upregulation of odonto-/osteoblastic markers and mineralized nodule formation. This suggests that this three-dimensional spheroid culturing system for DPMSCs may be suitable for inducing hard tissues. We further examined the effect of cell culture density on the properties of DPMSCs because the properties of stem cells can be altered depending on the cell density. DPMSCs cultured under the confluent cell density condition showed slight downregulation of some mesenchymal stem cell markers compared with those under the sparse condition. The ability of DPMSCs to differentiate into hard tissue-forming cells was found to be enhanced in the confluent condition, suggesting that the confluent culture condition may not be suitable for maintaining the stemness of DPMSCs. When DPMSCs are to be used for hard tissue regeneration, dense followed by sparse cell culture conditions may be a better alternative strategy. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Ontogeny of neuro-insular complexes and islets innervation in the human pancreas.

PubMed

Proshchina, Alexandra E; Krivova, Yulia S; Barabanov, Valeriy M; Saveliev, Sergey V

2014-01-01

The ontogeny of the neuro-insular complexes (NIC) and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used double-staining with antibodies specific to pan-neural markers [neuron-specific enolase (NSE) and S100 protein] and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw) 10 onward. Later the density of S100 and NSE-positive fibers increased. In adults, this network was sparse. The islets innervation started to form from gw 14. NSE-containing endocrine cells were identified from gw 12 onward. Additionally, S100-positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained NIC and the number of these complexes was reduced in adults. The highest density of NIC is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis.

Ontogeny of Neuro-Insular Complexes and Islets Innervation in the Human Pancreas

PubMed Central

Proshchina, Alexandra E.; Krivova, Yulia S.; Barabanov, Valeriy M.; Saveliev, Sergey V.

2014-01-01

The ontogeny of the neuro-insular complexes (NIC) and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used double-staining with antibodies specific to pan-neural markers [neuron-specific enolase (NSE) and S100 protein] and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw) 10 onward. Later the density of S100 and NSE-positive fibers increased. In adults, this network was sparse. The islets innervation started to form from gw 14. NSE-containing endocrine cells were identified from gw 12 onward. Additionally, S100-positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained NIC and the number of these complexes was reduced in adults. The highest density of NIC is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis. PMID:24795697

Yersinia pestis targets neutrophils via complement receptor 3

PubMed Central

Merritt, Peter M.; Nero, Thomas; Bohman, Lesley; Felek, Suleyman; Krukonis, Eric S.; Marketon, Melanie M.

2015-01-01

Yersinia species display a tropism for lymphoid tissues during infection, and the bacteria select innate immune cells for delivery of cytotoxic effectors by the type III secretion system. Yet the mechanism for target cell selection remains a mystery. Here we investigate the interaction of Yersinia pestis with murine splenocytes to identify factors that participate in the targeting process. We find that interactions with primary immune cells rely on multiple factors. First, the bacterial adhesin Ail is required for efficient targeting of neutrophils in vivo. However, Ail does not appear to directly mediate binding to a specific cell type. Instead, we find that host serum factors direct Y. pestis to specific innate immune cells, particularly neutrophils. Importantly, specificity towards neutrophils was increased in the absence of bacterial adhesins due to reduced targeting of other cell types, but this phenotype was only visible in the presence of mouse serum. Addition of antibodies against complement receptor 3 and CD14 blocked target cell selection, suggesting that a combination of host factors participate in steering bacteria toward neutrophils during plague infection. PMID:25359083

Basic anatomy and tumor biology of the RPS6KA6 gene that encodes the p90 ribosomal S6 kinase-4

PubMed Central

Sun, Yuan; Cao, Shousong; Yang, Min; Wu, Sihong; Wang, Zhe; Lin, Xiukun; Song, Xiangrang; Liao, D.J.

2012-01-01

The RPS6KA6 gene encodes the p90 ribosomal S6 kinase-4 (RSK4) that is still largely uncharacterized. In this study we identified a new RSK4 transcription initiation site and several alternative splice sites with a 5’RACE approach. The resulting mRNA variants encompass four possible first start codons. The first 15 nucleotides (nt) of exon 22 in mouse and the penultimate exon in both human (exon 21) and mouse (exon 24) RSK4 underwent alternative splicing, although the penultimate exon deleted variant appeared mainly in cell clines, but not in most normal tissues. Demethylation agent 5-azacytidine inhibited the deletion of the penultimate exon whereas two indolocarbazole-derived inhibitors of cyclin dependent kinase 4 or 6 induced deletion of the first 39 nt from exon 21 of human RSK4. In all human cancer cell lines studied, the 90-kD wild type RSK4 was sparse but, surprisingly, several isoforms at or smaller than 72-kD were expressed as detected by seven different antibodies. On immunoblots, each of these smaller isoforms often appeared as a duplet or triplet and the levels of these isoforms varied greatly among different cell lines and culture conditions. Cyclin D1 inhibited RSK4 expression and serum starvation enhanced the inhibition, whereas c-Myc and RSK4 inhibited cyclin D1. The effects of RSK4 on cell growth, cell death and chemoresponse depended on the mRNA variant or the protein isoform expressed, on the specificity of the cell lines, as well as on the anchorage-dependent or -independent growth conditions and the in vivo situation. Moreover, we also observed that even a given cDNA might be expressed to multiple proteins; therefore, when using a cDNA, one needs to exclude this possibility before attribution of the biological results from the cDNA to the anticipated protein. Collectively, our results suggest that whether RSK4 is oncogenic or tumor suppressive depends on many factors. PMID:22614021

A survey of ex vivo/in vitro transduction efficiency of mammalian primary cells and cell lines with Nine natural adeno-associated virus (AAV1-9) and one engineered adeno-associated virus serotype.

PubMed

Ellis, Brian L; Hirsch, Matthew L; Barker, Jenny C; Connelly, Jon P; Steininger, Robert J; Porteus, Matthew H

2013-03-06

The ability to deliver a gene of interest into a specific cell type is an essential aspect of biomedical research. Viruses can be a useful tool for this delivery, particularly in difficult to transfect cell types. Adeno-associated virus (AAV) is a useful gene transfer vector because of its ability to mediate efficient gene transduction in numerous dividing and quiescent cell types, without inducing any known pathogenicity. There are now a number of natural for that designed AAV serotypes that each has a differential ability to infect a variety of cell types. Although transduction studies have been completed, the bulk of the studies have been done in vivo, and there has never been a comprehensive study of transduction ex vivo/in vitro. Each cell type was infected with each serotype at a multiplicity of infection of 100,000 viral genomes/cell and transduction was analyzed by flow cytometry + . We found that AAV1 and AAV6 have the greatest ability to transduce a wide range of cell types, however, for particular cell types, there are specific serotypes that provide optimal transduction. In this work, we describe the transduction efficiency of ten different AAV serotypes in thirty-four different mammalian cell lines and primary cell types. Although these results may not be universal due to numerous factors such as, culture conditions and/ or cell growth rates and cell heterogeneity, these results provide an important and unique resource for investigators who use AAV as an ex vivo gene delivery vector or who work with cells that are difficult to transfect.

Establishing an unusual cell type: How to make a dikaryon

PubMed Central

Kruzel, Emilia K.; Hull, Christina M.

2010-01-01

Summary The dikaryons of basidiomycete fungi represent an unusual cell type required for complete sexual development. Dikaryon formation occurs via the activities of cell type-specific homeodomain transcription factors, which form regulatory complexes to establish the dikaryotic state. Decades of classical genetic and cell biological studies in mushrooms have provided a foundation for more recent molecular studies in the pathogenic species Ustilago maydis and Cryptococcus neoformans. Studies in these systems have revealed novel mechanisms of regulation that function downstream of classic homeodomain complexes to ensure that dikaryons are established and propagated. Comparisons of these dikaryon-specific networks promise to reveal the nature of regulatory network evolution and the adaptations responsible for driving complex eukaryotic development. PMID:21036099

Target-specific expression of presynaptic NMDA receptors in neocortical microcircuits.

PubMed

Buchanan, Katherine A; Blackman, Arne V; Moreau, Alexandre W; Elgar, Dale; Costa, Rui P; Lalanne, Txomin; Tudor Jones, Adam A; Oyrer, Julia; Sjöström, P Jesper

2012-08-09

Traditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns. Copyright © 2012 Elsevier Inc. All rights reserved.

Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity

PubMed Central

Mazzoni, Esteban O; Mahony, Shaun; Closser, Michael; Morrison, Carolyn A; Nedelec, Stephane; Williams, Damian J; An, Disi; Gifford, David K; Wichterle, Hynek

2013-01-01

Efficient transcriptional programming promises to open new frontiers in regenerative medicine. However, mechanisms by which programming factors transform cell fate are unknown, preventing more rational selection of factors to generate desirable cell types. Three transcription factors, Ngn2, Isl1 and Lhx3, were sufficient to program rapidly and efficiently spinal motor neuron identity when expressed in differentiating mouse embryonic stem cells. Replacement of Lhx3 by Phox2a led to specification of cranial, rather than spinal, motor neurons. Chromatin immunoprecipitation–sequencing analysis of Isl1, Lhx3 and Phox2a binding sites revealed that the two cell fates were programmed by the recruitment of Isl1-Lhx3 and Isl1-Phox2a complexes to distinct genomic locations characterized by a unique grammar of homeodomain binding motifs. Our findings suggest that synergistic interactions among transcription factors determine the specificity of their recruitment to cell type–specific binding sites and illustrate how a single transcription factor can be repurposed to program different cell types. PMID:23872598

Geographical and Geodemographic Connections between Different Types of Small Area as the Origins and Destinations of Migrants to Mid-Wales

ERIC Educational Resources Information Center

Walford, Nigel

2007-01-01

Exchanges of population between supposedly "urban" and "rural" spaces have occurred throughout history as people migrate between areas with relatively, densely and sparsely settled populations. However, comparatively little is known about whether the same small areas persistently contribute to the flow and what types of…

Systems Biology Analysis of Heterocellular Signaling.

PubMed

Tape, Christopher J

2016-08-01

Tissues comprise multiple heterotypic cell types (e.g., epithelial, mesenchymal, and immune cells). Communication between heterotypic cell types is essential for biological cohesion and is frequently dysregulated in disease. Despite the importance of heterocellular communication, most systems biology techniques do not report cell-specific signaling data from mixtures of cells. As a result, our existing perspective of cellular behavior under-represents the influence of heterocellular signaling. Recent technical advances now permit the resolution of systems-level cell-specific signaling data. This review discusses how new physical, spatial, and isotopic resolving methods are facilitating unique systems biology studies of heterocellular communication. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cuticular Waxes of Arabidopsis thaliana Shoots: Cell-Type-Specific Composition and Biosynthesis

PubMed Central

Hegebarth, Daniela; Jetter, Reinhard

2017-01-01

It is generally assumed that all plant epidermis cells are covered with cuticles, and the distinct surface geometries of pavement cells, guard cells, and trichomes imply functional differences and possibly different wax compositions. However, experiments probing cell-type-specific wax compositions and biosynthesis have been lacking until recently. This review summarizes new evidence showing that Arabidopsis trichomes have fewer wax compound classes than pavement cells, and higher amounts of especially long-chain hydrocarbons. The biosynthesis machinery generating this characteristic surface coating is discussed. Interestingly, wax compounds with similar, long hydrocarbon chains had been identified previously in some unrelated species, not all of them bearing trichomes. PMID:28686187

Adenovirus Vectors Target Several Cell Subtypes of Mammalian Inner Ear In Vivo

PubMed Central

Li, Wenyan; Shen, Jun

2016-01-01

Mammalian inner ear harbors diverse cell types that are essential for hearing and balance. Adenovirus is one of the major vectors to deliver genes into the inner ear for functional studies and hair cell regeneration. To identify adenovirus vectors that target specific cell subtypes in the inner ear, we studied three adenovirus vectors, carrying a reporter gene encoding green fluorescent protein (GFP) from two vendors or with a genome editing gene Cre recombinase (Cre), by injection into postnatal days 0 (P0) and 4 (P4) mouse cochlea through scala media by cochleostomy in vivo. We found three adenovirus vectors transduced mouse inner ear cells with different specificities and expression levels, depending on the type of adenoviral vectors and the age of mice. The most frequently targeted region was the cochlear sensory epithelium, including auditory hair cells and supporting cells. Adenovirus with GFP transduced utricular supporting cells as well. This study shows that adenovirus vectors are capable of efficiently and specifically transducing different cell types in the mammalian inner ear and provides useful tools to study inner ear gene function and to evaluate gene therapy to treat hearing loss and vestibular dysfunction. PMID:28116172

Tissue and cell-type co-expression networks of transcription factors and wood component genes in Populus trichocarpa.

PubMed

Shi, Rui; Wang, Jack P; Lin, Ying-Chung; Li, Quanzi; Sun, Ying-Hsuan; Chen, Hao; Sederoff, Ronald R; Chiang, Vincent L

2017-05-01

Co-expression networks based on transcriptomes of Populus trichocarpa major tissues and specific cell types suggest redundant control of cell wall component biosynthetic genes by transcription factors in wood formation. We analyzed the transcriptomes of five tissues (xylem, phloem, shoot, leaf, and root) and two wood forming cell types (fiber and vessel) of Populus trichocarpa to assemble gene co-expression subnetworks associated with wood formation. We identified 165 transcription factors (TFs) that showed xylem-, fiber-, and vessel-specific expression. Of these 165 TFs, 101 co-expressed (correlation coefficient, r > 0.7) with the 45 secondary cell wall cellulose, hemicellulose, and lignin biosynthetic genes. Each cell wall component gene co-expressed on average with 34 TFs, suggesting redundant control of the cell wall component gene expression. Co-expression analysis showed that the 101 TFs and the 45 cell wall component genes each has two distinct groups (groups 1 and 2), based on their co-expression patterns. The group 1 TFs (44 members) are predominantly xylem and fiber specific, and are all highly positively co-expressed with the group 1 cell wall component genes (30 members), suggesting their roles as major wood formation regulators. Group 1 TFs include a lateral organ boundary domain gene (LBD) that has the highest number of positively correlated cell wall component genes (36) and TFs (47). The group 2 TFs have 57 members, including 14 vessel-specific TFs, and are generally less correlated with the cell wall component genes. An exception is a vessel-specific basic helix-loop-helix (bHLH) gene that negatively correlates with 20 cell wall component genes, and may function as a key transcriptional suppressor. The co-expression networks revealed here suggest a well-structured transcriptional homeostasis for cell wall component biosynthesis during wood formation.

Single-Cell Tracking Reveals a Role for Pre-Existing CCR5+ Memory Th1 Cells in the Control of Rhinovirus-A39 After Experimental Challenge in Humans.

PubMed

Muehling, Lyndsey M; Turner, Ronald B; Brown, Kenneth B; Wright, Paul W; Patrie, James T; Lahtinen, Sampo J; Lehtinen, Markus J; Kwok, William W; Woodfolk, Judith A

2018-01-17

Little is known about T cells that respond to human rhinovirus in vivo, due to timing of infection, viral diversity, and complex T-cell specificities. We tracked circulating CD4+ T cells with identical epitope specificities that responded to intranasal challenge with rhinovirus (RV)-A39, and we assessed T-cell signatures in the nose. Cells were monitored using a mixture of 2 capsid-specific major histocompatibility complex II tetramers over a 7-week period, before and after RV-A39 challenge, in 16 human leukocyte antigen-DR4+ subjects who participated in a trial of Bifidobacterium lactis (Bl-04) supplementation. Pre-existing tetramer+ T cells were linked to delayed viral shedding, enriched for activated CCR5+ Th1 effectors, and included a minor interleukin-21+ T follicular helper cell subset. After RV challenge, expansion and activation of virus-specific CCR5+ Th1 effectors was restricted to subjects who had a rise in neutralizing antibodies, and tetramer-negative CCR5+ effector memory types were comodulated. In the nose, CXCR3-CCR5+ T cells present during acute infection were activated effector memory type, whereas CXCR3+ cells were central memory type, and cognate chemokine ligands were elevated over baseline. Probiotic had no T-cell effects. We conclude that virus-specific CCR5+ effector memory CD4+ T cells primed by previous exposure to related viruses contribute to the control of rhinovirus. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.