The neuroprotective role of boric acid on aluminum chloride-induced neurotoxicity.

PubMed

Colak, Suat; Geyikoglu, Fatime; Keles, Osman Nuri; Türkez, Hasan; Topal, Ahmet; Unal, Bünyami

2011-09-01

This study was designed to investigate the qualitative and quantitative changes in brain tissue following aluminum chloride (AlCl(3)) administration and to determine whether boric acid (BA) has a protective effect against brain damage induced by AlCl( 3). For this aim, Sprague-Dawley rats were randomly separated into eight groups: (1) control, (2) AlCl(3) (5 mg/kg/day), (3, 4 and 5) BA (3.25, 36 and 58.5 mg/kg/day), (6, 7 and 8) AlCl(3) (5 mg/kg/day) plus BA (3.25, 36 and 58.5 mg/kg/day). After the animals were killed, the total numbers of neuron in the brain of all groups were determined using an unbiased stereological analysis. In addition to the stereological analysis, all brains were examined histopathologically by using light and electron microscopy. The stereological and histopathological results indicated a high damage of the rat brain tissues in the AlCl(3) and AlCl(3) + high dose BA (36 and 58.5) treatment groups. However, protective effects on neuron were observed in the AlCl(3) + low dose BA (3.25) group when compared other AlCl(3) groups. Our stereological and histopathological findings show that low-dose BA, as a proteasome inhibitor, can decrease the adverse effects of AlCl(3) on the cerebral cortex.

Systematic versus random sampling in stereological studies.

PubMed

West, Mark J

2012-12-01

The sampling that takes place at all levels of an experimental design must be random if the estimate is to be unbiased in a statistical sense. There are two fundamental ways by which one can make a random sample of the sections and positions to be probed on the sections. Using a card-sampling analogy, one can pick any card at all out of a deck of cards. This is referred to as independent random sampling because the sampling of any one card is made without reference to the position of the other cards. The other approach to obtaining a random sample would be to pick a card within a set number of cards and others at equal intervals within the deck. Systematic sampling along one axis of many biological structures is more efficient than random sampling, because most biological structures are not randomly organized. This article discusses the merits of systematic versus random sampling in stereological studies.

Brain Volume Estimation Enhancement by Morphological Image Processing Tools.

PubMed

Zeinali, R; Keshtkar, A; Zamani, A; Gharehaghaji, N

2017-12-01

Volume estimation of brain is important for many neurological applications. It is necessary in measuring brain growth and changes in brain in normal/abnormal patients. Thus, accurate brain volume measurement is very important. Magnetic resonance imaging (MRI) is the method of choice for volume quantification due to excellent levels of image resolution and between-tissue contrast. Stereology method is a good method for estimating volume but it requires to segment enough MRI slices and have a good resolution. In this study, it is desired to enhance stereology method for volume estimation of brain using less MRI slices with less resolution. In this study, a program for calculating volume using stereology method has been introduced. After morphologic method, dilation was applied and the stereology method enhanced. For the evaluation of this method, we used T1-wighted MR images from digital phantom in BrainWeb which had ground truth. The volume of 20 normal brain extracted from BrainWeb, was calculated. The volumes of white matter, gray matter and cerebrospinal fluid with given dimension were estimated correctly. Volume calculation from Stereology method in different cases was made. In three cases, Root Mean Square Error (RMSE) was measured. Case I with T=5, d=5, Case II with T=10, D=10 and Case III with T=20, d=20 (T=slice thickness, d=resolution as stereology parameters). By comparing these results of two methods, it is obvious that RMSE values for our proposed method are smaller than Stereology method. Using morphological operation, dilation allows to enhance the estimation volume method, Stereology. In the case with less MRI slices and less test points, this method works much better compared to Stereology method.

Comparison of volume estimation methods for pancreatic islet cells

NASA Astrophysics Data System (ADS)

Dvořák, JiřÃ.­; Å vihlík, Jan; Habart, David; Kybic, Jan

2016-03-01

In this contribution we study different methods of automatic volume estimation for pancreatic islets which can be used in the quality control step prior to the islet transplantation. The total islet volume is an important criterion in the quality control. Also, the individual islet volume distribution is interesting -- it has been indicated that smaller islets can be more effective. A 2D image of a microscopy slice containing the islets is acquired. The input of the volume estimation methods are segmented images of individual islets. The segmentation step is not discussed here. We consider simple methods of volume estimation assuming that the islets have spherical or ellipsoidal shape. We also consider a local stereological method, namely the nucleator. The nucleator does not rely on any shape assumptions and provides unbiased estimates if isotropic sections through the islets are observed. We present a simulation study comparing the performance of the volume estimation methods in different scenarios and an experimental study comparing the methods on a real dataset.

High doses of nandrolone decanoate reduce volume of testis and length of seminiferous tubules in rats.

PubMed

Noorafshan, Ali; Karbalay-Doust, Saied; Ardekani, Fakhrodin Mesbah

2005-02-01

Anabolic-androgenic steroid (AAS) compounds rank among the drugs most widely abused with the goal of improving athletic ability, appearance, or muscle mass. It has been shown that these compounds have adverse effects on human and animal physiology and sperm quality, but quantitative structural changes of the testis have received less attention. The present study was conducted to evaluate the effects of nandrolone decanoate, which is one of the AAS compounds, on testis weight and volume, diameter and length of seminiferous tubules in rats by unbiased stereological methods. Adult rats were divided into three groups. The first comprised control rats; the second and third groups received low and high doses of nandrolone decanoate for 14 weeks. The rats were then left untreated for 14 weeks. After removal of the testis, stereological study of these tissues showed that the mean volume of testis and length of the seminiferous tubules in the animals that received high doses of nandrolone decanoate were reduced approximately 32% (p<0.01) and approximately 31% (p<0.04), respectively, in comparison with the control group. It can be concluded that the high doses of nandrolone decanoate produce structural changes in the rat testis that remain 14 weeks after stopping injection of the drug.

Stereological assessment of normal Persian squirrels (Sciurus anomalus) kidney.

PubMed

Akbari, Mohsen; Goodarzi, Nader; Tavafi, Majid

2017-03-01

The functions of the mammalian kidney are closely related to its structure. This suggests that renal function can be completely characterized by accurate knowledge of its quantitative morphological features. The aim of this study was to investigate the histomorphometric features of the kidney using design-based and unbiased stereological methods in the Persian squirrel (Sciurus anomalus), which is the only representative of the Sciuridae family in the Middle East. The left kidneys of five animals were examined. Total volume of the kidney, cortex, and medulla were determined to be 960.75 ± 87.4, 754.31 ± 77.09 and 206.1 ± 16.89 mm 3 , respectively. The glomerular number was 32844.03 ± 1069.19, and the total glomerular volume was estimated to be 36.7 ± 1.45 mm 3 . The volume and length of the proximal convoluted tubule were estimated at 585.67 ± 60.7 mm 3 and 328.8 ± 14.8 m, respectively, with both values being greater than those reported in the rat kidney. The volume and length of the distal convoluted tubule were calculated at 122.34 ± 7.38 mm 3 and 234.4 ± 17.45 m, respectively, which are also greater than those reported in the rat kidney. Despite the comparable body weight, the total number and mean individual volume of glomeruli in the Persian squirrel kidney were greater than those in the rat kidney. Overall, the stereological variables of the kidneys elucidated in this study are exclusive to the Persian squirrel. Our findings, together with future renal physiological data, will contribute to a better understanding of the renal structure-function relationship in the Persian squirrel.

Postmortem structural studies of the thalamus in schizophrenia

PubMed Central

Dorph-Petersen, Karl-Anton; Lewis, David A.

2017-01-01

In this review, we seek to answer the following question: Do findings in the current literature support the idea that thalamo-cortical dysfunction in schizophrenia is due to structural abnormalities in the thalamus? We base our review on the existing literature of design-unbiased stereological studies of the postmortem thalamus from subjects with schizophrenia. Thus, all reported results are based upon the use of unbiased principles of sampling to determine volume and/or total cell numbers of thalamus or its constituent nuclei. We found 28 such papers covering 26 studies. In a series of tables we list all positive and negative findings from the total thalamus, the mediodorsal, pulvinar and anterior nuclei, as well as less frequently studied thalamic regions. Only four studies examined the entire thalamus and the results were inconsistent. We found largely consistent evidence for structural changes (reduced volume and cell numbers) in the pulvinar located in the posterior thalamus. In contrast, findings in the mediodorsal thalamic nucleus are inconsistent, with the largest and most recent studies generally failing to support earlier reports of a lower number of neurons in schizophrenia. Thus, the current findings of stereological studies of the thalamus in schizophrenia support the idea that thalamo-cortical dysfunction in schizophrenia might be attributable, at least in part, to structural alterations in the pulvinar that could impair thalamic inputs to higher order cortical association areas in the frontal and parietal lobes. However, more studies are needed before robust conclusions can be drawn. PMID:27567291

Abdominal fat volume estimation by stereology on CT: a comparison with manual planimetry.

PubMed

Manios, G E; Mazonakis, M; Voulgaris, C; Karantanas, A; Damilakis, J

2016-03-01

To deploy and evaluate a stereological point-counting technique on abdominal CT for the estimation of visceral (VAF) and subcutaneous abdominal fat (SAF) volumes. Stereological volume estimations based on point counting and systematic sampling were performed on images from 14 consecutive patients who had undergone abdominal CT. For the optimization of the method, five sampling intensities in combination with 100 and 200 points were tested. The optimum stereological measurements were compared with VAF and SAF volumes derived by the standard technique of manual planimetry on the same scans. Optimization analysis showed that the selection of 200 points along with the sampling intensity 1/8 provided efficient volume estimations in less than 4 min for VAF and SAF together. The optimized stereology showed strong correlation with planimetry (VAF: r = 0.98; SAF: r = 0.98). No statistical differences were found between the two methods (VAF: P = 0.81; SAF: P = 0.83). The 95% limits of agreement were also acceptable (VAF: -16.5%, 16.1%; SAF: -10.8%, 10.7%) and the repeatability of stereology was good (VAF: CV = 4.5%, SAF: CV = 3.2%). Stereology may be successfully applied to CT images for the efficient estimation of abdominal fat volume and may constitute a good alternative to the conventional planimetric technique. Abdominal obesity is associated with increased risk of disease and mortality. Stereology may quantify visceral and subcutaneous abdominal fat accurately and consistently. The application of stereology to estimating abdominal volume fat reduces processing time. Stereology is an efficient alternative method for estimating abdominal fat volume.

Stereological Analysis of Liver Biopsy Histology Sections as a Reference Standard for Validating Non-Invasive Liver Fat Fraction Measurements by MRI

PubMed Central

St. Pierre, Tim G.; House, Michael J.; Bangma, Sander J.; Pang, Wenjie; Bathgate, Andrew; Gan, Eng K.; Ayonrinde, Oyekoya T.; Bhathal, Prithi S.; Clouston, Andrew; Olynyk, John K.; Adams, Leon A.

2016-01-01

Background and Aims Validation of non-invasive methods of liver fat quantification requires a reference standard. However, using standard histopathology assessment of liver biopsies is problematical because of poor repeatability. We aimed to assess a stereological method of measuring volumetric liver fat fraction (VLFF) in liver biopsies and to use the method to validate a magnetic resonance imaging method for measurement of VLFF. Methods VLFFs were measured in 59 subjects (1) by three independent analysts using a stereological point counting technique combined with the Delesse principle on liver biopsy histological sections and (2) by three independent analysts using the HepaFat-Scan® technique on magnetic resonance images of the liver. Bland Altman statistics and intraclass correlation (IC) were used to assess the repeatability of each method and the bias between the methods of liver fat fraction measurement. Results Inter-analyst repeatability coefficients for the stereology and HepaFat-Scan® methods were 8.2 (95% CI 7.7–8.8)% and 2.4 (95% CI 2.2–2.5)% VLFF respectively. IC coefficients were 0.86 (95% CI 0.69–0.93) and 0.990 (95% CI 0.985–0.994) respectively. Small biases (≤3.4%) were observable between two pairs of analysts using stereology while no significant biases were observable between any of the three pairs of analysts using HepaFat-Scan®. A bias of 1.4±0.5% VLFF was observed between the HepaFat-Scan® method and the stereological method. Conclusions Repeatability of the stereological method is superior to the previously reported performance of assessment of hepatic steatosis by histopathologists and is a suitable reference standard for validating non-invasive methods of measurement of VLFF. PMID:27501242

Unbiased estimation of chloroplast number in mesophyll cells: advantage of a genuine three-dimensional approach

PubMed Central

Kubínová, Zuzana

2014-01-01

Chloroplast number per cell is a frequently examined quantitative anatomical parameter, often estimated by counting chloroplast profiles in two-dimensional (2D) sections of mesophyll cells. However, a mesophyll cell is a three-dimensional (3D) structure and this has to be taken into account when quantifying its internal structure. We compared 2D and 3D approaches to chloroplast counting from different points of view: (i) in practical measurements of mesophyll cells of Norway spruce needles, (ii) in a 3D model of a mesophyll cell with chloroplasts, and (iii) using a theoretical analysis. We applied, for the first time, the stereological method of an optical disector based on counting chloroplasts in stacks of spruce needle optical cross-sections acquired by confocal laser-scanning microscopy. This estimate was compared with counting chloroplast profiles in 2D sections from the same stacks of sections. Comparing practical measurements of mesophyll cells, calculations performed in a 3D model of a cell with chloroplasts as well as a theoretical analysis showed that the 2D approach yielded biased results, while the underestimation could be up to 10-fold. We proved that the frequently used method for counting chloroplasts in a mesophyll cell by counting their profiles in 2D sections did not give correct results. We concluded that the present disector method can be efficiently used for unbiased estimation of chloroplast number per mesophyll cell. This should be the method of choice, especially in coniferous needles and leaves with mesophyll cells with lignified cell walls where maceration methods are difficult or impossible to use. PMID:24336344

Systematic random sampling of the comet assay.

PubMed

McArt, Darragh G; Wasson, Gillian R; McKerr, George; Saetzler, Kurt; Reed, Matt; Howard, C Vyvyan

2009-07-01

The comet assay is a technique used to quantify DNA damage and repair at a cellular level. In the assay, cells are embedded in agarose and the cellular content is stripped away leaving only the DNA trapped in an agarose cavity which can then be electrophoresed. The damaged DNA can enter the agarose and migrate while the undamaged DNA cannot and is retained. DNA damage is measured as the proportion of the migratory 'tail' DNA compared to the total DNA in the cell. The fundamental basis of these arbitrary values is obtained in the comet acquisition phase using fluorescence microscopy with a stoichiometric stain in tandem with image analysis software. Current methods deployed in such an acquisition are expected to be both objectively and randomly obtained. In this paper we examine the 'randomness' of the acquisition phase and suggest an alternative method that offers both objective and unbiased comet selection. In order to achieve this, we have adopted a survey sampling approach widely used in stereology, which offers a method of systematic random sampling (SRS). This is desirable as it offers an impartial and reproducible method of comet analysis that can be used both manually or automated. By making use of an unbiased sampling frame and using microscope verniers, we are able to increase the precision of estimates of DNA damage. Results obtained from a multiple-user pooled variation experiment showed that the SRS technique attained a lower variability than that of the traditional approach. The analysis of a single user with repetition experiment showed greater individual variances while not being detrimental to overall averages. This would suggest that the SRS method offers a better reflection of DNA damage for a given slide and also offers better user reproducibility.

White matter atrophy and myelinated fiber disruption in a rat model of depression.

PubMed

Gao, Yuan; Ma, Jing; Tang, Jing; Liang, Xin; Huang, Chun-Xia; Wang, San-Rong; Chen, Lin-Mu; Wang, Fei-Fei; Tan, Chuan-Xue; Chao, Feng-Lei; Zhang, Lei; Qiu, Xuan; Luo, Yan-Min; Xiao, Qian; Du, Lian; Xiao, Qian; Tang, Yong

2017-06-01

Brain imaging and postmortem studies have indicated that white matter abnormalities may contribute to the pathology and pathogenesis of depression. However, until now, no study has quantitatively investigated white matter changes in depression in rats. The current study used the chronic unpredictable stress (CUS) model of depression. Body weight and sucrose preference test (SPT) scores were assessed weekly. Upon successfully establishing the CUS animal model, all animals were tested using the SPT and the open field test (OFT). Then, transmission electron microscopy and unbiased stereological methods were used to investigate white matter changes in the rats. Compared with the control group, the body weight and sucrose preference of the CUS rats were significantly decreased (p < .001, p < .001, respectively). In the OFT, the total time spent and the total distance traveled in the inner area by the CUS rats were significantly lower than those of the control group (p = .002, p = .001, respectively). The stereological results revealed that white matter volume, the total volume, and the total length and mean diameter of myelinated fibers in the white matter of the CUS rats were significantly decreased compared to the control rats (p = .042, p = .038, p = .035, p = .019, respectively). The results of this study suggested that white matter atrophy and disruption of myelinated fibers in the white matter may contribute to the pathophysiology underlying depression, which might provide new targets for the development of novel therapeutic interventions for depression. © 2017 Wiley Periodicals, Inc.

Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease

PubMed Central

Borner, Roseane; Bento-Torres, João; Souza, Diego RV; Sadala, Danyelle B; Trevia, Nonata; Farias, José Augusto; Lins, Nara; Passos, Aline; Quintairos, Amanda; Diniz, José Antônio; Perry, Victor Hugh; Vasconcelos, Pedro Fernando; Cunningham, Colm

2011-01-01

Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression. PMID:21862877

Quantitative microscopy of the lung: a problem-based approach. Part 1: basic principles of lung stereology.

PubMed

Ochs, Matthias; Mühlfeld, Christian

2013-07-01

The growing awareness of the importance of accurate morphometry in lung research has recently motivated the publication of guidelines set forth by a combined task force of the American Thoracic Society and the European Respiratory Society (20). This official ATS/ERS Research Policy Statement provides general recommendations on which stereological methods are to be used in quantitative microscopy of the lung. However, to integrate stereology into a particular experimental study design, investigators are left with the problem of how to implement this in practice. Specifically, different animal models of human lung disease require the use of different stereological techniques and may determine the mode of lung fixation, tissue processing, preparation of sections, and other things. Therefore, the present companion articles were designed to allow a short practically oriented introduction into the concepts of design-based stereology (Part 1) and to provide recommendations for choosing the most appropriate methods to investigate a number of important disease models (Part 2). Worked examples with illustrative images will facilitate the practical performance of equivalent analyses. Study algorithms provide comprehensive surveys to ensure that no essential step gets lost during the multistage workflow. Thus, with this review, we hope to close the gap between theory and practice and enhance the use of stereological techniques in pulmonary research.

Assessment of cardiac fibrosis: a morphometric method comparison for collagen quantification.

PubMed

Schipke, Julia; Brandenberger, Christina; Rajces, Alexandra; Manninger, Martin; Alogna, Alessio; Post, Heiner; Mühlfeld, Christian

2017-04-01

Fibrotic remodeling of the heart is a frequent condition linked to various diseases and cardiac dysfunction. Collagen quantification is an important objective in cardiac fibrosis research; however, a variety of different histological methods are currently used that may differ in accuracy. Here, frequently applied collagen quantification techniques were compared. A porcine model of early stage heart failure with preserved ejection fraction was used as an example. Semiautomated threshold analyses were imprecise, mainly due to inclusion of noncollagen structures or failure to detect certain collagen deposits. In contrast, collagen assessment by automated image analysis and light microscopy (LM)-stereology was more sensitive. Depending on the quantification method, the amount of estimated collagen varied and influenced intergroup comparisons. PicroSirius Red, Masson's trichrome, and Azan staining protocols yielded similar results, whereas the measured collagen area increased with increasing section thickness. Whereas none of the LM-based methods showed significant differences between the groups, electron microscopy (EM)-stereology revealed a significant collagen increase between cardiomyocytes in the experimental group, but not at other localizations. In conclusion, in contrast to the staining protocol, section thickness and the quantification method being used directly influence the estimated collagen content and thus, possibly, intergroup comparisons. EM in combination with stereology is a precise and sensitive method for collagen quantification if certain prerequisites are considered. For subtle fibrotic alterations, consideration of collagen localization may be necessary. Among LM methods, LM-stereology and automated image analysis are appropriate to quantify fibrotic changes, the latter depending on careful control of algorithm and comparable section staining. NEW & NOTEWORTHY Direct comparison of frequently applied histological fibrosis assessment techniques revealed a distinct relation of measured collagen and utilized quantification method as well as section thickness. Besides electron microscopy-stereology, which was precise and sensitive, light microscopy-stereology and automated image analysis proved to be appropriate for collagen quantification. Moreover, consideration of collagen localization might be important in revealing minor fibrotic changes. Copyright © 2017 the American Physiological Society.

Practical application of stereological methods in experimental kidney animal models.

PubMed

Fernández García, María Teresa; Núñez Martínez, Paula; García de la Fuente, Vanessa; Sánchez Pitiot, Marta; Muñiz Salgueiro, María Del Carmen; Perillán Méndez, Carmen; Argüelles Luis, Juan; Astudillo González, Aurora

The kidneys are vital organs responsible for excretion, fluid and electrolyte balance and hormone production. The nephrons are the kidney's functional and structural units. The number, size and distribution of the nephron components contain relevant information on renal function. Stereology is a branch of morphometry that applies mathematical principles to obtain three-dimensional information from serial, parallel and equidistant two-dimensional microscopic sections. Because of the complexity of stereological studies and the lack of scientific literature on the subject, the aim of this paper is to clearly explain, through animal models, the basic concepts of stereology and how to calculate the main kidney stereological parameters that can be applied in future experimental studies. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Assessment of left ventricular function and mass by MR imaging: a stereological study based on the systematic slice sampling procedure.

PubMed

Mazonakis, Michalis; Sahin, Bunyamin; Pagonidis, Konstantin; Damilakis, John

2011-06-01

The aim of this study was to combine the stereological technique with magnetic resonance (MR) imaging data for the volumetric and functional analysis of the left ventricle (LV). Cardiac MR examinations were performed in 13 consecutive subjects with known or suspected coronary artery disease. The end-diastolic volume (EDV), end-systolic volume, ejection fraction (EF), and mass were estimated by stereology using the entire slice set depicting LV and systematic sampling intensities of 1/2 and 1/3 that provided samples with every second and third slice, respectively. The repeatability of stereology was evaluated. Stereological assessments were compared with the reference values derived by manually tracing the endocardial and epicardial contours on MR images. Stereological EDV and EF estimations obtained by the 1/3 systematic sampling scheme were significantly different from those by manual delineation (P < .05). No difference was observed between the reference values and the LV parameters estimated by the entire slice set or a sampling intensity of 1/2 (P > .05). For these stereological approaches, a high correlation (r(2) = 0.80-0.93) and clinically acceptable limits of agreement were found with the reference method. Stereological estimations obtained by both sample sizes presented comparable coefficient of variation values of 2.9-5.8%. The mean time for stereological measurements on the entire slice set was 3.4 ± 0.6 minutes and it was reduced to 2.5 ± 0.5 minutes with the 1/2 systematic sampling scheme. Stereological analysis on systematic samples of MR slices generated by the 1/2 sampling intensity provided efficient and quick assessment of LV volumes, function, and mass. Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.

Estimation of neuronal numbers in rat hippocampus following neonatal amphetamine exposure: a stereology study.

PubMed

Smith, Andrew M; Pappalardo, Dana; Chen, Wei-Jung A

2008-01-01

In this study, the effects of amphetamine exposure during a portion of the brain growth spurt on the total number of hippocampal pyramidal cells (CA1/CA3 subregions) and the granule cells (dentate gyrus) were examined in both neonatal and adult rats. Intragastric intubation was used to administer 5, 15 or 25 mg/kg/day of amphetamine to Sprague-Dawley rat pups from PDs 4-9. Unbiased stereology was used to estimate the total number of cells present within each hippocampal subregion at both PD 9 and PD 68. The results indicated that neonatal amphetamine exposure did not alter the cell number, the reference volume or the density in any of the hippocampal subregions assessed, regardless of age. However, amphetamine significantly altered the rate of neuronal incorporation in both the hippocampal CA3 subregion and the dentate gyrus, and this effect appeared to be dose-related with the most robust effect observed in the highest amphetamine dose. While these findings did not demonstrate significant injurious effects of neonatal amphetamine treatment on the number of hippocampal neurons, these data suggest that amphetamine may interfere with proper hippocampal development. Future studies employing more sensitive measurements or exposing amphetamine during an alternate period of development may provide more information regarding amphetamine-mediated developmental neurotoxicity.

Zone-specific cell biosynthetic activity in mature bovine articular cartilage: a new method using confocal microscopic stereology and quantitative autoradiography.

PubMed

Wong, M; Wuethrich, P; Eggli, P; Hunziker, E

1996-05-01

A new methodology was developed to measure spatial variations in chondrocyte/matrix structural parameters and chondrocyte biosynthetic activity in articular cartilage. This technique is based on the use of a laser scanning confocal microscope that can "optically" section chemically fixed, unembedded tissue. The confocal images are used for morphometric measurement of stereologic parameters such as cell density (cells/mm3), cell volume fraction (%), surface density (l/cm), mean cell volume (micron3), and mean cell surface area (micron2). Adjacent pieces of tissue are simultaneously processed for conventional liquid emulsion autoradiography, and a semiautomated grain counting program is used to measure the silver grain density at regions corresponding to the same sites used for structural measurements. An estimate of chondrocyte biosynthetic activity in terms of grains per cell is obtained by dividing the value for grain density by that for cell density. In this paper, the newly developed methodology was applied to characterize the zone-specific behavior of adult articular cartilage in the free-swelling state. Cylinders of young adult bovine articular cartilage were labelled with either [3H]proline or [35S]sulfate, and chondrocyte biosynthesis and structural parameters were measured from the articular surface to the tidemark. The results showed that chondrocytes of the radial zone occupied twice the volume and surface area of the chondrocytes of the superficial zone but were 10 times more synthetically active. This efficient and unbiased technique may prove useful in studying the correlation between mechanically induced changes in cell form and biosynthetic activity within inhomogeneous tissue as well as metabolic changes in cartilage due to ageing and disease.

Stereology techniques in radiation biology

NASA Technical Reports Server (NTRS)

Kubinova, Lucie; Mao, XiaoWen; Janacek, Jiri; Archambeau, John O.; Nelson, G. A. (Principal Investigator)

2003-01-01

Clinicians involved in conventional radiation therapy are very concerned about the dose-response relationships of normal tissues. Before proceeding to new clinical protocols, radiation biologists involved with conformal proton therapy believe it is necessary to quantify the dose response and tolerance of the organs and tissues that will be irradiated. An important focus is on the vasculature. This presentation reviews the methodology and format of using confocal microscopy and stereological methods to quantify tissue parameters, cell number, tissue volume and surface area, and vessel length using the microvasculature as a model tissue. Stereological methods and their concepts are illustrated using an ongoing study of the dose response of the microvessels in proton-irradiated hemibrain. Methods for estimating the volume of the brain and the brain cortex, the total number of endothelial cells in cortical microvessels, the length of cortical microvessels, and the total surface area of cortical microvessel walls are presented step by step in a way understandable for readers with little mathematical background. It is shown that stereological techniques, based on a sound theoretical basis, are powerful and reliable and have been used successfully.

Practical Stereology Applications for the Pathologist.

PubMed

Brown, Danielle L

2017-05-01

Qualitative histopathology is the gold standard for routine examination of morphological tissue changes in the regulatory or academic environment. The human eye is exceptional for pattern recognition but often cannot detect small changes in quantity. In cases where detection of subtle quantitative changes is critical, more sensitive methods are required. Two-dimensional histomorphometry can provide additional quantitative information and is quite useful in many cases. However, the provided data may not be referent to the entire tissue and, as such, it makes several assumptions, which are sources of bias. In contrast, stereology is design based rather than assumption based and uses stringent sampling methods to obtain accurate and precise 3-dimensional information using geometrical and statistical principles. Recent advances in technology have made stereology more approachable and practical for the pathologist in both regulatory and academic environments. This review introduces pathologists to the basic principles of stereology and walks the reader through some real-world examples for the application of these principles in the workplace.

A simple and efficient alternative to implementing systematic random sampling in stereological designs without a motorized microscope stage.

PubMed

Melvin, Neal R; Poda, Daniel; Sutherland, Robert J

2007-10-01

When properly applied, stereology is a very robust and efficient method to quantify a variety of parameters from biological material. A common sampling strategy in stereology is systematic random sampling, which involves choosing a random sampling [corrected] start point outside the structure of interest, and sampling relevant objects at [corrected] sites that are placed at pre-determined, equidistant intervals. This has proven to be a very efficient sampling strategy, and is used widely in stereological designs. At the microscopic level, this is most often achieved through the use of a motorized stage that facilitates the systematic random stepping across the structure of interest. Here, we report a simple, precise and cost-effective software-based alternative to accomplishing systematic random sampling under the microscope. We believe that this approach will facilitate the use of stereological designs that employ systematic random sampling in laboratories that lack the resources to acquire costly, fully automated systems.

MRI volumetry of prefrontal cortex

NASA Astrophysics Data System (ADS)

Sheline, Yvette I.; Black, Kevin J.; Lin, Daniel Y.; Pimmel, Joseph; Wang, Po; Haller, John W.; Csernansky, John G.; Gado, Mokhtar; Walkup, Ronald K.; Brunsden, Barry S.; Vannier, Michael W.

1995-05-01

Prefrontal cortex volumetry by brain magnetic resonance (MR) is required to estimate changes postulated to occur in certain psychiatric and neurologic disorders. A semiautomated method with quantitative characterization of its performance is sought to reliably distinguish small prefrontal cortex volume changes within individuals and between groups. Stereological methods were tested by a blinded comparison of measurements applied to 3D MR scans obtained using an MPRAGE protocol. Fixed grid stereologic methods were used to estimate prefrontal cortex volumes on a graphic workstation, after the images are scaled from 16 to 8 bits using a histogram method. In addition images were resliced into coronal sections perpendicular to the bicommissural plane. Prefrontal cortex volumes were defined as all sections of the frontal lobe anterior to the anterior commissure. Ventricular volumes were excluded. Stereological measurement yielded high repeatability and precision, and was time efficient for the raters. The coefficient of error was

Quantitative morphology of the vascularisation of organs: A stereological approach illustrated using the cardiac circulation.

PubMed

Mühlfeld, Christian

2014-01-01

The vasculature of the heart is able to adapt to various physiological and pathological stimuli and its failure to do so is well-reflected by the great impact of ischaemic heart disease on personal morbidity and mortality and on the health care systems of industrial countries. Studies on physiological or genetic interventions as well as therapeutic angiogenesis rely on quantitative data to characterize the effects in a statistically robust way. The gold standard for obtaining quantitative morphological data is design-based stereology which allows the estimation of volume, surface area, length and number of blood vessels as well as their thickness, diameter or wall composition. Unfortunately, the use of stereological methods for this purpose is still rare. One of the reasons for this is the fact that the transfer of the theoretical foundations into laboratory practice requires a remarkable amount of considerations before touching the first piece of tissue. These considerations, however, are often based on already acquired experience and are usually not dealt with in stereological review articles. The present article therefore delineates the procedures for estimating the most important characteristics of the cardiac vasculature and highlights potential problems and their practical solutions. Worked examples are used to illustrate the methods and provide examples of the calculations. Hopefully, the considerations and examples contained herein will provide researchers in this field with the necessary equipment to add stereological methods to their study designs. Copyright © 2012 Elsevier GmbH. All rights reserved.

An improved light microscopical histoquantitative method for the stereological analysis of the rat ventral prostate lobe.

PubMed

Romppanen, T; Huttunen, E; Helminen, H J

1980-07-01

An improved light microscopical histoquantitative method for the analysis of the stereologic structure of the ventral lobe of the rat prostate is introduced. From paraffin-embedded tissue sections, volumetric fractions of the acinar parenchyma, the glandular epithelium, the glandular lumen, and the interacinar tissue were determined. The surface density of the glandular epithelium and the length density of the glandular tubules per cubic millimeter of tissue were also calculated. The corresponding total amount/quantity of each tissue compartment was computed for the whole ventral lobe based on the weight of the lobe. Using established stereologic laws, the height of the epithelium, the diameter of the glandular tubules, the free distance between the glandular tubules, and the distance between the glandular centers (means) were determined. The fitness of the method was tested by analyzing, in addition to normal prostates, ventral prostates of rats castrated 30 days before sacrifice.

Stereological assessment of mouse lung parenchyma via nondestructive, multiscale micro-CT imaging validated by light microscopic histology

PubMed Central

Vasilescu, Dragoş M.; Klinge, Christine; Knudsen, Lars; Yin, Leilei; Wang, Ge; Weibel, Ewald R.; Ochs, Matthias

2013-01-01

Quantitative assessment of the lung microstructure using standard stereological methods such as volume fractions of tissue, alveolar surface area, or number of alveoli, are essential for understanding the state of normal and diseased lung. These measures are traditionally obtained from histological sections of the lung tissue, a process that ultimately destroys the three-dimensional (3-D) anatomy of the tissue. In comparison, a novel X-ray-based imaging method that allows nondestructive sectioning and imaging of fixed lungs at multiple resolutions can overcome this limitation. Scanning of the whole lung at high resolution and subsequent regional sampling at ultrahigh resolution without physically dissecting the organ allows the application of design-based stereology for assessment of the whole lung structure. Here we validate multiple stereological estimates performed on micro–computed tomography (μCT) images by comparing them with those obtained via conventional histology on the same mouse lungs. We explore and discuss the potentials and limitations of the two approaches. Histological examination offers higher resolution and the qualitative differentiation of tissues by staining, but ultimately loses 3-D tissue relationships, whereas μCT allows for the integration of morphometric data with the spatial complexity of lung structure. However, μCT has limited resolution satisfactory for the sterological estimates presented in this study but not for differentiation of tissues. We conclude that introducing stereological methods in μCT studies adds value by providing quantitative information on internal structures while not curtailing more complex approaches to the study of lung architecture in the context of physiological or pathological studies. PMID:23264542

Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice.

PubMed

Chang, Joshua C; Leung, Mark; Gokozan, Hamza Numan; Gygli, Patrick Edwin; Catacutan, Fay Patsy; Czeisler, Catherine; Otero, José Javier

2015-03-01

Late embryonic and postnatal cerebellar folial surface area expansion promotes cerebellar cortical cytoarchitectural lamination. We developed a streamlined sampling scheme to generate unbiased estimates of murine cerebellar surface area and volume using stereologic principles. We demonstrate that, during the proliferative phase of the external granular layer (EGL) and folial surface area expansion, EGL thickness does not change and thus is a topological proxy for progenitor self-renewal. The topological constraints indicate that, during proliferative phases, migration out of the EGL is balanced by self-renewal. Progenitor self-renewal must, therefore, include mitotic events yielding 2 cells in the same layer to increase surface area (β events) and mitotic events yielding 2 cells, with 1 cell in a superficial layer and 1 cell in a deeper layer (α events). As the cerebellum grows, therefore, β events lie upstream of α events. Using a mathematical model constrained by the measurements of volume and surface area, we could quantify intermitotic times for β events on a per-cell basis in postnatal mouse cerebellum. Furthermore, we found that loss of CCNA2, which decreases EGL proliferation and secondarily induces cerebellar cortical dyslamination, shows preserved α-type events. Thus, CCNA2-null cerebellar granule progenitor cells are capable of self-renewal of the EGL stem cell niche; this is concordant with prior findings of extensive apoptosis in CCNA2-null mice. Similar methodologies may provide another layer of depth to the interpretation of results from stereologic studies.

Population control of resident and immigrant microglia by mitosis and apoptosis.

PubMed

Wirenfeldt, Martin; Dissing-Olesen, Lasse; Anne Babcock, Alicia; Nielsen, Marianne; Meldgaard, Michael; Zimmer, Jens; Azcoitia, Iñigo; Leslie, Robert Graham Quinton; Dagnaes-Hansen, Frederik; Finsen, Bente

2007-08-01

Microglial population expansion occurs in response to neural damage via processes that involve mitosis and immigration of bone marrow-derived cells. However, little is known of the mechanisms that regulate clearance of reactive microglia, when microgliosis diminishes days to weeks later. We have investigated the mechanisms of microglial population control in a well-defined model of reactive microgliosis in the mouse dentate gyrus after perforant pathway axonal lesion. Unbiased stereological methods and flow cytometry demonstrate significant lesion-induced increases in microglial numbers. Reactive microglia often occurred in clusters, some having recently incorporated bromodeoxyuridine, showing that proliferation had occurred. Annexin V labeling and staining for activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling showed that apoptotic mechanisms participate in dissolution of the microglial response. Using bone marrow chimeric mice, we found that the lesion-induced proliferative capacity of resident microglia superseded that of immigrant microglia, whereas lesion-induced kinetics of apoptosis were comparable. Microglial numbers and responses were severely reduced in bone marrow chimeric mice. These results broaden our understanding of the microglial response to neural damage by demonstrating that simultaneously occurring mitosis and apoptosis regulate expansion and reduction of both resident and immigrant microglial cell populations.

[Simulation and data analysis of stereological modeling based on virtual slices].

PubMed

Wang, Hao; Shen, Hong; Bai, Xiao-yan

2008-05-01

To establish a computer-assisted stereological model for simulating the process of slice section and evaluate the relationship between section surface and estimated three-dimensional structure. The model was designed by mathematic method as a win32 software based on the MFC using Microsoft visual studio as IDE for simulating the infinite process of sections and analysis of the data derived from the model. The linearity of the fitting of the model was evaluated by comparison with the traditional formula. The win32 software based on this algorithm allowed random sectioning of the particles distributed randomly in an ideal virtual cube. The stereological parameters showed very high throughput (>94.5% and 92%) in homogeneity and independence tests. The data of density, shape and size of the section were tested to conform to normal distribution. The output of the model and that from the image analysis system showed statistical correlation and consistency. The algorithm we described can be used for evaluating the stereologic parameters of the structure of tissue slices.

The expression of MCM-2 in invasive breast carcinoma: a stereologic approach.

PubMed

Cobanoglu, Umit; Mungan, Sevdegul; Gundogdu, Cemal; Ersoz, Safak; Ozoran, Yavuz; Aydin, Fazil

2010-01-01

The aim of this study is to examine the expression of MCM-2 and conventional proliferation marker Ki-67 in breast carcinoma by stereologic technique and to compare it with various clinicopathologic parameters. The expression of MCM-2 and Ki-67 on paraffin-embedded tumor tissue sections of patients with invasive breast carcinoma was analyzed immunohistochemically. Stereologic method was used for evaluation of the percentage of positively stained tumor cells. Significant positive correlation was found between the expression of MCM-2 and that of Ki-67 (r = 0.74, p < 0.001). MCM-2 and Ki-67 expression was significantly associated with histologic grade (p < 0.05), and negative correlation was observed between MCM-2 or Ki-67 expression and estrogen status (p < 0.05). No significant association was observed between MCM-2 or Ki-67 expression and patient age, tumor size, lymph node status, clinical stage and menopausal status. Our results suggest that MCM-2 expression is significantly associated with histologic grade of breast carcinoma and with cell proliferation capacity (Ki-67 labelling index). Additional studies are required using the stereologic method to compare and understand the utility of Ki-67 and MCM-2 expression in invasive breast carcinoma (Tab. 1, Fig. 4, Ref. 34). Full Text (Free, PDF) www.bmj.sk.

The reliability of Cavalier's principle of stereological method in determining volumes of enchondromas using the computerized tomography tools.

PubMed

Acar, Nihat; Karakasli, Ahmet; Karaarslan, Ahmet; Mas, Nermin Ng; Hapa, Onur

2017-01-01

Volumetric measurements of benign tumors enable surgeons to trace volume changes during follow-up periods. For a volumetric measurement technique to be applicable, it should be easy, rapid, and inexpensive and should carry a high interobserver reliability. We aimed to assess the interobserver reliability of a volumetric measurement technique using the Cavalier's principle of stereological methods. The computerized tomography (CT) of 15 patients with a histopathologically confirmed diagnosis of enchondroma with variant tumor sizes and localizations was retrospectively reviewed for interobserver reliability evaluation of the volumetric stereological measurement with the Cavalier's principle, V = t × [((SU) × d) /SL]2 × Σ P. The volumes of the 15 tumors collected by the observers are demonstrated in Table 1. There was no statistical significance between the first and second observers ( p = 0.000 and intraclass correlation coefficient = 0.970) and between the first and third observers ( p = 0.000 and intraclass correlation coefficient = 0.981). No statistical significance was detected between the second and third observers ( p = 0.000 and intraclass correlation coefficient = 0.976). The Cavalier's principle with the stereological technique using the CT scans is an easy, rapid, and inexpensive technique in volumetric evaluation of enchondromas with a trustable interobserver reliability.

RandomSpot: A web-based tool for systematic random sampling of virtual slides.

PubMed

Wright, Alexander I; Grabsch, Heike I; Treanor, Darren E

2015-01-01

This paper describes work presented at the Nordic Symposium on Digital Pathology 2014, Linköping, Sweden. Systematic random sampling (SRS) is a stereological tool, which provides a framework to quickly build an accurate estimation of the distribution of objects or classes within an image, whilst minimizing the number of observations required. RandomSpot is a web-based tool for SRS in stereology, which systematically places equidistant points within a given region of interest on a virtual slide. Each point can then be visually inspected by a pathologist in order to generate an unbiased sample of the distribution of classes within the tissue. Further measurements can then be derived from the distribution, such as the ratio of tumor to stroma. RandomSpot replicates the fundamental principle of traditional light microscope grid-shaped graticules, with the added benefits associated with virtual slides, such as facilitated collaboration and automated navigation between points. Once the sample points have been added to the region(s) of interest, users can download the annotations and view them locally using their virtual slide viewing software. Since its introduction, RandomSpot has been used extensively for international collaborative projects, clinical trials and independent research projects. So far, the system has been used to generate over 21,000 sample sets, and has been used to generate data for use in multiple publications, identifying significant new prognostic markers in colorectal, upper gastro-intestinal and breast cancer. Data generated using RandomSpot also has significant value for training image analysis algorithms using sample point coordinates and pathologist classifications.

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

Bassuk, James; Lendvay, Thomas S.; Sweet, Robert

Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functionalmore » protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo.To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.« less

The changes of stage distribution of seminiferous epithelium cycle and its correlations with Leydig cell stereological parameters in aging men.

PubMed

Huang, Rui; Zhu, Wei-Jie; Li, Jing; Gu, Yi-Qun

2014-12-01

To evaluate the changes of stage distribution of seminiferous epithelium cycle and its correlations with Leydig cell stereological parameters in aging men. Point counting method was used to analyze the stereological parameters of Leydig cells. The stage number of seminiferous epithelium cycle was calculated in the same testicular tissue samples which were used for Leydig cell stereological analysis. The aging group had shown more severe pathological changes as well as higher pathologic scores than the young group. Compared with the control group, the volume density (VV) and surface density (NA) of Leydig cells in the aging group were increased significantly. The stage number of seminiferous epithelium cycle in the aging group was decreased coincidently compared to the young group. Leydig cell Vv in the young group has a positive relationship with stages I, II, III, V and VI of seminiferous epithelium cycle, and Leydig cell NA and numerical density (NV) were positively related to stage IV. However, only the correlation between NV and stage II was found in the aging group. The stage number of seminiferous epithelium cycle was decreased in aging testes. Changes in the stage distribution in aging testes were related to the Leydig cell stereological parameters which presented as a sign of morphological changes. Copyright © 2014 Elsevier GmbH. All rights reserved.

Digital immunohistochemistry wizard: image analysis-assisted stereology tool to produce reference data set for calibration and quality control

PubMed Central

2014-01-01

Background Digital image analysis (DIA) enables better reproducibility of immunohistochemistry (IHC) studies. Nevertheless, accuracy of the DIA methods needs to be ensured, demanding production of reference data sets. We have reported on methodology to calibrate DIA for Ki67 IHC in breast cancer tissue based on reference data obtained by stereology grid count. To produce the reference data more efficiently, we propose digital IHC wizard generating initial cell marks to be verified by experts. Methods Digital images of proliferation marker Ki67 IHC from 158 patients (one tissue microarray spot per patient) with an invasive ductal carcinoma of the breast were used. Manual data (mD) were obtained by marking Ki67-positive and negative tumour cells, using a stereological method for 2D object enumeration. DIA was used as an initial step in stereology grid count to generate the digital data (dD) marks by Aperio Genie and Nuclear algorithms. The dD were collected into XML files from the DIA markup images and overlaid on the original spots along with the stereology grid. The expert correction of the dD marks resulted in corrected data (cD). The percentages of Ki67 positive tumour cells per spot in the mD, dD, and cD sets were compared by single linear regression analysis. Efficiency of cD production was estimated based on manual editing effort. Results The percentage of Ki67-positive tumor cells was in very good agreement in the mD, dD, and cD sets: regression of cD from dD (R2=0.92) reflects the impact of the expert editing the dD as well as accuracy of the DIA used; regression of the cD from the mD (R2=0.94) represents the consistency of the DIA-assisted ground truth (cD) with the manual procedure. Nevertheless, the accuracy of detection of individual tumour cells was much lower: in average, 18 and 219 marks per spot were edited due to the Genie and Nuclear algorithm errors, respectively. The DIA-assisted cD production in our experiment saved approximately 2/3 of manual marking. Conclusions Digital IHC wizard enabled DIA-assisted stereology to produce reference data in a consistent and efficient way. It can provide quality control measure for appraising accuracy of the DIA steps. PMID:25565221

Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats.

PubMed

Li, Fang; Yan, Chao-Qun; Lin, Li-Ting; Li, Hui; Zeng, Xiang-Hong; Liu, Yi; Du, Si-Qi; Zhu, Wen; Liu, Cun-Zhi

2015-04-28

Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. Multi-infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P < 0.05) and tended to decrease the number of astrocytes (P = 0.063). However, there was no significant change in the synaptic bouton number of hippocampal CA1 area in any of the groups (P > 0.05). These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats.

[Morphometric and stereologic nuclear values obtained from the study of a population suffering from nasopharyngeal carcinoma].

PubMed

Pérez Plasencia, D; Flores Corral, T; Urrutia Avisrror, M; Santa Cruz Ruiz, S; Benito González, J; Mateos Pérez, M M; Gómez González, J L

2002-01-01

Computer nuclear morphometry and stereology are attractive methods because its objectivity and cheapness allowing histologic diagnosis when identifying minimal variations respectively the normality and also detect negligible disparities between anormal cells which could escape to the assessment of the pathologist. We present the data gained from several morphogenic and stereologic parameters resulting of measurements of tumoral cells procured from 40 patients with nasopharyngeal carcinomata. Middle values have been: nuclear area 27.70 microns 2; nuclear perimeter 20.80 microns; nuclear factor of form 0.81 microns; nuclear outline index 4.01; nuclear orientation angle 87.29 degrees; nuclear ellipsiticity 704.14; nuclear regularity 61.83; middle lineal length 4.30, middle linear distance 107.94; and nuclear volume 118.80 microns 3. Our series is the largest studied till now of all found in the literature. Comparison our data with those of previous publications.

Quantitative microscopy of the lung: a problem-based approach. Part 2: stereological parameters and study designs in various diseases of the respiratory tract.

PubMed

Mühlfeld, Christian; Ochs, Matthias

2013-08-01

Design-based stereology provides efficient methods to obtain valuable quantitative information of the respiratory tract in various diseases. However, the choice of the most relevant parameters in a specific disease setting has to be deduced from the present pathobiological knowledge. Often it is difficult to express the pathological alterations by interpretable parameters in terms of volume, surface area, length, or number. In the second part of this companion review article, we analyze the present pathophysiological knowledge about acute lung injury, diffuse parenchymal lung diseases, emphysema, pulmonary hypertension, and asthma to come up with recommendations for the disease-specific application of stereological principles for obtaining relevant parameters. Worked examples with illustrative images are used to demonstrate the work flow, estimation procedure, and calculation and to facilitate the practical performance of equivalent analyses.

Human Neural Stem Cell Transplantation Ameliorates Radiation-Induced Cognitive Dysfunction

PubMed Central

Acharya, Munjal M.; Christie, Lori-Ann; Lan, Mary L.; Giedzinski, Erich; Fike, John R.; Rosi, Susanna; Limoli, Charles L.

2012-01-01

Cranial radiotherapy induces progressive and debilitating declines in cognition that may, in part, be caused by the depletion of neural stem cells. The potential of using stem cell replacement as a strategy to combat radiation-induced cognitive decline was addressed by irradiating athymic nude rats followed 2 days later by intrahippocampal transplantation with human neural stem cells (hNSC). Measures of cognitive performance, hNSC survival, and phenotypic fate were assessed at 1 and 4 months after irradiation. Irradiated animals engrafted with hNSCs showed significantly less decline in cognitive function than irradiated, sham-engrafted animals and acted indistinguishably from unirradiated controls. Unbiased stereology revealed that 23% and 12% of the engrafted cells survived 1 and 4 months after transplantation, respectively. Engrafted cells migrated extensively, differentiated along glial and neuronal lineages, and expressed the activity-regulated cytoskeleton-associated protein (Arc), suggesting their capability to functionally integrate into the hippocampus. These data show that hNSCs afford a promising strategy for functionally restoring cognition in irradiated animals. PMID:21757460

Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats.

PubMed

Marcek, John; Okerberg, Carlin; Liu, Chang-Ning; Potter, David; Butler, Paul; Boucher, Magalie; Zorbas, Mark; Mouton, Peter; Nyengaard, Jens R; Somps, Chris

2016-10-01

Nerve growth factor (NGF) blocking therapies are an emerging and effective approach to pain management. However, concerns about the potential for adverse effects on the structure and function of the peripheral nervous system have slowed their development. Early studies using NGF antisera in adult rats reported effects on the size and number of neurons in the sympathetic chain ganglia. In the work described here, both young adult (6-8 week) and fully mature (7-8 month) rats were treated with muMab 911, a selective, murine, anti-NGF monoclonal antibody, to determine if systemic exposures to pharmacologically active levels of antibody for 1 month cause loss of neurons in the sympathetic superior cervical ganglia (SCG). State-of-the-art, unbiased stereology performed by two independent laboratories was used to determine the effects of muMab 911 on SCG neuronal number and size, as well as ganglion size. Following muMab 911 treatment, non-statistically significant trends toward smaller ganglia, and smaller and fewer neurons, were seen when routine, nonspecific stains were used in stereologic assessments. However, when noradrenergic neurons were identified using tyrosine hydroxylase (TH) immunoreactivity, trends toward fewer neurons observed with routine stains were not apparent. The only statistically significant effects detected were lower SCG weights in muMab 911-treated rats, and a smaller volume of TH immunoreactivity in neurons from younger rats treated with muMab 911. These results indicate that therapeutically relevant exposures to the anti-NGF monoclonal antibody muMab 911 for 1 month have no effect on neuron numbers within the SCG from young or old adult rats. Copyright © 2016 Elsevier B.V. All rights reserved.

Mild Traumatic Brain Injury Produces Neuron Loss That Can Be Rescued by Modulating Microglial Activation Using a CB2 Receptor Inverse Agonist

PubMed Central

Bu, Wei; Ren, Huiling; Deng, Yunping; Del Mar, Nobel; Guley, Natalie M.; Moore, Bob M.; Honig, Marcia G.; Reiner, Anton

2016-01-01

We have previously reported that mild TBI created by focal left-side cranial blast in mice produces widespread axonal injury, microglial activation, and a variety of functional deficits. We have also shown that these functional deficits are reduced by targeting microglia through their cannabinoid type-2 (CB2) receptors using 2-week daily administration of the CB2 inverse agonist SMM-189. CB2 inverse agonists stabilize the G-protein coupled CB2 receptor in an inactive conformation, leading to increased phosphorylation and nuclear translocation of the cAMP response element binding protein (CREB), and thus bias activated microglia from a pro-inflammatory M1 to a pro-healing M2 state. In the present study, we showed that SMM-189 boosts nuclear pCREB levels in microglia in several brain regions by 3 days after TBI, by using pCREB/CD68 double immunofluorescent labeling. Next, to better understand the basis of motor deficits and increased fearfulness after TBI, we used unbiased stereological methods to characterize neuronal loss in cortex, striatum, and basolateral amygdala (BLA) and assessed how neuronal loss was affected by SMM-189 treatment. Our stereological neuron counts revealed a 20% reduction in cortical and 30% reduction in striatal neurons bilaterally at 2–3 months post blast, with SMM-189 yielding about 50% rescue. Loss of BLA neurons was restricted to the blast side, with 33% of Thy1+ fear-suppressing pyramidal neurons and 47% of fear-suppressing parvalbuminergic (PARV) interneurons lost, and Thy1-negative fear-promoting pyramidal neurons not significantly affected. SMM-189 yielded 50–60% rescue of Thy1+ and PARV neuron loss in BLA. Thus, fearfulness after mild TBI may result from the loss of fear-suppressing neuron types in BLA, and SMM-189 may reduce fearfulness by their rescue. Overall, our findings indicate that SMM-189 rescues damaged neurons and thereby alleviates functional deficits resulting from TBI, apparently by selectively modulating microglia to the beneficial M2 state. CB2 inverse agonists thus represent a promising therapeutic approach for mitigating neuroinflammation and neurodegeneration. PMID:27766068

First and second order stereology of hyaline cartilage: Application on mice femoral cartilage.

PubMed

Noorafshan, Ali; Niazi, Behnam; Mohamadpour, Masoomeh; Hoseini, Leila; Hoseini, Najmeh; Owji, Ali Akbar; Rafati, Ali; Sadeghi, Yasaman; Karbalay-Doust, Saied

2016-11-01

Stereological techniques could be considered in research on cartilage to obtain quantitative data. The present study aimed to explain application of the first- and second-order stereological methods on articular cartilage of mice and the methods applied on the mice exposed to cadmium (Cd). The distal femoral articular cartilage of BALB/c mice (control and Cd-treated) was removed. Then, volume and surface area of the cartilage and number of chondrocytes were estimated using Cavalieri and optical dissector techniques on isotropic uniform random sections. Pair-correlation function [g(r)] and cross-correlation function were calculated to express the spatial arrangement of chondrocytes-chondrocytes and chondrocytes-matrix (chondrocyte clustering/dispersing), respectively. The mean±standard deviation of the cartilage volume, surface area, and thickness were 1.4±0.1mm 3 , 26.2±5.4mm 2 , and 52.8±6.7μm, respectively. Besides, the mean number of chondrocytes was 680±200 (×10 3 ). The cartilage volume, cartilage surface area, and number of chondrocytes were respectively reduced by 25%, 27%, and 27% in the Cd-treated mice in comparison to the control animals (p<0.03). Estimates of g(r) for the cells and matrix against the dipole distances, r, have been plotted. This plot showed that the chondrocytes and the matrix were neither dispersed nor clustered in the two study groups. Application of design-based stereological methods and also evaluation of spatial arrangement of the cartilage components carried potential advantages for investigating the cartilage in different joint conditions. Chondrocyte clustering/dispersing and cellularity can be evaluated in cartilage assessment in normal or abnormal situations. Copyright © 2016 Elsevier GmbH. All rights reserved.

Digital immunohistochemistry wizard: image analysis-assisted stereology tool to produce reference data set for calibration and quality control.

PubMed

Plancoulaine, Benoît; Laurinaviciene, Aida; Meskauskas, Raimundas; Baltrusaityte, Indra; Besusparis, Justinas; Herlin, Paulette; Laurinavicius, Arvydas

2014-01-01

Digital image analysis (DIA) enables better reproducibility of immunohistochemistry (IHC) studies. Nevertheless, accuracy of the DIA methods needs to be ensured, demanding production of reference data sets. We have reported on methodology to calibrate DIA for Ki67 IHC in breast cancer tissue based on reference data obtained by stereology grid count. To produce the reference data more efficiently, we propose digital IHC wizard generating initial cell marks to be verified by experts. Digital images of proliferation marker Ki67 IHC from 158 patients (one tissue microarray spot per patient) with an invasive ductal carcinoma of the breast were used. Manual data (mD) were obtained by marking Ki67-positive and negative tumour cells, using a stereological method for 2D object enumeration. DIA was used as an initial step in stereology grid count to generate the digital data (dD) marks by Aperio Genie and Nuclear algorithms. The dD were collected into XML files from the DIA markup images and overlaid on the original spots along with the stereology grid. The expert correction of the dD marks resulted in corrected data (cD). The percentages of Ki67 positive tumour cells per spot in the mD, dD, and cD sets were compared by single linear regression analysis. Efficiency of cD production was estimated based on manual editing effort. The percentage of Ki67-positive tumor cells was in very good agreement in the mD, dD, and cD sets: regression of cD from dD (R2=0.92) reflects the impact of the expert editing the dD as well as accuracy of the DIA used; regression of the cD from the mD (R2=0.94) represents the consistency of the DIA-assisted ground truth (cD) with the manual procedure. Nevertheless, the accuracy of detection of individual tumour cells was much lower: in average, 18 and 219 marks per spot were edited due to the Genie and Nuclear algorithm errors, respectively. The DIA-assisted cD production in our experiment saved approximately 2/3 of manual marking. Digital IHC wizard enabled DIA-assisted stereology to produce reference data in a consistent and efficient way. It can provide quality control measure for appraising accuracy of the DIA steps.

Computer-assisted stereology and automated image analysis for quantification of tumor infiltrating lymphocytes in colon cancer.

PubMed

Eriksen, Ann C; Andersen, Johnnie B; Kristensson, Martin; dePont Christensen, René; Hansen, Torben F; Kjær-Frifeldt, Sanne; Sørensen, Flemming B

2017-08-29

Precise prognostic and predictive variables allowing improved post-operative treatment stratification are missing in patients treated for stage II colon cancer (CC). Investigation of tumor infiltrating lymphocytes (TILs) may be rewarding, but the lack of a standardized analytic technique is a major concern. Manual stereological counting is considered the gold standard, but digital pathology with image analysis is preferred due to time efficiency. The purpose of this study was to compare manual stereological estimates of TILs with automatic counts obtained by image analysis, and at the same time investigate the heterogeneity of TILs. From 43 patients treated for stage II CC in 2002 three paraffin embedded, tumor containing tissue blocks were selected one of them representing the deepest invasive tumor front. Serial sections from each of the 129 blocks were immunohistochemically stained for CD3 and CD8, and the slides were scanned. Stereological estimates of the numerical density and area fraction of TILs were obtained using the computer-assisted newCAST stereology system. For the image analysis approach an app-based algorithm was developed using Visiopharm Integrator System software. For both methods the tumor areas of interest (invasive front and central area) were manually delineated by the observer. Based on all sections, the Spearman's correlation coefficients for density estimates varied from 0.9457 to 0.9638 (p < 0.0001), whereas the coefficients for area fraction estimates ranged from 0.9400 to 0.9603 (P < 0.0001). Regarding heterogeneity, intra-class correlation coefficients (ICC) for CD3+ TILs varied from 0.615 to 0.746 in the central area, and from 0.686 to 0.746 in the invasive area. ICC for CD8+ TILs varied from 0.724 to 0.775 in the central area, and from 0.746 to 0.765 in the invasive area. Exact objective and time efficient estimates of numerical densities and area fractions of CD3+ and CD8+ TILs in stage II colon cancer can be obtained by image analysis and are highly correlated to the corresponding estimates obtained by the gold standard based on stereology. Since the intra-tumoral heterogeneity was low, this method may be recommended for quantifying TILs in only one histological section representing the deepest invasive tumor front.

Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

PubMed Central

Sukstanskii, Alexander L.; Woods, Jason C.; Gierada, David S.; Quirk, James D.; Hogg, James C.; Cooper, Joel D.; Conradi, Mark S.

2009-01-01

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized 3He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii—parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials. PMID:19661452

Stereological study of developing glomerular forms during human fetal kidney development.

PubMed

Dakovic Bjelakovic, Marija; Vlajkovic, Slobodan; Petrovic, Aleksandar; Bjelakovic, Marko; Antic, Milorad

2018-05-01

Human fetal kidney development is a complex and stepwise process. The number, shape, size and distribution of glomeruli provide important information on kidney organization. The aim of this study was to quantify glomerular developing forms during human fetal kidney development using stereological methods. Kidney tissue specimens of 40 human fetuses with gestational ages ranging from 9 to 40 weeks were analyzed. Specimens were divided into eight groups based on gestational age, each corresponding to 1 lunar month. Stereological methods were used at the light microscopy level to estimate volume, surface and numerical density of the glomerular developing forms. During gestation, nephrogenesis continually advanced, and the number of nephrons increased. Volume, surface and numerical densities of vesicular forms and S-shaped bodies decreased gradually in parallel with gradual increases in estimated stereological parameters for vascularized glomeruli. Volume density and surface density of vascularized glomeruli increased gradually during fetal kidney development, and numerical density increased until the seventh lunar month. A relative decrease in vascularized glomeruli per unit volume of cortex occurred during the last 3 lunar months. Nephrogenesis began to taper off by 32 weeks and was completed by 36 weeks of gestation. The last sample in which we observed vesicles was from a fetus aged 32 weeks, and the last sample with S-shaped bodies was from a fetus aged 36 weeks. The present study is one of few quantitative studies conducted on human kidney development. Knowledge of normal human kidney morphogenesis during development could be important for future medical practice. Events occurring during fetal life may have significant consequences later in life.

A novel approach to non-biased systematic random sampling: a stereologic estimate of Purkinje cells in the human cerebellum.

PubMed

Agashiwala, Rajiv M; Louis, Elan D; Hof, Patrick R; Perl, Daniel P

2008-10-21

Non-biased systematic sampling using the principles of stereology provides accurate quantitative estimates of objects within neuroanatomic structures. However, the basic principles of stereology are not optimally suited for counting objects that selectively exist within a limited but complex and convoluted portion of the sample, such as occurs when counting cerebellar Purkinje cells. In an effort to quantify Purkinje cells in association with certain neurodegenerative disorders, we developed a new method for stereologic sampling of the cerebellar cortex, involving calculating the volume of the cerebellar tissues, identifying and isolating the Purkinje cell layer and using this information to extrapolate non-biased systematic sampling data to estimate the total number of Purkinje cells in the tissues. Using this approach, we counted Purkinje cells in the right cerebella of four human male control specimens, aged 41, 67, 70 and 84 years, and estimated the total Purkinje cell number for the four entire cerebella to be 27.03, 19.74, 20.44 and 22.03 million cells, respectively. The precision of the method is seen when comparing the density of the cells within the tissue: 266,274, 173,166, 167,603 and 183,575 cells/cm3, respectively. Prior literature documents Purkinje cell counts ranging from 14.8 to 30.5 million cells. These data demonstrate the accuracy of our approach. Our novel approach, which offers an improvement over previous methodologies, is of value for quantitative work of this nature. This approach could be applied to morphometric studies of other similarly complex tissues as well.

A novel approach to non-biased systematic random sampling: A stereologic estimate of Purkinje cells in the human cerebellum

PubMed Central

Agashiwala, Rajiv M.; Louis, Elan D.; Hof, Patrick R.; Perl, Daniel P.

2010-01-01

Non-biased systematic sampling using the principles of stereology provides accurate quantitative estimates of objects within neuroanatomic structures. However, the basic principles of stereology are not optimally suited for counting objects that selectively exist within a limited but complex and convoluted portion of the sample, such as occurs when counting cerebellar Purkinje cells. In an effort to quantify Purkinje cells in association with certain neurodegenerative disorders, we developed a new method for stereologic sampling of the cerebellar cortex, involving calculating the volume of the cerebellar tissues, identifying and isolating the Purkinje cell layer and using this information to extrapolate non-biased systematic sampling data to estimate the total number of Purkinje cells in the tissues. Using this approach, we counted Purkinje cells in the right cerebella of four human male control specimens, aged 41, 67, 70 and 84 years, and estimated the total Purkinje cell number for the four entire cerebella to be 27.03, 19.74, 20.44 and 22.03 million cells, respectively. The precision of the method is seen when comparing the density of the cells within the tissue: 266,274, 173,166, 167,603 and 183,575 cells/cm3, respectively. Prior literature documents Purkinje cell counts ranging from 14.8 to 30.5 million cells. These data demonstrate the accuracy of our approach. Our novel approach, which offers an improvement over previous methodologies, is of value for quantitative work of this nature. This approach could be applied to morphometric studies of other similarly complex tissues as well. PMID:18725208

The Effect of Estrogen Usage on Eccentric Exercise-Induced Damage in Rat Testes

PubMed Central

Can, Serpil; Selli, Jale; Buyuk, Basak; Aydin, Sergulen; Kocaaslan, Ramazan; Guvendi, Gulname Findik

2015-01-01

Background: Recent years, lots of scientific studies are focused on the possible mechanism of inflammatory response and oxidative stress which are the mechanism related with tissue damage and exercise fatigue. It is well-known that free oxygen radicals may be induced under invitro conditions as well as oxidative stress by exhaustive physical exercise. Objectives: The aim of this study was to investigate the effects of anabolic steroids in conjunction with exercise in the process of spermatogenesis in the testes, using histological and stereological methods. Materials and Methods: Thirty-six male Sprague Dawley rats were divided to six groups, including the control group, the eccentric exercise administered group, the estrogen applied group, the estrogen applied and dissected one hour after eccentric exercise group, the no estrogen applied and dissected 48 hours after eccentric exercise group and the estrogen applied and dissected 48 hours after eccentric exercise group. Eccentric exercise was performed on a motorized rodent treadmill and the estrogen applied groups received daily physiological doses by subcutaneous injections. Testicular tissues were examined using specific histopathological, immunohistochemical and stereological methods. Sections of the testes tissue were stained using the TUNEL method to identify apoptotic cells. Apoptosis was calculated as the percentage of positive cells, using stereological analysis. A statistical analysis of the data was carried out with one-way analysis of variance (ANOVA) for the data obtained from stereological analysis. Results: Conventional light microscopic results revealed that testes tissues of the eccentric exercise administered group and the estrogen supplemented group exhibited slight impairment. In groups that were both eccentrically exercised and estrogen supplemented, more deterioration was detected in testes tissues. Likewise, immunohistochemistry findings were also more prominent in the eccentrically exercised and estrogen supplemented groups. Conclusions: The findings suggest that estrogen supplementation increases damage in testicular tissue due to eccentric exercise. PMID:26023337

Design-based stereology: Planning, volumetry and sampling are crucial steps for a successful study.

PubMed

Tschanz, Stefan; Schneider, Jan Philipp; Knudsen, Lars

2014-01-01

Quantitative data obtained by means of design-based stereology can add valuable information to studies performed on a diversity of organs, in particular when correlated to functional/physiological and biochemical data. Design-based stereology is based on a sound statistical background and can be used to generate accurate data which are in line with principles of good laboratory practice. In addition, by adjusting the study design an appropriate precision can be achieved to find relevant differences between groups. For the success of the stereological assessment detailed planning is necessary. In this review we focus on common pitfalls encountered during stereological assessment. An exemplary workflow is included, and based on authentic examples, we illustrate a number of sampling principles which can be implemented to obtain properly sampled tissue blocks for various purposes. Copyright © 2013 Elsevier GmbH. All rights reserved.

Comparison of three‐dimensional analysis and stereological techniques for quantifying lithium‐ion battery electrode microstructures

PubMed Central

TAIWO, OLUWADAMILOLA O.; FINEGAN, DONAL P.; EASTWOOD, DAVID S.; FIFE, JULIE L.; BROWN, LEON D.; DARR, JAWWAD A.; LEE, PETER D.; BRETT, DANIEL J.L.

2016-01-01

Summary Lithium‐ion battery performance is intrinsically linked to electrode microstructure. Quantitative measurement of key structural parameters of lithium‐ion battery electrode microstructures will enable optimization as well as motivate systematic numerical studies for the improvement of battery performance. With the rapid development of 3‐D imaging techniques, quantitative assessment of 3‐D microstructures from 2‐D image sections by stereological methods appears outmoded; however, in spite of the proliferation of tomographic imaging techniques, it remains significantly easier to obtain two‐dimensional (2‐D) data sets. In this study, stereological prediction and three‐dimensional (3‐D) analysis techniques for quantitative assessment of key geometric parameters for characterizing battery electrode microstructures are examined and compared. Lithium‐ion battery electrodes were imaged using synchrotron‐based X‐ray tomographic microscopy. For each electrode sample investigated, stereological analysis was performed on reconstructed 2‐D image sections generated from tomographic imaging, whereas direct 3‐D analysis was performed on reconstructed image volumes. The analysis showed that geometric parameter estimation using 2‐D image sections is bound to be associated with ambiguity and that volume‐based 3‐D characterization of nonconvex, irregular and interconnected particles can be used to more accurately quantify spatially‐dependent parameters, such as tortuosity and pore‐phase connectivity. PMID:26999804

Comparison of three-dimensional analysis and stereological techniques for quantifying lithium-ion battery electrode microstructures.

PubMed

Taiwo, Oluwadamilola O; Finegan, Donal P; Eastwood, David S; Fife, Julie L; Brown, Leon D; Darr, Jawwad A; Lee, Peter D; Brett, Daniel J L; Shearing, Paul R

2016-09-01

Lithium-ion battery performance is intrinsically linked to electrode microstructure. Quantitative measurement of key structural parameters of lithium-ion battery electrode microstructures will enable optimization as well as motivate systematic numerical studies for the improvement of battery performance. With the rapid development of 3-D imaging techniques, quantitative assessment of 3-D microstructures from 2-D image sections by stereological methods appears outmoded; however, in spite of the proliferation of tomographic imaging techniques, it remains significantly easier to obtain two-dimensional (2-D) data sets. In this study, stereological prediction and three-dimensional (3-D) analysis techniques for quantitative assessment of key geometric parameters for characterizing battery electrode microstructures are examined and compared. Lithium-ion battery electrodes were imaged using synchrotron-based X-ray tomographic microscopy. For each electrode sample investigated, stereological analysis was performed on reconstructed 2-D image sections generated from tomographic imaging, whereas direct 3-D analysis was performed on reconstructed image volumes. The analysis showed that geometric parameter estimation using 2-D image sections is bound to be associated with ambiguity and that volume-based 3-D characterization of nonconvex, irregular and interconnected particles can be used to more accurately quantify spatially-dependent parameters, such as tortuosity and pore-phase connectivity. © 2016 The Authors. Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.

Counting Synapses Using FIB/SEM Microscopy: A True Revolution for Ultrastructural Volume Reconstruction.

PubMed

Merchán-Pérez, Angel; Rodriguez, José-Rodrigo; Alonso-Nanclares, Lidia; Schertel, Andreas; Defelipe, Javier

2009-01-01

The advent of transmission electron microscopy (TEM) in the 1950s represented a fundamental step in the study of neuronal circuits. The application of this technique soon led to the realization that the number of synapses changes during the course of normal life, as well as under certain pathological or experimental circumstances. Since then, one of the main goals in neurosciences has been to define simple and accurate methods to estimate the magnitude of these changes. Contrary to analysing single sections, TEM reconstructions are extremely time-consuming and difficult. Therefore, most quantitative studies use stereological methods to define the three-dimensional characteristics of synaptic junctions that are studied in two dimensions. Here, to count the exact number of synapses per unit of volume we have applied a new three-dimensional reconstruction method that involves the combination of focused ion beam milling and scanning electron microscopy (FIB/SEM). We show that the images obtained with FIB/SEM are similar to those obtained with TEM, but with the advantage that FIB/SEM permits serial reconstructions of large volumes of tissue to be generated rapidly and automatically. Furthermore, we compared the estimates of the number of synapses obtained with stereological methods with the values obtained by FIB/SEM reconstructions. We concluded that FIB/SEM not only provides the actual number of synapses per volume but it is also much easier and faster to use than other currently available TEM methods. More importantly, it also avoids most of the errors introduced by stereological methods and overcomes the difficulties associated with these techniques.

The effect of minimally invasive surgical repair on the lung volumes of patients with pectus excavatum.

PubMed

Sengul, Aysen Taslak; Sahin, Bunyamin; Celenk, Cetin; Basoglu, Ahmet; Sengul, Bilal

2014-04-01

To assess the increase in lung volume after Nuss surgery in patients with pectus excavatum (PE) by using stereological methods and to evaluate the correlation between the lung volume and spirometry findings. Twenty patients, treated for PE between 2008 and 2010, were evaluated prospectively. They underwent preoperative chest radiography, computed thorax tomography (CTT), and spirometry. Thereafter, the Haller index was calculated for each patient. In the third postoperative month, CTT and spirometry were repeated.Lung volumes and volume fractions were evaluated using CTT images, applying the Cavalieri principle for stereological methods. Then the correlation between the pre- and postoperative values of the lung volumes with spirometry findings was determined. Volumes of the right and left lungs were calculated stereologically, using CTT images. Postoperative volume increase of ∼417.6 ± 747.6 mL was detected. The maximum volume increase was observed in the left lung. In the postoperative period, the total volume increase and the volume increase detected in the left lung were found to be statistically significant (p < 0.05).The preoperative correlation coefficients (r) for forced vital capacity, forced expiratory volume in 1 second, and forced expiratory flow 25 to 75% were 0.67, 0.68, and 0.61, respectively; the postoperative r figures were 0.43, 0.42, and 0.35, respectively. Although there was a strong correlation between the preoperative lung volume and spirometry findings (p < 0.05), no correlation was observed between the postoperative lung volume and spirometry findings (p > 0.05). Postoperative pulmonary volume increase occurs in patients with PE after Nuss surgery. However, postoperative spirometry findings may not reflect morphological improvement because pain restricts thoracic movements. Therefore, in patients with PE, quantitative evaluation of the results of surgical repair is possible using the CTT images through a combination of stereological methods. Georg Thieme Verlag KG Stuttgart · New York.

Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys.

PubMed

Kanaan, Nicholas M; Kordower, Jeffrey H; Collier, Timothy J

2010-06-01

Aging remains the strongest risk factor for developing Parkinson's disease (PD), and there is selective vulnerability in midbrain dopamine (DA) neuron degeneration in PD. By tracking normal aging-related changes with an emphasis on regional specificity, factors involved in selective vulnerability and resistance to degeneration can be studied. Towards this end, we sought to determine whether age-related changes in microglia and astrocytes in rhesus monkeys are region-specific, suggestive of involvement in regional differences in vulnerability to degeneration that may be relevant to PD pathogenesis. Gliosis in midbrain DA subregions was measured by estimating glia number using unbiased stereology, assessing fluorescence intensity for proteins upregulated during activation, and rating morphology. With normal aging, microglia exhibited increased staining intensity and a shift to more activated morphologies preferentially in the vulnerable substantia nigra-ventral tier (vtSN). Astrocytes did not exhibit age-related changes consistent with an involvement in regional vulnerability in any measure. Our results suggest advancing age is associated with chronic mild inflammation in the vtSN, which may render these DA neurons more vulnerable to degeneration. Copyright 2008 Elsevier Inc. All rights reserved.

Brainstem Alzheimer’s-Like Pathology in the Triple Transgenic Mouse Model of Alzheimer’s Disease

PubMed Central

Overk, Cassia R.; Kelley, Christy M.; Mufson, Elliott J.

2011-01-01

The triple transgenic mouse (3xTgAD), harboring human APPSwe, PS1M146V and TauP301L genes, develops age-dependent forebrain intraneuronal Aβ and tau and extraneuronal plaques. We evaluated brainstem AD-like pathology using 6E10, AT8, and Alz50 antibodies and unbiased stereology in young and old 3xTgAD mice. Intraneuronal Aβ occurred in the tectum, periaqueductal gray, substantia nigra, red nucleus, tegmentum and mesencephalic V nucleus at all ages. Aβ-positive neuron numbers significantly decreased in the superior colliculus and substantia nigra while AT8-positive superior colliculus, red nucleus, principal sensory V, vestibular nuclei, and tegmental neurons significantly increased between 2 and 12 months. Alz50-positive neuron numbers increased only in the inferior colliculus between these ages. Dual labeling revealed a few Aβ- and tau- positive neurons. Plaques occurred only in the pons of female 3xTgAD mice starting at 9 months. 3xTgAD mice provide a platform to define in vivo mechanisms of Aβ and tau brainstem pathology. PMID:19524671

Kidney volume measurement methods for clinical studies on autosomal dominant polycystic kidney disease

PubMed Central

Sharma, Kanishka; Caroli, Anna; Quach, Le Van; Petzold, Katja; Bozzetto, Michela; Serra, Andreas L.; Remuzzi, Giuseppe; Remuzzi, Andrea

2017-01-01

Background In autosomal dominant polycystic kidney disease (ADPKD), total kidney volume (TKV) is regarded as an important biomarker of disease progression and different methods are available to assess kidney volume. The purpose of this study was to identify the most efficient kidney volume computation method to be used in clinical studies evaluating the effectiveness of treatments on ADPKD progression. Methods and findings We measured single kidney volume (SKV) on two series of MR and CT images from clinical studies on ADPKD (experimental dataset) by two independent operators (expert and beginner), twice, using all of the available methods: polyline manual tracing (reference method), free-hand manual tracing, semi-automatic tracing, Stereology, Mid-slice and Ellipsoid method. Additionally, the expert operator also measured the kidney length. We compared different methods for reproducibility, accuracy, precision, and time required. In addition, we performed a validation study to evaluate the sensitivity of these methods to detect the between-treatment group difference in TKV change over one year, using MR images from a previous clinical study. Reproducibility was higher on CT than MR for all methods, being highest for manual and semiautomatic contouring methods (planimetry). On MR, planimetry showed highest accuracy and precision, while on CT accuracy and precision of both planimetry and Stereology methods were comparable. Mid-slice and Ellipsoid method, as well as kidney length were fast but provided only a rough estimate of kidney volume. The results of the validation study indicated that planimetry and Stereology allow using an importantly lower number of patients to detect changes in kidney volume induced by drug treatment as compared to other methods. Conclusions Planimetry should be preferred over fast and simplified methods for accurately monitoring ADPKD progression and assessing drug treatment effects. Expert operators, especially on MR images, are required for performing reliable estimation of kidney volume. The use of efficient TKV quantification methods considerably reduces the number of patients to enrol in clinical investigations, making them more feasible and significant. PMID:28558028

Mutually unbiased bases and semi-definite programming

NASA Astrophysics Data System (ADS)

Brierley, Stephen; Weigert, Stefan

2010-11-01

A complex Hilbert space of dimension six supports at least three but not more than seven mutually unbiased bases. Two computer-aided analytical methods to tighten these bounds are reviewed, based on a discretization of parameter space and on Gröbner bases. A third algorithmic approach is presented: the non-existence of more than three mutually unbiased bases in composite dimensions can be decided by a global optimization method known as semidefinite programming. The method is used to confirm that the spectral matrix cannot be part of a complete set of seven mutually unbiased bases in dimension six.

Analysis of the Volumes of the Posterior Cranial Fossa, Cerebellum, and Herniated Tonsils Using the Stereological Methods in Patients with Chiari Type I Malformation

PubMed Central

Vurdem, Ümit Erkan; Acer, Niyazi; Ertekin, Tolga; Savranlar, Ahmet; İnci, Mehmet Fatih

2012-01-01

Objective. The aim of this study was to determine the posterior cranial fossa volume, cerebellar volume, and herniated tonsillar volume in patients with chiari type I malformation and control subjects using stereological methods. Material and Methods. These volumes were estimated retrospectively using the Cavalieri principle as a point-counting technique. We used magnetic resonance images taken from 25 control subjects and 30 patients with chiari type I malformation. Results. The posterior cranial fossa volume in patients with chiari type I malformation was significantly smaller than the volume in the control subjects (P < 0.05). In the chiari type I malformation group, the cerebellar volume was smaller than the control group, but this difference was not statistically significant (P > 0.05). In the chiari type I malformation group, the ratio of cerebellar volume to posterior cranial fossa volume was higher than in the control group. We also found a positive correlation between the posterior cranial fossa volume and cerebellar volume for each of the groups (r = 0.865, P < 0.001). The mean (±SD) herniated tonsillar volume and length were 0.89 ± 0.50 cm3 and 9.63 ± 3.37 mm in the chiari type I malformation group, respectively. Conclusion. This study has shown that posterior cranial fossa and cerebellum volumes can be measured by stereological methods, and the ratio of these measurements can contribute to the evaluation of chiari type I malformation cases. PMID:22629166

Quantification of myocardial fibrosis by digital image analysis and interactive stereology

PubMed Central

2014-01-01

Background Cardiac fibrosis disrupts the normal myocardial structure and has a direct impact on heart function and survival. Despite already available digital methods, the pathologist’s visual score is still widely considered as ground truth and used as a primary method in histomorphometric evaluations. The aim of this study was to compare the accuracy of digital image analysis tools and the pathologist’s visual scoring for evaluating fibrosis in human myocardial biopsies, based on reference data obtained by point counting performed on the same images. Methods Endomyocardial biopsy material from 38 patients diagnosed with inflammatory dilated cardiomyopathy was used. The extent of total cardiac fibrosis was assessed by image analysis on Masson’s trichrome-stained tissue specimens using automated Colocalization and Genie software, by Stereology grid count and manually by Pathologist’s visual score. Results A total of 116 slides were analyzed. The mean results obtained by the Colocalization software (13.72 ± 12.24%) were closest to the reference value of stereology (RVS), while the Genie software and Pathologist score gave a slight underestimation. RVS values correlated strongly with values obtained using the Colocalization and Genie (r > 0.9, p < 0.001) software as well as the pathologist visual score. Differences in fibrosis quantification by Colocalization and RVS were statistically insignificant. However, significant bias was found in the results obtained by using Genie versus RVS and pathologist score versus RVS with mean difference values of: -1.61% and 2.24%. Bland-Altman plots showed a bidirectional bias dependent on the magnitude of the measurement: Colocalization software overestimated the area fraction of fibrosis in the lower end, and underestimated in the higher end of the RVS values. Meanwhile, Genie software as well as the pathologist score showed more uniform results throughout the values, with a slight underestimation in the mid-range for both. Conclusion Both applied digital image analysis methods revealed almost perfect correlation with the criterion standard obtained by stereology grid count and, in terms of accuracy, outperformed the pathologist’s visual score. Genie algorithm proved to be the method of choice with the only drawback of a slight underestimation bias, which is considered acceptable for both clinical and research evaluations. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9857909611227193 PMID:24912374

Hippocampal Neuron Number Is Unchanged 1 Year After Fractionated Whole-Brain Irradiation at Middle Age

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

Shi Lei; Molina, Doris P.; Robbins, Michael E.

2008-06-01

Purpose: To determine whether hippocampal neurons are lost 12 months after middle-aged rats received a fractionated course of whole-brain irradiation (WBI) that is expected to be biologically equivalent to the regimens used clinically in the treatment of brain tumors. Methods and Materials: Twelve-month-old Fischer 344 X Brown Norway male rats were divided into WBI and control (CON) groups (n = 6 per group). Anesthetized WBI rats received 45 Gy of {sup 137}Cs {gamma} rays delivered as 9 5-Gy fractions twice per week for 4.5 weeks. Control rats were anesthetized but not irradiated. Twelve months after WBI completion, all rats weremore » anesthetized and perfused with paraformaldehyde, and hippocampal sections were immunostained with the neuron-specific antibody NeuN. Using unbiased stereology, total neuron number and the volume of the neuronal and neuropil layers were determined in the dentate gyrus, CA3, and CA1 subregions of hippocampus. Results: No differences in tissue integrity or neuron distribution were observed between the WBI and CON groups. Moreover, quantitative analysis demonstrated that neither total neuron number nor the volume of neuronal or neuropil layers differed between the two groups for any subregion. Conclusions: Impairment on a hippocampal-dependent learning and memory test occurs 1 year after fractionated WBI at middle age. The same WBI regimen, however, does not lead to a loss of neurons or a reduction in the volume of hippocampus.« less

Epigallocatechin gallate protects dopaminergic neurons against 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity by inhibiting microglial cell activation.

PubMed

Li, Rui; Peng, Ning; Du, Fang; Li, Xu-ping; Le, Wei-dong

2006-04-01

To observe whether the dopaminergic neuroprotective effect of (-)-epigallocatechin gallate (EGCG) is associated with its inhibition of microglial cell activation in vivo. The effects of EGCG at different doses on dopaminergic neuronal survival were tested in a methyl-4-phenyl-pyridinium (MPP+)-induced dopaminergic neuronal injury model in the primary mesencephalic cell cultures. With unbiased stereological method, tyrosine hydroxylase-immunoreactive (TH-ir) cells were counted in the A8, A9 and A10 regions of the substantia nigra (SN) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The effect of EGCG on microglial activation in the SN was also investigated. Pretreatment with EGCG (1 to 100 micromol/L) significantly attenuated MPP+-induced TH-ir cell loss by 22.2% to 80.5% in the mesencephalic cell cultures. In MPTP-treated C57BL/6 mice, EGCG at a low concentration (1 mg/kg) provided significant protection against MPTP-induced TH-ir cell loss by 50.9% in the whole nigral area and by 71.7% in the A9 region. EGCG at 5 mg/kg showed more prominent protective effect than at 1 or 10 mg/kg. EGCG pretreatment significantly inhibited microglial activation and CD11b expression induced by MPTP. EGCG exerts potent dopaminergic neuroprotective activity by means of microglial inhibition, which shed light on the potential use of EGCG in treatment of Parkinson's disease.

Stereological evaluation of the volume and volume fraction of newborns' brain compartment and brain in magnetic resonance images.

PubMed

Nisari, Mehtap; Ertekin, Tolga; Ozçelik, Ozlem; Cınar, Serife; Doğanay, Selim; Acer, Niyazi

2012-11-01

Brain development in early life is thought to be critical period in neurodevelopmental disorder. Knowledge relating to this period is currently quite limited. This study aimed to evaluate the volume relation of total brain (TB), cerebrum, cerebellum and bulbus+pons by the use of Archimedes' principle and stereological (point-counting) method and after that to compare these approaches with each other in newborns. This study was carried out on five newborn cadavers mean weighing 2.220 ± 1.056 g with no signs of neuropathology. The mean (±SD) age of the subjects was 39.7 (±1.5) weeks. The volume and volume fraction of the total brain, cerebrum, cerebellum and bulbus+pons were determined on magnetic resonance (MR) images using the point-counting approach of stereological methods and by the use of fluid displacement technique. The mean (±SD) TB, cerebrum, cerebellum and bulbus+pons volumes by fluid displacement were 271.48 ± 78.3, 256.6 ± 71.8, 12.16 ± 6.1 and 2.72 ± 1.6 cm3, respectively. By the Cavalieri principle (point-counting) using sagittal MRIs, they were 262.01 ± 74.9, 248.11 ± 68.03, 11.68 ± 6.1 and 2.21 ± 1.13 cm3, respectively. The mean (± SD) volumes by point-counting technique using axial MR images were 288.06 ± 88.5, 275.2 ± 83.1, 19.75 ± 5.3 and 2.11 ± 0.7 cm3, respectively. There were no differences between the fluid displacement and point-counting (using axial and sagittal images) for all structures (p > 0.05). This study presents the basic data for studies relative to newborn's brain volume fractions according to two methods. Stereological (point-counting) estimation may be accepted a beneficial and new tool for neurological evaluation in vivo research of the brain. Based on these techniques we introduce here, the clinician may evaluate the growth of the brain in a more efficient and precise manner.

A Quantitative Technique for Beginning Microscopists.

ERIC Educational Resources Information Center

Sundberg, Marshall D.

1984-01-01

Stereology is the study of three-dimensional objects through the interpretation of two-dimensional images. Stereological techniques used in introductory botany to quantitatively examine changes in leaf anatomy in response to different environments are discussed. (JN)

Age-related changes of nasal cavity and conchae volumes and volume fractions in children: a stereological study.

PubMed

Ertekin, T; Değermenci, M; Nisari, M; Unur, E; Coşkun, A

2016-01-01

The anatomy of the human nasal cavity (NC) is complex and its structures are closely related to the functions of the NC. Studies which assessing the mean volumes of NC and conchae are very infrequent. The purpose of current study is to investigate development of NC and conchae according to age and sex by using stereological method. This retrospective volumetric study was carried out on 342 individuals (166 females and 176 males) between 0 and 18 years old with no pathological conditions or medical procedures that affected the skeletal morphology of the NC. Volumetric estimations were determined on computed tomography (CT) images using point-counting approach of stereological methods. NC, inferior nasal conchae (INC) and middle nasal conchae (MNC) volume measurements that obtained using point-counting method were increased with age in both sexes until 15 years old. Regardless of gender; no significant difference was determined between the left and right values for NC, conchae volumes and choanae measurements. Generally, significant differences were determined in NC and INC volumes according to gender after they reached maximum growth period. According to age the volume ratios of INC to NC and MNC to NC were ranged from 18% to 32% and 9% to15%, respectively. The current study demonstrated that the point-counting method is effective in determining volume estimation of NC and is well suited for CT studies. Our results could provide volumetric indexes for the NC and conchae, which could help the physician for both patient selections for surgery, and for the assessment of any surgical technique used to treatment of nasal obstruction. (.

Quantification of myocardial fibrosis by digital image analysis and interactive stereology.

PubMed

Daunoravicius, Dainius; Besusparis, Justinas; Zurauskas, Edvardas; Laurinaviciene, Aida; Bironaite, Daiva; Pankuweit, Sabine; Plancoulaine, Benoit; Herlin, Paulette; Bogomolovas, Julius; Grabauskiene, Virginija; Laurinavicius, Arvydas

2014-06-09

Cardiac fibrosis disrupts the normal myocardial structure and has a direct impact on heart function and survival. Despite already available digital methods, the pathologist's visual score is still widely considered as ground truth and used as a primary method in histomorphometric evaluations. The aim of this study was to compare the accuracy of digital image analysis tools and the pathologist's visual scoring for evaluating fibrosis in human myocardial biopsies, based on reference data obtained by point counting performed on the same images. Endomyocardial biopsy material from 38 patients diagnosed with inflammatory dilated cardiomyopathy was used. The extent of total cardiac fibrosis was assessed by image analysis on Masson's trichrome-stained tissue specimens using automated Colocalization and Genie software, by Stereology grid count and manually by Pathologist's visual score. A total of 116 slides were analyzed. The mean results obtained by the Colocalization software (13.72 ± 12.24%) were closest to the reference value of stereology (RVS), while the Genie software and Pathologist score gave a slight underestimation. RVS values correlated strongly with values obtained using the Colocalization and Genie (r>0.9, p<0.001) software as well as the pathologist visual score. Differences in fibrosis quantification by Colocalization and RVS were statistically insignificant. However, significant bias was found in the results obtained by using Genie versus RVS and pathologist score versus RVS with mean difference values of: -1.61% and 2.24%. Bland-Altman plots showed a bidirectional bias dependent on the magnitude of the measurement: Colocalization software overestimated the area fraction of fibrosis in the lower end, and underestimated in the higher end of the RVS values. Meanwhile, Genie software as well as the pathologist score showed more uniform results throughout the values, with a slight underestimation in the mid-range for both. Both applied digital image analysis methods revealed almost perfect correlation with the criterion standard obtained by stereology grid count and, in terms of accuracy, outperformed the pathologist's visual score. Genie algorithm proved to be the method of choice with the only drawback of a slight underestimation bias, which is considered acceptable for both clinical and research evaluations. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9857909611227193.

Sampling theory and automated simulations for vertical sections, applied to human brain.

PubMed

Cruz-Orive, L M; Gelšvartas, J; Roberts, N

2014-02-01

In recent years, there have been substantial developments in both magnetic resonance imaging techniques and automatic image analysis software. The purpose of this paper is to develop stereological image sampling theory (i.e. unbiased sampling rules) that can be used by image analysts for estimating geometric quantities such as surface area and volume, and to illustrate its implementation. The methods will ideally be applied automatically on segmented, properly sampled 2D images - although convenient manual application is always an option - and they are of wide applicability in many disciplines. In particular, the vertical sections design to estimate surface area is described in detail and applied to estimate the area of the pial surface and of the boundary between cortex and underlying white matter (i.e. subcortical surface area). For completeness, cortical volume and mean cortical thickness are also estimated. The aforementioned surfaces were triangulated in 3D with the aid of FreeSurfer software, which provided accurate surface area measures that served as gold standards. Furthermore, a software was developed to produce digitized trace curves of the triangulated target surfaces automatically from virtual sections. From such traces, a new method (called the 'lambda method') is presented to estimate surface area automatically. In addition, with the new software, intersections could be counted automatically between the relevant surface traces and a cycloid test grid for the classical design. This capability, together with the aforementioned gold standard, enabled us to thoroughly check the performance and the variability of the different estimators by Monte Carlo simulations for studying the human brain. In particular, new methods are offered to split the total error variance into the orientations, sectioning and cycloid components. The latter prediction was hitherto unavailable--one is proposed here and checked by way of simulations on a given set of digitized vertical sections with automatically superimposed cycloid grids of three different sizes. Concrete and detailed recommendations are given to implement the methods. © 2013 The Authors Journal of Microscopy © 2013 Royal Microscopical Society.

Allowable SEM noise for unbiased LER measurement

NASA Astrophysics Data System (ADS)

Papavieros, George; Constantoudis, Vassilios; Gogolides, Evangelos

2018-03-01

Recently, a novel method for the calculation of unbiased Line Edge Roughness based on Power Spectral Density analysis has been proposed. In this paper first an alternative method is discussed and investigated, utilizing the Height-Height Correlation Function (HHCF) of edges. The HHCF-based method enables the unbiased determination of the whole triplet of LER parameters including besides rms the correlation length and roughness exponent. The key of both methods is the sensitivity of PSD and HHCF on noise at high frequencies and short distance respectively. Secondly, we elaborate a testbed of synthesized SEM images with controlled LER and noise to justify the effectiveness of the proposed unbiased methods. Our main objective is to find out the boundaries of the method in respect to noise levels and roughness characteristics, for which the method remains reliable, i.e the maximum amount of noise allowed, for which the output results cope with the controllable known inputs. At the same time, we will also set the extremes of roughness parameters for which the methods hold their accuracy.

Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum.

PubMed

Heaton, M B; Mitchell, J J; Paiva, M

2000-11-05

Transgenic mice overexpressing NGF in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter were exposed to ethanol via vapor inhalation on postnatal days 4 and 5 (P4-5), the period of maximal cerebellar Purkinje cell sensitivity to ethanol. Wild-type controls were exposed in a similar manner. There were no differences in body weight or size following these procedures, but the transgenic brain weights at this age were significantly greater than wild-type controls. In the wild-type animals, a significant 33.3% ethanol-mediated loss of Purkinje cells in lobule I was detected via unbiased three-dimensional stereological counting on P5. In the GFAP-NGF transgenic animals, however, the 17.6% difference in Purkinje cell number in control and ethanol-exposed animals was not significant. There was a similar difference in Purkinje cell density in both groups, which did reach statistical significance (-32.7% in wild-type ethanol-treated animals, -17% in transgenic ethanol-exposed animals). These results suggest that endogenous overexpression of neurotrophic factors, which have previously been shown to protect against ethanol neurotoxicity in culture, can serve a similar protective function in the intact animal. Copyright 2000 John Wiley & Sons, Inc.

Quantifying Golgi structure using EM: combining volume-SEM and stereology for higher throughput.

PubMed

Ferguson, Sophie; Steyer, Anna M; Mayhew, Terry M; Schwab, Yannick; Lucocq, John Milton

2017-06-01

Investigating organelles such as the Golgi complex depends increasingly on high-throughput quantitative morphological analyses from multiple experimental or genetic conditions. Light microscopy (LM) has been an effective tool for screening but fails to reveal fine details of Golgi structures such as vesicles, tubules and cisternae. Electron microscopy (EM) has sufficient resolution but traditional transmission EM (TEM) methods are slow and inefficient. Newer volume scanning EM (volume-SEM) methods now have the potential to speed up 3D analysis by automated sectioning and imaging. However, they produce large arrays of sections and/or images, which require labour-intensive 3D reconstruction for quantitation on limited cell numbers. Here, we show that the information storage, digital waste and workload involved in using volume-SEM can be reduced substantially using sampling-based stereology. Using the Golgi as an example, we describe how Golgi populations can be sensed quantitatively using single random slices and how accurate quantitative structural data on Golgi organelles of individual cells can be obtained using only 5-10 sections/images taken from a volume-SEM series (thereby sensing population parameters and cell-cell variability). The approach will be useful in techniques such as correlative LM and EM (CLEM) where small samples of cells are treated and where there may be variable responses. For Golgi study, we outline a series of stereological estimators that are suited to these analyses and suggest workflows, which have the potential to enhance the speed and relevance of data acquisition in volume-SEM.

In search for a gold-standard procedure to count motor neurons in the spinal cord.

PubMed

Ferrucci, Michela; Lazzeri, Gloria; Flaibani, Marina; Biagioni, Francesca; Cantini, Federica; Madonna, Michele; Bucci, Domenico; Limanaqi, Fiona; Soldani, Paola; Fornai, Francesco

2018-03-14

Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from the CNS. Motor neuron loss allows to assess the severity of motor neuron disorders while providing a tool to assess disease modifying effects. Counting motor neurons at first implies gold standard identification methods. In fact, motor neurons may occur within mixed nuclei housing a considerable amount of neurons other than motor neurons. In the present review, we analyse various approaches to count motor neurons emphasizing both the benefits and bias of each protocol. A special emphasis is placed on discussing automated stereology. When automated stereology does not take into account site-specificity and does not distinguish between heterogeneous neuronal populations, it may confound data making such a procedure a sort of "guide for the perplex". Thus, if on the one hand automated stereology improves our ability to quantify neuronal populations, it may also hide false positives/negatives in neuronal counts. For instance, classic staining for antigens such as SMI-32, SMN and ChAT, which are routinely considered to be specific for motor neurons, may also occur in other neuronal types of the spinal cord. Even site specificity within Lamina IX may be misleading due to neuronal populations having a size and shape typical of motor neurons. This is the case of spinal border cells, which often surpass the border of Lamina VII and intermingle with motor neurons of Lamina IX. The present article discusses the need to join automated stereology with a dedicated knowledge of each specific neuroanatomical setting.

An extension of the Saltykov method to quantify 3D grain size distributions in mylonites

NASA Astrophysics Data System (ADS)

Lopez-Sanchez, Marco A.; Llana-Fúnez, Sergio

2016-12-01

The estimation of 3D grain size distributions (GSDs) in mylonites is key to understanding the rheological properties of crystalline aggregates and to constraining dynamic recrystallization models. This paper investigates whether a common stereological method, the Saltykov method, is appropriate for the study of GSDs in mylonites. In addition, we present a new stereological method, named the two-step method, which estimates a lognormal probability density function describing the 3D GSD. Both methods are tested for reproducibility and accuracy using natural and synthetic data sets. The main conclusion is that both methods are accurate and simple enough to be systematically used in recrystallized aggregates with near-equant grains. The Saltykov method is particularly suitable for estimating the volume percentage of particular grain-size fractions with an absolute uncertainty of ±5 in the estimates. The two-step method is suitable for quantifying the shape of the actual 3D GSD in recrystallized rocks using a single value, the multiplicative standard deviation (MSD) parameter, and providing a precision in the estimate typically better than 5%. The novel method provides a MSD value in recrystallized quartz that differs from previous estimates based on apparent 2D GSDs, highlighting the inconvenience of using apparent GSDs for such tasks.

Sex Differences and Laterality in Astrocyte Number and Complexity in the Adult Rat Medial Amygdala

PubMed Central

JOHNSON, RYAN T.; BREEDLOVE, S. MARC; JORDAN, CYNTHIA L.

2008-01-01

The posterodorsal portion of the medial amygdala (MePD) is sexually dimorphic in several rodent species. In several other brain nuclei, astrocytes change morphology in response to steroid hormones. We visualized MePD astrocytes using glial-fibrillary acidic protein (GFAP) immunocytochemistry. We compared the number and process complexity of MePD astrocytes in adult wildtype male and female rats and testicular feminized mutant (TFM) male rats that lack functional androgen receptors (ARs) to determine whether MePD astrocytes are sexually differentiated and whether ARs have a role. Unbiased stereological methods revealed laterality and sex differences in MePD astrocyte number and complexity. The right MePD contained more astrocytes than the left in all three genotypes, and the number of astrocytes was also sexually differentiated in the right MePD, with males having more astrocytes than females. In contrast, the left MePD contained more complex astrocytes than did the right MePD in all three genotypes, and males had more complex astrocytes than females in this hemisphere. TFM males were comparable to wildtype females, having fewer astrocytes on the right and simpler astrocytes on the left than do wildtype males. Taken together, these results demonstrate that astrocytes are sexually dimorphic in the adult MePD and that the nature of the sex difference is hemisphere-dependent: a sex difference in astrocyte number in the right MePD and a sex difference in astrocyte complexity in the left MePD. Moreover, functional ARs appear to be critical in establishing these sex differences in MePD astrocyte morphology. PMID:18853427

Experience-dependent plasticity in the mushroom bodies of the solitary bee Osmia lignaria (Megachilidae).

PubMed

Withers, Ginger S; Day, Nancy F; Talbot, Emily F; Dobson, Heidi E M; Wallace, Christopher S

2008-01-01

All members of the solitary bee species Osmia lignaria (the orchard bee) forage upon emergence from their natal nest cell. Conversely, in the honey bee, days-to-weeks of socially regulated behavioral development precede the onset of foraging. The social honey bee's behavioral transition to foraging is accompanied by neuroanatomical changes in the mushroom bodies, a region of the insect brain implicated in learning. If these changes were general adaptations to foraging, they should also occur in the solitary orchard bee. Using unbiased stereological methods, we estimated the volume of the major compartments of the mushroom bodies, the neuropil and Kenyon cell body region, in adult orchard bees. We compared the mushroom bodies of recently emerged bees with mature bees that had extensive foraging experience. To separate effects of general maturation from field foraging, some orchard bees were confined to a cage indoors. The mushroom body neuropil of experienced field foragers was significantly greater than that of both recently emerged and mature caged orchard bees, suggesting that, like the honey bee, this increase is driven by outdoor foraging experience. Unlike the honey bee, where increases in the ratio of neuropil to Kenyon cell region occur in the worker after emerging from the hive cell, the orchard bee emerged from the natal nest cell with a ratio that did not change with maturation and was comparable to honey-bee foragers. These results suggest that a common developmental endpoint may be reached via different development paths in social and solitary species of foraging bees.

Exercise protects myelinated fibers of white matter in a rat model of depression.

PubMed

Xiao, Qian; Wang, Feifei; Luo, Yanmin; Chen, Linmu; Chao, Fenglei; Tan, Chuanxue; Gao, Yuan; Huang, Chunxia; Zhang, Lei; Liang, Xin; Tang, Jing; Qi, Yingqing; Jiang, Lin; Zhang, Yi; Zhou, Chunni; Tang, Yong

2018-02-15

The antidepressive effects of exercise have been a focus of research and are hypothesized to remodel the brain networks constructed by myelinated fibers. However, whether the antidepressant effects of exercise are dependent on changes in white matter myelination are unknown. Therefore, we chose chronic unpredictable stress (CUS) as a model of depression and designed an experiment. After a 4-week CUS period, 40 animals were tested using the sucrose preference test (SPT) and the open field test (OFT). The depressed rats then underwent 4-week running exercise. Next, electron microscopy and unbiased stereological methods were used to investigate white matter changes in the rats. After the 4-week CUS stimulation, body weight, sucrose preference and scores on the OFT were significantly lower in the depression rats than in the unstressed rats (p < .05). After undergoing a 4-week running exercise, the depression rats showed a significantly greater sucrose preference than the depression control rats without running exercise (p < .05). Furthermore, the white matter parameters of the depression rats (including the white matter volumes, the length and volumes of myelinated fibers, and the volumes and thickness of the myelin sheaths) were significantly reduced after the CUS period (p < .05). However, these white matter parameters were significantly increased after running exercise (p < .05). The present study is the first to provide evidence that running exercise has positive effects on white matter and the myelinated fibers of white matter in depressed rats, and this evidence might provide an important theoretical basis for the exercise-mediated treatment of depression. © 2017 Wiley Periodicals, Inc.

Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity

PubMed Central

Choi, Joungil; Chandrasekaran, Krish; Demarest, Tyler G; Kristian, Tibor; Xu, Su; Vijaykumar, Kadambari; Dsouza, Kevin Geoffrey; Qi, Nathan R; Yarowsky, Paul J; Gallipoli, Rao; Koch, Lauren G; Fiskum, Gary M; Britton, Steven L; Russell, James W

2014-01-01

Objectives Diabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts. Methods Hippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined. Results The levels of glutamate, myo-inositol, taurine, and choline-containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator-activated receptor-gamma coactivator 1α, the NAD+-dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus. Interpretation These data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged-related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well-described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction. PMID:25356430

Practicable methods for histological section thickness measurement in quantitative stereological analyses.

PubMed

Matenaers, Cyrill; Popper, Bastian; Rieger, Alexandra; Wanke, Rüdiger; Blutke, Andreas

2018-01-01

The accuracy of quantitative stereological analysis tools such as the (physical) disector method substantially depends on the precise determination of the thickness of the analyzed histological sections. One conventional method for measurement of histological section thickness is to re-embed the section of interest vertically to its original section plane. The section thickness is then measured in a subsequently prepared histological section of this orthogonally re-embedded sample. However, the orthogonal re-embedding (ORE) technique is quite work- and time-intensive and may produce inaccurate section thickness measurement values due to unintentional slightly oblique (non-orthogonal) positioning of the re-embedded sample-section. Here, an improved ORE method is presented, allowing for determination of the factual section plane angle of the re-embedded section, and correction of measured section thickness values for oblique (non-orthogonal) sectioning. For this, the analyzed section is mounted flat on a foil of known thickness (calibration foil) and both the section and the calibration foil are then vertically (re-)embedded. The section angle of the re-embedded section is then calculated from the deviation of the measured section thickness of the calibration foil and its factual thickness, using basic geometry. To find a practicable, fast, and accurate alternative to ORE, the suitability of spectral reflectance (SR) measurement for determination of plastic section thicknesses was evaluated. Using a commercially available optical reflectometer (F20, Filmetrics®, USA), the thicknesses of 0.5 μm thick semi-thin Epon (glycid ether)-sections and of 1-3 μm thick plastic sections (glycolmethacrylate/ methylmethacrylate, GMA/MMA), as regularly used in physical disector analyses, could precisely be measured within few seconds. Compared to the measured section thicknesses determined by ORE, SR measures displayed less than 1% deviation. Our results prove the applicability of SR to efficiently provide accurate section thickness measurements as a prerequisite for reliable estimates of dependent quantitative stereological parameters.

Practicable methods for histological section thickness measurement in quantitative stereological analyses

PubMed Central

Matenaers, Cyrill; Popper, Bastian; Rieger, Alexandra; Wanke, Rüdiger

2018-01-01

The accuracy of quantitative stereological analysis tools such as the (physical) disector method substantially depends on the precise determination of the thickness of the analyzed histological sections. One conventional method for measurement of histological section thickness is to re-embed the section of interest vertically to its original section plane. The section thickness is then measured in a subsequently prepared histological section of this orthogonally re-embedded sample. However, the orthogonal re-embedding (ORE) technique is quite work- and time-intensive and may produce inaccurate section thickness measurement values due to unintentional slightly oblique (non-orthogonal) positioning of the re-embedded sample-section. Here, an improved ORE method is presented, allowing for determination of the factual section plane angle of the re-embedded section, and correction of measured section thickness values for oblique (non-orthogonal) sectioning. For this, the analyzed section is mounted flat on a foil of known thickness (calibration foil) and both the section and the calibration foil are then vertically (re-)embedded. The section angle of the re-embedded section is then calculated from the deviation of the measured section thickness of the calibration foil and its factual thickness, using basic geometry. To find a practicable, fast, and accurate alternative to ORE, the suitability of spectral reflectance (SR) measurement for determination of plastic section thicknesses was evaluated. Using a commercially available optical reflectometer (F20, Filmetrics®, USA), the thicknesses of 0.5 μm thick semi-thin Epon (glycid ether)-sections and of 1–3 μm thick plastic sections (glycolmethacrylate/ methylmethacrylate, GMA/MMA), as regularly used in physical disector analyses, could precisely be measured within few seconds. Compared to the measured section thicknesses determined by ORE, SR measures displayed less than 1% deviation. Our results prove the applicability of SR to efficiently provide accurate section thickness measurements as a prerequisite for reliable estimates of dependent quantitative stereological parameters. PMID:29444158

Long-term Reductions in the Population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure.

PubMed

Bird, Clark W; Taylor, Devin H; Pinkowski, Natalie J; Chavez, G Jill; Valenzuela, C Fernando

2018-07-15

Developmental exposure to ethanol leads to a constellation of cognitive and behavioral abnormalities known as Fetal Alcohol Spectrum Disorders (FASDs). Many cell types throughout the central nervous system are negatively impacted by gestational alcohol exposure, including inhibitory, GABAergic interneurons. Little evidence exists, however, describing the long-term impact of fetal alcohol exposure on survival of interneurons within the hippocampal formation, which is critical for learning and memory processes that are impaired in individuals with FASDs. Mice expressing Venus yellow fluorescent protein in inhibitory interneurons were exposed to vaporized ethanol during the third trimester equivalent of human gestation (postnatal days 2-9), and the long-term effects on interneuron numbers were measured using unbiased stereology at P90. In adulthood, interneuron populations were reduced in every hippocampal region examined. Moreover, we found that a single exposure to ethanol at P7 caused robust activation of apoptotic neurodegeneration of interneurons in the hilus, granule cell layer, CA1 and CA3 regions of the hippocampus. These studies demonstrate that developmental ethanol exposure has a long-term impact on hippocampal interneuron survivability, and may provide a mechanism partially explaining deficits in hippocampal function and hippocampus-dependent behaviors in those afflicted with FASDs. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

A simple tool for stereological assessment of digital images: the STEPanizer.

PubMed

Tschanz, S A; Burri, P H; Weibel, E R

2011-07-01

STEPanizer is an easy-to-use computer-based software tool for the stereological assessment of digitally captured images from all kinds of microscopical (LM, TEM, LSM) and macroscopical (radiology, tomography) imaging modalities. The program design focuses on providing the user a defined workflow adapted to most basic stereological tasks. The software is compact, that is user friendly without being bulky. STEPanizer comprises the creation of test systems, the appropriate display of digital images with superimposed test systems, a scaling facility, a counting module and an export function for the transfer of results to spreadsheet programs. Here we describe the major workflow of the tool illustrating the application on two examples from transmission electron microscopy and light microscopy, respectively. © 2011 The Authors Journal of Microscopy © 2011 Royal Microscopical Society.

A Simple Joint Estimation Method of Residual Frequency Offset and Sampling Frequency Offset for DVB Systems

NASA Astrophysics Data System (ADS)

Kwon, Ki-Won; Cho, Yongsoo

This letter presents a simple joint estimation method for residual frequency offset (RFO) and sampling frequency offset (STO) in OFDM-based digital video broadcasting (DVB) systems. The proposed method selects a continual pilot (CP) subset from an unsymmetrically and non-uniformly distributed CP set to obtain an unbiased estimator. Simulation results show that the proposed method using a properly selected CP subset is unbiased and performs robustly.

Role of Recurrent Hypoxia-Ischemia in Preterm White Matter Injury Severity

PubMed Central

Hagen, Matthew W.; Riddle, Art; McClendon, Evelyn; Gong, Xi; Shaver, Daniel; Srivastava, Taasin; Dean, Justin M.; Bai, Ji-Zhong; Fowke, Tania M.; Gunn, Alistair J.; Jones, Daniel F.; Sherman, Larry S.; Grafe, Marjorie R.; Hohimer, A. Roger; Back, Stephen A.

2014-01-01

Objective Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI. Methods We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI. Results rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing. Conclusions rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20. PMID:25390897

A comparison of nephron number, glomerular volume and kidney weight in Senegalese Africans and African Americans

PubMed Central

McNamara, Bridgette J.; Diouf, Boucar; Douglas-Denton, Rebecca N.; Hughson, Michael D.; Hoy, Wendy E.; Bertram, John F.

2010-01-01

Background. Low nephron number is determined in utero and is a proposed risk for essential hypertension. Glomerular volume is inversely correlated with nephron number, and genetic and environmental factors that determine nephron number are thought to determine glomerular volume. This study compared total glomerular (nephron) number (Nglom), mean glomerular volume (Vglom) and kidney weight in two geographically separated black populations with significant common genetic ancestry. Methods. Unbiased stereology was used to determine Nglom and Vglom in kidneys collected at coronial autopsy in an age- and sex-matched sample of 39 adult Africans from Dakar in Senegal, West Africa and 39 African Americans from Mississippi in the USA. Results. African Americans were taller and heavier than their Senegalese counterparts. Nglom was remarkably similar—with a geometric mean of 937 967 in Senegalese and 904 412 in African Americans (P = 0.62). Vglom was correlated inversely with Nglom and directly with body surface area in both groups, but Vglom was 54% greater in African Americans than in Senegalese Africans [8.30 ± 2.92 (SD) and 5.38 ± 1.25  μm3 × 106, respectively] and remained significantly larger (38%) after adjustment for body size. Vglom increased with age in African Americans, but not in the Senegalese. Kidney weight was larger in African Americans (P < 0.0001), but kidney-to-body weight ratio was not different between groups. Conclusions. Despite similar nephron numbers, a common genetic constitution, and even in relation to current body size, African Americans have larger Vglom than Senegalese subjects. This may mark exposure to environmental stressors or hereditary traits concentrated in the population's relocation to North America. PMID:20154008

Organization of GABAergic synaptic circuits in the rat ventral tegmental area.

PubMed

Ciccarelli, Alessandro; Calza, Arianna; Panzanelli, Patrizia; Concas, Alessandra; Giustetto, Maurizio; Sassoè-Pognetto, Marco

2012-01-01

The ventral tegmental area (VTA) is widely implicated in drug addiction and other psychiatric disorders. This brain region is densely populated by dopaminergic (DA) neurons and also contains a sparse population of γ-aminobutyric acid (GABA)ergic cells that regulate the activity of the principal neurons. Therefore, an in-depth knowledge of the organization of VTA GABAergic circuits and of the plasticity induced by drug consumption is essential for understanding the mechanisms by which drugs induce stable changes in brain reward circuits. Using immunohistochemistry, we provide a detailed description of the localization of major GABA(A) and GABA(B) receptor subunits in the rat VTA. We show that DA and GABAergic cells express both GABA(A) and GABA(B) receptors. However VTA neurons differ considerably in the expression of GABA(A) receptor subunits, as the α1 subunit is associated predominantly with non-DA cells, whereas the α3 subunit is present at low levels in both types of VTA neurons. Using an unbiased stereological method, we then demonstrate that α1-positive elements represent only a fraction of non-DA neurons and that the ratio of DA and non-DA cells is quite variable throughout the rostro-caudal extent of the VTA. Interestingly, DA and non-DA cells receive a similar density of perisomatic synapses, whereas axo-dendritic synapses are significantly more abundant in non-DA cells, indicating that local interneurons receive prominent GABAergic inhibition. These findings reveal a differential expression of GABA receptor subtypes in the two major categories of VTA neurons and provide an anatomical basis for interpreting the plasticity of inhibitory circuits induced by drug exposure.

Asymmetric TDP pathology in primary progressive aphasia with right hemisphere language dominance.

PubMed

Kim, Garam; Vahedi, Shahrooz; Gefen, Tamar; Weintraub, Sandra; Bigio, Eileen H; Mesulam, Marek-Marsel; Geula, Changiz

2018-01-30

To quantitatively examine the regional densities and hemispheric distribution of the 43-kDa transactive response DNA-binding protein (TDP-43) inclusions, neurons, and activated microglia in a left-handed patient with right hemisphere language dominance and logopenic-variant primary progressive aphasia (PPA). Phosphorylated TDP-43 inclusions, neurons, and activated microglia were visualized with immunohistochemical and histologic methods. Markers were quantified bilaterally with unbiased stereology in language- and memory-related cortical regions. Clinical MRI indicated cortical atrophy in the right hemisphere, mostly in the temporal lobe. Significantly higher densities of TDP-43 inclusions were present in right language-related temporal regions compared to the left or to other right hemisphere regions. The memory-related entorhinal cortex (ERC) and language regions without significant atrophy showed no asymmetry. Activated microglia displayed extensive asymmetry (R > L). A substantial density of neurons remained in all areas and showed no hemispheric asymmetry. However, perikaryal size was significantly smaller in the right hemisphere across all regions except the ERC. To demonstrate the specificity of this finding, sizes of residual neurons were measured in a right-handed case with PPA and were found to be smaller in the language-dominant left hemisphere. The distribution of TDP-43 inclusions and microglial activation in right temporal language regions showed concordance with anatomic distribution of cortical atrophy and clinical presentation. The results revealed no direct relationship between density of TDP-43 inclusions and activated microglia. Reduced size of the remaining neurons is likely to contribute to cortical atrophy detected by MRI. These findings support the conclusion that there is no obligatory relationship between logopenic PPA and Alzheimer pathology. © 2018 American Academy of Neurology.

Evaluation of enamel damages following orthodontic bracket debonding in fluorosed teeth bonded with adhesion promoter.

PubMed

Baherimoghadam, Tahreh; Akbarian, Sahar; Rasouli, Reza; Naseri, Navid

2016-01-01

To evaluate shear bond strength (SBS) of the orthodontic brackets bonded to fluorosed and nonfluorosed teeth using Light Bond with and without adhesion promoters and compare their enamel damages following debonding. In this study, 30 fluorosed (Thylstrup and Fejerskov Index = 4-5) and 30 nonfluorosed teeth were randomly distributed between two subgroups according to the bonding materials: Group 1, fluorosed teeth bonded with Light Bond; Group 2, fluorosed teeth bonded with adhesion promoters and Light Bond; Group 3, nonfluorosed teeth bonded with Light Bond; Group 4, nonfluorosed bonded with adhesion promoters and Light Bond. After bonding, the SBS of the brackets was tested with a universal testing machine. Stereomicroscopic evaluation was performed by unbiased stereology in all teeth to determine the amount of adhesive remnants and the number and length of enamel cracks before bonding and after debonding. The data were analyzed using two-way analysis of variance, Kruskal-Wallis, Wilcoxon Signed Rank, and Mann-Whitney test. While fluorosis reduced the SBS of orthodontic bracket (P = 0.017), Enhance Locus Ceruleus LC significantly increased the SBS of the orthodontic bracket in fluorosed and nonfluorosed teeth (P = 0.039). Significant increasing in the number and length of enamel crack after debonding was found in all four groups. There were no significant differences in the length of enamel crack increased after debonding among four groups (P = 0.768) while increasing in the number of enamel cracks after debonding was significantly different among the four groups (P = 0.023). Teeth in Group 2 showed the highest enamel damages among four groups following debonding. Adhesion promoters could improve the bond strength of orthodontic brackets, but conservative debonding methods for decreasing enamel damages would be necessary.

The myelinated fiber loss in the corpus callosum of mouse model of schizophrenia induced by MK-801.

PubMed

Xiu, Yun; Kong, Xiang-ru; Zhang, Lei; Qiu, Xuan; Gao, Yuan; Huang, Chun-xia; Chao, Feng-lei; Wang, San-rong; Tang, Yong

2015-04-01

Previous magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) investigations have shown that the white matter volume and fractional anisotropy (FA) were decreased in schizophrenia (SZ), which indicated impaired white matter integrity in SZ. However, the mechanism underlying these abnormalities has been less studied. The current study was designed to investigate the possible reasons for white matter abnormalities in the mouse model of SZ induced by NMDA receptor antagonist using the unbiased stereological methods and transmission electron microscope technique. We found that the mice treated with MK-801 demonstrated a series of schizophrenia-like behaviors including hyperlocomotor activity and more anxiety. The myelinated fibers in the corpus callosum (CC) of the mice treated with MK-801 were impaired with splitting lamellae of myelin sheaths and segmental demyelination. The CC volume and the total length of the myelinated fibers in the CC of the mice treated with MK-801 were significantly decreased by 9.4% and 16.8% when compared to those of the mice treated with saline. We further found that the loss of the myelinated fibers length was mainly due to the marked loss of the myelinated nerve fibers with the diameter of 0.4-0.5 μm. These results indicated that the splitting myelin sheaths, demyelination and the loss of myelinated fibers with small diameter might provide one of the structural bases for impaired white matter integrity of CC in the mouse model of SZ. These results might also provide a baseline for further studies searching for the treatment of SZ through targeting white matter. Copyright © 2015 Elsevier Ltd. All rights reserved.

Quantification of healthy and atretic germ cells and follicles in the developing and post-natal ovary of the South American plains vizcacha, Lagostomus maximus: evidence of continuous rise of the germinal reserve.

PubMed

Inserra, P I F; Leopardo, N P; Willis, M A; Freysselinard, A L; Vitullo, A D

2014-02-01

The female germ line in mammals is subjected to massive cell death that eliminates 60-85% of the germinal reserve by birth and continues from birth to adulthood until the exhaustion of the germinal pool. Germ cell demise occurs mainly through apoptosis by means of a biased expression in favour of pro-apoptotic members of the BCL2 gene family. By contrast, the South American plains vizcacha, Lagostomus maximus, exhibits sustained expression of the anti-apoptotic BCL2 gene throughout gestation and a low incidence of germ cell apoptosis. This led to the proposal that, in the absence of death mechanisms other than apoptosis, the female germ line should increase continuously from foetal life until after birth. In this study, we quantified all healthy germ cells and follicles in the ovaries of L. maximus from early foetal life to day 60 after birth using unbiased stereological methods and detected apoptosis by labelling with TUNEL assay. The healthy germ cell population increased continuously from early-developing ovary reaching a 50 times higher population number by the end of gestation. TUNEL-positive germ cells were <0.5% of the germ cell number, except at mid-gestation (3.62%). Mitotic proliferation, entrance into prophase I stage and primordial follicle formation occurred as overlapping processes from early pregnancy to birth. Germ cell number remained constant in early post-natal life, but a remnant population of non-follicular VASA- and PCNA-positive germ cells still persisted at post-natal day 60. L. maximus is the first mammal so far described in which female germ line develops in the absence of constitutive massive germ cell elimination.

Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse.

PubMed

Evangelio, Marian; García-Amado, María; Clascá, Francisco

2018-01-01

A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ∼21,200 neurons, while LP complex contains ∼31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ∼20,000 and the LP complex ∼30,400 thalamocortical projection neurons (∼12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species.

Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse

PubMed Central

Evangelio, Marian; García-Amado, María; Clascá, Francisco

2018-01-01

A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ∼21,200 neurons, while LP complex contains ∼31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ∼20,000 and the LP complex ∼30,400 thalamocortical projection neurons (∼12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species. PMID:29706872

Simultaneous unbiased estimates of multiple downed wood attributes in perpendicular distance sampling

Treesearch

Mark J. Ducey; Jeffrey H. Gove; Harry T. Valentine

2008-01-01

Perpendicular distance sampling (PDS) is a fast probability-proportional-to-size method for inventory of downed wood. However, previous development of PDS had limited the method to estimating only one variable (such as volume per hectare, or surface area per hectare) at a time. Here, we develop a general design-unbiased estimator for PDS. We then show how that...

Quantitative analysis of the renal aging in rats. Stereological study.

PubMed

Melchioretto, Eduardo Felippe; Zeni, Marcelo; Veronez, Djanira Aparecida da Luz; Martins, Eduardo Lopes; Fraga, Rogério de

2016-05-01

To evaluate the renal function and the renal histological alterations through the stereology and morphometrics in rats submitted to the natural process of aging. Seventy two Wistar rats, divided in six groups. Each group was sacrificed in a different age: 3, 6, 9, 12, 18 and 24 months. It was performed right nephrectomy, stereological and morphometric analysis of the renal tissue (renal volume and weight, density of volume (Vv[glom]) and numerical density (Nv[glom]) of the renal glomeruli and average glomerular volume (Vol[glom])) and also it was evaluated the renal function for the dosage of serum creatinine and urea. There was significant decrease of the renal function in the oldest rats. The renal volume presented gradual increase during the development of the rats with the biggest values registered in the group of animals at 12 months of age and significant progressive decrease in older animals. Vv[glom] presented statistically significant gradual reduction between the groups and the Nv[glom] also decreased significantly. The renal function proved to be inferior in senile rats when compared to the young rats. The morphometric and stereological analysis evidenced renal atrophy, gradual reduction of the volume density and numerical density of the renal glomeruli associated to the aging process.

Hierarchical thinking in network biology: the unbiased modularization of biochemical networks.

PubMed

Papin, Jason A; Reed, Jennifer L; Palsson, Bernhard O

2004-12-01

As reconstructed biochemical reaction networks continue to grow in size and scope, there is a growing need to describe the functional modules within them. Such modules facilitate the study of biological processes by deconstructing complex biological networks into conceptually simple entities. The definition of network modules is often based on intuitive reasoning. As an alternative, methods are being developed for defining biochemical network modules in an unbiased fashion. These unbiased network modules are mathematically derived from the structure of the whole network under consideration.

Post-natal growth in the rat pineal gland: a stereological study.

PubMed

Erbagci, H; Kizilkan, N; Ozbag, D; Erkilic, S; Kervancioglu, P; Canan, S; Gumusburun, E

2012-10-01

The purpose was to observe the changes in a rat pineal gland using stereological techniques during lactation and post-weaning periods. Thirty Wistar albino rats were studied during different post-natal periods using light microscopy. Pineal gland volume was estimated using the Cavalieri Method. Additionally, the total number of pinealocytes was estimated using the optical fractionator technique. Pineal gland volume displayed statistically significant changes between lactation and after weaning periods. A significant increase in pineal gland volume was observed from post-natal day 10 to post-natal day 90. The numerical density of pinealocytes became stabilized during lactation and decreased rapidly after weaning. However, the total number of pinealocytes continuously increased during post-natal life of all rats in the study. However, this increment was not statistically significant when comparing the lactation and after weaning periods. The increase in post-natal pineal gland volume may depend on increment of immunoreactive fibres, capsule thickness or new synaptic bodies. © 2012 Blackwell Verlag GmbH.

A stereological analysis of ductile fracture by microvoid coalescence

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

Steele, J.H., Jr.

A stereological analysis for ductile fracture by microvoid coalescence is presented based upon the model of Widgery and Knott which postulates that microvoids link with a propagating crack if they lie within a certain interaction distance of its plane. A 3- dimensional analytical expression for dimple density and shape is developed from this model using projected image relationships for a thin slab. Void nucleation and growth are incorporated into the analysis using numerical integration of the Rice-Tracey growth equation over the appropriate strain range. An evaluation of the stereological approach is given using tensile data from a spheroidized 1045 steelmore » to predict the effect of hydrostatic pressure upon the dimple density. The analysis, which is consistent with observed correlations between dimple density and second phase particle density, is shown to provide an estimate of dimple size and microroughness parameter used in local stain models for microvoid coalescence. 24 refs., 10 figs.« less

An Unbiased Method To Build Benchmarking Sets for Ligand-Based Virtual Screening and its Application To GPCRs

PubMed Central

2015-01-01

Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the “artificial enrichment” and “analogue bias” of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD. PMID:24749745

An unbiased method to build benchmarking sets for ligand-based virtual screening and its application to GPCRs.

PubMed

Xia, Jie; Jin, Hongwei; Liu, Zhenming; Zhang, Liangren; Wang, Xiang Simon

2014-05-27

Benchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS. Herein, we propose an unbiased method to build benchmarking sets for LBVS and validate it on a multitude of GPCRs targets. To be more specific, our methods can (1) ensure chemical diversity of ligands, (2) maintain the physicochemical similarity between ligands and decoys, (3) make the decoys dissimilar in chemical topology to all ligands to avoid false negatives, and (4) maximize spatial random distribution of ligands and decoys. We evaluated the quality of our Unbiased Ligand Set (ULS) and Unbiased Decoy Set (UDS) using three common LBVS approaches, with Leave-One-Out (LOO) Cross-Validation (CV) and a metric of average AUC of the ROC curves. Our method has greatly reduced the "artificial enrichment" and "analogue bias" of a published GPCRs benchmarking set, i.e., GPCR Ligand Library (GLL)/GPCR Decoy Database (GDD). In addition, we addressed an important issue about the ratio of decoys per ligand and found that for a range of 30 to 100 it does not affect the quality of the benchmarking set, so we kept the original ratio of 39 from the GLL/GDD.

A Phenotypic Change But Not Proliferation Underlies Glial Responses in Alzheimer Disease

PubMed Central

Serrano-Pozo, Alberto; Gómez-Isla, Teresa; Growdon, John H.; Frosch, Matthew P.; Hyman, Bradley T.

2014-01-01

Classical immunohistochemical studies in the Alzheimer disease (AD) brain reveal prominent glial reactions, but whether this pathological feature is due primarily to cell proliferation or to a phenotypic change of existing resting cells remains controversial. We performed double-fluorescence immunohistochemical studies of astrocytes and microglia, followed by unbiased stereology-based quantitation in temporal cortex of 40 AD patients and 32 age-matched nondemented subjects. Glial fibrillary acidic protein (GFAP) and major histocompatibility complex II (MHC2) were used as markers of astrocytic and microglial activation, respectively. Aldehyde dehydrogenase 1 L1 and glutamine synthetase were used as constitutive astrocytic markers, and ionized calcium-binding adaptor molecule 1 (IBA1) as a constitutive microglial marker. As expected, AD patients had higher numbers of GFAP+ astrocytes and MHC2+ microglia than the nondemented subjects. However, both groups had similar numbers of total astrocytes and microglia and, in the AD group, these total numbers remained essentially constant over the clinical course of the disease. The GFAP immunoreactivity of astrocytes, but not the MHC2 immunoreactivity of microglia, increased in parallel with the duration of the clinical illness in the AD group. Cortical atrophy contributed to the perception of increased glia density. We conclude that a phenotypic change of existing glial cells, rather than a marked proliferation of glial precursors, accounts for the majority of the glial responses observed in the AD brain. PMID:23602650

Mild cognitive impairment and asymptomatic Alzheimer disease subjects: equivalent β-amyloid and tau loads with divergent cognitive outcomes.

PubMed

Iacono, Diego; Resnick, Susan M; O'Brien, Richard; Zonderman, Alan B; An, Yang; Pletnikova, Olga; Rudow, Gay; Crain, Barbara; Troncoso, Juan C

2014-04-01

Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed "asymptomatic AD subjects" (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.

Effects of bisphenol A treatment during pregnancy on kidney development in mice: a stereological and histopathological study.

PubMed

Nuñez, P; Fernandez, T; García-Arévalo, M; Alonso-Magdalena, P; Nadal, A; Perillan, C; Arguelles, J

2018-04-01

Bisphenol A (BPA) is a chemical found in plastics that resembles oestrogen in organisms. Developmental exposure to endocrine-disrupting chemicals, such as BPA, increases the susceptibility to type 2 diabetes (T2DM) and cardiovascular diseases. Animal studies have reported a nephron deficit in offspring exposed to maternal diabetes. The aim of this study was to investigate the prenatal BPA exposure effects on nephrogenesis in a mouse model that was predisposed to T2DM. This study quantitatively evaluated the renal structural changes using stereology and histomorphometry methods. The OF1 pregnant mice were treated with a vehicle or BPA (10 or 100 μg/kg/day) during days 9-16 of gestation (early nephrogenesis). The 30-day-old offspring were sacrificed, and tissue samples were collected and prepared for histopathological and stereology studies. Glomerular abnormalities and reduced glomerular formation were observed in the BPA offspring. The kidneys of the BPA10 and BPA100 female offspring had a significantly lower glomerular number and density than those of the CONTROL female offspring. The glomerular histomorphometry revealed a significant difference between the female and male CONTROL offspring for the analysed glomerular parameters that disappeared in the BPA10 and BPA100 offspring. In addition, the kidney histopathological examination showed typical male cuboidal epithelial cells of the Bowman capsule in the female BPA offspring. Exposure to environmentally relevant doses of BPA during embryonic development altered nephrogenesis. These structural changes could be associated with an increased risk of developing cardiometabolic diseases later in life.

Verapamil, a Calcium-Channel Blocker, Improves the Wound Healing Process in Rats with Excisional Full-Thickness Skin Wounds Based on Stereological Parameters.

PubMed

Ashkani-Esfahani, Soheil; Hosseinabadi, Omid Koohi; Moezzi, Parinaz; Moafpourian, Yalda; Kardeh, Sina; Rafiee, Shima; Fatheazam, Reza; Noorafshan, Ali; Nadimi, Elham; Mehrvarz, Shayan; Khoshneviszadeh, Mehdi; Khoshneviszadeh, Mahsima

2016-08-01

Calcium can play noticeable roles in the wound-healing process, such as its effects on organization of F-actinin collagen bundles by fibroblasts at the injury site. In addition, calcium-channel blockers such as verapamil have antioxidant activity by increasing nitric oxide production that promotes angiogenesis, proliferation of fibroblasts, and endothelial cells in the skin-regeneration process. Therefore, in this study, the authors' objective was to investigate the effects of verapamil on the process of wound healing in rat models according to stereological parameters. In this experimental study, 36 male Wistar rats were randomly divided into 3 groups (n = 12): the control group that received no treatment, gel-base-treated group, and the 5% verapamil gel-treated group. Treatments were done every 24 hours for 15 days. Wound closure rate, volume densities of the collagen bundles and the vessels, vessel's length density and mean diameter, and fibroblast populations were estimated using stereological methods and were analyzed by the Kruskal-Wallis and Mann-Whitney U tests; P < .05 was considered statistically significant. The verapamil-treated group showed a faster wound closure rate in comparison with control and gel-base groups (P = .007 and P = .011). The numerical density of fibroblasts, volume density of collagen bundles, mean diameter, and volume densities of the vessels in the verapamil group were significantly higher than those in the control and the base groups (P < .005). The authors showed that verapamil has the ability to improve wound healing by enhancing fibroblast proliferation, collagen bundle synthesis, and revascularization in skin injuries.

[Stereological analysis of rat bone tissue after a flight on the Kosmos-1129 biosatellite].

PubMed

Prokhonchukov, A A; Peschanskiĭ, V S

1982-01-01

Stereological measurements of volume fractions of 53 samples of compact and spongy structures of bones of 15 rats were carried out. The measurements were performed on cortical lamellae, trabecules and lacunae, channels of osteons and matrices of femoral, tibial and fibular bones of rats. Postflight no significant changes were seen in the above parameters as compared to the vivarium controls. During readaptation to I g a slight increase in the volume fraction of spongy bones was noted.

Epidemiologic research using probabilistic outcome definitions.

PubMed

Cai, Bing; Hennessy, Sean; Lo Re, Vincent; Small, Dylan S

2015-01-01

Epidemiologic studies using electronic healthcare data often define the presence or absence of binary clinical outcomes by using algorithms with imperfect specificity, sensitivity, and positive predictive value. This results in misclassification and bias in study results. We describe and evaluate a new method called probabilistic outcome definition (POD) that uses logistic regression to estimate the probability of a clinical outcome using multiple potential algorithms and then uses multiple imputation to make valid inferences about the risk ratio or other epidemiologic parameters of interest. We conducted a simulation to evaluate the performance of the POD method with two variables that can predict the true outcome and compared the POD method with the conventional method. The simulation results showed that when the true risk ratio is equal to 1.0 (null), the conventional method based on a binary outcome provides unbiased estimates. However, when the risk ratio is not equal to 1.0, the traditional method, either using one predictive variable or both predictive variables to define the outcome, is biased when the positive predictive value is <100%, and the bias is very severe when the sensitivity or positive predictive value is poor (less than 0.75 in our simulation). In contrast, the POD method provides unbiased estimates of the risk ratio both when this measure of effect is equal to 1.0 and not equal to 1.0. Even when the sensitivity and positive predictive value are low, the POD method continues to provide unbiased estimates of the risk ratio. The POD method provides an improved way to define outcomes in database research. This method has a major advantage over the conventional method in that it provided unbiased estimates of risk ratios and it is easy to use. Copyright © 2014 John Wiley & Sons, Ltd.

Stereological Cell Morphometry In Right Atrium Myocardium Of Primates

NASA Astrophysics Data System (ADS)

Mandarim-De-Lacerda, Carlos A...; Hureau, Jacques

1986-07-01

The mechanism by which the cardiac impulse is propagated in normal hearts from its origin in the sinus node to the atrio-ventricular node has not been agreed on fully. We studied the "internodal posterior tract" through the crista terminalis by light microscopy and stereological morphometry. The hearts of 12 Papio cynocephalus were perfused , after sacrifice,with phosphate-buffered formol saline. The regions of the crista terminalis (CT), interatrial septum (IAS), atrioventricular bundle (AVB) and interventricular septum (IVS) were cut off and embedded in paraplast and sectioned (10 4m). The multipurpose test system M 42 was superimposed over the photomicrographs (1,890 points test, ESR = 2%) to the stereological computing. The quantitative results show that the cells from CT were more closely relationed with IAS cells than others cells (IVS and AVB cells). This results are not a morphological evidence to establish the specificity of the "internodal posterior tract". The cellular arrangement and anatomical variation in CT myocardium is very important.

Reconfigurable generation and measurement of mutually unbiased bases for time-bin qudits

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

Lukens, Joseph M.; Islam, Nurul T.; Lim, Charles Ci Wen

Here, we propose a method for implementing mutually unbiased generation and measurement of time-bin qudits using a cascade of electro-optic phase modulator–coded fiber Bragg grating pairs. Our approach requires only a single spatial mode and can switch rapidly between basis choices. We obtain explicit solutions for dimensions d = 2, 3, and 4 that realize all d + 1 possible mutually unbiased bases and analyze the performance of our approach in quantum key distribution. Given its practicality and compatibility with current technology, our approach provides a promising springboard for scalable processing of high-dimensional time-bin states.

Reconfigurable generation and measurement of mutually unbiased bases for time-bin qudits

DOE PAGES

Lukens, Joseph M.; Islam, Nurul T.; Lim, Charles Ci Wen; ...

2018-03-12

Here, we propose a method for implementing mutually unbiased generation and measurement of time-bin qudits using a cascade of electro-optic phase modulator–coded fiber Bragg grating pairs. Our approach requires only a single spatial mode and can switch rapidly between basis choices. We obtain explicit solutions for dimensions d = 2, 3, and 4 that realize all d + 1 possible mutually unbiased bases and analyze the performance of our approach in quantum key distribution. Given its practicality and compatibility with current technology, our approach provides a promising springboard for scalable processing of high-dimensional time-bin states.

Reconfigurable generation and measurement of mutually unbiased bases for time-bin qudits

NASA Astrophysics Data System (ADS)

Lukens, Joseph M.; Islam, Nurul T.; Lim, Charles Ci Wen; Gauthier, Daniel J.

2018-03-01

We propose a method for implementing mutually unbiased generation and measurement of time-bin qudits using a cascade of electro-optic phase modulator-coded fiber Bragg grating pairs. Our approach requires only a single spatial mode and can switch rapidly between basis choices. We obtain explicit solutions for dimensions d = 2, 3, and 4 that realize all d + 1 possible mutually unbiased bases and analyze the performance of our approach in quantum key distribution. Given its practicality and compatibility with current technology, our approach provides a promising springboard for scalable processing of high-dimensional time-bin states.

Circulating tumor cell detection: A direct comparison between negative and unbiased enrichment in lung cancer.

PubMed

Xu, Yan; Liu, Biao; Ding, Fengan; Zhou, Xiaodie; Tu, Pin; Yu, Bo; He, Yan; Huang, Peilin

2017-06-01

Circulating tumor cells (CTCs), isolated as a 'liquid biopsy', may provide important diagnostic and prognostic information. Therefore, rapid, reliable and unbiased detection of CTCs are required for routine clinical analyses. It was demonstrated that negative enrichment, an epithelial marker-independent technique for isolating CTCs, exhibits a better efficiency in the detection of CTCs compared with positive enrichment techniques that only use specific anti-epithelial cell adhesion molecules. However, negative enrichment techniques incur significant cell loss during the isolation procedure, and as it is a method that uses only one type of antibody, it is inherently biased. The detection procedure and identification of cell types also relies on skilled and experienced technicians. In the present study, the detection sensitivity of using negative enrichment and a previously described unbiased detection method was compared. The results revealed that unbiased detection methods may efficiently detect >90% of cancer cells in blood samples containing CTCs. By contrast, only 40-60% of CTCs were detected by negative enrichment. Additionally, CTCs were identified in >65% of patients with stage I/II lung cancer. This simple yet efficient approach may achieve a high level of sensitivity. It demonstrates a potential for the large-scale clinical implementation of CTC-based diagnostic and prognostic strategies.

Advantages and pitfalls of using free-hand sections of frozen needles for three-dimensional analysis of mesophyll by stereology and confocal microscopy

PubMed Central

LHOTÁKOVÁ, Z; ALBRECHTOVÁ, J; JANÁČEK, J; KUBÍNOVÁ, L

2008-01-01

The anatomical structure of mesophyll tissue in the leaf is tightly connected with many physiological processes in plants. One of the most important mesophyll parameters related to photosynthesis is the internal leaf surface area, i.e. the surface area of mesophyll cell walls exposed to intercellular spaces. An efficient design-based stereological method can be applied for estimation of this parameter, using software-randomized virtual fakir test probes in stacks of optical sections acquired by a confocal microscope within thick physical free-hand sections (i.e. acquired using a hand microtome), as we have shown in the case of fresh Norway spruce needles recently. However, for wider practical use in plant ecophysiology, a suitable form of sample storage and other possible technical constraints of this methodology need to be checked. We tested the effect of freezing conifer needles on their anatomical structure as well as the effect of possible deformations due to the cutting of unembedded material by a hand microtome, which can result in distortions of cutting surfaces. In the present study we found a higher proportion of intercellular spaces in mesophyll in regions near to the surface of a physical section, which means that the measurements should be restricted only to the middle region of the optical section series. On the other hand, the proportion of intercellular spaces in mesophyll as well as the internal needle surface density in mesophyll did not show significant difference between fresh and frozen needles; therefore, we conclude that freezing represents a suitable form of storage of sampled material for proposed stereological evaluation. PMID:19017201

Advantages and pitfalls of using free-hand sections of frozen needles for three-dimensional analysis of mesophyll by stereology and confocal microscopy.

PubMed

Lhotáková, Z; Albrechtová, J; Janácek, J; Kubínová, L

2008-10-01

The anatomical structure of mesophyll tissue in the leaf is tightly connected with many physiological processes in plants. One of the most important mesophyll parameters related to photosynthesis is the internal leaf surface area, i.e. the surface area of mesophyll cell walls exposed to intercellular spaces. An efficient design-based stereological method can be applied for estimation of this parameter, using software-randomized virtual fakir test probes in stacks of optical sections acquired by a confocal microscope within thick physical free-hand sections (i.e. acquired using a hand microtome), as we have shown in the case of fresh Norway spruce needles recently. However, for wider practical use in plant ecophysiology, a suitable form of sample storage and other possible technical constraints of this methodology need to be checked. We tested the effect of freezing conifer needles on their anatomical structure as well as the effect of possible deformations due to the cutting of unembedded material by a hand microtome, which can result in distortions of cutting surfaces. In the present study we found a higher proportion of intercellular spaces in mesophyll in regions near to the surface of a physical section, which means that the measurements should be restricted only to the middle region of the optical section series. On the other hand, the proportion of intercellular spaces in mesophyll as well as the internal needle surface density in mesophyll did not show significant difference between fresh and frozen needles; therefore, we conclude that freezing represents a suitable form of storage of sampled material for proposed stereological evaluation.

Proliferation assessment in breast carcinomas using digital image analysis based on virtual Ki67/cytokeratin double staining.

PubMed

Røge, Rasmus; Riber-Hansen, Rikke; Nielsen, Søren; Vyberg, Mogens

2016-07-01

Manual estimation of Ki67 Proliferation Index (PI) in breast carcinoma classification is labor intensive and prone to intra- and interobserver variation. Standard Digital Image Analysis (DIA) has limitations due to issues with tumor cell identification. Recently, a computer algorithm, DIA based on Virtual Double Staining (VDS), segmenting Ki67-positive and -negative tumor cells using digitally fused parallel cytokeratin (CK) and Ki67-stained slides has been introduced. In this study, we compare VDS with manual stereological counting of Ki67-positive and -negative cells and examine the impact of the physical distance of the parallel slides on the alignment of slides. TMAs, containing 140 cores of consecutively obtained breast carcinomas, were stained for CK and Ki67 using optimized staining protocols. By means of stereological principles, Ki67-positive and -negative cell profiles were counted in sampled areas and used for the estimation of PIs of the whole tissue core. The VDS principle was applied to both the same sampled areas and the whole tissue core. Additionally, five neighboring slides were stained for CK in order to examine the alignment algorithm. Correlation between manual counting and VDS in both sampled areas and whole core was almost perfect (correlation coefficients above 0.97). Bland-Altman plots did not reveal any skewness in any data ranges. There was a good agreement in alignment (>85 %) in neighboring slides, whereas agreement decreased in non-neighboring slides. VDS gave similar results compared with manual counting using stereological principles. Introduction of this method in clinical and research practice may improve accuracy and reproducibility of Ki67 PI.

STEREO: a program on a PC-Windows 95 platform for recording and evaluating quantitative stereologic investigations of multistage hepatocarcinogenesis in rodents.

PubMed

Xu, Y H; Dragan, Y P; Campbell, H A; Pitot, H C

1998-04-01

The most common organ site of neoplasms induced by carcinogenic chemicals in the rodent bioassay is the liver. The development of cancer in rodent liver is a multistage process involving sequentially the stages of initiation, promotion, and progression. During the stages of promotion and progression, numerous lesions termed altered hepatic foci (AHF) develop. STEREO was developed for the purpose of efficient and accurate quantitation of AHF and related lesions in experimental and test rodents. The system utilized is equipped with a microcomputer (IBM-compatible PC running Windows 95) and a Summagraphics MICROGRID or SummaSketch tablet digitizer. The program records information from digitization of single or serial sections obtained randomly from rat liver tissue. With this information and the methods of quantitative stereology, both the number and volume percentage fraction of AHF in liver are calculated in three dimensions. The recorded data files can be printed graphically or in the format of tabular numerical data. The results of stereologic calculations are stored on floppy disks and can be sorted into different categories and analyzed or displayed with the use of statistics and graphic functions built into the overall program. Results may also be exported into Microsoft Excel for use at a later time. Any IBM-compatible PC capable of utilizing Windows 95 and MS Office can be used with STEREO, which offers inexpensive, easily operated software to obtain three-dimensional information from sections of two dimensions for the identification and relative potency of initiators, promoters, and progressors, and for the establishment of information potentially useful in developing estimations of risk for human cancer.

Effects of aluminum in red spruce (Picea rubens) cell cultures: Cell growth and viability, mitochondrial activity, ultrastructure and potential sites of intracellular aluminum accumulation

Treesearch

Rakesh Minocha; Carolyn McQuattie; Wayne Fagerberg; Stephanie Long; Eun Woon Noh

2001-01-01

The effects of Al on red spruce (Picea rubens Sarg.) cell suspension cultures were examined using biochemical, stereo-logical and microscopic methods. Exposure to Al for 24-48 h resulted in a loss of cell viability, inhibition of growth and a significant decrease in mitochondrial activity. Soluble protein content increased in cells treated with Al....

A Stereological Study of Synapse Number in the Epileptic Human Hippocampus

PubMed Central

Alonso-Nanclares, Lidia; Kastanauskaite, Asta; Rodriguez, Jose-Rodrigo; Gonzalez-Soriano, Juncal; DeFelipe, Javier

2011-01-01

Hippocampal sclerosis is the most frequent pathology encountered in resected mesial temporal structures from patients with intractable temporal lobe epilepsy (TLE). Here, we have used stereological methods to compare the overall density of synapses and neurons between non-sclerotic and sclerotic hippocampal tissue obtained by surgical resection from patients with TLE. Specifically, we examined the possible changes in the subiculum and CA1, regions that seem to be critical for the development and/or maintenance of seizures in these patients. We found a remarkable decrease in synaptic and neuronal density in the sclerotic CA1, and while the subiculum from the sclerotic hippocampus did not display changes in synaptic density, the neuronal density was higher. Since the subiculum from the sclerotic hippocampus displays a significant increase in neuronal density, as well as a various other neurochemical changes, we propose that the apparently normal subiculum from the sclerotic hippocampus suffers profound alterations in neuronal circuits at both the molecular and synaptic level that are likely to be critical for the development or maintenance of seizure activity. PMID:21390290

Comparison of estimators of standard deviation for hydrologic time series

USGS Publications Warehouse

Tasker, Gary D.; Gilroy, Edward J.

1982-01-01

Unbiasing factors as a function of serial correlation, ρ, and sample size, n for the sample standard deviation of a lag one autoregressive model were generated by random number simulation. Monte Carlo experiments were used to compare the performance of several alternative methods for estimating the standard deviation σ of a lag one autoregressive model in terms of bias, root mean square error, probability of underestimation, and expected opportunity design loss. Three methods provided estimates of σ which were much less biased but had greater mean square errors than the usual estimate of σ: s = (1/(n - 1) ∑ (xi −x¯)2)½. The three methods may be briefly characterized as (1) a method using a maximum likelihood estimate of the unbiasing factor, (2) a method using an empirical Bayes estimate of the unbiasing factor, and (3) a robust nonparametric estimate of σ suggested by Quenouille. Because s tends to underestimate σ, its use as an estimate of a model parameter results in a tendency to underdesign. If underdesign losses are considered more serious than overdesign losses, then the choice of one of the less biased methods may be wise.

Critical point relascope sampling for unbiased volume estimation of downed coarse woody debris

Treesearch

Jeffrey H. Gove; Michael S. Williams; Mark J. Ducey; Mark J. Ducey

2005-01-01

Critical point relascope sampling is developed and shown to be design-unbiased for the estimation of log volume when used with point relascope sampling for downed coarse woody debris. The method is closely related to critical height sampling for standing trees when trees are first sampled with a wedge prism. Three alternative protocols for determining the critical...

Unbiased nonorthogonal bases for tomographic reconstruction

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

Sainz, Isabel; Klimov, Andrei B.; Roa, Luis

2010-05-15

We have developed a general method for constructing a set of nonorthogonal bases with equal separations between all different basis states in prime dimensions. The results are that the corresponding biorthogonal counterparts are pairwise unbiased with the components of the original bases. Using these bases, we derive an explicit expression for the optimal tomography in nonorthogonal bases. A special two-dimensional case is analyzed separately.

Examining cerebral angiogenesis in response to physical exercise.

PubMed

Berggren, Kiersten L; Kay, Jacob J M; Swain, Rodney A

2014-01-01

Capillary growth and expansion (angiogenesis) is a prerequisite for many forms of neural and behavioral plasticity. It is commonly observed in both brain and muscle of aerobically exercising animals. As such, several histological methods have been used to quantify capillary density, including perfusion with India ink, various Nissl stains, and immunohistochemistry. In this chapter, we will describe these histological procedures and describe the stereological analysis used to quantify vessel growth in response to aerobic exercise.

Cerebellar Structure and Function in Male Wistar-Kyoto Hyperactive Rats

PubMed Central

Thanellou, Alexandra; Green, John T.

2014-01-01

Previous research has suggested that the Wistar-Kyoto Hyperactive (WKHA) rat strain may model some of the behavioral features associated with attention-deficit/hyperactivity disorder (ADHD). We have shown that, in cerebellar-dependent eyeblink conditioning, WKHA emit eyeblink CRs with shortened onset latencies. To further characterize the shortened CR onset latencies seen in WKHA rats, we examined 750-ms delay conditioning with either a tone CS or a light CS, we extended acquisition training, and we included Wistar rats as an additional, outbred control strain. Our results indicated that WKHAs learned more quickly and showed a shortened CR onset latency to a tone CS compared to both Wistar-Kyoto Hypertensive (WKHT) and Wistars. WKHAs and Wistars show a lengthening of CR onset latency over conditioning with a tone CS and an increasing confinement of CRs to the later part of the tone CS (inhibition of delay). WKHAs learned more quickly to a light CS only in comparison to WKHTs and showed a shortened CR onset latency only in comparison to Wistars. Wistars showed an increasing confinement of CRs to the late part of the light CS over conditioning. We used unbiased stereology to estimate the number of Purkinje and granule cells in the cerebellar cortex of the three strains. Our results indicated that WKHAs have more granule cells than Wistars and WKHTs and more Purkinje cells than Wistars. Results are discussed in terms of CS processing and cerebellar cortical contributions to EBC. PMID:23398437

FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development.

PubMed

Inglis-Broadgate, Suzanne L; Thomson, Rachel E; Pellicano, Francesca; Tartaglia, Michael A; Pontikis, Charlie C; Cooper, Jonathan D; Iwata, Tomoko

2005-03-01

Mice with the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3(+/K644E)) exhibited a marked enlargement of the brain. The brain size was increased as early as E11.5, not secondary to the possible effect of Fgfr3 activity in the skeleton. Furthermore, the mutant brains showed a dramatic increase in cortical thickness, a phenotype opposite to that in FGF2 knockout mice. Despite this increased thickness, cortical layer formation was largely unaffected and no cortical folding was observed during embryonic days 11.5-18.5 (E11.5-E18.5). Measurement of cortical thickness revealed an increase of 38.1% in the EIIa;Fgfr3(+/K644E) mice at E14.5 and the advanced appearance of the cortical plate was frequently observed at this stage. Unbiased stereological analysis revealed that the volume of the ventricular zone (VZ) was increased by more than two fold in the EIIa;Fgfr3(+/K644E) mutants at E14.5. A relatively mild increase in progenitor cell proliferation and a profound decrease in developmental apoptosis during E11.5-E14.5 most likely accounts for the dramatic increase in total telecephalic cell number. Taken together, our data suggest a novel function of Fgfr3 in controlling the development of the cortex, by regulating proliferation and apoptosis of cortical progenitors.

Sampling for Patient Exit Interviews: Assessment of Methods Using Mathematical Derivation and Computer Simulations.

PubMed

Geldsetzer, Pascal; Fink, Günther; Vaikath, Maria; Bärnighausen, Till

2018-02-01

(1) To evaluate the operational efficiency of various sampling methods for patient exit interviews; (2) to discuss under what circumstances each method yields an unbiased sample; and (3) to propose a new, operationally efficient, and unbiased sampling method. Literature review, mathematical derivation, and Monte Carlo simulations. Our simulations show that in patient exit interviews it is most operationally efficient if the interviewer, after completing an interview, selects the next patient exiting the clinical consultation. We demonstrate mathematically that this method yields a biased sample: patients who spend a longer time with the clinician are overrepresented. This bias can be removed by selecting the next patient who enters, rather than exits, the consultation room. We show that this sampling method is operationally more efficient than alternative methods (systematic and simple random sampling) in most primary health care settings. Under the assumption that the order in which patients enter the consultation room is unrelated to the length of time spent with the clinician and the interviewer, selecting the next patient entering the consultation room tends to be the operationally most efficient unbiased sampling method for patient exit interviews. © 2016 The Authors. Health Services Research published by Wiley Periodicals, Inc. on behalf of Health Research and Educational Trust.

Diallel analysis for sex-linked and maternal effects.

PubMed

Zhu, J; Weir, B S

1996-01-01

Genetic models including sex-linked and maternal effects as well as autosomal gene effects are described. Monte Carlo simulations were conducted to compare efficiencies of estimation by minimum norm quadratic unbiased estimation (MINQUE) and restricted maximum likelihood (REML) methods. MINQUE(1), which has 1 for all prior values, has a similar efficiency to MINQUE(θ), which requires prior estimates of parameter values. MINQUE(1) has the advantage over REML of unbiased estimation and convenient computation. An adjusted unbiased prediction (AUP) method is developed for predicting random genetic effects. AUP is desirable for its easy computation and unbiasedness of both mean and variance of predictors. The jackknife procedure is appropriate for estimating the sampling variances of estimated variances (or covariances) and of predicted genetic effects. A t-test based on jackknife variances is applicable for detecting significance of variation. Worked examples from mice and silkworm data are given in order to demonstrate variance and covariance estimation and genetic effect prediction.

Comparative modeling and benchmarking data sets for human histone deacetylases and sirtuin families.

PubMed

Xia, Jie; Tilahun, Ermias Lemma; Kebede, Eyob Hailu; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

2015-02-23

Histone deacetylases (HDACs) are an important class of drug targets for the treatment of cancers, neurodegenerative diseases, and other types of diseases. Virtual screening (VS) has become fairly effective approaches for drug discovery of novel and highly selective histone deacetylase inhibitors (HDACIs). To facilitate the process, we constructed maximal unbiased benchmarking data sets for HDACs (MUBD-HDACs) using our recently published methods that were originally developed for building unbiased benchmarking sets for ligand-based virtual screening (LBVS). The MUBD-HDACs cover all four classes including Class III (Sirtuins family) and 14 HDAC isoforms, composed of 631 inhibitors and 24609 unbiased decoys. Its ligand sets have been validated extensively as chemically diverse, while the decoy sets were shown to be property-matching with ligands and maximal unbiased in terms of "artificial enrichment" and "analogue bias". We also conducted comparative studies with DUD-E and DEKOIS 2.0 sets against HDAC2 and HDAC8 targets and demonstrate that our MUBD-HDACs are unique in that they can be applied unbiasedly to both LBVS and SBVS approaches. In addition, we defined a novel metric, i.e. NLBScore, to detect the "2D bias" and "LBVS favorable" effect within the benchmarking sets. In summary, MUBD-HDACs are the only comprehensive and maximal-unbiased benchmark data sets for HDACs (including Sirtuins) that are available so far. MUBD-HDACs are freely available at http://www.xswlab.org/ .

Correlation between liver cell necrosis and circulating alanine aminotransferase after ischaemia/reperfusion injuries in the rat liver.

PubMed

Knudsen, Anders R; Andersen, Kasper J; Hamilton-Dutoit, Stephen; Nyengaard, Jens R; Mortensen, Frank V

2016-04-01

Circulating liver enzymes such as alanine transaminase are often used as markers of hepatocellular damage. Ischaemia/reperfusion (I/R) injury is an inevitable consequence of prolonged liver ischaemia. The aim of this study was to examine the correlation between liver enzymes and volume of liver cell necrosis after ischaemia/reperfusion injuries, using design-unbiased stereological methods. Forty-seven male Wistar rats were subjected to 1 h of partial liver ischaemia, followed by either 4 or 24 h of reperfusion. Within each group, one-third of animals were subjected to ischaemic preconditioning and one-third to ischaemic postconditioning. At the end of reperfusion, blood and liver samples were collected for analysis. The volume of necrotic liver tissue was subsequently correlated to circulating markers of I/R injury. Correlation between histological findings and circulating markers was performed using Pearson's correlation coefficient. Alanine transferase peaked after 4 h of reperfusion; however, at this time-point, only mild necrosis was observed, with a Pearson's correlation coefficient of 0.663 (P = 0.001). After 24 h of reperfusion, alanine aminotransferase was found to be highly correlated to the degree of hepatocellular necrosis R = 0.836 (P = 0.000). Furthermore, alkaline phosphatase (R = 0.806) and α-2-macroglobulin (R = 0.655) levels were also correlated with the degree of necrosis. We show for the first time that there is a close correlation between the volume of hepatocellular necrosis and alanine aminotransferase levels in a model of I/R injury. This is especially apparent after 24 h of reperfusion. Similarly, increased levels of alkaline phosphatase and α-2-macroglobulin are correlated to the volume of liver necrosis. © 2016 The Authors. International Journal of Experimental Pathology © 2016 International Journal of Experimental Pathology.

Antenatal Dexamethasone after Asphyxia Increases Neural Injury in Preterm Fetal Sheep

PubMed Central

Koome, Miriam E.; Davidson, Joanne O.; Drury, Paul P.; Mathai, Sam; Booth, Lindsea C.; Gunn, Alistair Jan; Bennet, Laura

2013-01-01

Background and Purpose Maternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain. Methods Chronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10) or saline (n = 10). Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach. Results Maternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290±76 vs 484±98 neurons/mm2, mean±SEM, P<0.05) and basal ganglia (putamen, 538±112 vs 814±34 neurons/mm2, P<0.05) compared to asphyxia-saline, and with greater loss of both total (913±77 vs 1201±75/mm2, P<0.05) and immature/mature myelinating oligodendrocytes in periventricular white matter (66±8 vs 114±12/mm2, P<0.05, vs sham controls 165±10/mm2, P<0.001). This was associated with transient hyperglycemia (peak 3.5±0.2 vs. 1.4±0.2 mmol/L at 6 h, P<0.05) and reduced suppression of EEG power in the first 24 h after occlusion (maximum −1.5±1.2 dB vs. −5.0±1.4 dB in saline controls, P<0.01), but later onset and fewer overt seizures. Conclusions In preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage. PMID:24204840

Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease.

PubMed

Arcuri, Ludovico; Viaro, Riccardo; Bido, Simone; Longo, Francesco; Calcagno, Mariangela; Fernagut, Pierre-Olivier; Zaveri, Nurulain T; Calò, Girolamo; Bezard, Erwan; Morari, Michele

2016-05-01

To investigate whether the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) contributes to the death of dopamine neurons in Parkinson's disease, we undertook a genetic and a pharmacological approach using NOP receptor knockout (NOP(-/-)) mice, and the selective and potent small molecule NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). Stereological unbiased methods were used to estimate the total number of dopamine neurons in the substantia nigra of i) NOP(-/-) mice acutely treated with the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), ii) naïve mice subacutely treated with MPTP, alone or in combination with SB-612111, iii) rats injected with a recombinant adeno-associated viral (AAV) vector overexpressing human mutant p.A53T α-synuclein, treated with vehicle or SB-612111. NOP(-/-) mice showed a 50% greater amount of nigral dopamine neurons spared in response to acute MPTP compared to controls, which was associated with a milder motor impairment. SB-612111, given 4 days after MPTP treatment to mimic the clinical condition, prevented the loss of nigral dopamine neurons and striatal dopaminergic terminals caused by subacute MPTP. SB-612111, administered a week after the AAV injections in a clinically-driven protocol, also increased by 50% both the number of spared nigral dopamine neurons and striatal dopamine terminals, and prevented accompanying motor deficits induced by α-synuclein. We conclude that endogenous N/OFQ contributes to dopamine neuron loss in pathogenic and etiologic models of Parkinson's disease through NOP receptor-mediated mechanisms. NOP receptor antagonists might prove effective as disease-modifying agents in Parkinson's disease, through the rescue of degenerating nigral dopamine neurons and/or the protection of the healthy ones. Copyright © 2016. Published by Elsevier Inc.

White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

PubMed

Craggs, Lucinda J L; Yamamoto, Yumi; Ihara, Masafumi; Fenwick, Richard; Burke, Matthew; Oakley, Arthur E; Roeber, Sigrun; Duering, Marco; Kretzschmar, Hans; Kalaria, Raj N

2014-08-01

Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P<0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P<0.01), with most prominent axonal abnormalities observed in the frontal WM (P<0.05). The SIs of arterioles in CADASIL were increased by 25-45% throughout the regions assessed, with the highest change in the mid-frontal region (P=0.000). Our results suggest disruption of either cortico-cortical or subcortical-cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures. © 2013 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Joint modelling compared with two stage methods for analysing longitudinal data and prospective outcomes: A simulation study of childhood growth and BP.

PubMed

Sayers, A; Heron, J; Smith, Adac; Macdonald-Wallis, C; Gilthorpe, M S; Steele, F; Tilling, K

2017-02-01

There is a growing debate with regards to the appropriate methods of analysis of growth trajectories and their association with prospective dependent outcomes. Using the example of childhood growth and adult BP, we conducted an extensive simulation study to explore four two-stage and two joint modelling methods, and compared their bias and coverage in estimation of the (unconditional) association between birth length and later BP, and the association between growth rate and later BP (conditional on birth length). We show that the two-stage method of using multilevel models to estimate growth parameters and relating these to outcome gives unbiased estimates of the conditional associations between growth and outcome. Using simulations, we demonstrate that the simple methods resulted in bias in the presence of measurement error, as did the two-stage multilevel method when looking at the total (unconditional) association of birth length with outcome. The two joint modelling methods gave unbiased results, but using the re-inflated residuals led to undercoverage of the confidence intervals. We conclude that either joint modelling or the simpler two-stage multilevel approach can be used to estimate conditional associations between growth and later outcomes, but that only joint modelling is unbiased with nominal coverage for unconditional associations.

Stereological Study on the Positive Effect of Running Exercise on the Capillaries in the Hippocampus in a Depression Model.

PubMed

Chen, Linmu; Zhou, Chunni; Tan, Chuanxue; Wang, Feifei; Gao, Yuan; Huang, Chunxia; Zhang, Yi; Jiang, Lin; Tang, Yong

2017-01-01

Running exercise is an effective method to improve depressive symptoms when combined with drugs. However, the underlying mechanisms are not fully clear. Cerebral blood flow perfusion in depressed patients is significantly lower in the hippocampus. Physical activity can achieve cerebrovascular benefits. The purpose of this study was to evaluate the impacts of running exercise on capillaries in the hippocampal CA1 and dentate gyrus (DG) regions. The chronic unpredictable stress (CUS) depression model was used in this study. CUS rats were given 4 weeks of running exercise from the fifth week to the eighth week (20 min every day from Monday to Friday each week). The sucrose consumption test was used to measure anhedonia. Furthermore, stereological methods were used to investigate the capillary changes among the control group, CUS/Standard group and CUS/Running group. Sucrose consumption significantly increased in the CUS/Running group. Running exercise has positive effects on the capillaries parameters in the hippocampal CA1 and DG regions, such as the total volume, total length and total surface area. These results demonstrated that capillaries are protected by running exercise in the hippocampal CA1 and DG might be one of the structural bases for the exercise-induced treatment of depression-like behavior. These results suggest that drugs and behavior influence capillaries and may be considered as a new means for depression treatment in the future.

Comparative Modeling and Benchmarking Data Sets for Human Histone Deacetylases and Sirtuin Families

PubMed Central

Xia, Jie; Tilahun, Ermias Lemma; Kebede, Eyob Hailu; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

2015-01-01

Histone Deacetylases (HDACs) are an important class of drug targets for the treatment of cancers, neurodegenerative diseases and other types of diseases. Virtual screening (VS) has become fairly effective approaches for drug discovery of novel and highly selective Histone Deacetylases Inhibitors (HDACIs). To facilitate the process, we constructed the Maximal Unbiased Benchmarking Data Sets for HDACs (MUBD-HDACs) using our recently published methods that were originally developed for building unbiased benchmarking sets for ligand-based virtual screening (LBVS). The MUBD-HDACs covers all 4 Classes including Class III (Sirtuins family) and 14 HDACs isoforms, composed of 631 inhibitors and 24,609 unbiased decoys. Its ligand sets have been validated extensively as chemically diverse, while the decoy sets were shown to be property-matching with ligands and maximal unbiased in terms of “artificial enrichment” and “analogue bias”. We also conducted comparative studies with DUD-E and DEKOIS 2.0 sets against HDAC2 and HDAC8 targets, and demonstrate that our MUBD-HDACs is unique in that it can be applied unbiasedly to both LBVS and SBVS approaches. In addition, we defined a novel metric, i.e. NLBScore, to detect the “2D bias” and “LBVS favorable” effect within the benchmarking sets. In summary, MUBD-HDACs is the only comprehensive and maximal-unbiased benchmark data sets for HDACs (including Sirtuins) that is available so far. MUBD-HDACs is freely available at http://www.xswlab.org/. PMID:25633490

Basolateral amygdala volume and cell numbers in major depressive disorder: a postmortem stereological study.

PubMed

Rubinow, Marisa J; Mahajan, Gouri; May, Warren; Overholser, James C; Jurjus, George J; Dieter, Lesa; Herbst, Nicole; Steffens, David C; Miguel-Hidalgo, Jose J; Rajkowska, Grazyna; Stockmeier, Craig A

2016-01-01

Functional imaging studies consistently report abnormal amygdala activity in major depressive disorder (MDD). Neuroanatomical correlates are less clear: imaging studies have produced mixed results on amygdala volume, and postmortem neuroanatomic studies have only examined cell densities in portions of the amygdala or its subregions in MDD. Here, we present a stereological analysis of the volume of, and the total number of, neurons, glia, and neurovascular (pericyte and endothelial) cells in the basolateral amygdala in MDD. Postmortem tissues from 13 subjects with MDD and 10 controls were examined. Sections (~15/subject) taken throughout the rostral-caudal extent of the basolateral amygdala (BLA) were stained for Nissl substance and utilized for stereological estimation of volume and cell numbers. Results indicate that depressed subjects had a larger lateral nucleus than controls and a greater number of total BLA neurovascular cells than controls. There were no differences in the number or density of neurons or glia between depressed and control subjects. These findings present a more detailed picture of BLA cellular anatomy in depression than has previously been available. Further studies are needed to determine whether the greater number of neurovascular cells in depressed subjects may be related to increased amygdala activity in depression.

What Do We Know about Using Value-Added to Compare Teachers Who Work in Different Schools? What We Know Series: Value-Added Methods and Applications. Knowledge Brief 10

ERIC Educational Resources Information Center

Raudenbush, Stephen

2013-01-01

This brief considers the problem of using value-added scores to compare teachers who work in different schools. The author focuses on whether such comparisons can be regarded as fair, or, in statistical language, "unbiased." An unbiased measure does not systematically favor teachers because of the backgrounds of the students they are…

Autocorrelation analysis for the unbiased determination of power-law exponents in single-quantum-dot blinking.

PubMed

Houel, Julien; Doan, Quang T; Cajgfinger, Thomas; Ledoux, Gilles; Amans, David; Aubret, Antoine; Dominjon, Agnès; Ferriol, Sylvain; Barbier, Rémi; Nasilowski, Michel; Lhuillier, Emmanuel; Dubertret, Benoît; Dujardin, Christophe; Kulzer, Florian

2015-01-27

We present an unbiased and robust analysis method for power-law blinking statistics in the photoluminescence of single nanoemitters, allowing us to extract both the bright- and dark-state power-law exponents from the emitters' intensity autocorrelation functions. As opposed to the widely used threshold method, our technique therefore does not require discriminating the emission levels of bright and dark states in the experimental intensity timetraces. We rely on the simultaneous recording of 450 emission timetraces of single CdSe/CdS core/shell quantum dots at a frame rate of 250 Hz with single photon sensitivity. Under these conditions, our approach can determine ON and OFF power-law exponents with a precision of 3% from a comparison to numerical simulations, even for shot-noise-dominated emission signals with an average intensity below 1 photon per frame and per quantum dot. These capabilities pave the way for the unbiased, threshold-free determination of blinking power-law exponents at the microsecond time scale.

Examinations of tRNA Range of Motion Using Simulations of Cryo-EM Microscopy and X-Ray Data.

PubMed

Caulfield, Thomas R; Devkota, Batsal; Rollins, Geoffrey C

2011-01-01

We examined tRNA flexibility using a combination of steered and unbiased molecular dynamics simulations. Using Maxwell's demon algorithm, molecular dynamics was used to steer X-ray structure data toward that from an alternative state obtained from cryogenic-electron microscopy density maps. Thus, we were able to fit X-ray structures of tRNA onto cryogenic-electron microscopy density maps for hybrid states of tRNA. Additionally, we employed both Maxwell's demon molecular dynamics simulations and unbiased simulation methods to identify possible ribosome-tRNA contact areas where the ribosome may discriminate tRNAs during translation. Herein, we collected >500 ns of simulation data to assess the global range of motion for tRNAs. Biased simulations can be used to steer between known conformational stop points, while unbiased simulations allow for a general testing of conformational space previously unexplored. The unbiased molecular dynamics data describes the global conformational changes of tRNA on a sub-microsecond time scale for comparison with steered data. Additionally, the unbiased molecular dynamics data was used to identify putative contacts between tRNA and the ribosome during the accommodation step of translation. We found that the primary contact regions were H71 and H92 of the 50S subunit and ribosomal proteins L14 and L16.

A cross-correlation-based estimate of the galaxy luminosity function

NASA Astrophysics Data System (ADS)

van Daalen, Marcel P.; White, Martin

2018-06-01

We extend existing methods for using cross-correlations to derive redshift distributions for photometric galaxies, without using photometric redshifts. The model presented in this paper simultaneously yields highly accurate and unbiased redshift distributions and, for the first time, redshift-dependent luminosity functions, using only clustering information and the apparent magnitudes of the galaxies as input. In contrast to many existing techniques for recovering unbiased redshift distributions, the output of our method is not degenerate with the galaxy bias b(z), which is achieved by modelling the shape of the luminosity bias. We successfully apply our method to a mock galaxy survey and discuss improvements to be made before applying our model to real data.

Evaluation of gingival alterations in rats medicated with cyclosporine A, tacrolimus and sirolimus: a stereological study.

PubMed

Pamuk, F; Cetinkaya, B O; Ayas, B; Keles, G C; Gacar, A

2015-10-01

It has previously been shown that both cyclosporine A and tacrolimus cause gingival overgrowth in the rat. We proposed that sirolimus may play an important role in decreasing the severity of gingival overgrowth. Therefore, the aim of this study was to evaluate the gingival changes induced by immunosuppressants, in the presence and absence of sirolimus, using histopathology and stereological methods. Thirty-six male Sprague-Dawley rats were distributed into six treatment groups, each containing six rats, as follows: (i) cyclosporine A for 8 wk; (ii) tacrolimus for 8 wk; (iii) sirolimus for 8 wk; (iv) cyclosporine A + sirolimus for 8 wk; (v) tacrolimus + sirolimus for 8 wk; and (vi) distilled water for 8 wk. Histomorphometric analyses included measurements of epithelial thickness and connective tissue width and height. Stereological analyses included measurements of volumetric densities of fibroblasts (Vf ), collagen fibers (Vcf ) and blood vessels (Vbv ). Connective tissue width and height were significantly increased in cyclosporine A, tacrolimus and cyclosporine A + sirolimus groups compared with the control group (p < 0.05), and epithelial thickness was significantly increased in the cyclosporine A group and tacrolimus group compared with the control group (p < 0.05). Vf was significantly increased in the cyclosporine A group and the tacrolimus group compared with the control group (p < 0.05), whereas Vcf and Vbv were significantly increased in the cyclosporine A, tacrolimus and cyclosporine A + sirolimus groups compared with the control group (p < 0.05). The results of the study suggest that sirolimus seems not to be associated with gingival overgrowth, and combined usage of sirolimus and immunosuppressants decreases the severity of gingival overgrowth. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Particle detection, number estimation, and feature measurement in gene transfer studies: optical fractionator stereology integrated with digital image processing and analysis.

PubMed

King, Michael A; Scotty, Nicole; Klein, Ronald L; Meyer, Edwin M

2002-10-01

Assessing the efficacy of in vivo gene transfer often requires a quantitative determination of the number, size, shape, or histological visualization characteristics of biological objects. The optical fractionator has become a choice stereological method for estimating the number of objects, such as neurons, in a structure, such as a brain subregion. Digital image processing and analytic methods can increase detection sensitivity and quantify structural and/or spectral features located in histological specimens. We describe a hardware and software system that we have developed for conducting the optical fractionator process. A microscope equipped with a video camera and motorized stage and focus controls is interfaced with a desktop computer. The computer contains a combination live video/computer graphics adapter with a video frame grabber and controls the stage, focus, and video via a commercial imaging software package. Specialized macro programs have been constructed with this software to execute command sequences requisite to the optical fractionator method: defining regions of interest, positioning specimens in a systematic uniform random manner, and stepping through known volumes of tissue for interactive object identification (optical dissectors). The system affords the flexibility to work with count regions that exceed the microscope image field size at low magnifications and to adjust the parameters of the fractionator sampling to best match the demands of particular specimens and object types. Digital image processing can be used to facilitate object detection and identification, and objects that meet criteria for counting can be analyzed for a variety of morphometric and optical properties. Copyright 2002 Elsevier Science (USA)

Generation and evaluation of an ultra-high-field atlas with applications in DBS planning

NASA Astrophysics Data System (ADS)

Wang, Brian T.; Poirier, Stefan; Guo, Ting; Parrent, Andrew G.; Peters, Terry M.; Khan, Ali R.

2016-03-01

Purpose Deep brain stimulation (DBS) is a common treatment for Parkinson's disease (PD) and involves the use of brain atlases or intrinsic landmarks to estimate the location of target deep brain structures, such as the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi). However, these structures can be difficult to localize with conventional clinical magnetic resonance imaging (MRI), and thus targeting can be prone to error. Ultra-high-field imaging at 7T has the ability to clearly resolve these structures and thus atlases built with these data have the potential to improve targeting accuracy. Methods T1 and T2-weighted images of 12 healthy control subjects were acquired using a 7T MR scanner. These images were then used with groupwise registration to generate an unbiased average template with T1w and T2w contrast. Deep brain structures were manually labelled in each subject by two raters and rater reliability was assessed. We compared the use of this unbiased atlas with two other methods of atlas-based segmentation (single-template and multi-template) for subthalamic nucleus (STN) segmentation on 7T MRI data. We also applied this atlas to clinical DBS data acquired at 1.5T to evaluate its efficacy for DBS target localization as compared to using a standard atlas. Results The unbiased templates provide superb detail of subcortical structures. Through one-way ANOVA tests, the unbiased template is significantly (p <0.05) more accurate than a single-template in atlas-based segmentation and DBS target localization tasks. Conclusion The generated unbiased averaged templates provide better visualization of deep brain nuclei and an increase in accuracy over single-template and lower field strength atlases.

Unbiased estimators for spatial distribution functions of classical fluids

NASA Astrophysics Data System (ADS)

Adib, Artur B.; Jarzynski, Christopher

2005-01-01

We use a statistical-mechanical identity closely related to the familiar virial theorem, to derive unbiased estimators for spatial distribution functions of classical fluids. In particular, we obtain estimators for both the fluid density ρ(r) in the vicinity of a fixed solute and the pair correlation g(r) of a homogeneous classical fluid. We illustrate the utility of our estimators with numerical examples, which reveal advantages over traditional histogram-based methods of computing such distributions.

Brain-Derived Neurotrophic Factor (BDNF) Promotes Cochlear Spiral Ganglion Cell Survival and Function in Deafened, Developing Cats

PubMed Central

Leake, Patricia A.; Hradek, Gary T.; Hetherington, Alexander M.; Stakhovskaya, Olga

2011-01-01

Postnatal development and survival of spiral ganglion (SG) neurons depend upon both neural activity and neurotrophic support. Our previous studies showed that electrical stimulation from a cochlear implant only partly prevents SG degeneration after early deafness. Thus, neurotrophic agents that might be combined with an implant to improve neural survival are of interest. Recent studies reporting that BDNF promotes SG survival after deafness, have been conducted in rodents and limited to relatively short durations. Our study examined longer duration BDNF treatment in deafened cats that may better model the slow progression of SG degeneration in human cochleae and provides the first study of BDNF in the developing auditory system. Kittens were deafened neonatally, implanted at 4-5 weeks with intracochlear electrodes containing a drug-delivery cannula, and BDNF or artificial perilymph was infused for 10 weeks from a mini-osmotic pump. In BDNF-treated cochleae SG cells grew to normal size and were significantly larger than cells on the contralateral side. However, their morphology was not completely normal and many neurons lacked or had thinned perikaryl myelin. Unbiased stereology was employed to estimate SG cell density, independent of cell size. BDNF was effective in promoting significantly improved survival of SG neurons in these developing animals. BDNF treatment also resulted in higher density and larger size of myelinated radial nerve fibers, sprouting of fibers into the scala tympani, and improvement in electrically-evoked auditory brainstem response thresholds. Although BDNF may have potential therapeutic value in the developing auditory system, many serious obstacles currently preclude clinical application. PMID:21452221

Intralaminar nuclei of the thalamus in Lewy body diseases.

PubMed

Brooks, Daniel; Halliday, Glenda M

2009-02-16

Although the intralaminar thalamus is a target of alpha-synuclein pathology in Parkinson's disease, the degree of neuronal loss in Lewy body diseases has not been assessed. We have used unbiased stereological techniques to quantify neuronal loss in intralaminar thalamic nuclei concentrating alpha-synuclein pathology (the anterodorsal, cucullar, parataenial, paraventricular, central medial, central lateral and centre-median/parafascicular complex) in different clinical forms of Lewy body disease (Parkinson's disease with and without dementia, and dementia with Lewy bodies, N=21) compared with controls (N=5). Associations were performed in the Lewy body cases between intralaminar cell loss and the main diagnostic clinical (parkinsonism, dementia, fluctuation in consciousness, and visual hallucinations) and pathological (Braak stage of Parkinson's disease) features of these diseases, as well as between cell loss and the scaled severity of the alpha-synuclein deposition within the intralaminar thalamus. As expected, significant alpha-synuclein accumulation occurred in the intralaminar thalamus in the cases with Lewy body disease. Pathology concentrated anteriorly and in the central lateral and paraventricular nuclei was related to the Braak stage of Parkinson's disease, ageing, and the presence of dementia. Across all types of Lewy body cases there was substantial atrophy and neuronal loss in the central lateral, cucullar and parataenial nuclei, and neuronal loss without atrophy in the centre-median/parafascicular complex. Cases with visual hallucinations showed a greater degree of atrophy of the cucullar nucleus, possibly due to amygdala denervation. The significant degeneration demonstrated in the intralaminar thalamus is likely to contribute to the movement and cognitive dysfunction observed in Lewy body disorders.

Short-Term Exposure to Enriched Environment in Adult Rats Restores MK-801-Induced Cognitive Deficits and GABAergic Interneuron Immunoreactivity Loss.

PubMed

Murueta-Goyena, Ane; Ortuzar, Naiara; Gargiulo, Pascual Ángel; Lafuente, José Vicente; Bengoetxea, Harkaitz

2018-01-01

Perinatal injections of N-methyl-D-aspartate (NMDA) receptor antagonist in rodents emulate some cognitive impairments and neurochemical alterations, such as decreased GABAergic (gamma aminobutyric acid) interneuron immunoreactivity, also found in schizophrenia. These features are pervasive, and developing neuroprotective or neurorestorative strategies is of special interest. In this work, we aimed to investigate if a short exposure to enriched environment (EE) in early adulthood (P55-P73) was an effective strategy to improve cognitive dysfunction and to restore interneuron expression in medial prefrontal cortex (mPFC) and hippocampus (HPC). For that purpose, we administered MK-801 intraperitoneally to Long Evans rats from postnatal days 10 to 20. Twenty-four hours after the last injection, MK-801 produced a transient decrease in spontaneous motor activity and exploration, but those abnormalities were absent at P24 and P55. The open field test on P73 manifested that EE reduced anxiety-like behavior. In addition, MK-801-treated rats showed cognitive impairment in novel object recognition test that was reversed by EE. We quantified different interneuron populations based on their calcium-binding protein expression (parvalbumin, calretinin, and calbindin), glutamic acid decarboxylase 67, and neuronal nuclei-positive cells by means of unbiased stereology and found that EE enhanced interneuron immunoreactivity up to normal values in MK-801-treated rats. Our results demonstrate that a timely intervention with EE is a powerful tool to reverse long-lasting changes in cognition and neurochemical markers of interneurons in an animal model of schizophrenia.

PREFACE: Anti-counterfeit Image Analysis Methods (A Special Session of ICSXII)

NASA Astrophysics Data System (ADS)

Javidi, B.; Fournel, T.

2007-06-01

The International Congress for Stereology is dedicated to theoretical and applied aspects of stochastic tools, image analysis and mathematical morphology. A special emphasis on `anti-counterfeit image analysis methods' has been given this year for the XIIth edition (ICSXII). Facing the economic and social threat of counterfeiting, this devoted session presents recent advances and original solutions in the field. A first group of methods are related to marks located either on the product (physical marks) or on the data (hidden information) to be protected. These methods concern laser fs 3D encoding and source separation for machine-readable identification, moiré and `guilloche' engraving for visual verification and watermarking. Machine-readable travel documents are well-suited examples introducing the second group of methods which are related to cryptography. Used in passports for data authentication and identification (of people), cryptography provides some powerful tools. Opto-digital processing allows some efficient implementations described in the papers and promising applications. We would like to thank the reviewers who have contributed to a session of high quality, and the authors for their fine and hard work. We would like to address some special thanks to the invited lecturers, namely Professor Roger Hersch and Dr Isaac Amidror for their survey of moiré methods, Prof. Serge Vaudenay for his survey of existing protocols concerning machine-readable travel documents, and Dr Elisabet Pérez-Cabré for her presentation on optical encryption for multifactor authentication. We also thank Professor Dominique Jeulin, President of the International Society for Stereology, Professor Michel Jourlin, President of the organizing committee of ICSXII, for their help and advice, and Mr Graham Douglas, the Publisher of Journal of Physics: Conference Series at IOP Publishing, for his efficiency. We hope that this collection of papers will be useful as a tool to further develop a very important field. Bahram Javidi University of Connecticut (USA) Thierry Fournel University of Saint-Etienne (France) Chairs of the special session on `Anti-counterfeit image analysis methods', July 2007

Analysis of conditional genetic effects and variance components in developmental genetics.

PubMed

Zhu, J

1995-12-01

A genetic model with additive-dominance effects and genotype x environment interactions is presented for quantitative traits with time-dependent measures. The genetic model for phenotypic means at time t conditional on phenotypic means measured at previous time (t-1) is defined. Statistical methods are proposed for analyzing conditional genetic effects and conditional genetic variance components. Conditional variances can be estimated by minimum norm quadratic unbiased estimation (MINQUE) method. An adjusted unbiased prediction (AUP) procedure is suggested for predicting conditional genetic effects. A worked example from cotton fruiting data is given for comparison of unconditional and conditional genetic variances and additive effects.

Analysis of Conditional Genetic Effects and Variance Components in Developmental Genetics

PubMed Central

Zhu, J.

1995-01-01

A genetic model with additive-dominance effects and genotype X environment interactions is presented for quantitative traits with time-dependent measures. The genetic model for phenotypic means at time t conditional on phenotypic means measured at previous time (t - 1) is defined. Statistical methods are proposed for analyzing conditional genetic effects and conditional genetic variance components. Conditional variances can be estimated by minimum norm quadratic unbiased estimation (MINQUE) method. An adjusted unbiased prediction (AUP) procedure is suggested for predicting conditional genetic effects. A worked example from cotton fruiting data is given for comparison of unconditional and conditional genetic variances and additive effects. PMID:8601500

Examinations of tRNA Range of Motion Using Simulations of Cryo-EM Microscopy and X-Ray Data

PubMed Central

Caulfield, Thomas R.; Devkota, Batsal; Rollins, Geoffrey C.

2011-01-01

We examined tRNA flexibility using a combination of steered and unbiased molecular dynamics simulations. Using Maxwell's demon algorithm, molecular dynamics was used to steer X-ray structure data toward that from an alternative state obtained from cryogenic-electron microscopy density maps. Thus, we were able to fit X-ray structures of tRNA onto cryogenic-electron microscopy density maps for hybrid states of tRNA. Additionally, we employed both Maxwell's demon molecular dynamics simulations and unbiased simulation methods to identify possible ribosome-tRNA contact areas where the ribosome may discriminate tRNAs during translation. Herein, we collected >500 ns of simulation data to assess the global range of motion for tRNAs. Biased simulations can be used to steer between known conformational stop points, while unbiased simulations allow for a general testing of conformational space previously unexplored. The unbiased molecular dynamics data describes the global conformational changes of tRNA on a sub-microsecond time scale for comparison with steered data. Additionally, the unbiased molecular dynamics data was used to identify putative contacts between tRNA and the ribosome during the accommodation step of translation. We found that the primary contact regions were H71 and H92 of the 50S subunit and ribosomal proteins L14 and L16. PMID:21716650

Volumetric evaluation of the relations among the cerebrum, cerebellum and brain stem in young subjects: a combination of stereology and magnetic resonance imaging.

PubMed

Ekinci, Nihat; Acer, Niyazi; Akkaya, Akcan; Sankur, Seref; Kabadayi, Taner; Sahin, Bünyamin

2008-08-01

The Cavalieri estimator using a point grid is used to estimate the volume of three-dimensional structures based on two-dimensional slices of the object. The size of the components of intracranial neural structures should have proportional relations among them. The volume fraction approach of stereological methods provides information about volumetric relations of the components of structures. The purpose of our study is to estimate the volume and volume fraction data related to the cerebrum, cerebellum and brain stem. In this study, volume of the total brain, cerebrum, cerebellum and brain stem were estimated in 24 young Turkish volunteers (12 males and 12 females) who are free of any neurological symptoms and signs. The volume and volume fraction of the total brain, cerebrum, cerebellum and brain stem were determined on magnetic resonance (MR) images using the point-counting approach of stereological methods. The mean (+/-SD) total brain, cerebrum and cerebellum volumes were 1,202.05 +/- 103.51, 1,143.65 +/- 106.25 cm3 in males and females, 1,060.0 +/- 94.6, 1,008.9 +/- 104.3 cm3 in males and females, 117.75 +/- 10.7, 111.83 +/- 8.0 cm3 in males and females, respectively. The mean brain stem volumes were 24.3 +/- 2.89, 22.9 +/- 4.49 cm3 in males and females, respectively. Our results revealed that female subjects have less cerebral, cerebellar and brain stem volumes compared to males, although there was no statistically significant difference between genders (P > 0.05). The volume ratio of the cerebrum to total brain volume (TBV), cerebellum to TBV and brain stem to TBV were 88.16 and 88.13% in males and females, 9.8 and 9.8% in males and females, 2.03 and 2.03% in males and females, respectively. The volume ratio of the cerebellum to cerebrum, brain stem to cerebrum and brain stem to cerebellum were 11.12 and 11.16% in males and females, 2.30 and 2.31% in males and females, 20.7 and 20.6% in males and females, respectively. The difference between the genders was not statistically significant (P > 0.05). Our results revealed that the volumetric composition of the cerebrum, cerebellum and brain stem does not show sexual dimorphism.

x-y-recording in transmission electron microscopy. A versatile and inexpensive interface to personal computers with application to stereology.

PubMed

Rickmann, M; Siklós, L; Joó, F; Wolff, J R

1990-09-01

An interface for IBM XT/AT-compatible computers is described which has been designed to read the actual specimen stage position of electron microscopes. The complete system consists of (i) optical incremental encoders attached to the x- and y-stage drivers of the microscope, (ii) two keypads for operator input, (iii) an interface card fitted to the bus of the personal computer, (iv) a standard configuration IBM XT (or compatible) personal computer optionally equipped with a (v) HP Graphic Language controllable colour plotter. The small size of the encoders and their connection to the stage drivers by simple ribbed belts allows an easy adaptation of the system to most electron microscopes. Operation of the interface card itself is supported by any high-level language available for personal computers. By the modular concept of these languages, the system can be customized to various applications, and no computer expertise is needed for actual operation. The present configuration offers an inexpensive attachment, which covers a wide range of applications from a simple notebook to high-resolution (200-nm) mapping of tissue. Since section coordinates can be processed in real-time, stereological estimations can be derived directly "on microscope". This is exemplified by an application in which particle numbers were determined by the disector method.

Effects of Diabetes on Post-Menopausal Rat Submandibular Glands: A Histopathological and Stereological Examination

PubMed Central

Buyuk, Basak; Parlak, Secil Nazife; Keles, Osman Nuri; Can, Ismail; Yetim, Zeliha; Toktay, Erdem; Selli, Jale; Unal, Bunyami

2015-01-01

Objective: The menopause in elderly women is a physiological process where ovarian and uterine cycles end. Diabetes means higher blood glucose level that is a metabolic disease and has an increased incidence. The aim of the study was to examine the single or combined effects of menopause and diabetes that causes pathophysiological processes on submandibular gland on ovariectomy and diabetes induced rat models. Materials and Methods: Sprague Dawley twelve weeks old female (n=24) rats were divided randomly into four groups; Healthy control group (n=6), diabetic group (DM, n=6), ovariectomized group (OVX, n=6), post ovariectomy diabetes induced group (DM+OVX, n=6) individually. Histopathological, histochemical and stereological analyses were done in these groups. Results: Significant neutrophil cell infiltrations and myoepithelial cell proliferations, granular duct and seromucous acini damages and changes in the content of especially seromucous acini secretion in DM and/or OVX groups and distinctive interstitial and striated duct damages in post ovariectomy diabetes induced group were detected. Alterations ingranular ducts hypertrophic and in seromucous acini atrophic were determined in DM and/or OVX groups. Conclusion: The results revealed the pathophysiological processes that lead to morphological and functional alterations on the cellular level in submandibular glands. The molecular mechanisms related with pathogenesis of diabetes and menopause need further investigation. PMID:26644770

From gross anatomy to the nanomorphome: stereological tools provide a paradigm for advancing research in quantitative morphomics

PubMed Central

Mayhew, Terry M; Lucocq, John M

2015-01-01

The terms morphome and morphomics are not new but, recently, a group of morphologists and cell biologists has given them clear definitions and emphasised their integral importance in systems biology. By analogy to other ‘-omes’, the morphome refers to the distribution of matter within 3-dimensional (3D) space. It equates to the totality of morphological features within a biological system (virus, single cell, multicellular organism or populations thereof) and morphomics is the systematic study of those structures. Morphomics research has the potential to generate ‘big data’ because it includes all imaging techniques at all levels of achievable resolution and all structural scales from gross anatomy and medical imaging, via optical and electron microscopy, to molecular characterisation. As with other ‘-omics’, quantification is an important part of morphomics and, because biological systems exist and operate in 3D space, precise descriptions of form, content and spatial relationships require the quantification of structure in 3D. Revealing and quantifying structural detail inside the specimen is achieved currently in two main ways: (i) by some form of reconstruction from serial physical or tomographic slices or (ii) by using randomly-sampled sections and simple test probes (points, lines, areas, volumes) to derive stereological estimates of global and/or individual quantities. The latter include volumes, surfaces, lengths and numbers of interesting features and spatial relationships between them. This article emphasises the value of stereological design, sampling principles and estimation tools as a template for combining with alternative imaging techniques to tackle the ‘big data’ issue and advance knowledge and understanding of the morphome. The combination of stereology, TEM and immunogold cytochemistry provides a practical illustration of how this has been achieved in the sub-field of nanomorphomics. Applying these quantitative tools/techniques in a carefully managed study design offers us a deeper appreciation of the spatiotemporal relationships between the genome, metabolome and morphome which are integral to systems biology. PMID:25753334

Mutually unbiased product bases for multiple qudits

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

McNulty, Daniel; Pammer, Bogdan; Weigert, Stefan

We investigate the interplay between mutual unbiasedness and product bases for multiple qudits of possibly different dimensions. A product state of such a system is shown to be mutually unbiased to a product basis only if each of its factors is mutually unbiased to all the states which occur in the corresponding factors of the product basis. This result implies both a tight limit on the number of mutually unbiased product bases which the system can support and a complete classification of mutually unbiased product bases for multiple qubits or qutrits. In addition, only maximally entangled states can be mutuallymore » unbiased to a maximal set of mutually unbiased product bases.« less

Toward high-throughput phenotyping: unbiased automated feature extraction and selection from knowledge sources.

PubMed

Yu, Sheng; Liao, Katherine P; Shaw, Stanley Y; Gainer, Vivian S; Churchill, Susanne E; Szolovits, Peter; Murphy, Shawn N; Kohane, Isaac S; Cai, Tianxi

2015-09-01

Analysis of narrative (text) data from electronic health records (EHRs) can improve population-scale phenotyping for clinical and genetic research. Currently, selection of text features for phenotyping algorithms is slow and laborious, requiring extensive and iterative involvement by domain experts. This paper introduces a method to develop phenotyping algorithms in an unbiased manner by automatically extracting and selecting informative features, which can be comparable to expert-curated ones in classification accuracy. Comprehensive medical concepts were collected from publicly available knowledge sources in an automated, unbiased fashion. Natural language processing (NLP) revealed the occurrence patterns of these concepts in EHR narrative notes, which enabled selection of informative features for phenotype classification. When combined with additional codified features, a penalized logistic regression model was trained to classify the target phenotype. The authors applied our method to develop algorithms to identify patients with rheumatoid arthritis and coronary artery disease cases among those with rheumatoid arthritis from a large multi-institutional EHR. The area under the receiver operating characteristic curves (AUC) for classifying RA and CAD using models trained with automated features were 0.951 and 0.929, respectively, compared to the AUCs of 0.938 and 0.929 by models trained with expert-curated features. Models trained with NLP text features selected through an unbiased, automated procedure achieved comparable or slightly higher accuracy than those trained with expert-curated features. The majority of the selected model features were interpretable. The proposed automated feature extraction method, generating highly accurate phenotyping algorithms with improved efficiency, is a significant step toward high-throughput phenotyping. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reflection imaging of China ink-perfused brain vasculature using confocal laser-scanning microscopy after clarification of brain tissue by the Spalteholz method.

PubMed

Gutierre, R C; Vannucci Campos, D; Mortara, R A; Coppi, A A; Arida, R M

2017-04-01

Confocal laser-scanning microscopy is a useful tool for visualizing neurons and glia in transparent preparations of brain tissue from laboratory animals. Currently, imaging capillaries and venules in transparent brain tissues requires the use of fluorescent proteins. Here, we show that vessels can be imaged by confocal laser-scanning microscopy in transparent cortical, hippocampal and cerebellar preparations after clarification of China ink-injected specimens by the Spalteholz method. This method may be suitable for global, three-dimensional, quantitative analyses of vessels, including stereological estimations of total volume and length and of surface area of vessels, which constitute indirect approaches to investigate angiogenesis. © 2017 Anatomical Society.

Validation of a Three-Dimensional Method for Counting and Sizing Podocytes in Whole Glomeruli

PubMed Central

van der Wolde, James W.; Schulze, Keith E.; Short, Kieran M.; Wong, Milagros N.; Bensley, Jonathan G.; Cullen-McEwen, Luise A.; Caruana, Georgina; Hokke, Stacey N.; Li, Jinhua; Firth, Stephen D.; Harper, Ian S.; Nikolic-Paterson, David J.; Bertram, John F.

2016-01-01

Podocyte depletion is sufficient for the development of numerous glomerular diseases and can be absolute (loss of podocytes) or relative (reduced number of podocytes per volume of glomerulus). Commonly used methods to quantify podocyte depletion introduce bias, whereas gold standard stereologic methodologies are time consuming and impractical. We developed a novel approach for assessing podocyte depletion in whole glomeruli that combines immunofluorescence, optical clearing, confocal microscopy, and three-dimensional analysis. We validated this method in a transgenic mouse model of selective podocyte depletion, in which we determined dose-dependent alterations in several quantitative indices of podocyte depletion. This new approach provides a quantitative tool for the comprehensive and time-efficient analysis of podocyte depletion in whole glomeruli. PMID:26975438

The dependability of medical students' performance ratings as documented on in-training evaluations.

PubMed

van Barneveld, Christina

2005-03-01

To demonstrate an approach to obtain an unbiased estimate of the dependability of students' performance ratings during training, when the data-collection design includes nesting of student in rater, unbalanced nest sizes, and dependent observations. In 2003, two variance components analyses of in-training evaluation (ITE) report data were conducted using urGENOVA software. In the first analysis, the dependability for the nested and unbalanced data-collection design was calculated. In the second analysis, an approach using multiple generalizability studies was used to obtain an unbiased estimate of the student variance component, resulting in an unbiased estimate of dependability. Results suggested that there is bias in estimates of the dependability of students' performance on ITEs that are attributable to the data-collection design. When the bias was corrected, the results indicated that the dependability of ratings of student performance was almost zero. The combination of the multiple generalizability studies method and the use of specialized software provides an unbiased estimate of the dependability of ratings of student performance on ITE scores for data-collection designs that include nesting of student in rater, unbalanced nest sizes, and dependent observations.

Unbiased and targeted mass spectrometry for the HDL proteome.

PubMed

Singh, Sasha A; Aikawa, Masanori

2017-02-01

Mass spectrometry is an ever evolving technology that is equipped with a variety of tools for protein research. Some lipoprotein studies, especially those pertaining to HDL biology, have been exploiting the versatility of mass spectrometry to understand HDL function through its proteome. Despite the role of mass spectrometry in advancing research as a whole, however, the technology remains obscure to those without hands on experience, but still wishing to understand it. In this review, we walk the reader through the coevolution of common mass spectrometry workflows and HDL research, starting from the basic unbiased mass spectrometry methods used to profile the HDL proteome to the most recent targeted methods that have enabled an unprecedented view of HDL metabolism. Unbiased global proteomics have demonstrated that the HDL proteome is organized into subgroups across the HDL size fractions providing further evidence that HDL functional heterogeneity is in part governed by its varying protein constituents. Parallel reaction monitoring, a novel targeted mass spectrometry method, was used to monitor the metabolism of HDL apolipoproteins in humans and revealed that apolipoproteins contained within the same HDL size fraction exhibit diverse metabolic properties. Mass spectrometry provides a variety of tools and strategies to facilitate understanding, through its proteins, the complex biology of HDL.

Graph-state formalism for mutually unbiased bases

NASA Astrophysics Data System (ADS)

Spengler, Christoph; Kraus, Barbara

2013-11-01

A pair of orthonormal bases is called mutually unbiased if all mutual overlaps between any element of one basis and an arbitrary element of the other basis coincide. In case the dimension, d, of the considered Hilbert space is a power of a prime number, complete sets of d+1 mutually unbiased bases (MUBs) exist. Here we present a method based on the graph-state formalism to construct such sets of MUBs. We show that for n p-level systems, with p being prime, one particular graph suffices to easily construct a set of pn+1 MUBs. In fact, we show that a single n-dimensional vector, which is associated with this graph, can be used to generate a complete set of MUBs and demonstrate that this vector can be easily determined. Finally, we discuss some advantages of our formalism regarding the analysis of entanglement structures in MUBs, as well as experimental realizations.

Stereological analysis of sciatic nerve in chickens following neonatal pinealectomy: an experimental study

PubMed Central

2010-01-01

Background Although the injury to the peripheral nervous system is a common clinical problem, understanding of the role of melatonin in nerve degeneration and regeneration is incomplete. Methods The current study investigated the effects of neonatal pinealectomy on the sciatic nerve microarchitecture in the chicken. The chickens were divided into two equal groups: unpinealectomized controls and pinealectomized chickens. At the end of the study, biochemical examination of 10 sciatic nerve samples from both groups was performed and a quantitative stereological evaluation of 10 animals in each group was performed. The results were compared using Mann-Whitney test. Results In this study, the results of axon number and thickness of the myelin sheath of a nerve fiber in newly hatched pinealectomy group were higher than those in control group. Similarly, surgical pinealectomy group had significantly larger axonal cross-sectional area than the control group (p < 0.05). In addition, the average hydroxyproline content of the nerve tissue in neonatal pinealectomy group was higher than those found in control group. Our results suggest that melatonin may play a role on the morphologic features of the peripheral nerve tissue and that melatonin deficiency might be a pathophysiological mechanism in some degenerative diseases of peripheral nerves. The changes demonstrated by quantitative morphometric methods and biochemical analysis has been interpreted as a reflection of the effects of melatonin upon nerve tissue. Conclusion In the light of these results from present animal study, changes in sciatic nerve morphometry may be indicative of neuroprotective feature of melatonin, but this suggestion need to be validated in the human setting. PMID:20409336

Sodium metabisulphite, a preservative agent, decreases the heart capillary volume and length, and curcumin, the main component of Curcuma longa, cannot protect it.

PubMed

Noorafshan, A; Asadi-Golshan, R; Monjezi, S; Karbalay-Doust, S

2014-01-01

Sodium metabisulphite is used as an antioxidant agent in many pharmaceutical formulations. It is extensively used as a food preservative and disinfectant. It has been demonstrated that sulphite exposure can affect some organs. Curcumin, the main element of Curcuma longa, has been identified to have multiple protective properties. The present study extends the earlier works to quantitative evaluation of the effects of sulphite and curcumin on the heart structure using stereological methods. In this study, 28 rats were randomly divided into four experimental groups. The rats in groups I to IV received distilled water (group I), sodium metabisulphite (25 mg/ kg/day) (group II), curcumin (100 mg/kg/day) (group III), and sodium metabisulphite+curcumin (group IV), respectively, for 8 weeks. The left ventricle was subjected to stereological methods to estimate the quantitative parameters of the myocardium. A 20 % decrease was observed in the total volume of ventricular tissue in the sulphite-treated animals compared to the distilled water treatment (P < 0.02). Also, the volume and length of the capillaries were reduced by 43 % on average in the sulphite-treated rats in comparison to the distilled water-treated animals (P < 0.02). However, no significant change was seen in the mean and total volume of the myocardium and the cavity and diameter of the capillaries after sulphite ingestion. Treatment with curcumin did not protect the animals against the structural changes of the ventricle. Sulphite, as a preservative food agent, reduced the length and volume of the ventricular capillaries and curcumin could not protect them.

Protective role of curcumin against sulfite-induced structural changes in rats' medial prefrontal cortex.

PubMed

Noorafshan, Ali; Asadi-Golshan, Reza; Abdollahifar, Mohammad-Amin; Karbalay-Doust, Saied

2015-08-01

Sodium metabisulfite as a food preservative can affect the central nervous system. Curcumin, the main ingredient of turmeric has neuroprotective activity. This study was designed to evaluate the effects of sulfite and curcumin on the medial prefrontal cortex (mPFC) using stereological methods. Thirty rats were randomly divided into five groups. The rats in groups I-V received distilled water, olive oil, curcumin (100 mg/kg/day), sodium metabisulfite (25 mg/kg/day), and sulfite + curcumin, respectively, for 8 weeks. The brains were subjected to the stereological methods. Cavalieri and optical disector techniques were used to estimate the total volume of mPFC and the number of neurons and glial cells. Intersections counting were applied on the thick vertical uniform random sections to estimate the dendrites length, and classify the spines. Non-parametric tests were used to analyze the data. The mean mPFC volume, neurons number, glia number, dendritic length, and total spines per neuron were 3.7 mm(3), 365,000, 180,000, 1820 µm, and 1700 in distilled water group, respectively. A reduction was observed in the volume of mPFC (∼8%), number of neurons (∼15%), and number of glia (∼14%) in mPFC of the sulfite group compared to the control groups (P < 0.005). Beside, dendritic length per neuron (∼10%) and the total spines per neuron (mainly mushroom spines) (∼25%) were reduced in the sulfite group (P < 0.005). The sulfite-induced structural changes in mPFC and curcumin had a protective role against the changes in the rats.

Use of cryostat sections from snap-frozen nervous tissue for combining stereological estimates with histological, cellular, or molecular analyses on adjacent sections.

PubMed

Schmitz, C; Dafotakis, M; Heinsen, H; Mugrauer, K; Niesel, A; Popken, G J; Stephan, M; Van de Berg, W D; von Hörsten, S; Korr, H

2000-10-01

Adequate tissue preparation is essential for both modern stereological and immunohistochemical investigations. However, combining these methodologies in a single study presents a number of obstacles pertaining to optimal histological preparation. Tissue shrinkage and loss of nuclei/nucleoli from the unprotected section surfaces of unembedded tissue used for immunohistochemistry may be problematic with regard to adequate stereological design. In this study, frozen cryostat sections from hippocampal and cerebellar regions of two rat strains and cerebellar and cerebral regions from a human brain were analyzed to determine the potential impact of these factors on estimates of neuron number obtained using the optical disector. Neuronal nuclei and nucleoli were clearly present in thin sections of snap-frozen rat (3 microm) and human (6 microm) tissue, indicating that neuronal nuclei/nucleoli are not unavoidably lost from unprotected section surfaces of unembedded tissue. In order to quantify the potential impact of any nuclear loss, optical fractionator estimates of rat hippocampal pyramidal cells in areas CA1-3 and cerebellar granule and Purkinje cells were made using minimal (1 microm) upper guard zones. Estimates did not differ from data reported previously in the literature. This data indicates that cryostat sections of snap-frozen nervous tissue may successfully be used for estimating total neuronal numbers using optical disectors.

Density estimation in wildlife surveys

USGS Publications Warehouse

Bart, Jonathan; Droege, Sam; Geissler, Paul E.; Peterjohn, Bruce G.; Ralph, C. John

2004-01-01

Several authors have recently discussed the problems with using index methods to estimate trends in population size. Some have expressed the view that index methods should virtually never be used. Others have responded by defending index methods and questioning whether better alternatives exist. We suggest that index methods are often a cost-effective component of valid wildlife monitoring but that double-sampling or another procedure that corrects for bias or establishes bounds on bias is essential. The common assertion that index methods require constant detection rates for trend estimation is mathematically incorrect; the requirement is no long-term trend in detection "ratios" (index result/parameter of interest), a requirement that is probably approximately met by many well-designed index surveys. We urge that more attention be given to defining bird density rigorously and in ways useful to managers. Once this is done, 4 sources of bias in density estimates may be distinguished: coverage, closure, surplus birds, and detection rates. Distance, double-observer, and removal methods do not reduce bias due to coverage, closure, or surplus birds. These methods may yield unbiased estimates of the number of birds present at the time of the survey, but only if their required assumptions are met, which we doubt occurs very often in practice. Double-sampling, in contrast, produces unbiased density estimates if the plots are randomly selected and estimates on the intensive surveys are unbiased. More work is needed, however, to determine the feasibility of double-sampling in different populations and habitats. We believe the tension that has developed over appropriate survey methods can best be resolved through increased appreciation of the mathematical aspects of indices, especially the effects of bias, and through studies in which candidate methods are evaluated against known numbers determined through intensive surveys.

Stereological analysis of gravitropism in protonemata of the moss Ceratodon

NASA Technical Reports Server (NTRS)

Walker, L. M.; Sack, F. D.

1997-01-01

Apical cells of dark-grown protonemata of the moss Cerotodon purpureus are negatively gravitropic. Previous light microscopy has shown that reorientation to the horizontal induces amyloplast sedimentation and redistribution of microtubules. To determine whether other components become redistributed laterally or axially, the apical 35 micrometers of both vertical and horizontal apical cells were compared stereologically using transmission electron microscopy. Reorientation to the horizontal changed the longitudinal distributions of tubular ER, Golgi stacks, and vesicles but not cisternal ER, mitochondria, and plastids. Only plastids showed a statistically significant lateral redistribution after horizontal placement. Qualitative examination of the sedimentation zone showed plastids sedimented close to peripherally located ER with vacuoles displaced above plastids. These results argue against a model where differential tip growth results from a redistribution of Golgi stacks or exocytic vesicles.

Detection of sea otters in boat-based surveys of Prince William Sound, Alaska

USGS Publications Warehouse

Udevitz, Mark S.; Bodkin, James L.; Costa, Daniel P.

1995-01-01

Boat-based surveys have been commonly used to monitor sea otter populations, but there has been little quantitative work to evaluate detection biases that may affect these surveys. We used ground-based observers to investigate sea otter detection probabilities in a boat-based survey of Prince William Sound, Alaska. We estimated that 30% of the otters present on surveyed transects were not detected by boat crews. Approximately half (53%) of the undetected otters were missed because the otters left the transects, apparently in response to the approaching boat. Unbiased estimates of detection probabilities will be required for obtaining unbiased population estimates from boat-based surveys of sea otters. Therefore, boat-based surveys should include methods to estimate sea otter detection probabilities under the conditions specific to each survey. Unbiased estimation of detection probabilities with ground-based observers requires either that the ground crews detect all of the otters in observed subunits, or that there are no errors in determining which crews saw each detected otter. Ground-based observer methods may be appropriate in areas where nearly all of the sea otter habitat is potentially visible from ground-based vantage points.

Using Maximum Entropy to Find Patterns in Genomes

NASA Astrophysics Data System (ADS)

Liu, Sophia; Hockenberry, Adam; Lancichinetti, Andrea; Jewett, Michael; Amaral, Luis

The existence of over- and under-represented sequence motifs in genomes provides evidence of selective evolutionary pressures on biological mechanisms such as transcription, translation, ligand-substrate binding, and host immunity. To accurately identify motifs and other genome-scale patterns of interest, it is essential to be able to generate accurate null models that are appropriate for the sequences under study. There are currently no tools available that allow users to create random coding sequences with specified amino acid composition and GC content. Using the principle of maximum entropy, we developed a method that generates unbiased random sequences with pre-specified amino acid and GC content. Our method is the simplest way to obtain maximally unbiased random sequences that are subject to GC usage and primary amino acid sequence constraints. This approach can also be easily be expanded to create unbiased random sequences that incorporate more complicated constraints such as individual nucleotide usage or even di-nucleotide frequencies. The ability to generate correctly specified null models will allow researchers to accurately identify sequence motifs which will lead to a better understanding of biological processes. National Institute of General Medical Science, Northwestern University Presidential Fellowship, National Science Foundation, David and Lucile Packard Foundation, Camille Dreyfus Teacher Scholar Award.

Smoothed Biasing Forces Yield Unbiased Free Energies with the Extended-System Adaptive Biasing Force Method

PubMed Central

2016-01-01

We report a theoretical description and numerical tests of the extended-system adaptive biasing force method (eABF), together with an unbiased estimator of the free energy surface from eABF dynamics. Whereas the original ABF approach uses its running estimate of the free energy gradient as the adaptive biasing force, eABF is built on the idea that the exact free energy gradient is not necessary for efficient exploration, and that it is still possible to recover the exact free energy separately with an appropriate estimator. eABF does not directly bias the collective coordinates of interest, but rather fictitious variables that are harmonically coupled to them; therefore is does not require second derivative estimates, making it easily applicable to a wider range of problems than ABF. Furthermore, the extended variables present a smoother, coarse-grain-like sampling problem on a mollified free energy surface, leading to faster exploration and convergence. We also introduce CZAR, a simple, unbiased free energy estimator from eABF trajectories. eABF/CZAR converges to the physical free energy surface faster than standard ABF for a wide range of parameters. PMID:27959559

An Automatic Method for Generating an Unbiased Intensity Normalizing Factor in Positron Emission Tomography Image Analysis After Stroke.

PubMed

Nie, Binbin; Liang, Shengxiang; Jiang, Xiaofeng; Duan, Shaofeng; Huang, Qi; Zhang, Tianhao; Li, Panlong; Liu, Hua; Shan, Baoci

2018-06-07

Positron emission tomography (PET) imaging of functional metabolism has been widely used to investigate functional recovery and to evaluate therapeutic efficacy after stroke. The voxel intensity of a PET image is the most important indicator of cellular activity, but is affected by other factors such as the basal metabolic ratio of each subject. In order to locate dysfunctional regions accurately, intensity normalization by a scale factor is a prerequisite in the data analysis, for which the global mean value is most widely used. However, this is unsuitable for stroke studies. Alternatively, a specified scale factor calculated from a reference region is also used, comprising neither hyper- nor hypo-metabolic voxels. But there is no such recognized reference region for stroke studies. Therefore, we proposed a totally data-driven automatic method for unbiased scale factor generation. This factor was generated iteratively until the residual deviation of two adjacent scale factors was reduced by < 5%. Moreover, both simulated and real stroke data were used for evaluation, and these suggested that our proposed unbiased scale factor has better sensitivity and accuracy for stroke studies.

Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: A CLARITY-BPA consortium study.

PubMed

Arambula, Sheryl E; Fuchs, Joelle; Cao, Jinyan; Patisaul, Heather B

2017-12-01

Bisphenol A (BPA) is a high volume endocrine disrupting chemical found in a wide variety of products including plastics and epoxy resins. Human exposure is nearly ubiquitous, and higher in children than adults. Because BPA has been reported to interfere with sex steroid hormone signaling, there is concern that developmental exposure, even at levels below the current FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, can disrupt brain sexual differentiation. The current studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and tested the hypothesis that perinatal BPA exposure would induce morphological changes in hormone sensitive, sexually dimorphic brain regions. Sprague-Dawley rats were randomly assigned to 5 groups: BPA (2.5, 25, or 2500μg/kgbw/day), a reference estrogen (0.5μg ethinylestradiol (EE 2 )/kgbw/day), or vehicle. Exposure occurred by gavage to the dam from gestational day 6 until parturition, and then to the offspring from birth through weaning. Unbiased stereology was used to quantify the volume of the sexually dimorphic nucleus (SDN), the anteroventral periventricular nucleus (AVPV), the posterodorsal portion of the medial amygdala (MePD), and the locus coeruleus (LC) at postnatal day 28. No appreciable effects of BPA were observed on the volume of the SDN or LC. However, AVPV volume was enlarged in both sexes, even at levels below the FDA NOAEL. Collectively, these data suggest the developing brain is vulnerable to endocrine disruption by BPA at exposure levels below previous estimates by regulatory agencies. Copyright © 2017 Elsevier B.V. All rights reserved.

Widespread heterogeneous neuronal loss across the cerebral cortex in Huntington's disease.

PubMed

Nana, Alissa L; Kim, Eric H; Thu, Doris C V; Oorschot, Dorothy E; Tippett, Lynette J; Hogg, Virginia M; Synek, Beth J; Roxburgh, Richard; Waldvogel, Henry J; Faull, Richard L M

2014-01-01

Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntington's disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntington's disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094-1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntington's disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.

A comparison of nephron number, glomerular volume and kidney weight in Senegalese Africans and African Americans.

PubMed

McNamara, Bridgette J; Diouf, Boucar; Douglas-Denton, Rebecca N; Hughson, Michael D; Hoy, Wendy E; Bertram, John F

2010-05-01

Low nephron number is determined in utero and is a proposed risk for essential hypertension. Glomerular volume is inversely correlated with nephron number, and genetic and environmental factors that determine nephron number are thought to determine glomerular volume. This study compared total glomerular (nephron) number (N(glom)), mean glomerular volume (V(glom)) and kidney weight in two geographically separated black populations with significant common genetic ancestry. Unbiased stereology was used to determine N(glom) and V(glom) in kidneys collected at coronial autopsy in an age- and sex-matched sample of 39 adult Africans from Dakar in Senegal, West Africa and 39 African Americans from Mississippi in the USA. African Americans were taller and heavier than their Senegalese counterparts. N(glom) was remarkably similar-with a geometric mean of 937 967 in Senegalese and 904 412 in African Americans (P = 0.62). V(glom) was correlated inversely with N(glom) and directly with body surface area in both groups, but V(glom) was 54% greater in African Americans than in Senegalese Africans [8.30 +/- 2.92 (SD) and 5.38 +/- 1.25 microm(3) x 10(6), respectively] and remained significantly larger (38%) after adjustment for body size. V(glom) increased with age in African Americans, but not in the Senegalese. Kidney weight was larger in African Americans (P < 0.0001), but kidney-to-body weight ratio was not different between groups. Despite similar nephron numbers, a common genetic constitution, and even in relation to current body size, African Americans have larger V(glom) than Senegalese subjects. This may mark exposure to environmental stressors or hereditary traits concentrated in the population's relocation to North America.

Three-dimensional morphometric analysis of microglial changes in a mouse model of virus encephalitis: age and environmental influences.

PubMed

de Sousa, Aline A; Dos Reis, Renata R; de Lima, Camila M; de Oliveira, Marcus A; Fernandes, Taiany N; Gomes, Giovanni F; Diniz, Daniel G; Magalhães, Nara M; Diniz, Cristovam G; Sosthenes, Marcia C K; Bento-Torres, João; Diniz, José Antonio P; Vasconcelos, Pedro F da C; Diniz, Cristovam Wanderley P

2015-08-01

Many RNA virus CNS infections cause neurological disease. Because Piry virus has a limited human pathogenicity and exercise reduces activation of microglia in aged mice, possible influences of environment and aging on microglial morphology and behavior in mice sublethal encephalitis were investigated. Female albino Swiss mice were raised either in standard (S) or in enriched (EE) cages from age 2 to 6 months (young - Y), or from 2 to 16 months (aged - A). After behavioral tests, mice nostrils were instilled with Piry-virus-infected or with normal brain homogenates. Brain sections were immunolabeled for virus antigens or microglia at 8 days post-infection (dpi), when behavioral changes became apparent, and at 20 and 40 dpi, after additional behavioral testing. Young infected mice from standard (SYPy) and enriched (EYPy) groups showed similar transient impairment in burrowing activity and olfactory discrimination, whereas aged infected mice from both environments (EAPy, SAPy) showed permanent reduction in both tasks. The beneficial effects of an enriched environment were smaller in aged than in young mice. Six-hundred and forty microglial cells, 80 from each group were reconstructed. An unbiased, stereological sampling approach and multivariate statistical analysis were used to search for microglial morphological families. This procedure allowed distinguishing between microglial morphology of infected and control subjects. More severe virus-associated microglial changes were observed in young than in aged mice, and EYPy seem to recover microglial homeostatic morphology earlier than SYPy . Because Piry-virus encephalitis outcomes were more severe in aged mice, it is suggested that the reduced inflammatory response in those individuals may aggravate encephalitis outcomes. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Distinction of Neurons, Glia and Endothelial Cells in the Cerebral Cortex: An Algorithm Based on Cytological Features

PubMed Central

García-Cabezas, Miguel Á.; John, Yohan J.; Barbas, Helen; Zikopoulos, Basilis

2016-01-01

The estimation of the number or density of neurons and types of glial cells and their relative proportions in different brain areas are at the core of rigorous quantitative neuroanatomical studies. Unfortunately, the lack of detailed, updated, systematic and well-illustrated descriptions of the cytology of neurons and glial cell types, especially in the primate brain, makes such studies especially demanding, often limiting their scope and broad use. Here, following an extensive analysis of histological materials and the review of current and classical literature, we compile a list of precise morphological criteria that can facilitate and standardize identification of cells in stained sections examined under the microscope. We describe systematically and in detail the cytological features of neurons and glial cell types in the cerebral cortex of the macaque monkey and the human using semithin and thick sections stained for Nissl. We used this classical staining technique because it labels all cells in the brain in distinct ways. In addition, we corroborate key distinguishing characteristics of different cell types in sections immunolabeled for specific markers counterstained for Nissl and in ultrathin sections processed for electron microscopy. Finally, we summarize the core features that distinguish each cell type in easy-to-use tables and sketches, and structure these key features in an algorithm that can be used to systematically distinguish cellular types in the cerebral cortex. Moreover, we report high inter-observer algorithm reliability, which is a crucial test for obtaining consistent and reproducible cell counts in unbiased stereological studies. This protocol establishes a consistent framework that can be used to reliably identify and quantify cells in the cerebral cortex of primates as well as other mammalian species in health and disease. PMID:27847469

Total numbers of neurons and glial cells in cortex and basal ganglia of aged brains with Down syndrome--a stereological study.

PubMed

Karlsen, Anna Schou; Pakkenberg, Bente

2011-11-01

The total numbers of neurons and glial cells in the neocortex and basal ganglia in adults with Down syndrome (DS) were estimated with design-based stereological methods, providing quantitative data on brains affected by delayed development and accelerated aging. Cell numbers, volume of regions, and densities of neurons and glial cell subtypes were estimated in brains from 4 female DS subjects (mean age 66 years) and 6 female controls (mean age 70 years). The DS subjects were estimated to have about 40% fewer neocortical neurons in total (11.1 × 10(9) vs. 17.8 × 10(9), 2p ≤ 0.001) and almost 30% fewer neocortical glial cells with no overlap to controls (12.8 × 10(9) vs. 18.2 × 10(9), 2p = 0.004). In contrast, the total number of neurons in the basal ganglia was the same in the 2 groups, whereas the number of oligodendrocytes in the basal ganglia was reduced by almost 50% in DS (405 × 10(6) vs. 816 × 10(6), 2p = 0.01). We conclude that trisomy 21 affects cortical structures more than central gray matter emphasizing the differential impairment of brain development. Despite concomitant Alzheimer-like pathology, the neurodegenerative outcome in a DS brain deviates from common Alzheimer disease.

Effects of local vibration and pulsed electromagnetic field on bone fracture: A comparative study.

PubMed

Bilgin, Hakkı Murat; Çelik, Ferhat; Gem, Mehmet; Akpolat, Veysi; Yıldız, İsmail; Ekinci, Aysun; Özerdem, Mehmet Siraç; Tunik, Selçuk

2017-07-01

The effectiveness of various therapeutic methods on bone fracture has been demonstrated in several studies. In the present study, we tried to evaluate the effect of local low-magnitude, high-frequency vibration (LMHFV) on rat tibia fracture in comparison with pulsed electromagnetic fields (PEMF) during the healing process. Mid-diaphysis tibiae fractures were induced in 30 Sprague-Dawley rats. The rats were assigned into groups such as control (CONT), LMHFV (15 min/day, 7 days/week), and PEMF (3.5 h/day, 7 days/week) for a three-week treatment. Nothing was applied to control group. Radiographs, serum osteocalcin levels, and stereological bone analyses of the three groups were compared. The X-rays of tibiae were taken 21 days after the end of the healing process. PEMF and LMHFV groups had more callus formation when compared to CONT group; however, the difference was not statistically significant (P = 0.375). Serum osteocalcin levels were elevated in the experimental groups compared to CONT (P ≤ 0.001). Stereological tests also showed higher osteogenic results in experimental groups, especially in LMHFV group. The results of the present study suggest that application of direct local LMHFV on fracture has promoted bone formation, showing great potential in improving fracture outcome. Bioelectromagnetics. 38:339-348, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Neuronal Populations in the Basolateral Nuclei of the Amygdala Are Differentially Increased in Humans Compared With Apes: A Stereological Study

PubMed Central

Barger, Nicole; Stefanacci, Lisa; Schumann, Cynthia M.; Sherwood, Chet C.; Annese, Jacopo; Allman, John M.; Buckwalter, Joseph A.; Hof, Patrick R.; Semendeferi, Katerina

2016-01-01

In human and nonhuman primates, the amygdala is known to play critical roles in emotional and social behavior. Anatomically, individual amygdaloid nuclei are connected with many neural systems that are either differentially expanded or conserved over the course of primate evolution. To address amygdala evolution in humans and our closest living relatives, the apes, we used design-based stereological methods to obtain neuron counts for the amygdala and each of four major amygdaloid nuclei (the lateral, basal, accessory basal, and central nuclei) in humans, all great ape species, lesser apes, and one monkey species. Our goal was to determine whether there were significant differences in the number or percent of neurons distributed to individual nuclei among species. Additionally, regression analyses were performed on independent contrast data to determine whether any individual species deviated from allometric trends. There were two major findings. In humans, the lateral nucleus contained the highest number of neurons in the amygdala, whereas in apes the basal nucleus contained the highest number of neurons. Additionally, the human lateral nucleus contained 59% more neurons than predicted by allometric regressions on nonhuman primate data. Based on the largest sample ever analyzed in a comparative study of the hominoid amygdala, our findings suggest that an emphasis on the lateral nucleus is the main characteristic of amygdala specialization over the course of human evolution. PMID:22473387

Double sampling to estimate density and population trends in birds

USGS Publications Warehouse

Bart, Jonathan; Earnst, Susan L.

2002-01-01

We present a method for estimating density of nesting birds based on double sampling. The approach involves surveying a large sample of plots using a rapid method such as uncorrected point counts, variable circular plot counts, or the recently suggested double-observer method. A subsample of those plots is also surveyed using intensive methods to determine actual density. The ratio of the mean count on those plots (using the rapid method) to the mean actual density (as determined by the intensive searches) is used to adjust results from the rapid method. The approach works well when results from the rapid method are highly correlated with actual density. We illustrate the method with three years of shorebird surveys from the tundra in northern Alaska. In the rapid method, surveyors covered ~10 ha h-1 and surveyed each plot a single time. The intensive surveys involved three thorough searches, required ~3 h ha-1, and took 20% of the study effort. Surveyors using the rapid method detected an average of 79% of birds present. That detection ratio was used to convert the index obtained in the rapid method into an essentially unbiased estimate of density. Trends estimated from several years of data would also be essentially unbiased. Other advantages of double sampling are that (1) the rapid method can be changed as new methods become available, (2) domains can be compared even if detection rates differ, (3) total population size can be estimated, and (4) valuable ancillary information (e.g. nest success) can be obtained on intensive plots with little additional effort. We suggest that double sampling be used to test the assumption that rapid methods, such as variable circular plot and double-observer methods, yield density estimates that are essentially unbiased. The feasibility of implementing double sampling in a range of habitats needs to be evaluated.

Quantitative Assessment of In-solution Digestion Efficiency Identifies Optimal Protocols for Unbiased Protein Analysis*

PubMed Central

León, Ileana R.; Schwämmle, Veit; Jensen, Ole N.; Sprenger, Richard R.

2013-01-01

The majority of mass spectrometry-based protein quantification studies uses peptide-centric analytical methods and thus strongly relies on efficient and unbiased protein digestion protocols for sample preparation. We present a novel objective approach to assess protein digestion efficiency using a combination of qualitative and quantitative liquid chromatography-tandem MS methods and statistical data analysis. In contrast to previous studies we employed both standard qualitative as well as data-independent quantitative workflows to systematically assess trypsin digestion efficiency and bias using mitochondrial protein fractions. We evaluated nine trypsin-based digestion protocols, based on standard in-solution or on spin filter-aided digestion, including new optimized protocols. We investigated various reagents for protein solubilization and denaturation (dodecyl sulfate, deoxycholate, urea), several trypsin digestion conditions (buffer, RapiGest, deoxycholate, urea), and two methods for removal of detergents before analysis of peptides (acid precipitation or phase separation with ethyl acetate). Our data-independent quantitative liquid chromatography-tandem MS workflow quantified over 3700 distinct peptides with 96% completeness between all protocols and replicates, with an average 40% protein sequence coverage and an average of 11 peptides identified per protein. Systematic quantitative and statistical analysis of physicochemical parameters demonstrated that deoxycholate-assisted in-solution digestion combined with phase transfer allows for efficient, unbiased generation and recovery of peptides from all protein classes, including membrane proteins. This deoxycholate-assisted protocol was also optimal for spin filter-aided digestions as compared with existing methods. PMID:23792921

Unbiased Estimation of Refractive State of Aberrated Eyes

PubMed Central

Martin, Jesson; Vasudevan, Balamurali; Himebaugh, Nikole; Bradley, Arthur; Thibos, Larry

2011-01-01

To identify unbiased methods for estimating the target vergence required to maximize visual acuity based on wavefront aberration measurements. Experiments were designed to minimize the impact of confounding factors that have hampered previous research. Objective wavefront refractions and subjective acuity refractions were obtained for the same monochromatic wavelength. Accommodation and pupil fluctuations were eliminated by cycloplegia. Unbiased subjective refractions that maximize visual acuity for high contrast letters were performed with a computer controlled forced choice staircase procedure, using 0.125 diopter steps of defocus. All experiments were performed for two pupil diameters (3mm and 6mm). As reported in the literature, subjective refractive error does not change appreciably when the pupil dilates. For 3 mm pupils most metrics yielded objective refractions that were about 0.1D more hyperopic than subjective acuity refractions. When pupil diameter increased to 6 mm, this bias changed in the myopic direction and the variability between metrics also increased. These inaccuracies were small compared to the precision of the measurements, which implies that most metrics provided unbiased estimates of refractive state for medium and large pupils. A variety of image quality metrics may be used to determine ocular refractive state for monochromatic (635nm) light, thereby achieving accurate results without the need for empirical correction factors. PMID:21777601

Building unbiased estimators from non-gaussian likelihoods with application to shear estimation

DOE PAGES

Madhavacheril, Mathew S.; McDonald, Patrick; Sehgal, Neelima; ...

2015-01-15

We develop a general framework for generating estimators of a given quantity which are unbiased to a given order in the difference between the true value of the underlying quantity and the fiducial position in theory space around which we expand the likelihood. We apply this formalism to rederive the optimal quadratic estimator and show how the replacement of the second derivative matrix with the Fisher matrix is a generic way of creating an unbiased estimator (assuming choice of the fiducial model is independent of data). Next we apply the approach to estimation of shear lensing, closely following the workmore » of Bernstein and Armstrong (2014). Our first order estimator reduces to their estimator in the limit of zero shear, but it also naturally allows for the case of non-constant shear and the easy calculation of correlation functions or power spectra using standard methods. Both our first-order estimator and Bernstein and Armstrong’s estimator exhibit a bias which is quadratic in true shear. Our third-order estimator is, at least in the realm of the toy problem of Bernstein and Armstrong, unbiased to 0.1% in relative shear errors Δg/g for shears up to |g| = 0.2.« less

Building unbiased estimators from non-Gaussian likelihoods with application to shear estimation

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

Madhavacheril, Mathew S.; Sehgal, Neelima; McDonald, Patrick

2015-01-01

We develop a general framework for generating estimators of a given quantity which are unbiased to a given order in the difference between the true value of the underlying quantity and the fiducial position in theory space around which we expand the likelihood. We apply this formalism to rederive the optimal quadratic estimator and show how the replacement of the second derivative matrix with the Fisher matrix is a generic way of creating an unbiased estimator (assuming choice of the fiducial model is independent of data). Next we apply the approach to estimation of shear lensing, closely following the workmore » of Bernstein and Armstrong (2014). Our first order estimator reduces to their estimator in the limit of zero shear, but it also naturally allows for the case of non-constant shear and the easy calculation of correlation functions or power spectra using standard methods. Both our first-order estimator and Bernstein and Armstrong's estimator exhibit a bias which is quadratic in true shear. Our third-order estimator is, at least in the realm of the toy problem of Bernstein and Armstrong, unbiased to 0.1% in relative shear errors Δg/g for shears up to |g|=0.2.« less

AD620SQ/883B Total Ionizing Dose Radiation Lot Acceptance Report for RESTORE-LEO

NASA Technical Reports Server (NTRS)

Burton, Noah; Campola, Michael

2017-01-01

A Radiation Lot Acceptance Test was performed on the AD620SQ/883B, Lot 1708D, in accordance with MIL-STD-883, Method 1019, Condition D. Using a Co-60 source 4 biased parts and 4 unbiased parts were irradiated at 10 mrad/s (0.036 krad/hr) in intervals of approximately 1 krad from 3-10 krads, and ones of 5 krads from 10-25 krads, where it was annealed while unbiased at 25 degrees Celsius, for 2 days, and then, subsequently, annealed while biased at 25 degrees celsius, for another 7 days.

Quasi interpolation with Voronoi splines.

PubMed

Mirzargar, Mahsa; Entezari, Alireza

2011-12-01

We present a quasi interpolation framework that attains the optimal approximation-order of Voronoi splines for reconstruction of volumetric data sampled on general lattices. The quasi interpolation framework of Voronoi splines provides an unbiased reconstruction method across various lattices. Therefore this framework allows us to analyze and contrast the sampling-theoretic performance of general lattices, using signal reconstruction, in an unbiased manner. Our quasi interpolation methodology is implemented as an efficient FIR filter that can be applied online or as a preprocessing step. We present visual and numerical experiments that demonstrate the improved accuracy of reconstruction across lattices, using the quasi interpolation framework. © 2011 IEEE

Identification of Rare Lewis Oligosaccharide Conformers in Aqueous Solution Using Enhanced Sampling Molecular Dynamics.

PubMed

Alibay, Irfan; Burusco, Kepa K; Bruce, Neil J; Bryce, Richard A

2018-03-08

Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free-energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling, and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 μs trajectories; these simulations find a predominance of closed conformer and a range of low-occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the 4 C 1 form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 μs unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.

Mutually unbiased projectors and duality between lines and bases in finite quantum systems

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

Shalaby, M.; Vourdas, A., E-mail: a.vourdas@bradford.ac.uk

2013-10-15

Quantum systems with variables in the ring Z(d) are considered, and the concepts of weak mutually unbiased bases and mutually unbiased projectors are discussed. The lines through the origin in the Z(d)×Z(d) phase space, are classified into maximal lines (sets of d points), and sublines (sets of d{sub i} points where d{sub i}|d). The sublines are intersections of maximal lines. It is shown that there exists a duality between the properties of lines (resp., sublines), and the properties of weak mutually unbiased bases (resp., mutually unbiased projectors). -- Highlights: •Lines in discrete phase space. •Bases in finite quantum systems. •Dualitymore » between bases and lines. •Weak mutually unbiased bases.« less

Effect of acute heat stress on rat adrenal glands: a morphological and stereological study.

PubMed

Koko, Vesna; Djordjeviae, Jelena; Cvijiae, Gordana; Davidoviae, Vukosava

2004-11-01

The morphological and stereological structure of rat adrenal gland was analysed by light microscopy after an acute (60 min) exposure to high ambient temperature (38 degrees C). A significant increase in plasma corticotrophin (ACTH) and serum corticosterone (CORT) concentrations was observed, confirming that acute heat exposure has a strong stressful effect. Under these conditions the adrenal gland mass and volume were decreased, probably as the consequence of adrenal cortex reduction, especially that of the zona fasciculata (ZF). Histological examination revealed that many ZF cells were deprived of lipid droplets. Fibrosis was observed in all parts of the adrenal gland, both cortex and medulla, of heat stressed animals. Mitotic figures were absent in cortical cells after heat exposure, but there were no differences in ZF and zona reticularis (ZR) small blood vessels compared to nonstressed controls.

Stereological analysis of neuron, glial and endothelial cell numbers in the human amygdaloid complex.

PubMed

García-Amado, María; Prensa, Lucía

2012-01-01

Cell number alterations in the amygdaloid complex (AC) might coincide with neurological and psychiatric pathologies with anxiety imbalances as well as with changes in brain functionality during aging. This stereological study focused on estimating, in samples from 7 control individuals aged 20 to 75 years old, the number and density of neurons, glia and endothelial cells in the entire AC and in its 5 nuclear groups (including the basolateral (BL), corticomedial and central groups), 5 nuclei and 13 nuclear subdivisions. The volume and total cell number in these territories were determined on Nissl-stained sections with the Cavalieri principle and the optical fractionator. The AC mean volume was 956 mm(3) and mean cell numbers (x10(6)) were: 15.3 neurons, 60 glial cells and 16.8 endothelial cells. The numbers of endothelial cells and neurons were similar in each AC region and were one fourth the number of glial cells. Analysis of the influence of the individuals' age at death on volume, cell number and density in each of these 24 AC regions suggested that aging does not affect regional size or the amount of glial cells, but that neuron and endothelial cell numbers respectively tended to decrease and increase in territories such as AC or BL. These accurate stereological measures of volume and total cell numbers and densities in the AC of control individuals could serve as appropriate reference values to evaluate subtle alterations in this structure in pathological conditions.

Growth of alveoli during postnatal development in humans based on stereological estimation.

PubMed

Herring, Matt J; Putney, Lei F; Wyatt, Gregory; Finkbeiner, Walter E; Hyde, Dallas M

2014-08-15

Alveolarization in humans and nonhuman primates begins during prenatal development. Advances in stereological counting techniques allow accurate assessment of alveolar number; however, these techniques have not been applied to the developing human lung. Based on the recent American Thoracic Society guidelines for stereology, lungs from human autopsies, ages 2 mo to 15 yr, were fractionated and isometric uniform randomly sampled to count the number of alveoli. The number of alveoli was compared with age, weight, and height as well as growth between right and left lungs. The number of alveoli in the human lung increased exponentially during the first 2 yr of life but continued to increase albeit at a reduced rate through adolescence. Alveolar numbers also correlated with the indirect radial alveolar count technique. Growth curves for human alveolarization were compared using historical data of nonhuman primates and rats. The alveolar growth rate in nonhuman primates was nearly identical to the human growth curve. Rats were significantly different, showing a more pronounced exponential growth during the first 20 days of life. This evidence indicates that the human lung may be more plastic than originally thought, with alveolarization occurring well into adolescence. The first 20 days of life in rats implies a growth curve that may relate more to prenatal growth in humans. The data suggest that nonhuman primates are a better laboratory model for studies of human postnatal lung growth than rats. Copyright © 2014 the American Physiological Society.

Stereological Analysis of Neuron, Glial and Endothelial Cell Numbers in the Human Amygdaloid Complex

PubMed Central

García-Amado, María; Prensa, Lucía

2012-01-01

Cell number alterations in the amygdaloid complex (AC) might coincide with neurological and psychiatric pathologies with anxiety imbalances as well as with changes in brain functionality during aging. This stereological study focused on estimating, in samples from 7 control individuals aged 20 to 75 years old, the number and density of neurons, glia and endothelial cells in the entire AC and in its 5 nuclear groups (including the basolateral (BL), corticomedial and central groups), 5 nuclei and 13 nuclear subdivisions. The volume and total cell number in these territories were determined on Nissl-stained sections with the Cavalieri principle and the optical fractionator. The AC mean volume was 956 mm3 and mean cell numbers (x106) were: 15.3 neurons, 60 glial cells and 16.8 endothelial cells. The numbers of endothelial cells and neurons were similar in each AC region and were one fourth the number of glial cells. Analysis of the influence of the individuals’ age at death on volume, cell number and density in each of these 24 AC regions suggested that aging does not affect regional size or the amount of glial cells, but that neuron and endothelial cell numbers respectively tended to decrease and increase in territories such as AC or BL. These accurate stereological measures of volume and total cell numbers and densities in the AC of control individuals could serve as appropriate reference values to evaluate subtle alterations in this structure in pathological conditions. PMID:22719923

Stereological study of rat spleen following acute ethanol treatment.

PubMed

Budec, M; Milićević, Z; Koko, V

2000-05-01

To investigate the acute effect of ethanol (4 g/kg, i.p.) on spleen adult female Wistar rats were treated intraperitoneally with: a) ethanol (4 g/kg body wt), b) naltrexone (5 mg/kg body wt) followed 45 minutes later by ethanol (4 g/kg body wt) and c) naltrexone (5 mg/kg body wt) alone. Untreated and saline-treated rats were used as controls. Twenty hours after the ethanol treatment the animals were sacrificed and the spleens were removed. A piece of tissue from the central part of each organ was fixed in Bouin's solution. Paraffin sections were stained with hematoxylin-eosin and analysed using stereological measurements. The volume densities of the following tissue compartments: red pulp, white pulp (divided in follicles, periarterioral lymphatic sheath and marginal zone) and the connective tissue were determined. Stereological analysis also included parameters of follicles: the areal numerical density (the number of follicles per 1 mm2 of tissue section), the numerical density (the number of follicles per mm3 of tissue) and the mean follicle diameter. The immunoarchitecture of the spleen was preserved following acute ethanol treatment. Unlike other parameters that were unaffected, ethanol evoked a decrease in both volume density of follicle and the mean follicle diameter. Naltrexone pretreatment had no influence on ethanol-induced changes. The data obtained indicate that a single dose of ethanol has a profound effect on rat spleen affecting the follicles, but the mechanism of its action remains to be elucidated.

Unbiased phosphoproteomic method identifies the initial effects of a methacrylic acid copolymer on macrophages

PubMed Central

Chamberlain, Michael Dean; Wells, Laura A.; Lisovsky, Alexandra; Guo, Hongbo; Isserlin, Ruth; Talior-Volodarsky, Ilana; Mahou, Redouan; Emili, Andrew; Sefton, Michael V.

2015-01-01

An unbiased phosphoproteomic method was used to identify biomaterial-associated changes in the phosphorylation patterns of macrophage-like cells. The phosphorylation differences between differentiated THP1 (dTHP1) cells treated for 10, 20, or 30 min with a vascular regenerative methacrylic acid (MAA) copolymer or a control methyl methacrylate (MM) copolymer were determined by MS. There were 1,470 peptides (corresponding to 729 proteins) that were differentially phosphorylated in dTHP1 cells treated with the two materials with a greater cellular response to MAA treatment. In addition to identifying pathways (such as integrin signaling and cytoskeletal arrangement) that are well known to change with cell–material interaction, previously unidentified pathways, such as apoptosis and mRNA splicing, were also discovered. PMID:26261332

Mixed model approaches for diallel analysis based on a bio-model.

PubMed

Zhu, J; Weir, B S

1996-12-01

A MINQUE(1) procedure, which is minimum norm quadratic unbiased estimation (MINQUE) method with 1 for all the prior values, is suggested for estimating variance and covariance components in a bio-model for diallel crosses. Unbiasedness and efficiency of estimation were compared for MINQUE(1), restricted maximum likelihood (REML) and MINQUE theta which has parameter values for the prior values. MINQUE(1) is almost as efficient as MINQUE theta for unbiased estimation of genetic variance and covariance components. The bio-model is efficient and robust for estimating variance and covariance components for maternal and paternal effects as well as for nuclear effects. A procedure of adjusted unbiased prediction (AUP) is proposed for predicting random genetic effects in the bio-model. The jack-knife procedure is suggested for estimation of sampling variances of estimated variance and covariance components and of predicted genetic effects. Worked examples are given for estimation of variance and covariance components and for prediction of genetic merits.

Maximum unbiased validation (MUV) data sets for virtual screening based on PubChem bioactivity data.

PubMed

Rohrer, Sebastian G; Baumann, Knut

2009-02-01

Refined nearest neighbor analysis was recently introduced for the analysis of virtual screening benchmark data sets. It constitutes a technique from the field of spatial statistics and provides a mathematical framework for the nonparametric analysis of mapped point patterns. Here, refined nearest neighbor analysis is used to design benchmark data sets for virtual screening based on PubChem bioactivity data. A workflow is devised that purges data sets of compounds active against pharmaceutically relevant targets from unselective hits. Topological optimization using experimental design strategies monitored by refined nearest neighbor analysis functions is applied to generate corresponding data sets of actives and decoys that are unbiased with regard to analogue bias and artificial enrichment. These data sets provide a tool for Maximum Unbiased Validation (MUV) of virtual screening methods. The data sets and a software package implementing the MUV design workflow are freely available at http://www.pharmchem.tu-bs.de/lehre/baumann/MUV.html.

Estimating Unbiased Land Cover Change Areas In The Colombian Amazon Using Landsat Time Series And Statistical Inference Methods

NASA Astrophysics Data System (ADS)

Arevalo, P. A.; Olofsson, P.; Woodcock, C. E.

2017-12-01

Unbiased estimation of the areas of conversion between land categories ("activity data") and their uncertainty is crucial for providing more robust calculations of carbon emissions to the atmosphere, as well as their removals. This is particularly important for the REDD+ mechanism of UNFCCC where an economic compensation is tied to the magnitude and direction of such fluxes. Dense time series of Landsat data and statistical protocols are becoming an integral part of forest monitoring efforts, but there are relatively few studies in the tropics focused on using these methods to advance operational MRV systems (Monitoring, Reporting and Verification). We present the results of a prototype methodology for continuous monitoring and unbiased estimation of activity data that is compliant with the IPCC Approach 3 for representation of land. We used a break detection algorithm (Continuous Change Detection and Classification, CCDC) to fit pixel-level temporal segments to time series of Landsat data in the Colombian Amazon. The segments were classified using a Random Forest classifier to obtain annual maps of land categories between 2001 and 2016. Using these maps, a biannual stratified sampling approach was implemented and unbiased stratified estimators constructed to calculate area estimates with confidence intervals for each of the stable and change classes. Our results provide evidence of a decrease in primary forest as a result of conversion to pastures, as well as increase in secondary forest as pastures are abandoned and the forest allowed to regenerate. Estimating areas of other land transitions proved challenging because of their very small mapped areas compared to stable classes like forest, which corresponds to almost 90% of the study area. Implications on remote sensing data processing, sample allocation and uncertainty reduction are also discussed.

Protective Effects of 17β-Estradiol on Hippocampal Myelinated Fibers in Ovariectomized Middle-aged Rats.

PubMed

Xiao, Qian; Luo, Yanmin; Lv, Fulin; He, Qi; Wu, Hong; Chao, Fenglei; Qiu, Xuan; Zhang, Lei; Gao, Yuan; Huang, Chunxia; Wang, Sanrong; Zhou, Chunni; Zhang, Yi; Jiang, Lin; Tang, Yong

2018-06-14

Estrogen replacement therapy (ERT) improves hippocampus-dependent cognition. This study investigated the impact of estrogen on hippocampal volume, CA1 subfield volume and myelinated fibers in the CA1 subfield of middle-aged ovariectomized rats. Ten-month-old bilaterally ovariectomized (OVX) female rats were randomly divided into OVX + E2 and OVX + Veh groups. After four weeks of subcutaneous injection with 17β-estradiol or a placebo, the OVX + E2 rats exhibited significantly short mean escape latency in a spatial learning task than that in the OVX + Veh rats. Using stereological methods, we did not observe significant differences in the volumes of the hippocampus and CA1 subfields between the two groups. However, using stereological methods and electron microscopy techniques, the total length of myelinated fibers and the total volumes of myelinated fibers, myelin sheaths and myelinated axons in the CA1 subfields of OVX + E2 rats were significantly 38.1%, 34.2%, 36.1% and 32.5%, respectively, higher than those in the OVX + Veh rats. After the parameters were calculated according to different diameter ranges, the estrogen replacement-induced remodeling of myelinated fibers in CA1 was mainly manifested in the myelinated fibers with a diameter of <1.0 μm. Therefore, four weeks of continuous E2 replacement improved the spatial learning capabilities of middle-aged ovariectomized rats. The E2 replacement-induced protection of spatial learning abilities might be associated with the beneficial effects of estrogen on myelinated fibers, particularly those with the diameters less than 1.0 μm, in the hippocampal CA1 region of middle-aged ovariectomized rats. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Comparison of the morphometric features of the left and right horse kidneys: a stereological approach.

PubMed

Bolat, D; Bahar, S; Tipirdamaz, S; Selcuk, M L

2013-12-01

The aims of this study were to determine the total volume of the horse kidney and volume fractions of its functional subcomponents (cortex, medulla, renal pelvis) using stereological methods and investigate any possible difference in the functional subcomponents of the right and left kidneys that may arise from differences in shape. The study was carried out on the kidneys of 5 horses of different breed and sex. The weight of the kidneys was measured by a digital scale, and kidney volume was calculated by Archimedes' principle. Total kidney volume and volume fractions of subcomponents of the right and left kidneys were estimated by the Cavalieri's principle. The weights of the right and left kidneys were 550 ± 25 g and 585 ± 23 g, respectively. The volumes of the right and left kidneys estimated using the Cavalieri method were 542 ± 46 ml and 581 ± 29 ml. The relative organ weight of the kidneys was calculated as 1:330. The densities of the right and left kidneys were determined to be 1.01 and 1.00, respectively. The mean volume fractions of the cortex, medulla and renal pelvis were determined as 55.6, 42.7 and 1.7 in both kidneys. No statistically significant difference existed between morphometric data pertaining to the right and left kidneys (P > 0.05). To determine precisely whether differences in shape cause any difference in the functional subcomponents of the right and left kidneys requires further investigation of differences in the number of microscopically functional unit of the kidney such as renal glomeruli and nephrons. © 2013 Blackwell Verlag GmbH.

Entropic uncertainty relations and locking: Tight bounds for mutually unbiased bases

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

Ballester, Manuel A.; Wehner, Stephanie

We prove tight entropic uncertainty relations for a large number of mutually unbiased measurements. In particular, we show that a bound derived from the result by Maassen and Uffink [Phys. Rev. Lett. 60, 1103 (1988)] for two such measurements can in fact be tight for up to {radical}(d) measurements in mutually unbiased bases. We then show that using more mutually unbiased bases does not always lead to a better locking effect. We prove that the optimal bound for the accessible information using up to {radical}(d) specific mutually unbiased bases is log d/2, which is the same as can be achievedmore » by using only two bases. Our result indicates that merely using mutually unbiased bases is not sufficient to achieve a strong locking effect and we need to look for additional properties.« less

[Application of ordinary Kriging method in entomologic ecology].

PubMed

Zhang, Runjie; Zhou, Qiang; Chen, Cuixian; Wang, Shousong

2003-01-01

Geostatistics is a statistic method based on regional variables and using the tool of variogram to analyze the spatial structure and the patterns of organism. In simulating the variogram within a great range, though optimal simulation cannot be obtained, the simulation method of a dialogue between human and computer can be used to optimize the parameters of the spherical models. In this paper, the method mentioned above and the weighted polynomial regression were utilized to simulate the one-step spherical model, the two-step spherical model and linear function model, and the available nearby samples were used to draw on the ordinary Kriging procedure, which provided a best linear unbiased estimate of the constraint of the unbiased estimation. The sum of square deviation between the estimating and measuring values of varying theory models were figured out, and the relative graphs were shown. It was showed that the simulation based on the two-step spherical model was the best simulation, and the one-step spherical model was better than the linear function model.

On fixed-area plot sampling for downed coarse woody debris

Treesearch

Jeffrey H. Gove; Paul C. Van Deusen

2011-01-01

The use of fixed-area plots for sampling down coarse woody debris is reviewed. A set of clearly defined protocols for two previously described methods is established and a new method, which we call the 'sausage' method, is developed. All methods (protocols) are shown to be unbiased for volume estimation, but not necessarily for estimation of population...

Regression calibration for models with two predictor variables measured with error and their interaction, using instrumental variables and longitudinal data.

PubMed

Strand, Matthew; Sillau, Stefan; Grunwald, Gary K; Rabinovitch, Nathan

2014-02-10

Regression calibration provides a way to obtain unbiased estimators of fixed effects in regression models when one or more predictors are measured with error. Recent development of measurement error methods has focused on models that include interaction terms between measured-with-error predictors, and separately, methods for estimation in models that account for correlated data. In this work, we derive explicit and novel forms of regression calibration estimators and associated asymptotic variances for longitudinal models that include interaction terms, when data from instrumental and unbiased surrogate variables are available but not the actual predictors of interest. The longitudinal data are fit using linear mixed models that contain random intercepts and account for serial correlation and unequally spaced observations. The motivating application involves a longitudinal study of exposure to two pollutants (predictors) - outdoor fine particulate matter and cigarette smoke - and their association in interactive form with levels of a biomarker of inflammation, leukotriene E4 (LTE 4 , outcome) in asthmatic children. Because the exposure concentrations could not be directly observed, we used measurements from a fixed outdoor monitor and urinary cotinine concentrations as instrumental variables, and we used concentrations of fine ambient particulate matter and cigarette smoke measured with error by personal monitors as unbiased surrogate variables. We applied the derived regression calibration methods to estimate coefficients of the unobserved predictors and their interaction, allowing for direct comparison of toxicity of the different pollutants. We used simulations to verify accuracy of inferential methods based on asymptotic theory. Copyright © 2013 John Wiley & Sons, Ltd.

Unbiased Scanning Method and Data Banking Approach Using Ultra-High Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry for Quantitative Comparison of Metabolite Exposure in Plasma across Species Analyzed at Different Dates.

PubMed

Gao, Hongying; Deng, Shibing; Obach, R Scott

2015-12-01

An unbiased scanning methodology using ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry was used to bank data and plasma samples for comparing the data generated at different dates. This method was applied to bank the data generated earlier in animal samples and then to compare the exposure to metabolites in animal versus human for safety assessment. With neither authentic standards nor prior knowledge of the identities and structures of metabolites, full scans for precursor ions and all ion fragments (AIF) were employed with a generic gradient LC method to analyze plasma samples at positive and negative polarity, respectively. In a total of 22 tested drugs and metabolites, 21 analytes were detected using this unbiased scanning method except that naproxen was not detected due to low sensitivity at negative polarity and interference at positive polarity; and 4'- or 5-hydroxy diclofenac was not separated by a generic UPLC method. Statistical analysis of the peak area ratios of the analytes versus the internal standard in five repetitive analyses over approximately 1 year demonstrated that the analysis variation was significantly different from sample instability. The confidence limits for comparing the exposure using peak area ratio of metabolites in animal plasma versus human plasma measured over approximately 1 year apart were comparable to the analysis undertaken side by side on the same days. These statistical analysis results showed it was feasible to compare data generated at different dates with neither authentic standards nor prior knowledge of the analytes.

Stereological analysis of the epiphyseal growth cartilage in the brachymorphic (bm/bm) mouse, with special reference to the distribution of matrix vesicles.

PubMed

Wikström, B; Hjerpe, A; Hultenby, K; Reinholt, F P; Engfeldt, B

1984-01-01

The brachymorphic (bm/bm) mutation in the mouse leads to disproportional dwarfism due to a disturbance of endochondral bone formation. The morphological characteristics of bm/bm epiphyseal growth cartilage are signs of cellular degeneration and disintegration and alteration of the composition of the extracellular matrix, with an abnormal mineralization pattern. The present stereological study of the bm/bm growth plate revealed a clearly altered distribution of matrix vesicles as compared with the controls. It was also demonstrated that the bm/bm matrix vesicles have an abnormal size distribution, with an increased mean caliper diameter. The biological significance of these findings is discussed in relation to the different hypotheses on the origin of matrix vesicles and their possible role in the mineralization process. The results support the opinion that extracellular matrix vesicles, at least partly, constitute cellular debris.

Immediate versus delayed primary nerve repair in the rabbit sciatic nerve

PubMed Central

Piskin, Ahmet; Altunkaynak, Berrin Zühal; Çιtlak, Atilla; Sezgin, Hicabi; Yazιcι, Ozgür; Kaplan, Süleyman

2013-01-01

It is well known that peripheral nerve injury should be treated immediately in the clinic, but in some instances, repair can be delayed. This study investigated the effects of immediate versus delayed (3 days after injury) neurorrhaphy on repair of transected sciatic nerve in New Zealand rabbits using stereological, histomorphological and biomechanical methods. At 8 weeks after immediate and delayed neurorrhaphy, axon number and area in the sciatic nerve, myelin sheath and epineurium thickness, Schwann cell morphology, and the mechanical property of nerve fibers did not differ obviously. These results indicate that delayed neurorrhaphy do not produce any deleterious effect on sciatic nerve repair. PMID:25206663

Neuronal populations in the basolateral nuclei of the amygdala are differentially increased in humans compared with apes: a stereological study.

PubMed

Barger, Nicole; Stefanacci, Lisa; Schumann, Cynthia M; Sherwood, Chet C; Annese, Jacopo; Allman, John M; Buckwalter, Joseph A; Hof, Patrick R; Semendeferi, Katerina

2012-09-01

In human and nonhuman primates, the amygdala is known to play critical roles in emotional and social behavior. Anatomically, individual amygdaloid nuclei are connected with many neural systems that are either differentially expanded or conserved over the course of primate evolution. To address amygdala evolution in humans and our closest living relatives, the apes, we used design-based stereological methods to obtain neuron counts for the amygdala and each of four major amygdaloid nuclei (the lateral, basal, accessory basal, and central nuclei) in humans, all great ape species, lesser apes, and one monkey species. Our goal was to determine whether there were significant differences in the number or percent of neurons distributed to individual nuclei among species. Additionally, regression analyses were performed on independent contrast data to determine whether any individual species deviated from allometric trends. There were two major findings. In humans, the lateral nucleus contained the highest number of neurons in the amygdala, whereas in apes the basal nucleus contained the highest number of neurons. Additionally, the human lateral nucleus contained 59% more neurons than predicted by allometric regressions on nonhuman primate data. Based on the largest sample ever analyzed in a comparative study of the hominoid amygdala, our findings suggest that an emphasis on the lateral nucleus is the main characteristic of amygdala specialization over the course of human evolution. Copyright © 2012 Wiley Periodicals, Inc.

A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology

PubMed Central

Keller, Simon S.; Das, Kumar; Vidyasagar, Rishma; Parkes, Laura M.; Burnside, Girvan; Griffiths, Michael; Kopelman, Michael; Roberts, Neil; Solomon, Tom

2017-01-01

Objectives To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. Methods The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. Results Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. Conclusions This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis. PMID:28125598

Stereological estimation of ovarian oocyte volume, surface area and number: application on mice treated with nandrolone decanoate.

PubMed

Karbalay-Doust, Saied; Noorafshan, Ali

2012-07-05

Changes in the number and size of oocytes can lead to fertilization problems. The present study aimed to evaluate the number, volume, and surface area of oocytes in healthy as well as nandrolone decanoate-treated (ND) mice using stereological methods. Five control mice received vehicle, and five ND-treated mice received ND. Using the 'isotropic Cavalieri' design', the ovary was sectioned. The volume of the ovary (cortex and medulla) was estimated. The oocytes' volume and surface area were estimated using the invariator. The number of the oocytes was estimated using an optical disector. The volumes of the ovary, cortex, and medulla decreased ~50% in the ND-treated mice. The mean number (coefficient of variation) of preantral, antral, and atretic oocytes in the control ovary were 1,690 (0.29), 2,100 (0.52), and 3,900 (0.2), respectively, which decreased ~54%, ~87%, and ~91%, respectively in the ND-treated animals. The mean volume (coefficient of variation) of the preantral, antral, and atretic oocytes were 86,000 (0.27), 110,000 (0.48), and 27,000 (0.33) μm³, respectively. The mean surface area (coefficient of variation) of the three types of oocytes were 9,000 (0.24), 9,900 (0.28), and 4,700 (0.21) μm², respectively. These parameters remained unchanged in the ND-treated mice. ND induces reduction in the number of oocytes, but not in the volume or the surface area.

Empirical Benchmarks of Hidden Bias in Educational Research: Implication for Assessing How well Propensity Score Methods Approximate Experiments and Conducting Sensitivity Analysis

ERIC Educational Resources Information Center

Dong, Nianbo; Lipsey, Mark

2014-01-01

When randomized control trials (RCT) are not feasible, researchers seek other methods to make causal inference, e.g., propensity score methods. One of the underlined assumptions for the propensity score methods to obtain unbiased treatment effect estimates is the ignorability assumption, that is, conditional on the propensity score, treatment…

A UNIFIED FRAMEWORK FOR VARIANCE COMPONENT ESTIMATION WITH SUMMARY STATISTICS IN GENOME-WIDE ASSOCIATION STUDIES.

PubMed

Zhou, Xiang

2017-12-01

Linear mixed models (LMMs) are among the most commonly used tools for genetic association studies. However, the standard method for estimating variance components in LMMs-the restricted maximum likelihood estimation method (REML)-suffers from several important drawbacks: REML requires individual-level genotypes and phenotypes from all samples in the study, is computationally slow, and produces downward-biased estimates in case control studies. To remedy these drawbacks, we present an alternative framework for variance component estimation, which we refer to as MQS. MQS is based on the method of moments (MoM) and the minimal norm quadratic unbiased estimation (MINQUE) criterion, and brings two seemingly unrelated methods-the renowned Haseman-Elston (HE) regression and the recent LD score regression (LDSC)-into the same unified statistical framework. With this new framework, we provide an alternative but mathematically equivalent form of HE that allows for the use of summary statistics. We provide an exact estimation form of LDSC to yield unbiased and statistically more efficient estimates. A key feature of our method is its ability to pair marginal z -scores computed using all samples with SNP correlation information computed using a small random subset of individuals (or individuals from a proper reference panel), while capable of producing estimates that can be almost as accurate as if both quantities are computed using the full data. As a result, our method produces unbiased and statistically efficient estimates, and makes use of summary statistics, while it is computationally efficient for large data sets. Using simulations and applications to 37 phenotypes from 8 real data sets, we illustrate the benefits of our method for estimating and partitioning SNP heritability in population studies as well as for heritability estimation in family studies. Our method is implemented in the GEMMA software package, freely available at www.xzlab.org/software.html.

Beyond Bigotry: Teaching about Unconscious Prejudice

ERIC Educational Resources Information Center

Ghoshal, Raj Andrew; Lippard, Cameron; Ribas, Vanesa; Muir, Ken

2013-01-01

Researchers have demonstrated that unconscious prejudices around characteristics such as race, gender, and class are common, even among people who avow themselves unbiased. The authors present a method for teaching about implicit racial bias using online Implicit Association Tests. The authors do not claim that their method rids students of…

Migration monitoring with automated technology

Treesearch

Rhonda L. Millikin

2005-01-01

Automated technology can supplement ground-based methods of migration monitoring by providing: (1) unbiased and automated sampling; (2) independent validation of current methods; (3) a larger sample area for landscape-level analysis of habitat selection for stopover, and (4) an opportunity to study flight behavior. In particular, radar-acoustic sensor fusion can...

Preliminary report on macroscopic age changes in the human prosencephalon. A stereologic investigation.

PubMed

Eggers, R; Haug, H; Fischer, D

1984-01-01

The studies here reported were performed on the prosencephalons of 12 human brains between 37 and 86 years of age having no signs of neuropathological alteration. The evaluation was carried out on serial frontal sections with a mean thickness of 5 mm with stereological point counting procedures for volume and surface area. The results were mainly given in relative values since the range of variation is very high and the sample small. The aging process was evaluated with the aid of a linear regression function. The stereological investigation regarding the absolute values of volume and surface area (border face) of the macroscopical brain parts show a high interindividual variability. However, the relative volume of brain parts shows only small variations. Changes during aging could consequently only be revealed with the help of the relative values. The relative volumes and surface areas of the frontal lobe and the prosencephalic ganglia decrease with aging, while the parieto-occipital lobe and the striate cortex increase. However, if we refer these relative increases to the absolute decrease of brain volume, corresponding changes cannot be found in the parieto-occipital lobe until old age. The shrinkage of the frontal lobe, of the centrum semiovale and of the prosencephalic ganglia exceeds 10%. In the grays it is probably accompanied by a loss of neurons. The relative sizes of the surface area do not change significantly during aging with exception of the frontal cortex. The thickness of the cortex remains probably constant. The size of lateral ventricles increases with aging.

Long live the liver: immunohistochemical and stereological study of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells of male and female rats throughout ageing.

PubMed

Marcos, Ricardo; Correia-Gomes, Carla

2016-12-01

Male/female differences in enzyme activity and gene expression in the liver are known to be attenuated with ageing. Nevertheless, the effect of ageing on liver structure and quantitative cell morphology remains unknown. Male and female Wistar rats aged 2, 6, 12 and 18 months were examined by means of stereological techniques and immunohistochemical tagging of hepatocytes (HEP), liver sinusoidal endothelial cells (LSEC), Kupffer cells (KC) and hepatic stellate cells (HSC) in order to assess the total number and number per gram of these cells throughout life. The mean cell volume of HEP and HSC, the lobular position and the collagen content of the liver were also evaluated with stereological techniques. The number per gram of HSC was similar for both genders and was maintained throughout ageing. The mean volume of HSC was also conserved but differences in the cell body and lobular location were observed. Statistically significant gender differences in HEP were noted in young rats (females had smaller and more binucleated HEP) but were attenuated with ageing. The same occurred for KC and LSEC, since the higher number per gram in young females disappeared in older animals. Liver collagen increased with ageing but only in males. Thus, the numbers of these four cell types are related throughout ageing, with well-defined cell ratios. The shape and lobular position of HSC change with ageing in both males and females. Gender dimorphism in HEP, KC and LSEC of young rat liver disappears with ageing.

Differential estimates of southern flying squirrel (Glaucomys volans) population structure based on capture method

Treesearch

Kevin S. Laves; Susan C. Loeb

2005-01-01

It is commonly assumed that population estimates derived from trapping small mammals are accurate and unbiased or that estimates derived from different capture methods are comparable. We captured southern flying squirrels (Glaucmrtys volam) using two methods to study their effect on red-cockaded woodpecker (Picoides bumah) reproductive success. Southern flying...

Conformational free energies of methyl-α-L-iduronic and methyl-β-D-glucuronic acids in water

NASA Astrophysics Data System (ADS)

Babin, Volodymyr; Sagui, Celeste

2010-03-01

We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a nonequilibrium umbrella sampling method, in this case, the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the weighted histogram analysis technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of α-L-iduronic acid and its C5 epimer β-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.

Conformational free energies of methyl-alpha-L-iduronic and methyl-beta-D-glucuronic acids in water.

PubMed

Babin, Volodymyr; Sagui, Celeste

2010-03-14

We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a nonequilibrium umbrella sampling method, in this case, the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the weighted histogram analysis technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of alpha-L-iduronic acid and its C5 epimer beta-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.

Detection of seizures from small samples using nonlinear dynamic system theory.

PubMed

Yaylali, I; Koçak, H; Jayakar, P

1996-07-01

The electroencephalogram (EEG), like many other biological phenomena, is quite likely governed by nonlinear dynamics. Certain characteristics of the underlying dynamics have recently been quantified by computing the correlation dimensions (D2) of EEG time series data. In this paper, D2 of the unbiased autocovariance function of the scalp EEG data was used to detect electrographic seizure activity. Digital EEG data were acquired at a sampling rate of 200 Hz per channel and organized in continuous frames (duration 2.56 s, 512 data points). To increase the reliability of D2 computations with short duration data, raw EEG data were initially simplified using unbiased autocovariance analysis to highlight the periodic activity that is present during seizures. The D2 computation was then performed from the unbiased autocovariance function of each channel using the Grassberger-Procaccia method with Theiler's box-assisted correlation algorithm. Even with short duration data, this preprocessing proved to be computationally robust and displayed no significant sensitivity to implementation details such as the choices of embedding dimension and box size. The system successfully identified various types of seizures in clinical studies.

Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against β-Lactamase

PubMed Central

Babaoglu, Kerim; Simeonov, Anton; Irwin, John J.; Nelson, Michael E.; Feng, Brian; Thomas, Craig J.; Cancian, Laura; Costi, M. Paola; Maltby, David A.; Jadhav, Ajit; Inglese, James; Austin, Christopher P.; Shoichet, Brian K.

2009-01-01

High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate “hit lists”; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against β-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting β-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 µM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens. PMID:18333608

Construction of mutually unbiased bases with cyclic symmetry for qubit systems

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

Seyfarth, Ulrich; Ranade, Kedar S.

2011-10-15

For the complete estimation of arbitrary unknown quantum states by measurements, the use of mutually unbiased bases has been well established in theory and experiment for the past 20 years. However, most constructions of these bases make heavy use of abstract algebra and the mathematical theory of finite rings and fields, and no simple and generally accessible construction is available. This is particularly true in the case of a system composed of several qubits, which is arguably the most important case in quantum information science and quantum computation. In this paper, we close this gap by providing a simple andmore » straightforward method for the construction of mutually unbiased bases in the case of a qubit register. We show that our construction is also accessible to experiments, since only Hadamard and controlled-phase gates are needed, which are available in most practical realizations of a quantum computer. Moreover, our scheme possesses the optimal scaling possible, i.e., the number of gates scales only linearly in the number of qubits.« less

Unbiased Sampling of Globular Lattice Proteins in Three Dimensions

NASA Astrophysics Data System (ADS)

Jacobsen, Jesper Lykke

2008-03-01

We present a Monte Carlo method that allows efficient and unbiased sampling of Hamiltonian walks on a cubic lattice. Such walks are self-avoiding and visit each lattice site exactly once. They are often used as simple models of globular proteins, upon adding suitable local interactions. Our algorithm can easily be equipped with such interactions, but we study here mainly the flexible homopolymer case where each conformation is generated with uniform probability. We argue that the algorithm is ergodic and has dynamical exponent z=0. We then use it to study polymers of size up to 643=262144 monomers. Results are presented for the effective interaction between end points, and the interaction with the boundaries of the system.

Unbiased free energy estimates in fast nonequilibrium transformations using Gaussian mixtures

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

Procacci, Piero

2015-04-21

In this paper, we present an improved method for obtaining unbiased estimates of the free energy difference between two thermodynamic states using the work distribution measured in nonequilibrium driven experiments connecting these states. The method is based on the assumption that any observed work distribution is given by a mixture of Gaussian distributions, whose normal components are identical in either direction of the nonequilibrium process, with weights regulated by the Crooks theorem. Using the prototypical example for the driven unfolding/folding of deca-alanine, we show that the predicted behavior of the forward and reverse work distributions, assuming a combination of onlymore » two Gaussian components with Crooks derived weights, explains surprisingly well the striking asymmetry in the observed distributions at fast pulling speeds. The proposed methodology opens the way for a perfectly parallel implementation of Jarzynski-based free energy calculations in complex systems.« less

Bias and Efficiency in Structural Equation Modeling: Maximum Likelihood versus Robust Methods

ERIC Educational Resources Information Center

Zhong, Xiaoling; Yuan, Ke-Hai

2011-01-01

In the structural equation modeling literature, the normal-distribution-based maximum likelihood (ML) method is most widely used, partly because the resulting estimator is claimed to be asymptotically unbiased and most efficient. However, this may not hold when data deviate from normal distribution. Outlying cases or nonnormally distributed data,…

Can We Spin Straw Into Gold? An Evaluation of Immigrant Legal Status Imputation Approaches

PubMed Central

Van Hook, Jennifer; Bachmeier, James D.; Coffman, Donna; Harel, Ofer

2014-01-01

Researchers have developed logical, demographic, and statistical strategies for imputing immigrants’ legal status, but these methods have never been empirically assessed. We used Monte Carlo simulations to test whether, and under what conditions, legal status imputation approaches yield unbiased estimates of the association of unauthorized status with health insurance coverage. We tested five methods under a range of missing data scenarios. Logical and demographic imputation methods yielded biased estimates across all missing data scenarios. Statistical imputation approaches yielded unbiased estimates only when unauthorized status was jointly observed with insurance coverage; when this condition was not met, these methods overestimated insurance coverage for unauthorized relative to legal immigrants. We next showed how bias can be reduced by incorporating prior information about unauthorized immigrants. Finally, we demonstrated the utility of the best-performing statistical method for increasing power. We used it to produce state/regional estimates of insurance coverage among unauthorized immigrants in the Current Population Survey, a data source that contains no direct measures of immigrants’ legal status. We conclude that commonly employed legal status imputation approaches are likely to produce biased estimates, but data and statistical methods exist that could substantially reduce these biases. PMID:25511332

A statistical test of unbiased evolution of body size in birds.

PubMed

Bokma, Folmer

2002-12-01

Of the approximately 9500 bird species, the vast majority is small-bodied. That is a general feature of evolutionary lineages, also observed for instance in mammals and plants. The avian interspecific body size distribution is right-skewed even on a logarithmic scale. That has previously been interpreted as evidence that body size evolution has been biased. However, a procedure to test for unbiased evolution from the shape of body size distributions was lacking. In the present paper unbiased body size evolution is defined precisely, and a statistical test is developed based on Monte Carlo simulation of unbiased evolution. Application of the test to birds suggests that it is highly unlikely that avian body size evolution has been unbiased as defined. Several possible explanations for this result are discussed. A plausible explanation is that the general model of unbiased evolution assumes that population size and generation time do not affect the evolutionary variability of body size; that is, that micro- and macroevolution are decoupled, which theory suggests is not likely to be the case.

A comparison of the weights-of-evidence method and probabilistic neural networks

USGS Publications Warehouse

Singer, Donald A.; Kouda, Ryoichi

1999-01-01

The need to integrate large quantities of digital geoscience information to classify locations as mineral deposits or nondeposits has been met by the weights-of-evidence method in many situations. Widespread selection of this method may be more the result of its ease of use and interpretation rather than comparisons with alternative methods. A comparison of the weights-of-evidence method to probabilistic neural networks is performed here with data from Chisel Lake-Andeson Lake, Manitoba, Canada. Each method is designed to estimate the probability of belonging to learned classes where the estimated probabilities are used to classify the unknowns. Using these data, significantly lower classification error rates were observed for the neural network, not only when test and training data were the same (0.02 versus 23%), but also when validation data, not used in any training, were used to test the efficiency of classification (0.7 versus 17%). Despite these data containing too few deposits, these tests of this set of data demonstrate the neural network's ability at making unbiased probability estimates and lower error rates when measured by number of polygons or by the area of land misclassified. For both methods, independent validation tests are required to ensure that estimates are representative of real-world results. Results from the weights-of-evidence method demonstrate a strong bias where most errors are barren areas misclassified as deposits. The weights-of-evidence method is based on Bayes rule, which requires independent variables in order to make unbiased estimates. The chi-square test for independence indicates no significant correlations among the variables in the Chisel Lake–Andeson Lake data. However, the expected number of deposits test clearly demonstrates that these data violate the independence assumption. Other, independent simulations with three variables show that using variables with correlations of 1.0 can double the expected number of deposits as can correlations of −1.0. Studies done in the 1970s on methods that use Bayes rule show that moderate correlations among attributes seriously affect estimates and even small correlations lead to increases in misclassifications. Adverse effects have been observed with small to moderate correlations when only six to eight variables were used. Consistent evidence of upward biased probability estimates from multivariate methods founded on Bayes rule must be of considerable concern to institutions and governmental agencies where unbiased estimates are required. In addition to increasing the misclassification rate, biased probability estimates make classification into deposit and nondeposit classes an arbitrary subjective decision. The probabilistic neural network has no problem dealing with correlated variables—its performance depends strongly on having a thoroughly representative training set. Probabilistic neural networks or logistic regression should receive serious consideration where unbiased estimates are required. The weights-of-evidence method would serve to estimate thresholds between anomalies and background and for exploratory data analysis.

Influence of grazing management on the seasonal change in testicular morphology in Corriedale rams.

PubMed

Bielli, A; Pedrana, G; Gastel, M T; Castrillejo, A; Moraña, A; Lundeheim, N; Forsberg, M; Rodriguez-Martinez, H

1999-06-28

The present study was conducted: (a) to determine the degree of seasonal variation in testis stereology in Corriedale rams between autumn and winter; (b) to test the hypothesis that testis stereology of Corriedale rams grazing native pastures during autumn and winter would differ from those of Corriedale rams grazing sown pastures and supplemented with grain during the same period; and (c) to determine whether Sertoli cell numbers differ in adult rams between the breeding season (autumn) and the following non-breeding season (winter). Twenty experimental animals were studied. Six rams (autumn control group, C-A) that had been grazing on native pasture (stocking rate = 2-3 animals ha(-1)) were castrated at the beginning of the experiment (March, early autumn). Seven rams (winter control group, C-W) continued to graze on native pasture at the same stocking rate until the end of the experiment (August, late winter). Another seven rams (treated group, T) grazed on improved pasture (stocking rate = 1-2 animals ha(-1)) and were supplemented with 1 kg grain ram(-1) day(-1) until the end of the experiment. Live weight, scrotal circumference, serum testosterone concentration and selected testicular stereological parameters were measured. The treatment did not impede the winter reduction in testicular activity and reduced its magnitude slightly (group T) compared with controls (group C-W). Sertoli cell numbers were higher in autumn (group C-A) than in winter, both on native (group C-W) and sown pastures (group T). Diminishing Sertoli cell numbers between autumn and the following winter suggest the occurrence of that Sertoli cell death during this period. The results indicate that, although the reproductive activity of Corriedale rams is moderately seasonal, a restricted change in grazing and grain supplementation can only modify it to a limited extent.

Empirical best linear unbiased prediction method for small areas with restricted maximum likelihood and bootstrap procedure to estimate the average of household expenditure per capita in Banjar Regency

NASA Astrophysics Data System (ADS)

Aminah, Agustin Siti; Pawitan, Gandhi; Tantular, Bertho

2017-03-01

So far, most of the data published by Statistics Indonesia (BPS) as data providers for national statistics are still limited to the district level. Less sufficient sample size for smaller area levels to make the measurement of poverty indicators with direct estimation produced high standard error. Therefore, the analysis based on it is unreliable. To solve this problem, the estimation method which can provide a better accuracy by combining survey data and other auxiliary data is required. One method often used for the estimation is the Small Area Estimation (SAE). There are many methods used in SAE, one of them is Empirical Best Linear Unbiased Prediction (EBLUP). EBLUP method of maximum likelihood (ML) procedures does not consider the loss of degrees of freedom due to estimating β with β ^. This drawback motivates the use of the restricted maximum likelihood (REML) procedure. This paper proposed EBLUP with REML procedure for estimating poverty indicators by modeling the average of household expenditures per capita and implemented bootstrap procedure to calculate MSE (Mean Square Error) to compare the accuracy EBLUP method with the direct estimation method. Results show that EBLUP method reduced MSE in small area estimation.

Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity.

PubMed

Mennenga, Sarah E; Gerson, Julia E; Koebele, Stephanie V; Kingston, Melissa L; Tsang, Candy W S; Engler-Chiurazzi, Elizabeth B; Baxter, Leslie C; Bimonte-Nelson, Heather A

2015-04-01

Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high injection doses of EE reduced the number of ChAt-immunoreactive cells in the basal forebrain, and cell population estimates in the vertical/diagonal bands negatively correlated with working memory errors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Microstructural analysis of aluminum high pressure die castings

NASA Astrophysics Data System (ADS)

David, Maria Diana

Microstructural analysis of aluminum high pressure die castings (HPDC) is challenging and time consuming. Automating the stereology method is an efficient way in obtaining quantitative data; however, validating the accuracy of this technique can also pose some challenges. In this research, a semi-automated algorithm to quantify microstructural features in aluminum HPDC was developed. Analysis was done near the casting surface where it exhibited fine microstructure. Optical and Secondary electron (SE) and backscatter electron (BSE) SEM images were taken to characterize the features in the casting. Image processing steps applied on SEM and optical micrographs included median and range filters, dilation, erosion, and a hole-closing function. Measurements were done on different image pixel resolutions that ranged from 3 to 35 pixel/μm. Pixel resolutions below 6 px/μm were too low for the algorithm to distinguish the phases from each other. At resolutions higher than 6 px/μm, the volume fraction of primary α-Al and the line intercept count curves plateaued. Within this range, comparable results were obtained validating the assumption that there is a range of image pixel resolution relative to the size of the casting features at which stereology measurements become independent of the image resolution. Volume fraction within this curve plateau was consistent with the manual measurements while the line intercept count was significantly higher using the computerized technique for all resolutions. This was attributed to the ragged edges of some primary α-Al; hence, the algorithm still needs some improvements. Further validation of the code using other castings or alloys with known phase amount and size may also be beneficial.

GROWTH AND DIFFERENTIATION OF MITOCHONDRIA IN THE REGENERATING RAT ADRENAL CORTEX

PubMed Central

Yago, Nagasumi; Seki, Masatoshi; Sekiyama, Shigetaka; Kobayashi, Shigeru; Kurokawa, Hiromi; Iwai, Yuko; Sato, Fumiaki; Shiragai, Akihiro

1972-01-01

Diameters of the circular profiles of spherical mitochondria in parenchymal cells of the zona fasciculata in rat adrenal cortex were measured for intact controls and for the regenerating adrenal cortex on electron micrographs recorded at random. The diameter data were then processed by Bach's method which deals with the sphere size distribution. The structural parameters of the mitochondria were computed with the aid of an electronic computer. The total number of mitochondria in all the parenchymal cells of the zona fasciculata were calculated. The surface area of the inner mitochondrial membrane was then determined stereologically. Biochemical parameters were obtained for the protein, the phospholipid, and the cytochrome P-450 content, per averaged mitochondrion. The number of cytochrome P-450 molecules contained in the inner membrane was determined in terms of the unit surface area and of the unit amount of phospholipid. These correlated biochemical and stereological parameters have led to the following conclusions. (a) The genesis of the mitochondria after the adrenal enucleation is almost completed within 10 days. (b) During the period of mitochondrial proliferation, the mitochondria are small in size and also immature both in the structure and in the function of their inner membrane, (c) These small and immature mitochondria grow through an increase of the phospholipid and protein, and this increase is accompanied by expansion of the area of the membrane surface, (d) An enrichment of the inner membrane with cytochrome P-450 molecules occurs, thus indicating the differentiation of adrenocortical mitochondria. The process of membrane differentiation is not tightly coupled with that of membrane growth. PMID:5009515

Machine learning based analytics of micro-MRI trabecular bone microarchitecture and texture in type 1 Gaucher disease.

PubMed

Sharma, Gulshan B; Robertson, Douglas D; Laney, Dawn A; Gambello, Michael J; Terk, Michael

2016-06-14

Type 1 Gaucher disease (GD) is an autosomal recessive lysosomal storage disease, affecting bone metabolism, structure and strength. Current bone assessment methods are not ideal. Semi-quantitative MRI scoring is unreliable, not standardized, and only evaluates bone marrow. DXA BMD is also used but is a limited predictor of bone fragility/fracture risk. Our purpose was to measure trabecular bone microarchitecture, as a biomarker of bone disease severity, in type 1 GD individuals with different GD genotypes and to apply machine learning based analytics to discriminate between GD patients and healthy individuals. Micro-MR imaging of the distal radius was performed on 20 type 1 GD patients and 10 healthy controls (HC). Fifteen stereological and textural measures (STM) were calculated from the MR images. General linear models demonstrated significant differences between GD and HC, and GD genotypes. Stereological measures, main contributors to the first two principal components (PCs), explained ~50% of data variation and were significantly different between males and females. Subsequent PCs textural measures were significantly different between GD patients and HC individuals. Textural measures also significantly differed between GD genotypes, and distinguished between GD patients with normal and pathologic DXA scores. PCA and SVM predictive analyses discriminated between GD and HC with maximum accuracy of 73% and area under ROC curve of 0.79. Trabecular STM differences can be quantified between GD patients and HC, and GD sub-types using micro-MRI and machine learning based analytics. Work is underway to expand this approach to evaluate GD disease burden and treatment efficacy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparison of estimates of hardwood bole volume using importance sampling, the centroid method, and some taper equations

Treesearch

Harry V., Jr. Wiant; Michael L. Spangler; John E. Baumgras

2002-01-01

Various taper systems and the centroid method were compared to unbiased volume estimates made by importance sampling for 720 hardwood trees selected throughout the state of West Virginia. Only the centroid method consistently gave volumes estimates that did not differ significantly from those made by importance sampling, although some taper equations did well for most...

Piecewise SALT sampling for estimating suspended sediment yields

Treesearch

Robert B. Thomas

1989-01-01

A probability sampling method called SALT (Selection At List Time) has been developed for collecting and summarizing data on delivery of suspended sediment in rivers. It is based on sampling and estimating yield using a suspended-sediment rating curve for high discharges and simple random sampling for low flows. The method gives unbiased estimates of total yield and...

An evaluation of flow-stratified sampling for estimating suspended sediment loads

Treesearch

Robert B. Thomas; Jack Lewis

1995-01-01

Abstract - Flow-stratified sampling is a new method for sampling water quality constituents such as suspended sediment to estimate loads. As with selection-at-list-time (SALT) and time-stratified sampling, flow-stratified sampling is a statistical method requiring random sampling, and yielding unbiased estimates of load and variance. It can be used to estimate event...

Initial Correction versus Negative Marking in Multiple Choice Examinations

ERIC Educational Resources Information Center

Van Hecke, Tanja

2015-01-01

Optimal assessment tools should measure in a limited time the knowledge of students in a correct and unbiased way. A method for automating the scoring is multiple choice scoring. This article compares scoring methods from a probabilistic point of view by modelling the probability to pass: the number right scoring, the initial correction (IC) and…

Prediction and measurement results of radiation damage to CMOS devices on board spacecraft

NASA Technical Reports Server (NTRS)

Stassinopoulos, E. G.; Danchenko, V.; Cliff, R. A.; Sing, M.; Brucker, G. J.; Ohanian, R. S.

1977-01-01

Final results from the CMOS Radiation Effects Measurement (CREM) experiment flown on Explorer 55 are presented and discussed, based on about 15 months of observations and measurements. Conclusions are given relating to long-range annealing, effects of operating temperature on semiconductor performance in space, biased and unbiased P-MOS device degradation, unbiased n-channel device performance, changes in device transconductance, and the difference in ionization efficiency between Co-60 gamma rays and 1-Mev Van de Graaff electrons. The performance of devices in a heavily shielded electronic subsystem box within the spacecraft is evaluated and compared. Environment models and computational methods and their impact on device-degradation estimates are being reviewed to determine whether they permit cost-effective design of spacecraft.

Bases for qudits from a nonstandard approach to SU(2)

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

Kibler, M. R., E-mail: kibler@ipnl.in2p3.fr

2011-06-15

Bases of finite-dimensional Hilbert spaces (in dimension d) of relevance for quantum information and quantum computation are constructed from angular momentum theory and su(2) Lie algebraic methods. We report on a formula for deriving in one step the (1 + p)p qupits (i.e., qudits with d = p a prime integer) of a complete set of 1 + p mutually unbiased bases in C{sup p}. Repeated application of the formula can be used for generating mutually unbiased bases in C{sup d} with d = p{sup e} (e {>=} 2) a power of a prime integer. A connection between mutually unbiasedmore » bases and the unitary group SU(d) is briefly discussed in the case d = p{sup e}.« less

Unbiasedness

USGS Publications Warehouse

Link, W.A.; Armitage, Peter; Colton, Theodore

1998-01-01

Unbiasedness is probably the best known criterion for evaluating the performance of estimators. This note describes unbiasedness, demonstrating various failings of the criterion. It is shown that unbiased estimators might not exist, or might not be unique; an example of a unique but clearly unacceptable unbiased estimator is given. It is shown that unbiased estimators are not translation invariant. Various alternative criteria are described, and are illustrated through examples.

FAST TRACK COMMUNICATION: Affine constellations without mutually unbiased counterparts

NASA Astrophysics Data System (ADS)

Weigert, Stefan; Durt, Thomas

2010-10-01

It has been conjectured that a complete set of mutually unbiased bases in a space of dimension d exists if and only if there is an affine plane of order d. We introduce affine constellations and compare their existence properties with those of mutually unbiased constellations. The observed discrepancies make a deeper relation between the two existence problems unlikely.

Implementation of a Comprehensive Curriculum in Personal Finance for Medical Fellows

PubMed Central

Bar-Or, Yuval D; Fessler, Henry E; Desai, Dipan A

2018-01-01

Introduction: Many residents and fellows complete graduate medical education having received minimal unbiased financial planning guidance. This places them at risk of making ill-informed financial decisions, which may lead to significant harm to them and their families. Therefore, we sought to provide fellows with comprehensive unbiased financial education and empower them to make timely, constructive financial decisions. Methods: A self-selected cohort of cardiovascular disease, pulmonary and critical care, and infectious disease fellows (n = 18) at a single institution attended a live, eight-hour interactive course on personal finance. The course consisted of four two-hour sessions delivered over four weeks, facilitated by an unbiased business school faculty member with expertise in personal finance. Prior to the course, all participants completed a demographic survey. After course completion, participants were offered an exit survey evaluating the course, which also asked respondents for any tangible financial decisions made as a result of the course learning.  Results: Participants included 12 women and six men, with a mean age of 33 and varying amounts of debt and financial assets. Twelve respondents completed the exit survey, and all “Strongly Agreed” that courses on financial literacy are important for trainees. In addition, 11 reported that the course helped them make important financial decisions, providing 21 examples. Conclusions: Fellows derive a significant benefit from objective financial literacy education. Graduate medical education programs should offer comprehensive financial literacy education to all graduating trainees, and that education should be provided by an unbiased expert who has no incentive to sell financial products and services. PMID:29515942

Unbiased classification of spatial strategies in the Barnes maze.

PubMed

Illouz, Tomer; Madar, Ravit; Clague, Charlotte; Griffioen, Kathleen J; Louzoun, Yoram; Okun, Eitan

2016-11-01

Spatial learning is one of the most widely studied cognitive domains in neuroscience. The Morris water maze and the Barnes maze are the most commonly used techniques to assess spatial learning and memory in rodents. Despite the fact that these tasks are well-validated paradigms for testing spatial learning abilities, manual categorization of performance into behavioral strategies is subject to individual interpretation, and thus to bias. We have previously described an unbiased machine-learning algorithm to classify spatial strategies in the Morris water maze. Here, we offer a support vector machine-based, automated, Barnes-maze unbiased strategy (BUNS) classification algorithm, as well as a cognitive score scale that can be used for memory acquisition, reversal training and probe trials. The BUNS algorithm can greatly benefit Barnes maze users as it provides a standardized method of strategy classification and cognitive scoring scale, which cannot be derived from typical Barnes maze data analysis. Freely available on the web at http://okunlab.wix.com/okunlab as a MATLAB application. eitan.okun@biu.ac.ilSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Unbiased Strain-Typing of Arbovirus Directly from Mosquitoes Using Nanopore Sequencing: A Field-forward Biosurveillance Protocol.

PubMed

Russell, Joseph A; Campos, Brittany; Stone, Jennifer; Blosser, Erik M; Burkett-Cadena, Nathan; Jacobs, Jonathan L

2018-04-03

The future of infectious disease surveillance and outbreak response is trending towards smaller hand-held solutions for point-of-need pathogen detection. Here, samples of Culex cedecei mosquitoes collected in Southern Florida, USA were tested for Venezuelan Equine Encephalitis Virus (VEEV), a previously-weaponized arthropod-borne RNA-virus capable of causing acute and fatal encephalitis in animal and human hosts. A single 20-mosquito pool tested positive for VEEV by quantitative reverse transcription polymerase chain reaction (RT-qPCR) on the Biomeme two3. The virus-positive sample was subjected to unbiased metatranscriptome sequencing on the Oxford Nanopore MinION and shown to contain Everglades Virus (EVEV), an alphavirus in the VEEV serocomplex. Our results demonstrate, for the first time, the use of unbiased sequence-based detection and subtyping of a high-consequence biothreat pathogen directly from an environmental sample using field-forward protocols. The development and validation of methods designed for field-based diagnostic metagenomics and pathogen discovery, such as those suitable for use in mobile "pocket laboratories", will address a growing demand for public health teams to carry out their mission where it is most urgent: at the point-of-need.

Microglia in the Cerebral Cortex in Autism

ERIC Educational Resources Information Center

Tetreault, Nicole A.; Hakeem, Atiya Y.; Jiang, Sue; Williams, Brian A.; Allman, Elizabeth; Wold, Barbara J.; Allman, John M.

2012-01-01

We immunocytochemically identified microglia in fronto-insular (FI) and visual cortex (VC) in autopsy brains of well-phenotyped subjects with autism and matched controls, and stereologically quantified the microglial densities. Densities were determined blind to phenotype using an optical fractionator probe. In FI, individuals with autism had…

NullSeq: A Tool for Generating Random Coding Sequences with Desired Amino Acid and GC Contents.

PubMed

Liu, Sophia S; Hockenberry, Adam J; Lancichinetti, Andrea; Jewett, Michael C; Amaral, Luís A N

2016-11-01

The existence of over- and under-represented sequence motifs in genomes provides evidence of selective evolutionary pressures on biological mechanisms such as transcription, translation, ligand-substrate binding, and host immunity. In order to accurately identify motifs and other genome-scale patterns of interest, it is essential to be able to generate accurate null models that are appropriate for the sequences under study. While many tools have been developed to create random nucleotide sequences, protein coding sequences are subject to a unique set of constraints that complicates the process of generating appropriate null models. There are currently no tools available that allow users to create random coding sequences with specified amino acid composition and GC content for the purpose of hypothesis testing. Using the principle of maximum entropy, we developed a method that generates unbiased random sequences with pre-specified amino acid and GC content, which we have developed into a python package. Our method is the simplest way to obtain maximally unbiased random sequences that are subject to GC usage and primary amino acid sequence constraints. Furthermore, this approach can easily be expanded to create unbiased random sequences that incorporate more complicated constraints such as individual nucleotide usage or even di-nucleotide frequencies. The ability to generate correctly specified null models will allow researchers to accurately identify sequence motifs which will lead to a better understanding of biological processes as well as more effective engineering of biological systems.

Nurse Practitioners, Certified Nurse Midwives, and Physician Assistants in Physician Offices

MedlinePlus

... on Vital and Health Statistics Annual Reports Health Survey Research Methods Conference Reports from the National Medical Care ... each sample visit that takes all stages of design into account. The survey data are inflated or weighted to produce unbiased ...

COGNITIVE IMPAIRMENT AND MORPHOLOGICAL CHANGES IN THE DORSAL HIPPOCAMPUS OF VERY OLD FEMALE RATS

PubMed Central

Morel, Gustavo R.; Andersen, Tomás; Pardo, Joaquín; Zuccolilli, Gustavo O.; Cambiaggi, Vanina L.; Hereñú, Claudia B.; Goya, Rodolfo G.

2015-01-01

The hippocampus, a medial temporal lobe structure necessary for the formation of spatial memory, is particularly affected by both normal and pathologic aging. In previous studies, we observed a significant age-related increase in dopaminergic neuron loss in the hypothalamus and the substantia nigra of female rats, which becomes more conspicuous at extreme ages. Here, we extend our studies by assessing spatial memory 4–6 months old (young), 26 months old (old) and 29–32 months old (senile) Sprague–Dawley female rats as well as the age-related histopathological changes in their dorsal hippocampus. Age changes in spatial memory performance were assessed with a modified version of the Barnes maze test. We employed two probe trials (PT), one and five days after training, respectively, in order to evaluate learning ability as well as short-term and longer-term spatial memory retention. A set of relevant hippocampal cell markers was also quantitated in the animals by means of an unbiased stereological approach. The results revealed that old rats perform better than senile rats in acquisition trials and young rats perform better than both aging groups. However, during short-term PT both aging groups showed a preserved spatial memory while in longer-term PT, spatial memory showed deterioration in both aged groups. Morphological analysis showed a marked decrease (94–97%) in doublecortin neuron number in the dentate gyrus in both aged groups and a reduction in glial fibrillary acidic protein-positive cell number in the stratum radiatum of aging rats. Astroglial process length and branching complexity decreased in the aged rats. We conclude that while target-seeking activity and learning ability decrease in aged females, spatial memory only declines in the longer-term tests. The reduction in neuroblast number and astroglial arborescence complexity in the dorsal hippocampus are likely to play a role in the cognitive deficits of aging rats. PMID:26141841

Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain.

PubMed

Duncan, Jeremy; Wang, Niping; Zhang, Xiao; Johnson, Shakevia; Harris, Sharonda; Zheng, Baoying; Zhang, Qinli; Rajkowska, Grazyna; Miguel-Hidalgo, Jose Javier; Sittman, Donald; Ou, Xiao-Ming; Stockmeier, Craig A; Wang, Jun Ming

2015-07-01

Major depressive disorder and alcoholism are significant health burdens that can affect executive functioning, cognitive ability, job responsibilities, and personal relationships. Studies in animal models related to depression or alcoholism reveal that the expression of Krüppel-like factor 11 (KLF11, also called TIEG2) is elevated in frontal cortex, which suggests that KLF11 may play a role in stress- or ethanol-induced psychiatric conditions. KLF11 is a transcriptional activator of monoamine oxidase A and B, but also serves other functions in cell cycle regulation and apoptotic cell death. In the present study, immunohistochemistry was used to quantify intensity of nuclear KLF11, combined with an unbiased stereological approach to assess nuclei in fronto-limbic, limbic, and other brain regions of rats exposed chronically to social defeat or ethanol. KLF11 immunoreactivity was increased significantly in the medial prefrontal cortex, frontal cortex, and hippocampus of both stressed rats and rats fed ethanol. However, expression of KLF11 protein was not significantly affected in the thalamus, hypothalamus, or amygdala in either treatment group compared to respective control rats. Triple-label immunofluorescence revealed that KLF11 protein was localized in nuclei of neurons and astrocytes. KLF11 was also co-localized with the immunoreactivity of cleaved caspase-3. In addition, Western blot analysis revealed a significant reduction in anti-apoptotic protein, Bcl-xL, but an increase of caspase-3 expression in the frontal cortex of ethanol-treated rats compared to ethanol-preferring controls. Thus, KLF11 protein is up-regulated following chronic exposure to stress or ethanol in a region-specific manner and may contribute to pro-apoptotic signaling in ethanol-treated rats. Further investigation into the KLF11 signaling cascade as a mechanism for neurotoxicity and cell death in depression and alcoholism may provide novel pharmacological targets to lessen brain damage and maximize neuroprotection in these disorders.

A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

PubMed

Delbary-Gossart, Sandrine; Lee, Sangmi; Baroni, Marco; Lamarche, Isabelle; Arnone, Michele; Canolle, Benoit; Lin, Amity; Sacramento, Jeffrey; Salegio, Ernesto A; Castel, Marie-Noelle; Delesque-Touchard, Nathalie; Alam, Antoine; Laboudie, Patricia; Ferzaz, Badia; Savi, Pierre; Herbert, Jean-Marc; Manley, Geoffrey T; Ferguson, Adam R; Bresnahan, Jacqueline C; Bono, Françoise; Beattie, Michael S

2016-06-01

The p75 neurotrophin receptor is important in multiple physiological actions including neuronal survival and neurite outgrowth during development, and after central nervous system injury. We have discovered a novel piperazine-derived compound, EVT901, which interferes with p75 neurotrophin receptor oligomerization through direct interaction with the first cysteine-rich domain of the extracellular region. Using ligand binding assays with cysteine-rich domains-fused p75 neurotrophin receptor, we confirmed that EVT901 interferes with oligomerization of full-length p75 neurotrophin receptor in a dose-dependent manner. Here we report that EVT901 reduces binding of pro-nerve growth factor to p75 neurotrophin receptor, blocks pro-nerve growth factor induced apoptosis in cells expressing p75 neurotrophin receptor, and enhances neurite outgrowth in vitro Furthermore, we demonstrate that EVT901 abrogates p75 neurotrophin receptor signalling by other ligands, such as prion peptide and amyloid-β. To test the efficacy of EVT901 in vivo, we evaluated the outcome in two models of traumatic brain injury. We generated controlled cortical impacts in adult rats. Using unbiased stereological analysis, we found that EVT901 delivered intravenously daily for 1 week after injury, reduced lesion size, protected cortical neurons and oligodendrocytes, and had a positive effect on neurological function. After lateral fluid percussion injury in adult rats, oral treatment with EVT901 reduced neuronal death in the hippocampus and thalamus, reduced long-term cognitive deficits, and reduced the occurrence of post-traumatic seizure activity. Together, these studies provide a new reagent for altering p75 neurotrophin receptor actions after injury and suggest that EVT901 may be useful in treatment of central nervous system trauma and other neurological disorders where p75 neurotrophin receptor signalling is affected. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Antenatal dexamethasone after asphyxia increases neural injury in preterm fetal sheep.

PubMed

Koome, Miriam E; Davidson, Joanne O; Drury, Paul P; Mathai, Sam; Booth, Lindsea C; Gunn, Alistair Jan; Bennet, Laura

2013-01-01

Maternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain. Chronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10) or saline (n = 10). Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach. Maternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290 ± 76 vs 484 ± 98 neurons/mm(2), mean ± SEM, P<0.05) and basal ganglia (putamen, 538 ± 112 vs 814 ± 34 neurons/mm(2), P<0.05) compared to asphyxia-saline, and with greater loss of both total (913 ± 77 vs 1201 ± 75/mm(2), P<0.05) and immature/mature myelinating oligodendrocytes in periventricular white matter (66 ± 8 vs 114 ± 12/mm(2), P<0.05, vs sham controls 165 ± 10/mm(2), P<0.001). This was associated with transient hyperglycemia (peak 3.5 ± 0.2 vs. 1.4 ± 0.2 mmol/L at 6 h, P<0.05) and reduced suppression of EEG power in the first 24 h after occlusion (maximum -1.5 ± 1.2 dB vs. -5.0 ± 1.4 dB in saline controls, P<0.01), but later onset and fewer overt seizures. In preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage.

The contribution of the swimbladder to buoyancy in the adult zebrafish (Danio rerio): a morphometric analysis.

PubMed

Robertson, George N; Lindsey, Benjamin W; Dumbarton, Tristan C; Croll, Roger P; Smith, Frank M

2008-06-01

Many teleost fishes use a swimbladder, a gas-filled organ in the coelomic cavity, to reduce body density toward neutral buoyancy, thus minimizing the locomotory cost of maintaining a constant depth in the water column. However, for most swimbladder-bearing teleosts, the contribution of this organ to the attainment of neutral buoyancy has not been quantified. Here, we examined the quantitative contribution of the swimbladder to buoyancy and three-dimensional stability in a small cyprinid, the zebrafish (Danio rerio). In aquaria during daylight hours, adult animals were observed at mean depths from 10.1 +/- 6.0 to 14.2 +/- 5.6 cm below the surface. Fish mass and whole-body volume were linearly correlated (r(2) = 0.96) over a wide range of body size (0.16-0.73 g); mean whole-body density was 1.01 +/- 0.09 g cm(-3). Stereological estimations of swimbladder volume from linear dimensions of lateral X-ray images and direct measurements of gas volumes recovered by puncture from the same swimbladders showed that results from these two methods were highly correlated (r(2) = 0.85). The geometric regularity of the swimbladder thus permitted its volume to be accurately estimated from a single lateral image. Mean body density in the absence of the swimbladder was 1.05 +/- 0.04 g cm(-3). The swimbladder occupied 5.1 +/- 1.4% of total body volume, thus reducing whole-body density significantly. The location of the centers of mass and buoyancy along rostro-caudal and dorso-ventral axes overlapped near the ductus communicans, a constriction between the anterior and posterior swimbladder chambers. Our work demonstrates that the swimbladder of the adult zebrafish contributes significantly to buoyancy and attitude stability. Furthermore, we describe and verify a stereological method for estimating swimbladder volume that will aid future studies of the functions of this organ. 2008 Wiley-Liss, Inc

Empirical Likelihood in Nonignorable Covariate-Missing Data Problems.

PubMed

Xie, Yanmei; Zhang, Biao

2017-04-20

Missing covariate data occurs often in regression analysis, which frequently arises in the health and social sciences as well as in survey sampling. We study methods for the analysis of a nonignorable covariate-missing data problem in an assumed conditional mean function when some covariates are completely observed but other covariates are missing for some subjects. We adopt the semiparametric perspective of Bartlett et al. (Improving upon the efficiency of complete case analysis when covariates are MNAR. Biostatistics 2014;15:719-30) on regression analyses with nonignorable missing covariates, in which they have introduced the use of two working models, the working probability model of missingness and the working conditional score model. In this paper, we study an empirical likelihood approach to nonignorable covariate-missing data problems with the objective of effectively utilizing the two working models in the analysis of covariate-missing data. We propose a unified approach to constructing a system of unbiased estimating equations, where there are more equations than unknown parameters of interest. One useful feature of these unbiased estimating equations is that they naturally incorporate the incomplete data into the data analysis, making it possible to seek efficient estimation of the parameter of interest even when the working regression function is not specified to be the optimal regression function. We apply the general methodology of empirical likelihood to optimally combine these unbiased estimating equations. We propose three maximum empirical likelihood estimators of the underlying regression parameters and compare their efficiencies with other existing competitors. We present a simulation study to compare the finite-sample performance of various methods with respect to bias, efficiency, and robustness to model misspecification. The proposed empirical likelihood method is also illustrated by an analysis of a data set from the US National Health and Nutrition Examination Survey (NHANES).

Inferring animal densities from tracking data using Markov chains.

PubMed

Whitehead, Hal; Jonsen, Ian D

2013-01-01

The distributions and relative densities of species are keys to ecology. Large amounts of tracking data are being collected on a wide variety of animal species using several methods, especially electronic tags that record location. These tracking data are effectively used for many purposes, but generally provide biased measures of distribution, because the starts of the tracks are not randomly distributed among the locations used by the animals. We introduce a simple Markov-chain method that produces unbiased measures of relative density from tracking data. The density estimates can be over a geographical grid, and/or relative to environmental measures. The method assumes that the tracked animals are a random subset of the population in respect to how they move through the habitat cells, and that the movements of the animals among the habitat cells form a time-homogenous Markov chain. We illustrate the method using simulated data as well as real data on the movements of sperm whales. The simulations illustrate the bias introduced when the initial tracking locations are not randomly distributed, as well as the lack of bias when the Markov method is used. We believe that this method will be important in giving unbiased estimates of density from the growing corpus of animal tracking data.

An examination of effect estimation in factorial and standardly-tailored designs

PubMed Central

Allore, Heather G; Murphy, Terrence E

2012-01-01

Background Many clinical trials are designed to test an intervention arm against a control arm wherein all subjects are equally eligible for all interventional components. Factorial designs have extended this to test multiple intervention components and their interactions. A newer design referred to as a ‘standardly-tailored’ design, is a multicomponent interventional trial that applies individual interventional components to modify risk factors identified a priori and tests whether health outcomes differ between treatment arms. Standardly-tailored designs do not require that all subjects be eligible for every interventional component. Although standardly-tailored designs yield an estimate for the net effect of the multicomponent intervention, it has not yet been shown if they permit separate, unbiased estimation of individual component effects. The ability to estimate the most potent interventional components has direct bearing on conducting second stage translational research. Purpose We present statistical issues related to the estimation of individual component effects in trials of geriatric conditions using factorial and standardly-tailored designs. The medical community is interested in second stage translational research involving the transfer of results from a randomized clinical trial to a community setting. Before such research is undertaken, main effects and synergistic and or antagonistic interactions between them should be identified. Knowledge of the relative strength and direction of the effects of the individual components and their interactions facilitates the successful transfer of clinically significant findings and may potentially reduce the number of interventional components needed. Therefore the current inability of the standardly-tailored design to provide unbiased estimates of individual interventional components is a serious limitation in their applicability to second stage translational research. Methods We discuss estimation of individual component effects from the family of factorial designs and this limitation for standardly-tailored designs. We use the phrase ‘factorial designs’ to describe full-factorial designs and their derivatives including the fractional factorial, partial factorial, incomplete factorial and modified reciprocal designs. We suggest two potential directions for designing multicomponent interventions to facilitate unbiased estimates of individual interventional components. Results Full factorial designs and their variants are the most common multicomponent trial design described in the literature and differ meaningfully from standardly-tailored designs. Factorial and standardly-tailored designs result in similar estimates of net effect with different levels of precision. Unbiased estimation of individual component effects from a standardly-tailored design will require new methodology. Limitations Although clinically relevant in geriatrics, previous applications of standardly-tailored designs have not provided unbiased estimates of the effects of individual interventional components. Discussion Future directions to estimate individual component effects from standardly-tailored designs include applying D-optimal designs and creating independent linear combinations of risk factors analogous to factor analysis. Conclusion Methods are needed to extract unbiased estimates of the effects of individual interventional components from standardly-tailored designs. PMID:18375650

A comparison of selection at list time and time-stratified sampling for estimating suspended sediment loads

Treesearch

Robert B. Thomas; Jack Lewis

1993-01-01

Time-stratified sampling of sediment for estimating suspended load is introduced and compared to selection at list time (SALT) sampling. Both methods provide unbiased estimates of load and variance. The magnitude of the variance of the two methods is compared using five storm populations of suspended sediment flux derived from turbidity data. Under like conditions,...

Numerical Quantification of Perkinsus Marinus in the American Oyster Crassostrea virginicata (Gmelin 1791) (Mollusca: Bivalvia) by Modern Stereology

EPA Science Inventory

Species of Perkinsus are responsible for high mortalities of bivalve molluscs world-wide. Techniques to accurately estimate parasites in tissues are required to improve understanding of perkinsosis. This study quantifies the number and tissue distribution of Perkinsus marinus in ...

A brief introduction to computer-intensive methods, with a view towards applications in spatial statistics and stereology.

PubMed

Mattfeldt, Torsten

2011-04-01

Computer-intensive methods may be defined as data analytical procedures involving a huge number of highly repetitive computations. We mention resampling methods with replacement (bootstrap methods), resampling methods without replacement (randomization tests) and simulation methods. The resampling methods are based on simple and robust principles and are largely free from distributional assumptions. Bootstrap methods may be used to compute confidence intervals for a scalar model parameter and for summary statistics from replicated planar point patterns, and for significance tests. For some simple models of planar point processes, point patterns can be simulated by elementary Monte Carlo methods. The simulation of models with more complex interaction properties usually requires more advanced computing methods. In this context, we mention simulation of Gibbs processes with Markov chain Monte Carlo methods using the Metropolis-Hastings algorithm. An alternative to simulations on the basis of a parametric model consists of stochastic reconstruction methods. The basic ideas behind the methods are briefly reviewed and illustrated by simple worked examples in order to encourage novices in the field to use computer-intensive methods. © 2010 The Authors Journal of Microscopy © 2010 Royal Microscopical Society.

Unbiased Rare Event Sampling in Spatial Stochastic Systems Biology Models Using a Weighted Ensemble of Trajectories

PubMed Central

Donovan, Rory M.; Tapia, Jose-Juan; Sullivan, Devin P.; Faeder, James R.; Murphy, Robert F.; Dittrich, Markus; Zuckerman, Daniel M.

2016-01-01

The long-term goal of connecting scales in biological simulation can be facilitated by scale-agnostic methods. We demonstrate that the weighted ensemble (WE) strategy, initially developed for molecular simulations, applies effectively to spatially resolved cell-scale simulations. The WE approach runs an ensemble of parallel trajectories with assigned weights and uses a statistical resampling strategy of replicating and pruning trajectories to focus computational effort on difficult-to-sample regions. The method can also generate unbiased estimates of non-equilibrium and equilibrium observables, sometimes with significantly less aggregate computing time than would be possible using standard parallelization. Here, we use WE to orchestrate particle-based kinetic Monte Carlo simulations, which include spatial geometry (e.g., of organelles, plasma membrane) and biochemical interactions among mobile molecular species. We study a series of models exhibiting spatial, temporal and biochemical complexity and show that although WE has important limitations, it can achieve performance significantly exceeding standard parallel simulation—by orders of magnitude for some observables. PMID:26845334

Benchmarking methods and data sets for ligand enrichment assessment in virtual screening.

PubMed

Xia, Jie; Tilahun, Ermias Lemma; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

2015-01-01

Retrospective small-scale virtual screening (VS) based on benchmarking data sets has been widely used to estimate ligand enrichments of VS approaches in the prospective (i.e. real-world) efforts. However, the intrinsic differences of benchmarking sets to the real screening chemical libraries can cause biased assessment. Herein, we summarize the history of benchmarking methods as well as data sets and highlight three main types of biases found in benchmarking sets, i.e. "analogue bias", "artificial enrichment" and "false negative". In addition, we introduce our recent algorithm to build maximum-unbiased benchmarking sets applicable to both ligand-based and structure-based VS approaches, and its implementations to three important human histone deacetylases (HDACs) isoforms, i.e. HDAC1, HDAC6 and HDAC8. The leave-one-out cross-validation (LOO CV) demonstrates that the benchmarking sets built by our algorithm are maximum-unbiased as measured by property matching, ROC curves and AUCs. Copyright © 2014 Elsevier Inc. All rights reserved.

Benchmarking Methods and Data Sets for Ligand Enrichment Assessment in Virtual Screening

PubMed Central

Xia, Jie; Tilahun, Ermias Lemma; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

2014-01-01

Retrospective small-scale virtual screening (VS) based on benchmarking data sets has been widely used to estimate ligand enrichments of VS approaches in the prospective (i.e. real-world) efforts. However, the intrinsic differences of benchmarking sets to the real screening chemical libraries can cause biased assessment. Herein, we summarize the history of benchmarking methods as well as data sets and highlight three main types of biases found in benchmarking sets, i.e. “analogue bias”, “artificial enrichment” and “false negative”. In addition, we introduced our recent algorithm to build maximum-unbiased benchmarking sets applicable to both ligand-based and structure-based VS approaches, and its implementations to three important human histone deacetylase (HDAC) isoforms, i.e. HDAC1, HDAC6 and HDAC8. The Leave-One-Out Cross-Validation (LOO CV) demonstrates that the benchmarking sets built by our algorithm are maximum-unbiased in terms of property matching, ROC curves and AUCs. PMID:25481478

Efficient Determination of Free Energy Landscapes in Multiple Dimensions from Biased Umbrella Sampling Simulations Using Linear Regression.

PubMed

Meng, Yilin; Roux, Benoît

2015-08-11

The weighted histogram analysis method (WHAM) is a standard protocol for postprocessing the information from biased umbrella sampling simulations to construct the potential of mean force with respect to a set of order parameters. By virtue of the WHAM equations, the unbiased density of state is determined by satisfying a self-consistent condition through an iterative procedure. While the method works very effectively when the number of order parameters is small, its computational cost grows rapidly in higher dimension. Here, we present a simple and efficient alternative strategy, which avoids solving the self-consistent WHAM equations iteratively. An efficient multivariate linear regression framework is utilized to link the biased probability densities of individual umbrella windows and yield an unbiased global free energy landscape in the space of order parameters. It is demonstrated with practical examples that free energy landscapes that are comparable in accuracy to WHAM can be generated at a small fraction of the cost.

Efficient Determination of Free Energy Landscapes in Multiple Dimensions from Biased Umbrella Sampling Simulations Using Linear Regression

PubMed Central

2015-01-01

The weighted histogram analysis method (WHAM) is a standard protocol for postprocessing the information from biased umbrella sampling simulations to construct the potential of mean force with respect to a set of order parameters. By virtue of the WHAM equations, the unbiased density of state is determined by satisfying a self-consistent condition through an iterative procedure. While the method works very effectively when the number of order parameters is small, its computational cost grows rapidly in higher dimension. Here, we present a simple and efficient alternative strategy, which avoids solving the self-consistent WHAM equations iteratively. An efficient multivariate linear regression framework is utilized to link the biased probability densities of individual umbrella windows and yield an unbiased global free energy landscape in the space of order parameters. It is demonstrated with practical examples that free energy landscapes that are comparable in accuracy to WHAM can be generated at a small fraction of the cost. PMID:26574437

Unbiased mean direction of paleomagnetic data and better estimate of paleolatitude

NASA Astrophysics Data System (ADS)

Hatakeyama, T.; Shibuya, H.

2010-12-01

In paleomagnetism, when we obtain only paleodirection data without paleointensities we calculate Fisher-mean directions (I, D) and Fisher-mean VGP positions as the description of the mean field. However, Kono (1997) and Hatakeyama and Kono (2001) indicated that these averaged directions does not show the unbiased estimated mean directions derived from the time-averaged field (TAF). Hatakeyama and Kono (2002) calculated the TAF and paleosecular variation (PSV) models for the past 5My with considering the biases due to the averaging of the nonlinear functions such as the summation of the unit vectors in the Fisher statistics process. Here we will show a zonal TAF model based on the Hatakeyama and Kono TAF model. Moreover, we will introduce the biased angles due to the PSV in the mean direction and a method for determining true paleolatitudes, which represents the TAF, from paleodirections. This method will helps tectonics studies, especially in the estimation of the accurate paleolatitude in the middle latitude regions.

Low-coverage single-cell mRNA sequencing reveals cellular heterogeneity and activated signaling pathways in developing cerebral cortex.

PubMed

Pollen, Alex A; Nowakowski, Tomasz J; Shuga, Joe; Wang, Xiaohui; Leyrat, Anne A; Lui, Jan H; Li, Nianzhen; Szpankowski, Lukasz; Fowler, Brian; Chen, Peilin; Ramalingam, Naveen; Sun, Gang; Thu, Myo; Norris, Michael; Lebofsky, Ronald; Toppani, Dominique; Kemp, Darnell W; Wong, Michael; Clerkson, Barry; Jones, Brittnee N; Wu, Shiquan; Knutsson, Lawrence; Alvarado, Beatriz; Wang, Jing; Weaver, Lesley S; May, Andrew P; Jones, Robert C; Unger, Marc A; Kriegstein, Arnold R; West, Jay A A

2014-10-01

Large-scale surveys of single-cell gene expression have the potential to reveal rare cell populations and lineage relationships but require efficient methods for cell capture and mRNA sequencing. Although cellular barcoding strategies allow parallel sequencing of single cells at ultra-low depths, the limitations of shallow sequencing have not been investigated directly. By capturing 301 single cells from 11 populations using microfluidics and analyzing single-cell transcriptomes across downsampled sequencing depths, we demonstrate that shallow single-cell mRNA sequencing (~50,000 reads per cell) is sufficient for unbiased cell-type classification and biomarker identification. In the developing cortex, we identify diverse cell types, including multiple progenitor and neuronal subtypes, and we identify EGR1 and FOS as previously unreported candidate targets of Notch signaling in human but not mouse radial glia. Our strategy establishes an efficient method for unbiased analysis and comparison of cell populations from heterogeneous tissue by microfluidic single-cell capture and low-coverage sequencing of many cells.

Morphometric analysis of the placenta in the New World mouse Necromys lasiurus (Rodentia, Cricetidae): a comparison of placental development in cricetids and murids

PubMed Central

2013-01-01

Background Stereology is an established method to extrapolate three-dimensional quantities from two-dimensional images. It was applied to placentation in the mouse, but not yet for other rodents. Herein, we provide the first study on quantitative placental development in a sigmodontine rodent species with relatively similar gestational time. Placental structure was also compared to the mouse, in order to evaluate similarities and differences in developmental patterns at the end of gestation. Methods Fetal and placental tissues of Necromys lasiurus were collected and weighed at 3 different stages of gestation (early, mid and late gestation) for placental stereology. The total and relative volumes of placenta and of its main layers were investigated. Volume fractions of labyrinth components were quantified by the One Stop method in 31 placentae collected from different individuals, using the Mercator® software. Data generated at the end of gestation from N. lasiurus placentae were compared to those of Mus musculus domesticus obtained at the same stage. Results A significant increase in the total absolute volumes of the placenta and its main layers occurred from early to mid-gestation, followed by a reduction near term, with the labyrinth layer becoming the most prominent area. Moreover, at the end of gestation, the total volume of the mouse placenta was significantly increased compared to that of N. lasiurus although the proportions of the labyrinth layer and junctional zones were similar. Analysis of the volume fractions of the components in the labyrinth indicated a significant increase in fetal vessels and sinusoidal giant cells, a decrease in labyrinthine trophoblast whereas the proportion of maternal blood space remained stable in the course of gestation. On the other hand, in the mouse, volume fractions of fetal vessels and sinusoidal giant cells decreased whereas the volume fraction of labyrinthine trophoblast increased compared to N. lasiurus placenta. Conclusions Placental development differed between N. lasiurus and M. musculus domesticus. In particular, the low placental efficiency in N. lasiurus seemed to induce morphological optimization of fetomaternal exchanges. In conclusion, despite similar structural aspects of placentation in these species, the quantitative dynamics showed important differences. PMID:23433040

Optimal reconstruction of the states in qutrit systems

NASA Astrophysics Data System (ADS)

Yan, Fei; Yang, Ming; Cao, Zhuo-Liang

2010-10-01

Based on mutually unbiased measurements, an optimal tomographic scheme for the multiqutrit states is presented explicitly. Because the reconstruction process of states based on mutually unbiased states is free of information waste, we refer to our scheme as the optimal scheme. By optimal we mean that the number of the required conditional operations reaches the minimum in this tomographic scheme for the states of qutrit systems. Special attention will be paid to how those different mutually unbiased measurements are realized; that is, how to decompose each transformation that connects each mutually unbiased basis with the standard computational basis. It is found that all those transformations can be decomposed into several basic implementable single- and two-qutrit unitary operations. For the three-qutrit system, there exist five different mutually unbiased-bases structures with different entanglement properties, so we introduce the concept of physical complexity to minimize the number of nonlocal operations needed over the five different structures. This scheme is helpful for experimental scientists to realize the most economical reconstruction of quantum states in qutrit systems.

Neosphincter surgery for fecal incontinence: a critical and unbiased review of the relevant literature.

PubMed

Belyaev, Orlin; Müller, Christophe; Uhl, Waldemar

2006-01-01

Up until about 15 years ago the only realistic option for end-stage fecal incontinence was the creation of a permanent stoma. There have since been several developments. Dynamic graciloplasty (DGP) and artificial bowel sphincter (ABS) are well-established surgical techniques, which offer the patient a chance for continence restoration and improved quality of life; however, they are unfortunately associated with high morbidity and low success rates. Several trials have been done in an attempt to clarify the advantages and disadvantages of these methods and define their place in the second-line treatment of severe, refractory fecal incontinence. This review presents a critical and unbiased overview of the current status of neosphincter surgery according to the available data in the world literature.

Missing data and multiple imputation in clinical epidemiological research.

PubMed

Pedersen, Alma B; Mikkelsen, Ellen M; Cronin-Fenton, Deirdre; Kristensen, Nickolaj R; Pham, Tra My; Pedersen, Lars; Petersen, Irene

2017-01-01

Missing data are ubiquitous in clinical epidemiological research. Individuals with missing data may differ from those with no missing data in terms of the outcome of interest and prognosis in general. Missing data are often categorized into the following three types: missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). In clinical epidemiological research, missing data are seldom MCAR. Missing data can constitute considerable challenges in the analyses and interpretation of results and can potentially weaken the validity of results and conclusions. A number of methods have been developed for dealing with missing data. These include complete-case analyses, missing indicator method, single value imputation, and sensitivity analyses incorporating worst-case and best-case scenarios. If applied under the MCAR assumption, some of these methods can provide unbiased but often less precise estimates. Multiple imputation is an alternative method to deal with missing data, which accounts for the uncertainty associated with missing data. Multiple imputation is implemented in most statistical software under the MAR assumption and provides unbiased and valid estimates of associations based on information from the available data. The method affects not only the coefficient estimates for variables with missing data but also the estimates for other variables with no missing data.

Missing data and multiple imputation in clinical epidemiological research

PubMed Central

Pedersen, Alma B; Mikkelsen, Ellen M; Cronin-Fenton, Deirdre; Kristensen, Nickolaj R; Pham, Tra My; Pedersen, Lars; Petersen, Irene

2017-01-01

Missing data are ubiquitous in clinical epidemiological research. Individuals with missing data may differ from those with no missing data in terms of the outcome of interest and prognosis in general. Missing data are often categorized into the following three types: missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). In clinical epidemiological research, missing data are seldom MCAR. Missing data can constitute considerable challenges in the analyses and interpretation of results and can potentially weaken the validity of results and conclusions. A number of methods have been developed for dealing with missing data. These include complete-case analyses, missing indicator method, single value imputation, and sensitivity analyses incorporating worst-case and best-case scenarios. If applied under the MCAR assumption, some of these methods can provide unbiased but often less precise estimates. Multiple imputation is an alternative method to deal with missing data, which accounts for the uncertainty associated with missing data. Multiple imputation is implemented in most statistical software under the MAR assumption and provides unbiased and valid estimates of associations based on information from the available data. The method affects not only the coefficient estimates for variables with missing data but also the estimates for other variables with no missing data. PMID:28352203

Methods for the quantification of coarse woody debris and an examination of its spatial patterning: A study from the Tenderfoot Creek Experimental Forest, MT

Treesearch

Paul B. Alaback; Duncan C. Lutes

1997-01-01

Methods for the quantification of coarse woody debris volume and the description of spatial patterning were studied in the Tenderfoot Creek Experimental Forest, Montana. The line transect method was found to be an accurate, unbiased estimator of down debris volume (> 10cm diameter) on 1/4 hectare fixed-area plots, when perpendicular lines were used. The Fischer...

Aspects of mutually unbiased bases in odd-prime-power dimensions

NASA Astrophysics Data System (ADS)

Chaturvedi, S.

2002-04-01

We rephrase the Wootters-Fields construction [W. K. Wootters and B. C. Fields, Ann. Phys. 191, 363 (1989)] of a full set of mutually unbiased bases in a complex vector space of dimensions N=pr, where p is an odd prime, in terms of the character vectors of the cyclic group G of order p. This form may be useful in explicitly writing down mutually unbiased bases for N=pr.

Constructing statistically unbiased cortical surface templates using feature-space covariance

NASA Astrophysics Data System (ADS)

Parvathaneni, Prasanna; Lyu, Ilwoo; Huo, Yuankai; Blaber, Justin; Hainline, Allison E.; Kang, Hakmook; Woodward, Neil D.; Landman, Bennett A.

2018-03-01

The choice of surface template plays an important role in cross-sectional subject analyses involving cortical brain surfaces because there is a tendency toward registration bias given variations in inter-individual and inter-group sulcal and gyral patterns. In order to account for the bias and spatial smoothing, we propose a feature-based unbiased average template surface. In contrast to prior approaches, we factor in the sample population covariance and assign weights based on feature information to minimize the influence of covariance in the sampled population. The mean surface is computed by applying the weights obtained from an inverse covariance matrix, which guarantees that multiple representations from similar groups (e.g., involving imaging, demographic, diagnosis information) are down-weighted to yield an unbiased mean in feature space. Results are validated by applying this approach in two different applications. For evaluation, the proposed unbiased weighted surface mean is compared with un-weighted means both qualitatively and quantitatively (mean squared error and absolute relative distance of both the means with baseline). In first application, we validated the stability of the proposed optimal mean on a scan-rescan reproducibility dataset by incrementally adding duplicate subjects. In the second application, we used clinical research data to evaluate the difference between the weighted and unweighted mean when different number of subjects were included in control versus schizophrenia groups. In both cases, the proposed method achieved greater stability that indicated reduced impacts of sampling bias. The weighted mean is built based on covariance information in feature space as opposed to spatial location, thus making this a generic approach to be applicable to any feature of interest.

Common Variable Immunodeficiency Non-Infectious Disease Endotypes Redefined Using Unbiased Network Clustering in Large Electronic Datasets.

PubMed

Farmer, Jocelyn R; Ong, Mei-Sing; Barmettler, Sara; Yonker, Lael M; Fuleihan, Ramsay; Sullivan, Kathleen E; Cunningham-Rundles, Charlotte; Walter, Jolan E

2017-01-01

Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease development. Herein, we demonstrate the utility of unbiased network clustering as a novel method to analyze inter-relationships between non-infectious disease outcomes in CVID using databases at the United States Immunodeficiency Network (USIDNET), the centralized immunodeficiency registry of the United States, and Partners, a tertiary care network in Boston, MA, USA, with a shared electronic medical record amenable to natural language processing. Immunophenotypes were comparable in terms of native antibody deficiencies, low titer response to pneumococcus, and B cell maturation arrest. However, recorded non-infectious disease outcomes were more substantial in the Partners cohort across the spectrum of lymphoproliferation, cytopenias, autoimmunity, atopy, and malignancy. Using unbiased network clustering to analyze 34 non-infectious disease outcomes in the Partners cohort, we further identified unique patterns of lymphoproliferative (two clusters), autoimmune (two clusters), and atopic (one cluster) disease that were defined as CVID non-infectious endotypes according to discrete and non-overlapping immunophenotypes. Markers were both previously described {high serum IgE in the atopic cluster [odds ratio (OR) 6.5] and low class-switched memory B cells in the total lymphoproliferative cluster (OR 9.2)} and novel [low serum C3 in the total lymphoproliferative cluster (OR 5.1)]. Mortality risk in the Partners cohort was significantly associated with individual non-infectious disease outcomes as well as lymphoproliferative cluster 2, specifically (OR 5.9). In contrast, unbiased network clustering failed to associate known comorbidities in the adult USIDNET cohort. Together, these data suggest that unbiased network clustering can be used in CVID to redefine non-infectious disease inter-relationships; however, applicability may be limited to datasets well annotated through mechanisms such as natural language processing. The lymphoproliferative, autoimmune, and atopic Partners CVID endotypes herein described can be used moving forward to streamline genetic and biomarker discovery and to facilitate early screening and intervention in CVID patients at highest risk for autoimmune and inflammatory progression.

Suitability of the line intersect method for sampling hardwood logging residues

Treesearch

A. Jeff Martin

1976-01-01

The line intersect method of sampling logging residues was tested in Appalachian hardwoods and was found to provide unbiased estimates of the volume of residue in cubic feet per acre. Thirty-two chains of sample line were established on each of sixteen 1-acre plots on cutover areas in a variety of conditions. Estimates from these samples were then compared to actual...

Influence of feeding habits in the endocrine pancreas of insectivore bat Pteronotus personatus and nectarivore bat Anoura geoffroyi: A comparative stereological and immunohistochemical study.

PubMed

Machado-Santos, Clarice; Aquino, Júlio Cesar Fraulob; da Rocha, Patrício Adriano; Abidu-Figueiredo, Marcelo; de Brito-Gitirana, Lycia; Sales, Armando

2017-02-01

Pteronotus personatus as an insectivore bat and has a diet that consists of a high protein diet, whereas the diet of Anoura geoffroyi, a predominantly nectarivore bat, is rich in simple sugars like sucrose, glucose and fructose. Considering that diet influences the activation of different pathways, which may influence morphological adaptations in the gastrointestinal system, the aim of this study was to compare the morphology of the endocrine pancreas in P. personatus and A. geoffroyi. For this, histological, stereological and immunohistochemical methods were used. In P. personatus, the average diameter of the pancreatic islet was 40.47μm±13.94, while in A. geoffroyi was 88.16μm±36.40. The total number of pancreatic islets in P. personatus was 26150±2346 and in A. geoffroyi was 15970±1666. In P. personatus, the volume density of the pancreatic islets was 3.4%± 2.6, whereas in A. geoffroyi the volume density was 6.1%±3.7. In addition, the immunodensity of the α, β and δ cells, in P. personatus was 25.8%±11.9, 35.5%±13.5, 3.9%±0.7, respectively, and in A. geoffroyi was 33.10%±12.7, 55.08%±7.4, 6.2%±4.6, respectively. In conclusion, the results of this study indicate differences in the pancreatic weight/body, weight ratio, diameter and volume density of pancreatic islets and in immunodensity of the β and α cells between both species, which have different dietary habits. Copyright © 2017 Elsevier Ltd. All rights reserved.

Histopathological, immunohistochemical, and stereological analysis of the effect of Ginkgo biloba (Egb761) on the hippocampus of rats exposed to long-term cellphone radiation.

PubMed

Gevrek, Fikret

2018-05-01

Cellular phones are major sources of electromagnetic radiation (EMR) that can penetrate the human body and pose serious health hazards. The increasingly widespread use of mobile communication systems has raised concerns about the effects of cellphone radiofrequency (RF) on the hippocampus because of its close proximity to radiation during cellphone use. The effects of cellphone EMR exposure on the hippocampus of rats and the possible counteractive effects of Ginkgo biloba (Egb761) were aimed to investigate. Rats were divided into three groups: Control, EMR, and EMR+Egb761. The EMR and EMR+Egb761 groups were exposed to cellphone EMR for one month. Egb761 was also administered to the EMR+Egb761 group. Specifically, we evaluated the effect of RF exposure on rat hippocampi at harmful EMR levels (0.96 W/kg specific absorption rate [SAR]) for one month and also investigated the possible impact of Ginkgo biloba (Egb761) using stereological, TUNEL-staining, and immunohistochemical methods. An increase in apoptotic proteins (Bax, Acas-3) and a decrease in anti-apoptotic protein (Bcl-2) immunoreactivity along with a decrease in the total granule and pyramidal cell count were noted in the EMR group. A decrease in Bax and Acas-3 and an increase in Bcl-2 immunoreactivity were observed in rats treated with Egb761 in addition to a decrease in TUNEL-stained apoptotic cells and a higher total viable cell number. In conclusion, chronic cellphone EMR exposure may affect hippocampal cell viability, and Egb761 may be used to mitigate some of the deleterious effects.

The Neocortex of Indian River Dolphins (Genus Platanista): Comparative, Qualitative and Quantitative Analysis.

PubMed

Knopf, Julian P; Hof, Patrick R; Oelschläger, Helmut H A

2016-01-01

We investigated the morphology of four primary neocortical projection areas (somatomotor, somatosensory, auditory, visual) qualitatively and quantitatively in the Indian river dolphins (Platanista gangetica gangetica, P. gangetica minor) with histological and stereological methods. For comparison, we included brains of other toothed whale species. Design-based stereology was applied to the primary neocortical areas (M1, S1, A1, V1) of the Indian river dolphins and compared to those of the bottlenose dolphin with respect to layers III and V. These neocortical fields were identified using existing electrophysiological and morphological data from marine dolphins as to their topography and histological structure, including the characteristics of the neuron populations concerned. In contrast to other toothed whales, the visual area (V1) of the 'blind' river dolphins seems to be rather small. M1 is displaced laterally and the auditory area (A1) is larger than in marine species with respect to total brain size. The layering is similar in the cortices of all the toothed whale brains investigated; a layer IV could not be identified. Cell density in layer III is always higher than in layer V. The maximal neuron density in P. gangetica gangetica is found in layer III of A1, followed by layers III in V1, S1, and M1. The cell density in layer V is at a similar level in all primary areas. There are, however, some differences in neuron density between the two subspecies of Indian river dolphins. Taken as a whole, it appears that the neocortex of platanistids exhibits a considerable expansion of the auditory field. Even more than other toothed whales, they seem to depend on their biosonar abilities for navigation, hunting, and communication in their riverine habitat. © 2016 S. Karger AG, Basel.

An improved stereologic method for three-dimensional estimation of particle size distribution from observations in two dimensions and its application.

PubMed

Xu, Yi-Hua; Pitot, Henry C

2003-09-01

Single enzyme-altered hepatocytes; altered hepatic foci (AHF); and nodular lesions have been implicated, respectively in the processes of initiation, promotion, and progression in rodent hepatocarcinogenesis. Qualitative and quantitative analyses of such lesions have been utilized both to identify and to determine the potency of initiating, promoting, and progressor agents in rodent liver. Of a number of possible parameters determined in the study of such lesions, estimation of the number of foci or nodules in the liver is very important. The method of Saltykov has been used for estimating the number of AHF in rat liver. However, in practice, the Saltykov calculation has at least two weak points: (a) the size class range is limited to 12, which in many instances is too narrow to cover the range of AHF data obtained; and (b) under some conditions, the Saltykov equation generates negative values in several size classes, an obvious impossibility in the real world. In order to overcome these limitations in the Saltykov calculations, a study of the particle size distribution in a wide-range, polydispersed sphere system was performed. A stereologic method, termed the 25F Association method, was developed from this study. This method offers 25 association factors that are derived from the frequency of different-sized transections obtained from transecting a spherical particle, thus expanding the size class range to be analyzed up to 25, which is sufficiently wide to encompass all rat AHF found in most cases. This method exhibits greater flexibility, which allows adjustments to be made within the calculation process when NA((k,k)), the net number of transections from the same size spheres, was found to be a negative value, which is not possible in real situations. The reliability of the 25F Association method was tested thoroughly by computer simulation in both monodispersed and polydispersed sphere systems. The test results were compared with the original Saltykov method. We found that the 25F Association method yielded a better estimate of the total number of spheres in the three-dimensional tissue sample as well as the detailed size distribution information. Although the 25F Association method was derived from the study of a polydispersed sphere system, it can be used for continuous size distribution sphere systems. Application of this method to the estimation of parameters of preneoplastic foci in rodent liver is presented as an example of its utility. An application software program, 3D_estimation.exe, which uses the 25F Association method to estimate the number of AHF in rodent liver, has been developed and is now available at the website of this laboratory.

Appreciating the difference between design-based and model-based sampling strategies in quantitative morphology of the nervous system.

PubMed

Geuna, S

2000-11-20

Quantitative morphology of the nervous system has undergone great developments over recent years, and several new technical procedures have been devised and applied successfully to neuromorphological research. However, a lively debate has arisen on some issues, and a great deal of confusion appears to exist that is definitely responsible for the slow spread of the new techniques among scientists. One such element of confusion is related to uncertainty about the meaning, implications, and advantages of the design-based sampling strategy that characterize the new techniques. In this article, to help remove this uncertainty, morphoquantitative methods are described and contrasted on the basis of the inferential paradigm of the sampling strategy: design-based vs model-based. Moreover, some recommendations are made to help scientists judge the appropriateness of a method used for a given study in relation to its specific goals. Finally, the use of the term stereology to label, more or less expressly, only some methods is critically discussed. Copyright 2000 Wiley-Liss, Inc.

Effect of hindlimb unloading on stereological parameters of the motor cortex and hippocampus in male rats.

PubMed

Salehi, Mohammad Saied; Mirzaii-Dizgah, Iraj; Vasaghi-Gharamaleki, Behnoosh; Zamiri, Mohammad Javad

2016-11-09

Hindlimb unloading (HU) can cause motion and cognition dysfunction, although its cellular and molecular mechanisms are not well understood. The aim of the present study was to determine the stereological parameters of the brain areas involved in motion (motor cortex) and spatial learning - memory (hippocampus) under an HU condition. Sixteen adult male rats, kept under a 12 : 12 h light-dark cycle, were divided into two groups of freely moving (n=8) and HU (n=8) rats. The volume of motor cortex and hippocampus, the numerical cell density of neurons in layers I, II-III, V, and VI of the motor cortex, the entire motor cortex as well as the primary motor cortex, and the numerical density of the CA1, CA3, and dentate gyrus subregions of the hippocampus were estimated. No significant differences were observed in the evaluated parameters. Our results thus indicated that motor cortical and hippocampal atrophy and cell loss may not necessarily be involved in the motion and spatial learning memory impairment in the rat.

The olfactory bulbectomized rat model is not an appropriate model for studying depression based on morphological/stereological studies of the hippocampus.

PubMed

Yurttas, Canan; Schmitz, Christoph; Turgut, Mehmet; Strekalova, Tatyana; Steinbusch, Harry W M

2017-09-01

Bilateral olfactory bulbectomy (OBX) has been used as an animal model for major depression that results in behavioral, neurochemical, and neuroendocrinological changes were reversed by chronic treatment with antidepressants, including fluoxetine. However, both etiological and construct validities are lacking in OBX for rats. In the present study, we investigated the morphological changes in the hippocampi of rats undergoing OBX that were treated with fluoxetine (10mg/kg, p.o. once daily for 4 and 12 weeks) using stereological techniques. Our results revealed that OBX caused a reduction in the volumes of the CA1/2, CA3, and dentate gyrus regions 4 weeks after OBX without fluoxetine treatment. With fluoxetine treatment, these reductions were achieved 12 weeks after OBX and the volumes were comparable to normal control rats. Nevertheless, fluoxetine treatment did not reverse neuron loss in all hippocampal regions 12 weeks after OBX. Therefore, we suggest that the OBX rat model should not be used to detect the antidepressant activity of various pharmacological agents such as fluoxetine. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of the landmark method to address immortal person-time bias in comparative effectiveness research: a simulation study.

PubMed

Mi, Xiaojuan; Hammill, Bradley G; Curtis, Lesley H; Lai, Edward Chia-Cheng; Setoguchi, Soko

2016-11-20

Observational comparative effectiveness and safety studies are often subject to immortal person-time, a period of follow-up during which outcomes cannot occur because of the treatment definition. Common approaches, like excluding immortal time from the analysis or naïvely including immortal time in the analysis, are known to result in biased estimates of treatment effect. Other approaches, such as the Mantel-Byar and landmark methods, have been proposed to handle immortal time. Little is known about the performance of the landmark method in different scenarios. We conducted extensive Monte Carlo simulations to assess the performance of the landmark method compared with other methods in settings that reflect realistic scenarios. We considered four landmark times for the landmark method. We found that the Mantel-Byar method provided unbiased estimates in all scenarios, whereas the exclusion and naïve methods resulted in substantial bias when the hazard of the event was constant or decreased over time. The landmark method performed well in correcting immortal person-time bias in all scenarios when the treatment effect was small, and provided unbiased estimates when there was no treatment effect. The bias associated with the landmark method tended to be small when the treatment rate was higher in the early follow-up period than it was later. These findings were confirmed in a case study of chronic obstructive pulmonary disease. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

An Unbiased Estimate of Global Interrater Agreement

ERIC Educational Resources Information Center

Cousineau, Denis; Laurencelle, Louis

2017-01-01

Assessing global interrater agreement is difficult as most published indices are affected by the presence of mixtures of agreements and disagreements. A previously proposed method was shown to be specifically sensitive to global agreement, excluding mixtures, but also negatively biased. Here, we propose two alternatives in an attempt to find what…

Essays on Policy Evaluation with Endogenous Adoption

ERIC Educational Resources Information Center

Gentile, Elisabetta

2011-01-01

Over the last decade, experimental and quasi-experimental methods have been favored by researchers in empirical economics, as they provide unbiased causal estimates. However, when implementing a program, it is often not possible to randomly assign subjects to treatment, leading to a possible endogeneity bias. This dissertation consists of two…

Assessing Methods for Generalizing Experimental Impact Estimates to Target Populations

ERIC Educational Resources Information Center

Kern, Holger L.; Stuart, Elizabeth A.; Hill, Jennifer; Green, Donald P.

2016-01-01

Randomized experiments are considered the gold standard for causal inference because they can provide unbiased estimates of treatment effects for the experimental participants. However, researchers and policymakers are often interested in using a specific experiment to inform decisions about other target populations. In education research,…

Transcriptome analysis of Pseudomonas syringae identifies new genes, ncRNAs, and antisense activity

USDA-ARS?s Scientific Manuscript database

To fully understand how bacteria respond to their environment, it is essential to assess genome-wide transcriptional activity. New high throughput sequencing technologies make it possible to query the transcriptome of an organism in an efficient unbiased manner. We applied a strand-specific method t...

Near-infrared spectroscopy for detection of hailstorm damage on olive fruit

USDA-ARS?s Scientific Manuscript database

A rapid, robust, unbiased and inexpensive discriminant method capable of classifying olive fruit (Olea europaea L.) on the basis of the presence of hailstorm damage is economically important to the olive oil milling industry. Thus, in the present study, the feasibility of Near-Infrared (NIR) spectro...

Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response.

PubMed

Inoue, Naoki; Hirouchi, Taisei; Kasai, Atsushi; Higashi, Shintaro; Hiraki, Natsumi; Tanaka, Shota; Nakazawa, Takanobu; Nunomura, Kazuto; Lin, Bangzhong; Omori, Akiko; Hayata-Takano, Atsuko; Kim, Yoon-Jeong; Doi, Takefumi; Baba, Akemichi; Hashimoto, Hitoshi; Shintani, Norihito

2018-01-08

We recently showed that a 13-kDa protein (p13), the homolog protein of formation of mitochondrial complex V assembly factor 1 in yeast, acts as a potential protective factor in pancreatic islets under diabetes. Here, we aimed to identify known compounds regulating p13 mRNA expression to obtain therapeutic insight into the cellular stress response. A luciferase reporter system was developed using the putative promoter region of the human p13 gene. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1α, a master player regulating mitochondrial metabolism, increased both reporter activity and p13 expression. Following unbiased screening with 2320 known compounds in HeLa cells, 12 pharmacological agents (including 8 cardiotonics and 2 anthracyclines) that elicited >2-fold changes in p13 mRNA expression were identified. Among them, four cardiac glycosides decreased p13 expression and concomitantly elevated cellular oxidative stress. Additional database analyses showed highest p13 expression in heart, with typically decreased expression in cardiac disease. Accordingly, our results illustrate the usefulness of unbiased compound screening as a method for identifying novel functional roles of unfamiliar genes. Our findings also highlight the importance of p13 in the cellular stress response in heart. Copyright © 2017. Published by Elsevier Inc.

Evaluation of the Effects of Photobiomodulation on Partial Osteotomy in Streptozotocin-Induced Diabetes in Rats.

PubMed

Mostafavinia, Ataroalsadat; Masteri Farahani, Reza; Abdollahifar, Mohammad-Amin; Ghatrehsamani, Mahdi; Ghoreishi, Seyed Kamran; Hajihossainlou, Behnam; Chien, Sufan; Dadras, Sara; Rezaei, Fatemehalsadat; Bayat, Mohammad

2018-05-31

We examined the effects of photobiomodulation (PBM) on stereological parameters, and gene expression of Runt-related transcription factor 2 (RUNX2), osteocalcin, and receptor activator of nuclear factor kappa-B ligand (RANKL) in repairing tissue of tibial bone defect in streptozotocin (STZ)-induced type 1 diabetes mellitus (TIDM) in rats during catabolic response of fracture healing. There were conflicting results regarding the efficacy of PBM on bone healing process in healthy and diabetic animals. Forty-eight rats have been distributed into four groups: group 1 (healthy control, no TIDM and no PBM), group 2 (healthy test, no TIDM and PBM), group 3 (diabetic control, TIDM and no PBM), and group 4 (diabetic test, no TIDM and PBM). TIDM was induced in the groups 3 and 4. A partial bone defect in tibia was made in all groups. The bone defects of groups second and fourth were irradiated by a laser (890 nm, 80 Hz, 1.5 J/cm 2 ). Thirty days after the surgery, all bone defects were extracted and were submitted to stereological examination and real-time polymerase chain reaction (RT-PCR). PBM significantly increased volumes of total callus, total bone, bone marrow, trabecular bone, and cortical bone, and the numbers of osteocytes and osteoblasts of callus in TIDM rats compared to those of callus in diabetic control. In addition, TIDM increased RUNX2, and osteocalcin in callus of tibial bone defect compared to healthy group. PBM significantly decreased osteocalcin gene expression in TIDM rats. PBM significantly increased many stereological parameters of bone repair in an STZ-induced TIDM during catabolic response of fracture healing. Further RT-PCR test demonstrated that bone repair was modulated in diabetic rats during catabolic response of fracture healing by significant increase in mRNA expression of RUNX2, and osteocalcin compared to healthy control rats. PBM also decreased osteocalcin mRNA expression in TIDM rats.

Microstructure characterization via stereological relations — A shortcut for beginners

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

Pabst, Willi, E-mail: pabstw@vscht.cz; Gregorová, Eva; Uhlířová, Tereza

Stereological relations that can be routinely applied for the quantitative characterization of microstructures of heterogeneous single- and two-phase materials via global microstructural descriptors are reviewed. It is shown that in the case of dense, single-phase polycrystalline materials (e.g., transparent yttrium aluminum garnet ceramics) two quantities have to be determined, the interface density (or, equivalently, the mean chord length of the grains) and the mean curvature integral density (or, equivalently, the Jeffries grain size), while for two-phase materials (e.g., highly porous, cellular alumina ceramics), one additional quantity, the volume fraction (porosity), is required. The Delesse–Rosiwal law is recalled and size measuresmore » are discussed. It is shown that the Jeffries grain size is based on the triple junction line length density, while the mean chord length of grains is based on the interface density (grain boundary area density). In contrast to widespread belief, however, these two size measures are not alternative, but independent (and thus complementary), measures of grain size. Concomitant with this fact, a clear distinction between linear and planar grain size numbers is proposed. Finally, based on our concept of phase-specific quantities, it is shown that under certain conditions it is possible to define a Jeffries size also for two-phase materials and that the ratio of the mean chord length and the Jeffries size has to be considered as an invariant number for a certain type of microstructure, i.e., a characteristic value that is independent of the absolute size of the microstructural features (e.g., grains, inclusions or pores). - Highlights: • Stereology-based image analysis is reviewed, including error considerations. • Recipes are provided for measuring global metric microstructural descriptors. • Size measures are based on interface density and mean curvature integral density. • Phase-specific quantities and a generalized Jeffries size are introduced. • Linear and planar grain size numbers are clearly distinguished and explained.« less

FALCON: fast and unbiased reconstruction of high-density super-resolution microscopy data

NASA Astrophysics Data System (ADS)

Min, Junhong; Vonesch, Cédric; Kirshner, Hagai; Carlini, Lina; Olivier, Nicolas; Holden, Seamus; Manley, Suliana; Ye, Jong Chul; Unser, Michael

2014-04-01

Super resolution microscopy such as STORM and (F)PALM is now a well known method for biological studies at the nanometer scale. However, conventional imaging schemes based on sparse activation of photo-switchable fluorescent probes have inherently slow temporal resolution which is a serious limitation when investigating live-cell dynamics. Here, we present an algorithm for high-density super-resolution microscopy which combines a sparsity-promoting formulation with a Taylor series approximation of the PSF. Our algorithm is designed to provide unbiased localization on continuous space and high recall rates for high-density imaging, and to have orders-of-magnitude shorter run times compared to previous high-density algorithms. We validated our algorithm on both simulated and experimental data, and demonstrated live-cell imaging with temporal resolution of 2.5 seconds by recovering fast ER dynamics.

FALCON: fast and unbiased reconstruction of high-density super-resolution microscopy data

PubMed Central

Min, Junhong; Vonesch, Cédric; Kirshner, Hagai; Carlini, Lina; Olivier, Nicolas; Holden, Seamus; Manley, Suliana; Ye, Jong Chul; Unser, Michael

2014-01-01

Super resolution microscopy such as STORM and (F)PALM is now a well known method for biological studies at the nanometer scale. However, conventional imaging schemes based on sparse activation of photo-switchable fluorescent probes have inherently slow temporal resolution which is a serious limitation when investigating live-cell dynamics. Here, we present an algorithm for high-density super-resolution microscopy which combines a sparsity-promoting formulation with a Taylor series approximation of the PSF. Our algorithm is designed to provide unbiased localization on continuous space and high recall rates for high-density imaging, and to have orders-of-magnitude shorter run times compared to previous high-density algorithms. We validated our algorithm on both simulated and experimental data, and demonstrated live-cell imaging with temporal resolution of 2.5 seconds by recovering fast ER dynamics. PMID:24694686

Maximum likelihood: Extracting unbiased information from complex networks

NASA Astrophysics Data System (ADS)

Garlaschelli, Diego; Loffredo, Maria I.

2008-07-01

The choice of free parameters in network models is subjective, since it depends on what topological properties are being monitored. However, we show that the maximum likelihood (ML) principle indicates a unique, statistically rigorous parameter choice, associated with a well-defined topological feature. We then find that, if the ML condition is incompatible with the built-in parameter choice, network models turn out to be intrinsically ill defined or biased. To overcome this problem, we construct a class of safely unbiased models. We also propose an extension of these results that leads to the fascinating possibility to extract, only from topological data, the “hidden variables” underlying network organization, making them “no longer hidden.” We test our method on World Trade Web data, where we recover the empirical gross domestic product using only topological information.

Evolution of learning strategies in temporally and spatially variable environments: A review of theory

PubMed Central

Aoki, Kenichi; Feldman, Marcus W.

2013-01-01

The theoretical literature from 1985 to the present on the evolution of learning strategies in variable environments is reviewed, with the focus on deterministic dynamical models that are amenable to local stability analysis, and on deterministic models yielding evolutionarily stable strategies. Individual learning, unbiased and biased social learning, mixed learning, and learning schedules are considered. A rapidly changing environment or frequent migration in a spatially heterogeneous environment favors individual learning over unbiased social learning. However, results are not so straightforward in the context of learning schedules or when biases in social learning are introduced. The three major methods of modeling temporal environmental change – coevolutionary, two-timescale, and information decay – are compared and shown to sometimes yield contradictory results. The so-called Rogers’ paradox is inherent in the two-timescale method as originally applied to the evolution of pure strategies, but is often eliminated when the other methods are used. Moreover, Rogers’ paradox is not observed for the mixed learning strategies and learning schedules that we review. We believe that further theoretical work is necessary on learning schedules and biased social learning, based on models that are logically consistent and empirically pertinent. PMID:24211681

Evolution of learning strategies in temporally and spatially variable environments: a review of theory.

PubMed

Aoki, Kenichi; Feldman, Marcus W

2014-02-01

The theoretical literature from 1985 to the present on the evolution of learning strategies in variable environments is reviewed, with the focus on deterministic dynamical models that are amenable to local stability analysis, and on deterministic models yielding evolutionarily stable strategies. Individual learning, unbiased and biased social learning, mixed learning, and learning schedules are considered. A rapidly changing environment or frequent migration in a spatially heterogeneous environment favors individual learning over unbiased social learning. However, results are not so straightforward in the context of learning schedules or when biases in social learning are introduced. The three major methods of modeling temporal environmental change--coevolutionary, two-timescale, and information decay--are compared and shown to sometimes yield contradictory results. The so-called Rogers' paradox is inherent in the two-timescale method as originally applied to the evolution of pure strategies, but is often eliminated when the other methods are used. Moreover, Rogers' paradox is not observed for the mixed learning strategies and learning schedules that we review. We believe that further theoretical work is necessary on learning schedules and biased social learning, based on models that are logically consistent and empirically pertinent. Copyright © 2013 Elsevier Inc. All rights reserved.

Adaptive enhanced sampling with a path-variable for the simulation of protein folding and aggregation

NASA Astrophysics Data System (ADS)

Peter, Emanuel K.

2017-12-01

In this article, we present a novel adaptive enhanced sampling molecular dynamics (MD) method for the accelerated simulation of protein folding and aggregation. We introduce a path-variable L based on the un-biased momenta p and displacements dq for the definition of the bias s applied to the system and derive 3 algorithms: general adaptive bias MD, adaptive path-sampling, and a hybrid method which combines the first 2 methodologies. Through the analysis of the correlations between the bias and the un-biased gradient in the system, we find that the hybrid methodology leads to an improved force correlation and acceleration in the sampling of the phase space. We apply our method on SPC/E water, where we find a conservation of the average water structure. We then use our method to sample dialanine and the folding of TrpCage, where we find a good agreement with simulation data reported in the literature. Finally, we apply our methodologies on the initial stages of aggregation of a hexamer of Alzheimer's amyloid β fragment 25-35 (Aβ 25-35) and find that transitions within the hexameric aggregate are dominated by entropic barriers, while we speculate that especially the conformation entropy plays a major role in the formation of the fibril as a rate limiting factor.

An approach to checking case-crossover analyses based on equivalence with time-series methods.

PubMed

Lu, Yun; Symons, James Morel; Geyh, Alison S; Zeger, Scott L

2008-03-01

The case-crossover design has been increasingly applied to epidemiologic investigations of acute adverse health effects associated with ambient air pollution. The correspondence of the design to that of matched case-control studies makes it inferentially appealing for epidemiologic studies. Case-crossover analyses generally use conditional logistic regression modeling. This technique is equivalent to time-series log-linear regression models when there is a common exposure across individuals, as in air pollution studies. Previous methods for obtaining unbiased estimates for case-crossover analyses have assumed that time-varying risk factors are constant within reference windows. In this paper, we rely on the connection between case-crossover and time-series methods to illustrate model-checking procedures from log-linear model diagnostics for time-stratified case-crossover analyses. Additionally, we compare the relative performance of the time-stratified case-crossover approach to time-series methods under 3 simulated scenarios representing different temporal patterns of daily mortality associated with air pollution in Chicago, Illinois, during 1995 and 1996. Whenever a model-be it time-series or case-crossover-fails to account appropriately for fluctuations in time that confound the exposure, the effect estimate will be biased. It is therefore important to perform model-checking in time-stratified case-crossover analyses rather than assume the estimator is unbiased.

Adaptive enhanced sampling with a path-variable for the simulation of protein folding and aggregation.

PubMed

Peter, Emanuel K

2017-12-07

In this article, we present a novel adaptive enhanced sampling molecular dynamics (MD) method for the accelerated simulation of protein folding and aggregation. We introduce a path-variable L based on the un-biased momenta p and displacements dq for the definition of the bias s applied to the system and derive 3 algorithms: general adaptive bias MD, adaptive path-sampling, and a hybrid method which combines the first 2 methodologies. Through the analysis of the correlations between the bias and the un-biased gradient in the system, we find that the hybrid methodology leads to an improved force correlation and acceleration in the sampling of the phase space. We apply our method on SPC/E water, where we find a conservation of the average water structure. We then use our method to sample dialanine and the folding of TrpCage, where we find a good agreement with simulation data reported in the literature. Finally, we apply our methodologies on the initial stages of aggregation of a hexamer of Alzheimer's amyloid β fragment 25-35 (Aβ 25-35) and find that transitions within the hexameric aggregate are dominated by entropic barriers, while we speculate that especially the conformation entropy plays a major role in the formation of the fibril as a rate limiting factor.

An Unbiased Estimator of Gene Diversity with Improved Variance for Samples Containing Related and Inbred Individuals of any Ploidy

PubMed Central

Harris, Alexandre M.; DeGiorgio, Michael

2016-01-01

Gene diversity, or expected heterozygosity (H), is a common statistic for assessing genetic variation within populations. Estimation of this statistic decreases in accuracy and precision when individuals are related or inbred, due to increased dependence among allele copies in the sample. The original unbiased estimator of expected heterozygosity underestimates true population diversity in samples containing relatives, as it only accounts for sample size. More recently, a general unbiased estimator of expected heterozygosity was developed that explicitly accounts for related and inbred individuals in samples. Though unbiased, this estimator’s variance is greater than that of the original estimator. To address this issue, we introduce a general unbiased estimator of gene diversity for samples containing related or inbred individuals, which employs the best linear unbiased estimator of allele frequencies, rather than the commonly used sample proportion. We examine the properties of this estimator, H∼BLUE, relative to alternative estimators using simulations and theoretical predictions, and show that it predominantly has the smallest mean squared error relative to others. Further, we empirically assess the performance of H∼BLUE on a global human microsatellite dataset of 5795 individuals, from 267 populations, genotyped at 645 loci. Additionally, we show that the improved variance of H∼BLUE leads to improved estimates of the population differentiation statistic, FST, which employs measures of gene diversity within its calculation. Finally, we provide an R script, BestHet, to compute this estimator from genomic and pedigree data. PMID:28040781

A Novel Application for the Cavalieri Principle: A Stereological and Methodological Study

PubMed Central

Altunkaynak, Berrin Zuhal; Altunkaynak, Eyup; Unal, Deniz; Unal, Bunyamin

2009-01-01

Objective The Cavalieri principle was applied to consecutive pathology sections that were photographed at the same magnification and used to estimate tissue volumes via superimposing a point counting grid on these images. The goal of this study was to perform the Cavalieri method quickly and practically. Materials and Methods In this study, 10 adult female Sprague Dawley rats were used. Brain tissue was removed and sampled both systematically and randomly. Brain volumes were estimated using two different methods. First, all brain slices were scanned with an HP ScanJet 3400C scanner, and their images were shown on a PC monitor. Brain volume was then calculated based on these images. Second, all brain slices were photographed in 10× magnification with a microscope camera, and brain volumes were estimated based on these micrographs. Results There was no statistically significant difference between the volume measurements of the two techniques (P>0.05; Paired Samples t Test). Conclusion This study demonstrates that personal computer scanning of serial tissue sections allows for easy and reliable volume determination based on the Cavalieri method. PMID:25610077

Antibody incubation at 37°C improves fluorescent immunolabeling in free-floating thick tissue sections.

PubMed

Xiao, Xia; Feng, Ya-Ping; Du, Bin; Sun, Han-Ru; Ding, You-Quan; Qi, Jian-Guo

2017-03-01

Fluorescent immunolabeling and imaging in free-floating thick (50-60 μm) tissue sections is relatively simple in practice and enables design-based non-biased stereology, or 3-D reconstruction and analysis. This method is widely used for 3-D in situ quantitative biology in many areas of biological research. However, the labeling quality and efficiency of standard protocols for fluorescent immunolabeling of these tissue sections are not always satisfactory. Here, we systematically evaluate the effects of raising the conventional antibody incubation temperatures (4°C or 21°C) to mammalian body temperature (37°C) in these protocols. Our modification significantly enhances the quality (labeling sensitivity, specificity, and homogeneity) and efficiency (antibody concentration and antibody incubation duration) of fluorescent immunolabeling of free-floating thick tissue sections.

Quantum cryptography with 3-state systems.

PubMed

Bechmann-Pasquinucci, H; Peres, A

2000-10-09

We consider quantum cryptographic schemes where the carriers of information are 3-state particles. One protocol uses four mutually unbiased bases and appears to provide better security than obtainable with 2-state carriers. Another possible method allows quantum states to belong to more than one basis. Security is not better, but many curious features arise.

Unbiased Causal Inference from an Observational Study: Results of a Within-Study Comparison

ERIC Educational Resources Information Center

Pohl, Steffi; Steiner, Peter M.; Eisermann, Jens; Soellner, Renate; Cook, Thomas D.

2009-01-01

Adjustment methods such as propensity scores and analysis of covariance are often used for estimating treatment effects in nonexperimental data. Shadish, Clark, and Steiner used a within-study comparison to test how well these adjustments work in practice. They randomly assigned participating students to a randomized or nonrandomized experiment.…

Multi-Armed RCTs: A Design-Based Framework. NCEE 2017-4027

ERIC Educational Resources Information Center

Schochet, Peter Z.

2017-01-01

Design-based methods have recently been developed as a way to analyze data from impact evaluations of interventions, programs, and policies (Imbens and Rubin, 2015; Schochet, 2015, 2016). The estimators are derived using the building blocks of experimental designs with minimal assumptions, and are unbiased and normally distributed in large samples…

The Environmental Impact of Electrical Generation: Nuclear vs. Conventional.

ERIC Educational Resources Information Center

McDermott, John J., Ed.

This minicourse, partially supported by the Division of Nuclear Education and Training of the U.S. Atomic Energy Commission, is an effort to describe the benefit-to-risk ratio of various methods of generating electrical power. It attempts to present an unbiased, straightforward, and objective view of the advantages and disadvantages of nuclear…

An automated benchmarking platform for MHC class II binding prediction methods.

PubMed

Andreatta, Massimo; Trolle, Thomas; Yan, Zhen; Greenbaum, Jason A; Peters, Bjoern; Nielsen, Morten

2018-05-01

Computational methods for the prediction of peptide-MHC binding have become an integral and essential component for candidate selection in experimental T cell epitope discovery studies. The sheer amount of published prediction methods-and often discordant reports on their performance-poses a considerable quandary to the experimentalist who needs to choose the best tool for their research. With the goal to provide an unbiased, transparent evaluation of the state-of-the-art in the field, we created an automated platform to benchmark peptide-MHC class II binding prediction tools. The platform evaluates the absolute and relative predictive performance of all participating tools on data newly entered into the Immune Epitope Database (IEDB) before they are made public, thereby providing a frequent, unbiased assessment of available prediction tools. The benchmark runs on a weekly basis, is fully automated, and displays up-to-date results on a publicly accessible website. The initial benchmark described here included six commonly used prediction servers, but other tools are encouraged to join with a simple sign-up procedure. Performance evaluation on 59 data sets composed of over 10 000 binding affinity measurements suggested that NetMHCIIpan is currently the most accurate tool, followed by NN-align and the IEDB consensus method. Weekly reports on the participating methods can be found online at: http://tools.iedb.org/auto_bench/mhcii/weekly/. mniel@bioinformatics.dtu.dk. Supplementary data are available at Bioinformatics online.

The face of equipoise - delivering a structured education programme within a randomized controlled trial: qualitative study

PubMed Central

2014-01-01

Background In trials of behavioural interventions, the individuals who deliver the intervention are in a position of key influence on the success of the trial. Their fidelity to the intervention is crucial. Yet little is understood about the experiences of this group of trial personnel. This study aimed to investigate the views and experiences of educators who delivered a structured education intervention to people with type 2 diabetes, which incorporated training in self-monitoring of either blood glucose (SMBG) or urine glucose (SMUG) as part of a randomized controlled trial (RCT). Methods Educators’ views were explored through focus groups before and after training (N = 18) and approximately 1 year into the trial (N = 14), and semi-structured telephone interviews at approximately 2 years (N = 7). Analysis was based on the constant comparative method. Results Educators held preferences regarding the intervention variants; thus, they were not in individual equipoise. Training raised awareness of preferences and their potential to impact on delivery. Educators were confident in their unbiased delivery, but acknowledged the challenges involved. Concealing their preferences was helped by a sense of professionalism, the patient-centred nature of the intervention, and concessions in the trial protocol (enabling participants to swap monitoring methods if needed). Commitment to unbiased delivery was explained through a desire for evidence-based knowledge in the contentious area of SMBG. Conclusions The findings provide insight into a previously unexplored group of trial personnel - intervention deliverers in trials of behavioural interventions - which will be useful to those designing and running similar trials. Rather than individual equipoise, it is intervention deliverers’ awareness of personal preferences and their potential impact on the trial outcome that facilitates unbiased delivery. Further, awareness of community equipoise, the need for evidence, and relevance to the individual enhance commitment to the RCT. Trial registration ISRCTN95696668 PMID:24405854

Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab.

PubMed

Solomon, Isaac H; Spera, Kristyn M; Ryan, Sophia L; Helgager, Jeffrey; Andrici, Juliana; Zaki, Sherif R; Vaitkevicius, Henrikas; Leon, Kristoffer E; Wilson, Michael R; DeRisi, Joseph L; Koo, Sophia; Smirnakis, Stelios M; De Girolami, Umberto

2018-06-01

Powassan virus is a rare but increasingly recognized cause of severe neurological disease. To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. Infection with Powassan virus. Results of individual assays compared retrospectively. In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

Unbiased split variable selection for random survival forests using maximally selected rank statistics.

PubMed

Wright, Marvin N; Dankowski, Theresa; Ziegler, Andreas

2017-04-15

The most popular approach for analyzing survival data is the Cox regression model. The Cox model may, however, be misspecified, and its proportionality assumption may not always be fulfilled. An alternative approach for survival prediction is random forests for survival outcomes. The standard split criterion for random survival forests is the log-rank test statistic, which favors splitting variables with many possible split points. Conditional inference forests avoid this split variable selection bias. However, linear rank statistics are utilized by default in conditional inference forests to select the optimal splitting variable, which cannot detect non-linear effects in the independent variables. An alternative is to use maximally selected rank statistics for the split point selection. As in conditional inference forests, splitting variables are compared on the p-value scale. However, instead of the conditional Monte-Carlo approach used in conditional inference forests, p-value approximations are employed. We describe several p-value approximations and the implementation of the proposed random forest approach. A simulation study demonstrates that unbiased split variable selection is possible. However, there is a trade-off between unbiased split variable selection and runtime. In benchmark studies of prediction performance on simulated and real datasets, the new method performs better than random survival forests if informative dichotomous variables are combined with uninformative variables with more categories and better than conditional inference forests if non-linear covariate effects are included. In a runtime comparison, the method proves to be computationally faster than both alternatives, if a simple p-value approximation is used. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Spectroscopic observation of SN2017gkk by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Onori, F.; Benetti, S.; Cappellaro, E.; Losada, Illa R.; Gafton, E.; NUTS Collaboration

2017-09-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of supernova SN2017gkk (=MASTER OT J091344.71762842.5) in host galaxy NGC 2748.

Spectroscopic observation of ASASSN-17he by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Kostrzewa-Rutkowska, Z.; Benetti, S.; Dong, S.; Stritzinger, M.; Stanek, K.; Brimacombe, J.; Sagues, A.; Galindo, P.; Losada, I. Rivero

2017-10-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of ASASSN-17he. The candidate was discovered by by the All-Sky Automated Survey for Supernovae.

Motor activity as an unbiased variable to assess anaphylaxis in allergic rats

PubMed Central

Abril-Gil, Mar; Garcia-Just, Alba; Cambras, Trinitat; Pérez-Cano, Francisco J; Castellote, Cristina; Franch, Àngels

2015-01-01

The release of mediators by mast cells triggers allergic symptoms involving various physiological systems and, in the most severe cases, the development of anaphylactic shock compromising mainly the nervous and cardiovascular systems. We aimed to establish variables to objectively study the anaphylactic response (AR) after an oral challenge in an allergy model. Brown Norway rats were immunized by intraperitoneal injection of ovalbumin with alum and toxin from Bordetella pertussis. Specific immunoglobulin (Ig) E antibodies were developed in immunized animals. Forty days after immunization, the rats were orally challenged with the allergen, and motor activity, body temperature and serum mast cell protease concentration were determined. The anaphylaxis induced a reduction in body temperature and a decrease in the number of animal movements, which was inversely correlated with serum mast cell protease release. In summary, motor activity is a reliable tool for assessing AR and also an unbiased method for screening new anti-allergic drugs. PMID:25716015

Convergence of Free Energy Profile of Coumarin in Lipid Bilayer

PubMed Central

2012-01-01

Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from “pulling” coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives. PMID:22545027

Convergence of Free Energy Profile of Coumarin in Lipid Bilayer.

PubMed

Paloncýová, Markéta; Berka, Karel; Otyepka, Michal

2012-04-10

Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (∼7 μs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z-constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from "pulling" coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives.

℮-conome: an automated tissue counting platform of cone photoreceptors for rodent models of retinitis pigmentosa.

PubMed

Clérin, Emmanuelle; Wicker, Nicolas; Mohand-Saïd, Saddek; Poch, Olivier; Sahel, José-Alain; Léveillard, Thierry

2011-12-20

Retinitis pigmentosa is characterized by the sequential loss of rod and cone photoreceptors. The preservation of cones would prevent blindness due to their essential role in human vision. Rod-derived Cone Viability Factor is a thioredoxin-like protein that is secreted by rods and is involved in cone survival. To validate the activity of Rod-derived Cone Viability Factors (RdCVFs) as therapeutic agents for treating retinitis Pigmentosa, we have developed e-conome, an automated cell counting platform for retinal flat mounts of rodent models of cone degeneration. This automated quantification method allows for faster data analysis thereby accelerating translational research. An inverted fluorescent microscope, motorized and coupled to a CCD camera records images of cones labeled with fluorescent peanut agglutinin lectin on flat-mounted retinas. In an average of 300 fields per retina, nine Z-planes at magnification X40 are acquired after two-stage autofocus individually for each field. The projection of the stack of 9 images is subject to a threshold, filtered to exclude aberrant images based on preset variables. The cones are identified by treating the resulting image using 13 variables empirically determined. The cone density is calculated over the 300 fields. The method was validated by comparison to the conventional stereological counting. The decrease in cone density in rd1 mouse was found to be equivalent to the decrease determined by stereological counting. We also studied the spatiotemporal pattern of the degeneration of cones in the rd1 mouse and show that while the reduction in cone density starts in the central part of the retina, cone degeneration progresses at the same speed over the whole retinal surface. We finally show that for mice with an inactivation of the Nucleoredoxin-like genes Nxnl1 or Nxnl2 encoding RdCVFs, the loss of cones is more pronounced in the ventral retina. The automated platform ℮-conome used here for retinal disease is a tool that can broadly accelerate translational research for neurodegenerative diseases.

Spectroscopic classification of Gaia18adv by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Gall, C.; Benetti, S.; Wyrzykowski, L.; Stritzinger, M.; Holmbo, S.; Dong, S.; Siltala, Lauri; NUTS Collaboration

2018-01-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) collaboration reports the spectroscopic classification of Gaia18adv (SN2018hh) near the host galaxy SDSS J121341.37+282640.0.

On representation of mechanical behavior and stereological measures of microstructure

NASA Technical Reports Server (NTRS)

Onat, E. T.; Wright, S. I.

1991-01-01

Macroscopic homogeneity of a heterogeneous body is defined from various points of view. The applicability of the principle of Delesse to a single macroscopically homogeneous body is discussed. It is then seen that a function derived from a consideration of the area fraction of a phase can serve as a measure of clustering of particles of that phase.

Hippocampal neuropathology of domoic acid-induced epilepsy in California sea lions (Zalophus californianus)

PubMed Central

Buckmaster, Paul S.; Wen, Xiling; Toyoda, Izumi; Gulland, Frances M. D.; Van Bonn, William

2014-01-01

California sea lions (Zalophus californianus) are abundant human-sized carnivores with large gyrencephalic brains. They develop epilepsy after experiencing status epilepticus when naturally exposed to domoic acid. We tested whether sea lions previously exposed to DA (chronic DA sea lions) display hippocampal neuropathology similar to that of human patients with temporal lobe epilepsy. Hippocampi were obtained from control and chronic DA sea lions. Stereology was used to estimate numbers of Nissl-stained neurons per hippocampus in the granule cell layer, hilus, and the pyramidal cell layer of CA3, CA2, and CA1 subfields. Adjacent sections were processed for somatostatin-immunoreactivity or Timm-stained, and the extent of mossy fiber sprouting was measured stereologically. Chronic DA sea lions displayed hippocampal neuron loss in patterns and extents similar but not identical to those reported previously for human patients with temporal lobe epilepsy. Similar to human patients, hippocampal sclerosis in sea lions was unilateral in 79% of cases, mossy fiber sprouting was a common neuropathological abnormality, and somatostatin-immunoreactive axons were exuberant in the dentate gyrus despite loss of immunopositive hilar neurons. Thus, hippocampal neuropathology of chronic DA sea lions is similar to that of human patients with temporal lobe epilepsy. PMID:24638960

An Evaluation of Auditory Verbal Therapy Using the Rate of Early Language Development as an Outcome Measure

ERIC Educational Resources Information Center

Hogan, Sarah; Stokes, Jacqueline; White, Catherine; Tyszkiewicz, Elizabeth; Woolgar, Alexandra

2008-01-01

Providing unbiased data concerning the outcomes of particular intervention methods is imperative if professionals and parents are to assimilate information which could contribute to an "informed choice". An evaluation of Auditory Verbal Therapy (AVT) was conducted using a formal assessment of spoken language as an outcome measure. Spoken…

Spectroscopic classification of supernovae SN 2018aei and SN 2018aej by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Cannizzaro, G.; Kuncarayakti, H.; Fraser, M.; Hamanowicz, A.; Jonker, P.; Kankare, E.; Kostrzewa-Rutkowska, Z.; Onori, F.; Wevers, T.; Wyrzykowski, L.; Galbany, L.

2018-03-01

The NOT Unbiased Transient Survey (NUTS; ATel #8992) collaboration reports the spectroscopic classification of supernovae SN 2018aei and SN 2018aej, discovered by PanSTARSS Survey for Transients (ATel #11408).

Predicting longitudinal trajectories of health probabilities with random-effects multinomial logit regression.

PubMed

Liu, Xian; Engel, Charles C

2012-12-20

Researchers often encounter longitudinal health data characterized with three or more ordinal or nominal categories. Random-effects multinomial logit models are generally applied to account for potential lack of independence inherent in such clustered data. When parameter estimates are used to describe longitudinal processes, however, random effects, both between and within individuals, need to be retransformed for correctly predicting outcome probabilities. This study attempts to go beyond existing work by developing a retransformation method that derives longitudinal growth trajectories of unbiased health probabilities. We estimated variances of the predicted probabilities by using the delta method. Additionally, we transformed the covariates' regression coefficients on the multinomial logit function, not substantively meaningful, to the conditional effects on the predicted probabilities. The empirical illustration uses the longitudinal data from the Asset and Health Dynamics among the Oldest Old. Our analysis compared three sets of the predicted probabilities of three health states at six time points, obtained from, respectively, the retransformation method, the best linear unbiased prediction, and the fixed-effects approach. The results demonstrate that neglect of retransforming random errors in the random-effects multinomial logit model results in severely biased longitudinal trajectories of health probabilities as well as overestimated effects of covariates on the probabilities. Copyright © 2012 John Wiley & Sons, Ltd.

A novel method for automated assessment of megakaryocyte differentiation and proplatelet formation.

PubMed

Salzmann, M; Hoesel, B; Haase, M; Mussbacher, M; Schrottmaier, W C; Kral-Pointner, J B; Finsterbusch, M; Mazharian, A; Assinger, A; Schmid, J A

2018-06-01

Transfusion of platelet concentrates represents an important treatment for various bleeding complications. However, the short half-life and frequent contaminations with bacteria restrict the availability of platelet concentrates and raise a clear demand for platelets generated ex vivo. Therefore, in vitro platelet generation from megakaryocytes represents an important research topic. A vital step for this process represents accurate analysis of thrombopoiesis and proplatelet formation, which is usually conducted manually. We aimed to develop a novel method for automated classification and analysis of proplatelet-forming megakaryocytes in vitro. After fluorescent labelling of surface and nucleus, MKs were automatically categorized and analysed with a novel pipeline of the open source software CellProfiler. Our new workflow is able to detect and quantify four subtypes of megakaryocytes undergoing thrombopoiesis: proplatelet-forming, spreading, pseudopodia-forming and terminally differentiated, anucleated megakaryocytes. Furthermore, we were able to characterize the inhibitory effect of dasatinib on thrombopoiesis in more detail. Our new workflow enabled rapid, unbiased, quantitative and qualitative in-depth analysis of proplatelet formation based on morphological characteristics. Clinicians and basic researchers alike will benefit from this novel technique that allows reliable and unbiased quantification of proplatelet formation. It thereby provides a valuable tool for the development of methods to generate platelets ex vivo and to detect effects of drugs on megakaryocyte differentiation.

[Morphometry of pulmonary tissue: From manual to high throughput automation].

PubMed

Sallon, C; Soulet, D; Tremblay, Y

2017-12-01

Weibel's research has shown that any alteration of the pulmonary structure has effects on function. This demonstration required a quantitative analysis of lung structures called morphometry. This is possible thanks to stereology, a set of methods based on principles of geometry and statistics. His work has helped to better understand the morphological harmony of the lung, which is essential for its proper functioning. An imbalance leads to pathophysiology such as chronic obstructive pulmonary disease in adults and bronchopulmonary dysplasia in neonates. It is by studying this imbalance that new therapeutic approaches can be developed. These advances are achievable only through morphometric analytical methods, which are increasingly precise and focused, in particular thanks to the high-throughput automation of these methods. This review makes a comparison between an automated method that we developed in the laboratory and semi-manual methods of morphometric analyzes. The automation of morphometric measurements is a fundamental asset in the study of pulmonary pathophysiology because it is an assurance of robustness, reproducibility and speed. This tool will thus contribute significantly to the acceleration of the race for the development of new drugs. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Classification of polycystic ovary based on ultrasound images using competitive neural network

NASA Astrophysics Data System (ADS)

Dewi, R. M.; Adiwijaya; Wisesty, U. N.; Jondri

2018-03-01

Infertility in the women reproduction system due to inhibition of follicles maturation process causing the number of follicles which is called polycystic ovaries (PCO). PCO detection is still operated manually by a gynecologist by counting the number and size of follicles in the ovaries, so it takes a long time and needs high accuracy. In general, PCO can be detected by calculating stereology or feature extraction and classification. In this paper, we designed a system to classify PCO by using the feature extraction (Gabor Wavelet method) and Competitive Neural Network (CNN). CNN was selected because this method is the combination between Hemming Net and The Max Net so that the data classification can be performed based on the specific characteristics of ultrasound data. Based on the result of system testing, Competitive Neural Network obtained the highest accuracy is 80.84% and the time process is 60.64 seconds (when using 32 feature vectors as well as weight and bias values respectively of 0.03 and 0.002).

A novel application for the cavalieri principle: a stereological and methodological study.

PubMed

Altunkaynak, Berrin Zuhal; Altunkaynak, Eyup; Unal, Deniz; Unal, Bunyamin

2009-08-01

The Cavalieri principle was applied to consecutive pathology sections that were photographed at the same magnification and used to estimate tissue volumes via superimposing a point counting grid on these images. The goal of this study was to perform the Cavalieri method quickly and practically. In this study, 10 adult female Sprague Dawley rats were used. Brain tissue was removed and sampled both systematically and randomly. Brain volumes were estimated using two different methods. First, all brain slices were scanned with an HP ScanJet 3400C scanner, and their images were shown on a PC monitor. Brain volume was then calculated based on these images. Second, all brain slices were photographed in 10× magnification with a microscope camera, and brain volumes were estimated based on these micrographs. There was no statistically significant difference between the volume measurements of the two techniques (P>0.05; Paired Samples t Test). This study demonstrates that personal computer scanning of serial tissue sections allows for easy and reliable volume determination based on the Cavalieri method.

Microwave energy fixation for electron microscopy.

PubMed Central

Login, G. R.; Dvorak, A. M.

1985-01-01

We have demonstrated that microwave energy (MW) can be used in conjunction with chemical cross-linking agents in order to rapidly fix cell suspensions and tissue blocks for electron microscopy in 7-9 seconds. The optimal MW fixation method involved immersing tissues up to 1 cu cm in dilute aldehyde fixation and immediately irradiating the specimens in a conventional microwave oven for 9 seconds to 50 C. Ultrastructural preservation of samples irradiated by MW energy was comparable to that of the control samples immersed in aldehyde fixative for 2 hours at 25 C. Stereologic analysis showed that tissue blocks fixed by the MW fixation method did not cause organelles such as liver mitochondria and salivary gland granules to shrink or to swell. Potential applications for this new fixation technology include the investigation of rapid intracellular processes (eg, vesicular transport) and preservation of proteins that are difficult to demonstrate with routine fixation methods (eg, antigens and enzymes). Images Figure 4 Figure 5 Figure 2 Figure 3 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 PMID:3927740

Unbiased methods for removing systematics from galaxy clustering measurements

NASA Astrophysics Data System (ADS)

Elsner, Franz; Leistedt, Boris; Peiris, Hiranya V.

2016-02-01

Measuring the angular clustering of galaxies as a function of redshift is a powerful method for extracting information from the three-dimensional galaxy distribution. The precision of such measurements will dramatically increase with ongoing and future wide-field galaxy surveys. However, these are also increasingly sensitive to observational and astrophysical contaminants. Here, we study the statistical properties of three methods proposed for controlling such systematics - template subtraction, basic mode projection, and extended mode projection - all of which make use of externally supplied template maps, designed to characterize and capture the spatial variations of potential systematic effects. Based on a detailed mathematical analysis, and in agreement with simulations, we find that the template subtraction method in its original formulation returns biased estimates of the galaxy angular clustering. We derive closed-form expressions that should be used to correct results for this shortcoming. Turning to the basic mode projection algorithm, we prove it to be free of any bias, whereas we conclude that results computed with extended mode projection are biased. Within a simplified setup, we derive analytical expressions for the bias and discuss the options for correcting it in more realistic configurations. Common to all three methods is an increased estimator variance induced by the cleaning process, albeit at different levels. These results enable unbiased high-precision clustering measurements in the presence of spatially varying systematics, an essential step towards realizing the full potential of current and planned galaxy surveys.

Spectroscopic observation of SN 2017jzp and SN 2018bf by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Kuncarayakti, H.; Mattila, S.; Kotak, R.; Harmanen, J.; Reynolds, T.; Wyrzykowski, L.; Stritzinger, M.; Onori, F.; Somero, A.; Kangas, T.; Lundqvist, P.; Taddia, F.; Ergon, M.

2018-01-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of SNe 2017jzp and 2018bf in host galaxies KUG 1326+679 and SDSS J225746.53+253833.5, respectively.

Spectroscopic observation of ASASSN-17nb and CSS170922:172546+342249 by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Harmanen, J.; Mattila, S.; Kuncarayakti, H.; Reynolds, T.; Somero, A.; Kangas, T.; Lundqvist, P.; Taddia, F.; Ergon, M.; Dong, S.; Pastorello, A.; Pursimo, T.; NUTS Collaboration

2017-10-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of ASASSN-17nb in MCG+06-17-007 and CSS170922:172546+342249 in an unknown host galaxy.

Losing the rose tinted glasses: neural substrates of unbiased belief updating in depression

PubMed Central

Garrett, Neil; Sharot, Tali; Faulkner, Paul; Korn, Christoph W.; Roiser, Jonathan P.; Dolan, Raymond J.

2014-01-01

Recent evidence suggests that a state of good mental health is associated with biased processing of information that supports a positively skewed view of the future. Depression, on the other hand, is associated with unbiased processing of such information. Here, we use brain imaging in conjunction with a belief update task administered to clinically depressed patients and healthy controls to characterize brain activity that supports unbiased belief updating in clinically depressed individuals. Our results reveal that unbiased belief updating in depression is mediated by strong neural coding of estimation errors in response to both good news (in left inferior frontal gyrus and bilateral superior frontal gyrus) and bad news (in right inferior parietal lobule and right inferior frontal gyrus) regarding the future. In contrast, intact mental health was linked to a relatively attenuated neural coding of bad news about the future. These findings identify a neural substrate mediating the breakdown of biased updating in major depression disorder, which may be essential for mental health. PMID:25221492

Pernicious effects of long-term, continuous 900-MHz electromagnetic field throughout adolescence on hippocampus morphology, biochemistry and pyramidal neuron numbers in 60-day-old Sprague Dawley male rats.

PubMed

Kerimoğlu, Gökçen; Hancı, Hatice; Baş, Orhan; Aslan, Ali; Erol, Hüseyin Serkan; Turgut, Alpgiray; Kaya, Haydar; Çankaya, Soner; Sönmez, Osman Fikret; Odacı, Ersan

2016-11-01

The central nervous system (CNS) begins developing in the intrauterine period, a process that continues until adulthood. Contact with chemical substances, drugs or environmental agents such as electromagnetic field (EMF) during adolescence therefore has the potential to disturb the development of the morphological architecture of components of the CNS (such as the hippocampus). The hippocampus is essential to such diverse functions as memory acquisition and integration and spatial maneuvering. EMF can result in severe damage to both the morphology of the hippocampus and its principal functions during adolescence. Although children and adolescents undergo greater exposure to EMF than adults, the information currently available regarding the effects of exposure to EMF during this period is as yet insufficient. This study investigated the 60-day-old male rat hippocampus following exposure to 900 megahertz (MHz) EMF throughout the adolescent period using stereological, histopathological and biochemical analysis techniques. Eighteen male Sprague Dawley rats aged 21days were assigned into control, sham and EMF groups on a random basis. No procedure was performed on the control group rats. The EMF group (EMFGr) was exposed to a 900-MHz EMF for 1h daily from beginning to end of adolescence. The sham group rats were held in the EMF cage but were not exposed to EMF. All rats were sacrificed at 60days of age. Their brains were extracted and halved. The left hemispheres were set aside for biochemical analyses and the right hemispheres were subjected to stereological and histopathological evaluation. Histopathological examination revealed increased numbers of pyknotic neurons with black or dark blue cytoplasm on EMFGr slides stained with cresyl violet. Stereological analyses revealed fewer pyramidal neurons in EMFGr than in the other two groups. Biochemical analyses showed an increase in malondialdehyde and glutathione levels, but a decrease in catalase levels in EMFGr. Our results indicate that oxidative stress-related morphological damage and pyramidal neuron loss may be observed in the rat hippocampus following exposure to 900-MHz EMF throughout the adolescent period. Copyright © 2016 Elsevier B.V. All rights reserved.

Efficiency of using first-generation information during second-generation selection: results of computer simulation.

Treesearch

T.Z. Ye; K.J.S. Jayawickrama; G.R. Johnson

2004-01-01

BLUP (Best linear unbiased prediction) method has been widely used in forest tree improvement programs. Since one of the properties of BLUP is that related individuals contribute to the predictions of each other, it seems logical that integrating data from all generations and from all populations would improve both the precision and accuracy in predicting genetic...

The Failure of the U.S. Education Research Establishment to Identify Effective Practices: Beware "Effective Practices Policies"

ERIC Educational Resources Information Center

Pogrow, Stanley

2017-01-01

One of the major successes of advanced quantitative methods has been its seeming ability to provide unbiased determinations of which education practices are effective for education in general and for improving the educational achievement and opportunity of the neediest students. The power of this methodology as applied in the top education…

Biochemical Systematics and Population Genetic Structure of Anopheles Pseudopunctipennis, Vector of Malaria in Central and South America

DTIC Science & Technology

1995-01-01

statistics. Nei’s23 unbiased and Rogers’24 genetic distances were clus- tered by the unweighted pair group method using the arith- metic average ( UPGMA ...Franc0 and others’ and were clustered by UPGMA to produce the phen- ograms shown in Figures 3 and 4. Phenograms produced using other distance measures

Neurocognitive Outcomes of Individuals with a Sex Chromosome Trisomy: XXX, XYY, or XXY--A Systematic Review

ERIC Educational Resources Information Center

Leggett, Victoria; Jacobs, Patricia; Nation, Kate; Scerif, Gaia; Bishop, Dorothy V. M.

2010-01-01

Aim: To review systematically the neurodevelopmental characteristics of individuals with sex chromosome trisomies (SCTs). Method: A bibliographic search identified English-language articles on SCTs. The focus was on studies unbiased by clinical referral, with power of at least 0.69 to detect an effect size of 1.0. Results: We identified 35…

Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner.

PubMed

Ikeda, Mizuko; Swide, Thomas; Vayl, Alexandra; Lahm, Tim; Anderson, Sharon; Hutchens, Michael P

2015-09-18

There is a sex difference in the risk of ischemic acute kidney injury (AKI), and estrogen mediates the protective effect of female sex. We previously demonstrated that preprocedural chronic restoration of physiologic estrogen to ovariectomized female mice ameliorated AKI after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). In the present study, we hypothesized that male mice and aged female mice would benefit from estrogen administration after CA/CPR. We tested the effect of estrogen in a clinically relevant manner by administrating it after CA/CPR. CA/CPR was performed in young (10-15 weeks), middle-aged (43-48 weeks), and aged (78-87 weeks) C57BL/6 male and female mice. Mice received intravenous 17β-estradiol or vehicle 15 min after resuscitation. Serum chemistries and unbiased stereological assessment of renal injury were completed 24 h after CA. Regional renal cortical blood flow was measured by a laser Doppler, and renal levels of estrogen receptor alpha (ERα) and G protein-coupled estrogen receptor (GPER) were evaluated with immunoblotting. Post-arrest estrogen administration reduced injury in young males without significant changes in renal blood flow (percentage reduction compared with vehicle: serum urea nitrogen, 30 %; serum creatinine (sCr), 41 %; volume of necrotic tubules (VNT), 31 %; P < 0.05). In contrast, estrogen did not affect any outcomes in young females. In aged mice, estrogen significantly reduced sCr (80 %) and VNT (73 %) in males and VNT (51 %) in females. Serum estrogen levels in aged female mice after CA/CPR were the same as levels in male mice. With age, renal ERα was upregulated in females. Estrogen administration after resuscitation from CA ameliorates renal injury in young males and aged mice in both sexes. Because injury was small, young females were not affected. The protective effect of exogenous estrogen may be detectable with loss of endogenous estrogen in aged females and could be mediated by differences in renal ERs. Post-arrest estrogen administration is renoprotective in a sex- and age-dependent manner.

A Comparison of Methods for a Priori Bias Correction in Soil Moisture Data Assimilation

NASA Technical Reports Server (NTRS)

Kumar, Sujay V.; Reichle, Rolf H.; Harrison, Kenneth W.; Peters-Lidard, Christa D.; Yatheendradas, Soni; Santanello, Joseph A.

2011-01-01

Data assimilation is being increasingly used to merge remotely sensed land surface variables such as soil moisture, snow and skin temperature with estimates from land models. Its success, however, depends on unbiased model predictions and unbiased observations. Here, a suite of continental-scale, synthetic soil moisture assimilation experiments is used to compare two approaches that address typical biases in soil moisture prior to data assimilation: (i) parameter estimation to calibrate the land model to the climatology of the soil moisture observations, and (ii) scaling of the observations to the model s soil moisture climatology. To enable this research, an optimization infrastructure was added to the NASA Land Information System (LIS) that includes gradient-based optimization methods and global, heuristic search algorithms. The land model calibration eliminates the bias but does not necessarily result in more realistic model parameters. Nevertheless, the experiments confirm that model calibration yields assimilation estimates of surface and root zone soil moisture that are as skillful as those obtained through scaling of the observations to the model s climatology. Analysis of innovation diagnostics underlines the importance of addressing bias in soil moisture assimilation and confirms that both approaches adequately address the issue.

Accelerated stress testing of thin film solar cells: Development of test methods and preliminary results

NASA Technical Reports Server (NTRS)

Lathrop, J. W.

1985-01-01

If thin film cells are to be considered a viable option for terrestrial power generation their reliability attributes will need to be explored and confidence in their stability obtained through accelerated testing. Development of a thin film accelerated test program will be more difficult than was the case for crystalline cells because of the monolithic construction nature of the cells. Specially constructed test samples will need to be fabricated, requiring committment to the concept of accelerated testing by the manufacturers. A new test schedule appropriate to thin film cells will need to be developed which will be different from that used in connection with crystalline cells. Preliminary work has been started to seek thin film schedule variations to two of the simplest tests: unbiased temperature and unbiased temperature humidity. Still to be examined are tests which involve the passage of current during temperature and/or humidity stress, either by biasing in the forward (or reverse) directions or by the application of light during stress. Investigation of these current (voltage) accelerated tests will involve development of methods of reliably contacting the thin conductive films during stress.

Automated 4D analysis of dendritic spine morphology: applications to stimulus-induced spine remodeling and pharmacological rescue in a disease model

PubMed Central

2011-01-01

Uncovering the mechanisms that regulate dendritic spine morphology has been limited, in part, by the lack of efficient and unbiased methods for analyzing spines. Here, we describe an automated 3D spine morphometry method and its application to spine remodeling in live neurons and spine abnormalities in a disease model. We anticipate that this approach will advance studies of synapse structure and function in brain development, plasticity, and disease. PMID:21982080

Parameter estimation in linear models of the human operator in a closed loop with application of deterministic test signals

NASA Technical Reports Server (NTRS)

Vanlunteren, A.; Stassen, H. G.

1973-01-01

Parameter estimation techniques are discussed with emphasis on unbiased estimates in the presence of noise. A distinction between open and closed loop systems is made. A method is given based on the application of external forcing functions consisting of a sun of sinusoids; this method is thus based on the estimation of Fourier coefficients and is applicable for models with poles and zeros in open and closed loop systems.

Genomic Methods for Clinical and Translational Pain Research

PubMed Central

Wang, Dan; Kim, Hyungsuk; Wang, Xiao-Min; Dionne, Raymond

2012-01-01

Pain is a complex sensory experience for which the molecular mechanisms are yet to be fully elucidated. Individual differences in pain sensitivity are mediated by a complex network of multiple gene polymorphisms, physiological and psychological processes, and environmental factors. Here, we present the methods for applying unbiased molecular-genetic approaches, genome-wide association study (GWAS), and global gene expression analysis, to help better understand the molecular basis of pain sensitivity in humans and variable responses to analgesic drugs. PMID:22351080

Block-circulant matrices with circulant blocks, Weil sums, and mutually unbiased bases. II. The prime power case

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

Combescure, Monique

2009-03-15

In our previous paper [Combescure, M., 'Circulant matrices, Gauss sums and the mutually unbiased bases. I. The prime number case', Cubo A Mathematical Journal (unpublished)] we have shown that the theory of circulant matrices allows to recover the result that there exists p+1 mutually unbiased bases in dimension p, p being an arbitrary prime number. Two orthonormal bases B, B{sup '} of C{sup d} are said mutually unbiased if for all b(set-membership sign)B, for all b{sup '}(set-membership sign)B{sup '} one has that |b{center_dot}b{sup '}|=1/{radical}(d) (b{center_dot}b{sup '} Hermitian scalar product in C{sup d}). In this paper we show that the theorymore » of block-circulant matrices with circulant blocks allows to show very simply the known result that if d=p{sup n} (p a prime number and n any integer) there exists d+1 mutually unbiased bases in C{sup d}. Our result relies heavily on an idea of Klimov et al. [''Geometrical approach to the discrete Wigner function,'' J. Phys. A 39, 14471 (2006)]. As a subproduct we recover properties of quadratic Weil sums for p{>=}3, which generalizes the fact that in the prime case the quadratic Gauss sum properties follow from our results.« less

Epidemiologic Evaluation of Measurement Data in the Presence of Detection Limits

PubMed Central

Lubin, Jay H.; Colt, Joanne S.; Camann, David; Davis, Scott; Cerhan, James R.; Severson, Richard K.; Bernstein, Leslie; Hartge, Patricia

2004-01-01

Quantitative measurements of environmental factors greatly improve the quality of epidemiologic studies but can pose challenges because of the presence of upper or lower detection limits or interfering compounds, which do not allow for precise measured values. We consider the regression of an environmental measurement (dependent variable) on several covariates (independent variables). Various strategies are commonly employed to impute values for interval-measured data, including assignment of one-half the detection limit to nondetected values or of “fill-in” values randomly selected from an appropriate distribution. On the basis of a limited simulation study, we found that the former approach can be biased unless the percentage of measurements below detection limits is small (5–10%). The fill-in approach generally produces unbiased parameter estimates but may produce biased variance estimates and thereby distort inference when 30% or more of the data are below detection limits. Truncated data methods (e.g., Tobit regression) and multiple imputation offer two unbiased approaches for analyzing measurement data with detection limits. If interest resides solely on regression parameters, then Tobit regression can be used. If individualized values for measurements below detection limits are needed for additional analysis, such as relative risk regression or graphical display, then multiple imputation produces unbiased estimates and nominal confidence intervals unless the proportion of missing data is extreme. We illustrate various approaches using measurements of pesticide residues in carpet dust in control subjects from a case–control study of non-Hodgkin lymphoma. PMID:15579415

Missing continuous outcomes under covariate dependent missingness in cluster randomised trials

PubMed Central

Diaz-Ordaz, Karla; Bartlett, Jonathan W

2016-01-01

Attrition is a common occurrence in cluster randomised trials which leads to missing outcome data. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. This paper compares the performance of unadjusted cluster-level analysis, baseline covariate adjusted cluster-level analysis and linear mixed model analysis, under baseline covariate dependent missingness in continuous outcomes, in terms of bias, average estimated standard error and coverage probability. The methods of complete records analysis and multiple imputation are used to handle the missing outcome data. We considered four scenarios, with the missingness mechanism and baseline covariate effect on outcome either the same or different between intervention groups. We show that both unadjusted cluster-level analysis and baseline covariate adjusted cluster-level analysis give unbiased estimates of the intervention effect only if both intervention groups have the same missingness mechanisms and there is no interaction between baseline covariate and intervention group. Linear mixed model and multiple imputation give unbiased estimates under all four considered scenarios, provided that an interaction of intervention and baseline covariate is included in the model when appropriate. Cluster mean imputation has been proposed as a valid approach for handling missing outcomes in cluster randomised trials. We show that cluster mean imputation only gives unbiased estimates when missingness mechanism is the same between the intervention groups and there is no interaction between baseline covariate and intervention group. Multiple imputation shows overcoverage for small number of clusters in each intervention group. PMID:27177885

Self-aligned blocking integration demonstration for critical sub-30nm pitch Mx level patterning with EUV self-aligned double patterning

NASA Astrophysics Data System (ADS)

Raley, Angélique; Lee, Joe; Smith, Jeffrey T.; Sun, Xinghua; Farrell, Richard A.; Shearer, Jeffrey; Xu, Yongan; Ko, Akiteru; Metz, Andrew W.; Biolsi, Peter; Devilliers, Anton; Arnold, John; Felix, Nelson

2018-04-01

We report a sub-30nm pitch self-aligned double patterning (SADP) integration scheme with EUV lithography coupled with self-aligned block technology (SAB) targeting the back end of line (BEOL) metal line patterning applications for logic nodes beyond 5nm. The integration demonstration is a validation of the scalability of a previously reported flow, which used 193nm immersion SADP targeting a 40nm pitch with the same material sets (Si3N4 mandrel, SiO2 spacer, Spin on carbon, spin on glass). The multi-color integration approach is successfully demonstrated and provides a valuable method to address overlay concerns and more generally edge placement error (EPE) as a whole for advanced process nodes. Unbiased LER/LWR analysis comparison between EUV SADP and 193nm immersion SADP shows that both integrations follow the same trend throughout the process steps. While EUV SADP shows increased LER after mandrel pull, metal hardmask open and dielectric etch compared to 193nm immersion SADP, the final process performance is matched in terms of LWR (1.08nm 3 sigma unbiased) and is only 6% higher than 193nm immersion SADP for average unbiased LER. Using EUV SADP enables almost doubling the line density while keeping most of the remaining processes and films unchanged, and provides a compelling alternative to other multipatterning integrations, which present their own sets of challenges.

Missing continuous outcomes under covariate dependent missingness in cluster randomised trials.

PubMed

Hossain, Anower; Diaz-Ordaz, Karla; Bartlett, Jonathan W

2017-06-01

Attrition is a common occurrence in cluster randomised trials which leads to missing outcome data. Two approaches for analysing such trials are cluster-level analysis and individual-level analysis. This paper compares the performance of unadjusted cluster-level analysis, baseline covariate adjusted cluster-level analysis and linear mixed model analysis, under baseline covariate dependent missingness in continuous outcomes, in terms of bias, average estimated standard error and coverage probability. The methods of complete records analysis and multiple imputation are used to handle the missing outcome data. We considered four scenarios, with the missingness mechanism and baseline covariate effect on outcome either the same or different between intervention groups. We show that both unadjusted cluster-level analysis and baseline covariate adjusted cluster-level analysis give unbiased estimates of the intervention effect only if both intervention groups have the same missingness mechanisms and there is no interaction between baseline covariate and intervention group. Linear mixed model and multiple imputation give unbiased estimates under all four considered scenarios, provided that an interaction of intervention and baseline covariate is included in the model when appropriate. Cluster mean imputation has been proposed as a valid approach for handling missing outcomes in cluster randomised trials. We show that cluster mean imputation only gives unbiased estimates when missingness mechanism is the same between the intervention groups and there is no interaction between baseline covariate and intervention group. Multiple imputation shows overcoverage for small number of clusters in each intervention group.

Testing assumptions for unbiased estimation of survival of radiomarked harlequin ducks

USGS Publications Warehouse

Esler, Daniel N.; Mulcahy, Daniel M.; Jarvis, Robert L.

2000-01-01

Unbiased estimates of survival based on individuals outfitted with radiotransmitters require meeting the assumptions that radios do not affect survival, and animals for which the radio signal is lost have the same survival probability as those for which fate is known. In most survival studies, researchers have made these assumptions without testing their validity. We tested these assumptions by comparing interannual recapture rates (and, by inference, survival) between radioed and unradioed adult female harlequin ducks (Histrionicus histrionicus), and for radioed females, between right-censored birds (i.e., those for which the radio signal was lost during the telemetry monitoring period) and birds with known fates. We found that recapture rates of birds equipped with implanted radiotransmitters (21.6 ± 3.0%; x̄ ± SE) were similar to unradioed birds (21.7 ± 8.6%), suggesting that radios did not affect survival. Recapture rates also were similar between right-censored (20.6 ± 5.1%) and known-fate individuals (22.1 ± 3.8%), suggesting that missing birds were not subject to differential mortality. We also determined that capture and handling resulted in short-term loss of body mass for both radioed and unradioed females and that this effect was more pronounced for radioed birds (the difference between groups was 15.4 ± 7.1 g). However, no difference existed in body mass after recapture 1 year later. Our study suggests that implanted radios are an unbiased method for estimating survival of harlequin ducks and likely other species under similar circumstances.

Evaluation and construction of diagnostic criteria for inclusion body myositis

PubMed Central

Mammen, Andrew L.; Amato, Anthony A.; Weiss, Michael D.; Needham, Merrilee

2014-01-01

Objective: To use patient data to evaluate and construct diagnostic criteria for inclusion body myositis (IBM), a progressive disease of skeletal muscle. Methods: The literature was reviewed to identify all previously proposed IBM diagnostic criteria. These criteria were applied through medical records review to 200 patients diagnosed as having IBM and 171 patients diagnosed as having a muscle disease other than IBM by neuromuscular specialists at 2 institutions, and to a validating set of 66 additional patients with IBM from 2 other institutions. Machine learning techniques were used for unbiased construction of diagnostic criteria. Results: Twenty-four previously proposed IBM diagnostic categories were identified. Twelve categories all performed with high (≥97%) specificity but varied substantially in their sensitivities (11%–84%). The best performing category was European Neuromuscular Centre 2013 probable (sensitivity of 84%). Specialized pathologic features and newly introduced strength criteria (comparative knee extension/hip flexion strength) performed poorly. Unbiased data-directed analysis of 20 features in 371 patients resulted in construction of higher-performing data-derived diagnostic criteria (90% sensitivity and 96% specificity). Conclusions: Published expert consensus–derived IBM diagnostic categories have uniformly high specificity but wide-ranging sensitivities. High-performing IBM diagnostic category criteria can be developed directly from principled unbiased analysis of patient data. Classification of evidence: This study provides Class II evidence that published expert consensus–derived IBM diagnostic categories accurately distinguish IBM from other muscle disease with high specificity but wide-ranging sensitivities. PMID:24975859

No correlation between ultrasound placental grading at 31-34 weeks of gestation and a surrogate estimate of organ function at term obtained by stereological analysis.

PubMed

Yin, T T; Loughna, P; Ong, S S; Padfield, J; Mayhew, T M

2009-08-01

We test the experimental hypothesis that early changes in the ultrasound appearance of the placenta reflect poor or reduced placental function. The sonographic (Grannum) grade of placental maturity was compared to placental function as expressed by the morphometric oxygen diffusive conductance of the villous membrane. Ultrasonography was used to assess the Grannum grade of 32 placentas at 31-34 weeks of gestation. Indications for the scans included a history of previous fetal abnormalities, previous fetal growth problems or suspicion of IUGR. Placentas were classified from grade 0 (most immature) to grade III (most mature). We did not exclude smokers or complicated pregnancies as we aimed to correlate the early appearance of mature placentas with placental function. After delivery, microscopical fields on formalin-fixed, trichrome-stained histological sections of each placenta were obtained by multistage systematic uniform random sampling. Using design-based stereological methods, the exchange surface areas of peripheral (terminal and intermediate) villi and their fetal capillaries and the arithmetic and harmonic mean thicknesses of the villous membrane (maternal surface of villous trophoblast to adluminal surface of vascular endothelium) were estimated. An index of the variability in thickness of this membrane, and an estimate of its oxygen diffusive conductance, were derived secondarily as were estimates of the mean diameters and total lengths of villi and fetal capillaries. Group comparisons were drawn using analysis of variance. We found no significant differences in placental volume or composition or in the dimensions or diffusive conductances of the villous membrane. Subsequent exclusion of smokers did not alter these main findings. Grannum grades at 31-34 weeks of gestation appear not to provide reliable predictors of the functional capacity of the term placenta as expressed by the surrogate measure, morphometric diffusive conductance.

Morphological respiratory diffusion capacity of the lungs of ball pythons (Python regius).

PubMed

Starck, J Matthias; Aupperle, Heike; Kiefer, Ingmar; Weimer, Isabel; Krautwald-Junghanns, Maria-Elisabeth; Pees, Michael

2012-08-01

This study aims at a functional and morphological characterization of the lung of a boid snake. In particular, we were interested to see if the python's lungs are designed with excess capacity as compared to resting and working oxygen demands. Therefore, the morphological respiratory diffusion capacity of ball pythons (Python regius) was examined following a stereological, hierarchically nested approach. The volume of the respiratory exchange tissue was determined using computed tomography. Tissue compartments were quantified using stereological methods on light microscopic images. The tissue diffusion barrier for oxygen transport was characterized and measured using transmission electron micrographs. We found a significant negative correlation between body mass and the volume of respiratory tissue; the lungs of larger snakes had relatively less respiratory tissue. Therefore, mass-specific respiratory tissue was calculated to exclude effects of body mass. The volume of the lung that contains parenchyma was 11.9±5.0mm(3)g(-1). The volume fraction, i.e., the actual pulmonary exchange tissue per lung parenchyma, was 63.22±7.3%; the total respiratory surface was, on average, 0.214±0.129m(2); it was significantly negatively correlated to body mass, with larger snakes having proportionally smaller respiratory surfaces. For the air-blood barrier, a harmonic mean of 0.78±0.05μm was found, with the epithelial layer representing the thickest part of the barrier. Based on these findings, a median diffusion capacity of the tissue barrier ( [Formula: see text] ) of 0.69±0.38ml O(2)min(-1)mmHg(-1) was calculated. Based on published values for blood oxygen concentration, a total oxygen uptake capacity of 61.16mlO(2)min(-1)kg(-1) can be assumed. This value exceeds the maximum demand for oxygen in ball pythons by a factor of 12. We conclude that healthy individuals of P. regius possess a considerable spare capacity for tissue oxygen exchange. Copyright © 2012 Elsevier GmbH. All rights reserved.

Evaluation of biodegradable electric conductive tube-guides and mesenchymal stem cells

PubMed Central

Ribeiro, Jorge; Pereira, Tiago; Caseiro, Ana Rita; Armada-da-Silva, Paulo; Pires, Isabel; Prada, Justina; Amorim, Irina; Amado, Sandra; França, Miguel; Gonçalves, Carolina; Lopes, Maria Ascensão; Santos, José Domingos; Silva, Dina Morais; Geuna, Stefano; Luís, Ana Lúcia; Maurício, Ana Colette

2015-01-01

AIM: To study the therapeutic effect of three tube-guides with electrical conductivity associated to mesenchymal stem cells (MSCs) on neuro-muscular regeneration after neurotmesis. METHODS: Rats with 10-mm gap nerve injury were tested using polyvinyl alcohol (PVA), PVA-carbon nanotubes (CNTs) and MSCs, and PVA-polypyrrole (PPy). The regenerated nerves and tibialis anterior muscles were processed for stereological studies after 20 wk. The functional recovery was assessed serially for gait biomechanical analysis, by extensor postural thrust, sciatic functional index and static sciatic functional index (SSI), and by withdrawal reflex latency (WRL). In vitro studies included cytocompatibility, flow cytometry, reverse transcriptase polymerase chain reaction and karyotype analysis of the MSCs. Histopathology of lung, liver, kidneys, and regional lymph nodes ensured the biomaterials biocompatibility. RESULTS: SSI remained negative throughout and independently from treatment. Differences between treted groups in the severity of changes in WRL existed, showing a faster regeneration for PVA-CNTs-MSCs (P < 0.05). At toe-off, less acute ankle joint angles were seen for PVA-CNTs-MSCs group (P = 0.051) suggesting improved ankle muscles function during the push off phase of the gait cycle. In PVA-PPy and PVA-CNTs groups, there was a 25% and 42% increase of average fiber area and a 13% and 21% increase of the “minimal Feret’s diameter” respectively. Stereological analysis disclosed a significantly (P < 0.05) increased myelin thickness (M), ratio myelin thickness/axon diameter (M/d) and ratio axon diameter/fiber diameter (d/D; g-ratio) in PVA-CNT-MSCs group (P < 0.05). CONCLUSION: Results revealed that treatment with MSCs and PVA-CNTs tube-guides induced better nerve fiber regeneration. Functional and kinematics analysis revealed positive synergistic effects brought by MSCs and PVA-CNTs. The PVA-CNTs and PVA-PPy are promising scaffolds with electric conductive properties, bio- and cytocompatible that might prevent the secondary neurogenic muscular atrophy by improving the reestablishment of the neuro-muscular junction. PMID:26240682

Restorative effects of curcumin on sleep-deprivation induced memory impairments and structural changes of the hippocampus in a rat model.

PubMed

Noorafshan, Ali; Karimi, Fatemeh; Kamali, Ali-Mohammad; Karbalay-Doust, Saied; Nami, Mohammad

2017-11-15

The present study examined the consequences of rapid eye-movement sleep-deprivation (REM-SD) with or without curcumin treatment. The outcome measures comprised quantitative features in the three-dimensional reconstruction (3DR) CA1 and dentate gyrus in experimental and control animals using stereological procedures. Male rats were arbitrarily assigned to nine groups based on the intervention and treatment administered including: 1-cage control+distilled water, 2-cage control+curcumin (100mg/kg/day), 3-cage control+olive oil, 4-REM-SD+distilled water, 5-REM-SD+curcumin, 6-REM-SD+olive oil, 7-grid-floor control+distilled water, 8-grid-floor control+curcumin, and 9-grid-floor control+olive oil. Animals in the latter three groups were placed on wire-mesh grids in the sleep-deprivation box. REM-SD was induced by an apparatus comprising a water tank and multiple platforms. After a period of 21days, rats were submitted to the novel object-recognition task. Later, their brains were excised and evaluated using stereological methods. Our results indicated a respective 29% and 31% reduction in the total volume of CA1, and dentate gyrus in REM-SD+distilled water group as compared to the grid-floor control+distilled water group (p<0.05). Other than the above, the overall number of the pyramidal cells of CA1 and granular cells of dentate gyrus in the sleep-deprived group were found to be reduced by 48% and 25%, respectively. The REM-SD+distilled water group also exhibited impaired object recognition memory and deformed three-dimensional reconstructions of these regions. The volume, cell number, reconstruction, object recognition time, and body weight were however recovered in the REM-SD+curcumin compared to the REM-SD+distilled water group. This suggests the potential neuro-restorative effects of curcumin in our model. Copyright © 2017 Elsevier Inc. All rights reserved.

Unbiased Estimates of Variance Components with Bootstrap Procedures

ERIC Educational Resources Information Center

Brennan, Robert L.

2007-01-01

This article provides general procedures for obtaining unbiased estimates of variance components for any random-model balanced design under any bootstrap sampling plan, with the focus on designs of the type typically used in generalizability theory. The results reported here are particularly helpful when the bootstrap is used to estimate standard…

Definition and Measurement of Selection Bias: From Constant Ratio to Constant Difference

ERIC Educational Resources Information Center

Cahan, Sorel; Gamliel, Eyal

2006-01-01

Despite its intuitive appeal and popularity, Thorndike's constant ratio (CR) model for unbiased selection is inherently inconsistent in "n"-free selection. Satisfaction of the condition for unbiased selection, when formulated in terms of success/acceptance probabilities, usually precludes satisfaction by the converse probabilities of…

Spectroscopic observation of Gaia17dht and Gaia17diu by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Fraser, M.; Dyrbye, S.; Cappella, E.

2017-12-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of Gaia17dht/SN2017izz and Gaia17diu/SN2017jdb (in host galaxies SDSS J145121.24+283521.6 and LEDA 2753585 respectively).

Statistics as Unbiased Estimators: Exploring the Teaching of Standard Deviation

ERIC Educational Resources Information Center

Wasserman, Nicholas H.; Casey, Stephanie; Champion, Joe; Huey, Maryann

2017-01-01

This manuscript presents findings from a study about the knowledge for and planned teaching of standard deviation. We investigate how understanding variance as an unbiased (inferential) estimator--not just a descriptive statistic for the variation (spread) in data--is related to teachers' instruction regarding standard deviation, particularly…

Generalized approach for using unbiased symmetric metrics with negative values: normalized mean bias factor and normalized mean absolute error factor

EPA Science Inventory

Unbiased symmetric metrics provide a useful measure to quickly compare two datasets, with similar interpretations for both under and overestimations. Two examples include the normalized mean bias factor and normalized mean absolute error factor. However, the original formulations...

Three statistical models for estimating length of stay.

PubMed Central

Selvin, S

1977-01-01

The probability density functions implied by three methods of collecting data on the length of stay in an institution are derived. The expected values associated with these density functions are used to calculate unbiased estimates of the expected length of stay. Two of the methods require an assumption about the form of the underlying distribution of length of stay; the third method does not. The three methods are illustrated with hypothetical data exhibiting the Poisson distribution, and the third (distribution-independent) method is used to estimate the length of stay in a skilled nursing facility and in an intermediate care facility for patients enrolled in California's MediCal program. PMID:914532

Three statistical models for estimating length of stay.

PubMed

Selvin, S

1977-01-01

The probability density functions implied by three methods of collecting data on the length of stay in an institution are derived. The expected values associated with these density functions are used to calculate unbiased estimates of the expected length of stay. Two of the methods require an assumption about the form of the underlying distribution of length of stay; the third method does not. The three methods are illustrated with hypothetical data exhibiting the Poisson distribution, and the third (distribution-independent) method is used to estimate the length of stay in a skilled nursing facility and in an intermediate care facility for patients enrolled in California's MediCal program.

Maximum likelihood solution for inclination-only data in paleomagnetism

NASA Astrophysics Data System (ADS)

Arason, P.; Levi, S.

2010-08-01

We have developed a new robust maximum likelihood method for estimating the unbiased mean inclination from inclination-only data. In paleomagnetic analysis, the arithmetic mean of inclination-only data is known to introduce a shallowing bias. Several methods have been introduced to estimate the unbiased mean inclination of inclination-only data together with measures of the dispersion. Some inclination-only methods were designed to maximize the likelihood function of the marginal Fisher distribution. However, the exact analytical form of the maximum likelihood function is fairly complicated, and all the methods require various assumptions and approximations that are often inappropriate. For some steep and dispersed data sets, these methods provide estimates that are significantly displaced from the peak of the likelihood function to systematically shallower inclination. The problem locating the maximum of the likelihood function is partly due to difficulties in accurately evaluating the function for all values of interest, because some elements of the likelihood function increase exponentially as precision parameters increase, leading to numerical instabilities. In this study, we succeeded in analytically cancelling exponential elements from the log-likelihood function, and we are now able to calculate its value anywhere in the parameter space and for any inclination-only data set. Furthermore, we can now calculate the partial derivatives of the log-likelihood function with desired accuracy, and locate the maximum likelihood without the assumptions required by previous methods. To assess the reliability and accuracy of our method, we generated large numbers of random Fisher-distributed data sets, for which we calculated mean inclinations and precision parameters. The comparisons show that our new robust Arason-Levi maximum likelihood method is the most reliable, and the mean inclination estimates are the least biased towards shallow values.

Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

PubMed

Robertson, David S; Prevost, A Toby; Bowden, Jack

2016-09-30

Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Efficient Stochastic Rendering of Static and Animated Volumes Using Visibility Sweeps.

PubMed

von Radziewsky, Philipp; Kroes, Thomas; Eisemann, Martin; Eisemann, Elmar

2017-09-01

Stochastically solving the rendering integral (particularly visibility) is the de-facto standard for physically-based light transport but it is computationally expensive, especially when displaying heterogeneous volumetric data. In this work, we present efficient techniques to speed-up the rendering process via a novel visibility-estimation method in concert with an unbiased importance sampling (involving environmental lighting and visibility inside the volume), filtering, and update techniques for both static and animated scenes. Our major contributions include a progressive estimate of partial occlusions based on a fast sweeping-plane algorithm. These occlusions are stored in an octahedral representation, which can be conveniently transformed into a quadtree-based hierarchy suited for a joint importance sampling. Further, we propose sweep-space filtering, which suppresses the occurrence of fireflies and investigate different update schemes for animated scenes. Our technique is unbiased, requires little precomputation, is highly parallelizable, and is applicable to a various volume data sets, dynamic transfer functions, animated volumes and changing environmental lighting.

Motor activity as an unbiased variable to assess anaphylaxis in allergic rats.

PubMed

Abril-Gil, Mar; Garcia-Just, Alba; Cambras, Trinitat; Pérez-Cano, Francisco J; Castellote, Cristina; Franch, Àngels; Castell, Margarida

2015-10-01

The release of mediators by mast cells triggers allergic symptoms involving various physiological systems and, in the most severe cases, the development of anaphylactic shock compromising mainly the nervous and cardiovascular systems. We aimed to establish variables to objectively study the anaphylactic response (AR) after an oral challenge in an allergy model. Brown Norway rats were immunized by intraperitoneal injection of ovalbumin with alum and toxin from Bordetella pertussis. Specific immunoglobulin (Ig) E antibodies were developed in immunized animals. Forty days after immunization, the rats were orally challenged with the allergen, and motor activity, body temperature and serum mast cell protease concentration were determined. The anaphylaxis induced a reduction in body temperature and a decrease in the number of animal movements, which was inversely correlated with serum mast cell protease release. In summary, motor activity is a reliable tool for assessing AR and also an unbiased method for screening new anti-allergic drugs. © 2015 by the Society for Experimental Biology and Medicine.

Mutually unbiased bases in six dimensions: The four most distant bases

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

Raynal, Philippe; Lue Xin; Englert, Berthold-Georg

2011-06-15

We consider the average distance between four bases in six dimensions. The distance between two orthonormal bases vanishes when the bases are the same, and the distance reaches its maximal value of unity when the bases are unbiased. We perform a numerical search for the maximum average distance and find it to be strictly smaller than unity. This is strong evidence that no four mutually unbiased bases exist in six dimensions. We also provide a two-parameter family of three bases which, together with the canonical basis, reach the numerically found maximum of the average distance, and we conduct a detailedmore » study of the structure of the extremal set of bases.« less

Extreme Mean and Its Applications

NASA Technical Reports Server (NTRS)

Swaroop, R.; Brownlow, J. D.

1979-01-01

Extreme value statistics obtained from normally distributed data are considered. An extreme mean is defined as the mean of p-th probability truncated normal distribution. An unbiased estimate of this extreme mean and its large sample distribution are derived. The distribution of this estimate even for very large samples is found to be nonnormal. Further, as the sample size increases, the variance of the unbiased estimate converges to the Cramer-Rao lower bound. The computer program used to obtain the density and distribution functions of the standardized unbiased estimate, and the confidence intervals of the extreme mean for any data are included for ready application. An example is included to demonstrate the usefulness of extreme mean application.

Estimating oxygen diffusive conductances of gas-exchange systems: A stereological approach illustrated with the human placenta.

PubMed

Mayhew, Terry M

2014-01-01

For many organisms, respiratory gas exchange is a vital activity and different types of gas-exchange apparatus have evolved to meet individual needs. They include not only skin, gills, tracheal systems and lungs but also transient structures such as the chorioallantois of avian eggs and the placenta of eutherian mammals. The ability of these structures to allow passage of oxygen by passive diffusion can be expressed as a diffusive conductance (units: cm(3) O2 min(-1) kPa(-1)). Occasionally, the ability to estimate diffusive conductance by physiological techniques is compromised by the difficulty of obtaining O2 partial pressures on opposite sides of the tissue interface between the delivery medium (air, water, blood) and uptake medium (usually blood). An alternative strategy is to estimate a morphometric diffusive conductance by combining stereological estimates of key structural quantities (volumes, surface areas, membrane thicknesses) with complementary physicochemical data (O2-haemoglobin chemical reaction rates and Krogh's permeability coefficients). This approach has proved valuable in a variety of comparative studies on respiratory organs from diverse species. The underlying principles were formulated in pioneering studies on the pulmonary lung but are illustrated here by taking the human placenta as the gas exchanger. Copyright © 2012 Elsevier GmbH. All rights reserved.

Hippocampal neuropathology of domoic acid-induced epilepsy in California sea lions (Zalophus californianus).

PubMed

Buckmaster, Paul S; Wen, Xiling; Toyoda, Izumi; Gulland, Frances M D; Van Bonn, William

2014-05-01

California sea lions (Zalophus californianus) are abundant human-sized carnivores with large gyrencephalic brains. They develop epilepsy after experiencing status epilepticus when naturally exposed to domoic acid. We tested whether sea lions previously exposed to DA (chronic DA sea lions) display hippocampal neuropathology similar to that of human patients with temporal lobe epilepsy. Hippocampi were obtained from control and chronic DA sea lions. Stereology was used to estimate numbers of Nissl-stained neurons per hippocampus in the granule cell layer, hilus, and pyramidal cell layer of CA3, CA2, and CA1 subfields. Adjacent sections were processed for somatostatin immunoreactivity or Timm-stained, and the extent of mossy fiber sprouting was measured stereologically. Chronic DA sea lions displayed hippocampal neuron loss in patterns and extents similar but not identical to those reported previously for human patients with temporal lobe epilepsy. Similar to human patients, hippocampal sclerosis in sea lions was unilateral in 79% of cases, mossy fiber sprouting was a common neuropathological abnormality, and somatostatin-immunoreactive axons were exuberant in the dentate gyrus despite loss of immunopositive hilar neurons. Thus, hippocampal neuropathology of chronic DA sea lions is similar to that of human patients with temporal lobe epilepsy. Copyright © 2013 Wiley Periodicals, Inc.

Systematic, Cross-Cortex Variation in Neuron Numbers in Rodents and Primates

PubMed Central

Charvet, Christine J.; Cahalane, Diarmuid J.; Finlay, Barbara L.

2015-01-01

Uniformity, local variability, and systematic variation in neuron numbers per unit of cortical surface area across species and cortical areas have been claimed to characterize the isocortex. Resolving these claims has been difficult, because species, techniques, and cortical areas vary across studies. We present a stereological assessment of neuron numbers in layers II–IV and V–VI per unit of cortical surface area across the isocortex in rodents (hamster, Mesocricetus auratus; agouti, Dasyprocta azarae; paca, Cuniculus paca) and primates (owl monkey, Aotus trivigratus; tamarin, Saguinus midas; capuchin, Cebus apella); these chosen to vary systematically in cortical size. The contributions of species, cortical areas, and techniques (stereology, “isotropic fractionator”) to neuron estimates were assessed. Neurons per unit of cortical surface area increase across the rostro-caudal (RC) axis in primates (varying by a factor of 1.64–2.13 across the rostral and caudal poles) but less in rodents (varying by a factor of 1.15–1.54). Layer II–IV neurons account for most of this variation. When integrated into the context of species variation, and this RC gradient in neuron numbers, conflicts between studies can be accounted for. The RC variation in isocortical neurons in adulthood mirrors the gradients in neurogenesis duration in development. PMID:23960207

Comparison of data analysis strategies for intent-to-treat analysis in pre-test-post-test designs with substantial dropout rates.

PubMed

Salim, Agus; Mackinnon, Andrew; Christensen, Helen; Griffiths, Kathleen

2008-09-30

The pre-test-post-test design (PPD) is predominant in trials of psychotherapeutic treatments. Missing data due to withdrawals present an even bigger challenge in assessing treatment effectiveness under the PPD than under designs with more observations since dropout implies an absence of information about response to treatment. When confronted with missing data, often it is reasonable to assume that the mechanism underlying missingness is related to observed but not to unobserved outcomes (missing at random, MAR). Previous simulation and theoretical studies have shown that, under MAR, modern techniques such as maximum-likelihood (ML) based methods and multiple imputation (MI) can be used to produce unbiased estimates of treatment effects. In practice, however, ad hoc methods such as last observation carried forward (LOCF) imputation and complete-case (CC) analysis continue to be used. In order to better understand the behaviour of these methods in the PPD, we compare the performance of traditional approaches (LOCF, CC) and theoretically sound techniques (MI, ML), under various MAR mechanisms. We show that the LOCF method is seriously biased and conclude that its use should be abandoned. Complete-case analysis produces unbiased estimates only when the dropout mechanism does not depend on pre-test values even when dropout is related to fixed covariates including treatment group (covariate-dependent: CD). However, CC analysis is generally biased under MAR. The magnitude of the bias is largest when the correlation of post- and pre-test is relatively low.

Unbiased, scalable sampling of protein loop conformations from probabilistic priors.

PubMed

Zhang, Yajia; Hauser, Kris

2013-01-01

Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences. Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (>10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints. Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion.

Unbiased, scalable sampling of protein loop conformations from probabilistic priors

PubMed Central

2013-01-01

Background Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences. Results Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (>10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints. Conclusion Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion. PMID:24565175

Barrier screens: a method to sample blood-fed and host-seeking exophilic mosquitoes

PubMed Central

2013-01-01

Background Determining the proportion of blood meals on humans by outdoor-feeding and resting mosquitoes is challenging. This is largely due to the difficulty of finding an adequate and unbiased sample of resting, engorged mosquitoes to enable the identification of host blood meal sources. This is particularly difficult in the south-west Pacific countries of Indonesia, the Solomon Islands and Papua New Guinea where thick vegetation constitutes the primary resting sites for the exophilic mosquitoes that are the primary malaria and filariasis vectors. Methods Barrier screens of shade-cloth netting attached to bamboo poles were constructed between villages and likely areas where mosquitoes might seek blood meals or rest. Flying mosquitoes, obstructed by the barrier screens, would temporarily stop and could then be captured by aspiration at hourly intervals throughout the night. Results In the three countries where this method was evaluated, blood-fed females of Anopheles farauti, Anopheles bancroftii, Anopheles longirostris, Anopheles sundaicus, Anopheles vagus, Anopheles kochi, Anopheles annularis, Anopheles tessellatus, Culex vishnui, Culex quinquefasciatus and Mansonia spp were collected while resting on the barrier screens. In addition, female Anopheles punctulatus and Armigeres spp as well as male An. farauti, Cx. vishnui, Cx. quinquefasciatus and Aedes species were similarly captured. Conclusions Building barrier screens as temporary resting sites in areas where mosquitoes were likely to fly was an extremely time-effective method for collecting an unbiased representative sample of engorged mosquitoes for determining the human blood index. PMID:23379959

Estimating Unbiased Treatment Effects in Education Using a Regression Discontinuity Design

ERIC Educational Resources Information Center

Smith, William C.

2014-01-01

The ability of regression discontinuity (RD) designs to provide an unbiased treatment effect while overcoming the ethical concerns plagued by Random Control Trials (RCTs) make it a valuable and useful approach in education evaluation. RD is the only explicitly recognized quasi-experimental approach identified by the Institute of Education…

Particle infectivity of HIV-1 full-length genome infectious molecular clones in a subtype C heterosexual transmission pair following high fidelity amplification and unbiased cloning

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

Deymier, Martin J., E-mail: mdeymie@emory.edu; Claiborne, Daniel T., E-mail: dclaibo@emory.edu; Ende, Zachary, E-mail: zende@emory.edu

The high genetic diversity of HIV-1 impedes high throughput, large-scale sequencing and full-length genome cloning by common restriction enzyme based methods. Applying novel methods that employ a high-fidelity polymerase for amplification and an unbiased fusion-based cloning strategy, we have generated several HIV-1 full-length genome infectious molecular clones from an epidemiologically linked transmission pair. These clones represent the transmitted/founder virus and phylogenetically diverse non-transmitted variants from the chronically infected individual's diverse quasispecies near the time of transmission. We demonstrate that, using this approach, PCR-induced mutations in full-length clones derived from their cognate single genome amplicons are rare. Furthermore, all eight non-transmittedmore » genomes tested produced functional virus with a range of infectivities, belying the previous assumption that a majority of circulating viruses in chronic HIV-1 infection are defective. Thus, these methods provide important tools to update protocols in molecular biology that can be universally applied to the study of human viral pathogens. - Highlights: • Our novel methodology demonstrates accurate amplification and cloning of full-length HIV-1 genomes. • A majority of plasma derived HIV variants from a chronically infected individual are infectious. • The transmitted/founder was more infectious than the majority of the variants from the chronically infected donor.« less

A Simple "Boxed Molecular Kinetics" Approach To Accelerate Rare Events in the Stochastic Kinetic Master Equation.

PubMed

Shannon, Robin; Glowacki, David R

2018-02-15

The chemical master equation is a powerful theoretical tool for analyzing the kinetics of complex multiwell potential energy surfaces in a wide range of different domains of chemical kinetics spanning combustion, atmospheric chemistry, gas-surface chemistry, solution phase chemistry, and biochemistry. There are two well-established methodologies for solving the chemical master equation: a stochastic "kinetic Monte Carlo" approach and a matrix-based approach. In principle, the results yielded by both approaches are identical; the decision of which approach is better suited to a particular study depends on the details of the specific system under investigation. In this Article, we present a rigorous method for accelerating stochastic approaches by several orders of magnitude, along with a method for unbiasing the accelerated results to recover the "true" value. The approach we take in this paper is inspired by the so-called "boxed molecular dynamics" (BXD) method, which has previously only been applied to accelerate rare events in molecular dynamics simulations. Here we extend BXD to design a simple algorithmic strategy for accelerating rare events in stochastic kinetic simulations. Tests on a number of systems show that the results obtained using the BXD rare event strategy are in good agreement with unbiased results. To carry out these tests, we have implemented a kinetic Monte Carlo approach in MESMER, which is a cross-platform, open-source, and freely available master equation solver.

Maximum likelihood estimation for life distributions with competing failure modes

NASA Technical Reports Server (NTRS)

Sidik, S. M.

1979-01-01

Systems which are placed on test at time zero, function for a period and die at some random time were studied. Failure may be due to one of several causes or modes. The parameters of the life distribution may depend upon the levels of various stress variables the item is subject to. Maximum likelihood estimation methods are discussed. Specific methods are reported for the smallest extreme-value distributions of life. Monte-Carlo results indicate the methods to be promising. Under appropriate conditions, the location parameters are nearly unbiased, the scale parameter is slight biased, and the asymptotic covariances are rapidly approached.

Investigation of Procedures for Automatic Resonance Extraction from Noisy Transient Electromagnetics Data. Volume III. Translation of Prony’s Original Paper and Bibliography of Prony’s Method

DTIC Science & Technology

1981-08-17

Van Blaricum, "On the Source of Parameter Bias in Prony’s Method," 1980 NEM Conference, Disneyland Hotel, August 1980. Auton, J.R., "An Unbiased...Method for the Estimation of the SEM Parameters of an Electromagnetic System," 1980 NEM Conference, Disneyland Hotel, August 1980. Auton, J.R. and M.L...34 1980 NEM Conference, Disneyland Hotel, August 5-7, 1980. Chuang, C.W. and D.L. Moffatt, "Complex Natural Responances of Radar Targets via Prony’s

Counting glomeruli and podocytes: rationale and methodologies

PubMed Central

Puelles, Victor G.; Bertram, John F.

2015-01-01

Purpose of review There is currently much interest in the numbers of both glomeruli and podocytes. This interest stems from greater understanding of the effects of suboptimal fetal events on nephron endowment, the associations between low nephron number and chronic cardiovascular and kidney disease in adults, and the emergence of the podocyte depletion hypothesis. Recent findings Obtaining accurate and precise estimates of glomerular and podocyte number has proven surprisingly difficult. When whole kidneys or large tissue samples are available, design-based stereological methods are considered gold-standard because they are based on principles that negate systematic bias. However, these methods are often tedious and time-consuming, and oftentimes inapplicable when dealing with small samples such as biopsies. Therefore, novel methods suitable for small tissue samples, and innovative approaches to facilitate high through put measurements, such as magnetic resonance imaging (MRI) to estimate glomerular number and flow cytometry to estimate podocyte number, have recently been described. Summary This review describes current gold-standard methods for estimating glomerular and podocyte number, as well as methods developed in the past 3 years. We are now better placed than ever before to accurately and precisely estimate glomerular and podocyte number, and to examine relationships between these measurements and kidney health and disease. PMID:25887899

Five instruments for measuring tree height: an evaluation

Treesearch

Michael S. Williams; William A. Bechtold; V.J. LaBau

1994-01-01

Five instruments were tested for reliability in measuring tree heights under realistic conditions. Four linear models were used to determine if tree height can be measured unbiasedly over all tree sizes and if any of the instruments were more efficient in estimating tree height. The laser height finder was the only instrument to produce unbiased estimates of the true...

Spectroscopic observations of ATLAS17lcs (SN 2017guv) and ASASSN-17mq (AT 2017gvo) by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Dong, Subo; Bose, Subhash; Stritzinger, M.; Holmbo, S.; Fraser, M.; Fedorets, G.

2017-10-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of ATLAS17lcs (SN 2017guv) and ASASSN-17mq (AT 2017gvo) in host galaxies 2MASX J19132225-1648031 and CGCG 225-050, respectively.

Spectroscopic observations of ASASSN-17io and ATLAS17hpt (SN 2017faf) by NUTS (NOT Un-biased Transient Survey)

NASA Astrophysics Data System (ADS)

Pastorello, Andrea; Benetti, Stefano; Cappellaro, Enrico; Terreran, Giacomo; Tomasella, Lina; Fedorets, Grigori; NUTS Collaboration

2017-07-01

The Nordic Optical Telescope (NOT) Unbiased Transient Survey (NUTS; ATel #8992) reports the spectroscopic classification of ASASSN-17io in the galaxy CGCG 316-010, along with the re classification of ATLAS17hpt (SN 2017faf), which was previously classified as a SLSN-I (ATel #10549).

Contextual classification of multispectral image data: An unbiased estimator for the context distribution

NASA Technical Reports Server (NTRS)

Tilton, J. C.; Swain, P. H. (Principal Investigator); Vardeman, S. B.

1981-01-01

A key input to a statistical classification algorithm, which exploits the tendency of certain ground cover classes to occur more frequently in some spatial context than in others, is a statistical characterization of the context: the context distribution. An unbiased estimator of the context distribution is discussed which, besides having the advantage of statistical unbiasedness, has the additional advantage over other estimation techniques of being amenable to an adaptive implementation in which the context distribution estimate varies according to local contextual information. Results from applying the unbiased estimator to the contextual classification of three real LANDSAT data sets are presented and contrasted with results from non-contextual classifications and from contextual classifications utilizing other context distribution estimation techniques.

Estimation of the simple correlation coefficient.

PubMed

Shieh, Gwowen

2010-11-01

This article investigates some unfamiliar properties of the Pearson product-moment correlation coefficient for the estimation of simple correlation coefficient. Although Pearson's r is biased, except for limited situations, and the minimum variance unbiased estimator has been proposed in the literature, researchers routinely employ the sample correlation coefficient in their practical applications, because of its simplicity and popularity. In order to support such practice, this study examines the mean squared errors of r and several prominent formulas. The results reveal specific situations in which the sample correlation coefficient performs better than the unbiased and nearly unbiased estimators, facilitating recommendation of r as an effect size index for the strength of linear association between two variables. In addition, related issues of estimating the squared simple correlation coefficient are also considered.

Boron Carbide Aluminum Cermets for External Pressure Housing Applications

DTIC Science & Technology

1992-09-01

CHEMISTRY AND MICROSTRUCTURES OF THE B4C/Al SYSTEM ......................................... 4 3.2 MECHANICAL PROPERTIES OF B4C/AI COMPOSITES ....... 10...TABLES 1. Phase chemistry of B4C/A1 composites as a function of baking temperature (by stereology) .................. ...... 10 2. Summary of the...diffractometer using CuKo radiation and a scan rate of 2° per minute. The chemistry of all phases was determined from electron microprobe analysis of

An Analysis Method for Superconducting Resonator Parameter Extraction with Complex Baseline Removal

NASA Technical Reports Server (NTRS)

Cataldo, Giuseppe

2014-01-01

A new semi-empirical model is proposed for extracting the quality (Q) factors of arrays of superconducting microwave kinetic inductance detectors (MKIDs). The determination of the total internal and coupling Q factors enables the computation of the loss in the superconducting transmission lines. The method used allows the simultaneous analysis of multiple interacting discrete resonators with the presence of a complex spectral baseline arising from reflections in the system. The baseline removal allows an unbiased estimate of the device response as measured in a cryogenic instrumentation setting.

An Integrated Approach for Gear Health Prognostics

NASA Technical Reports Server (NTRS)

He, David; Bechhoefer, Eric; Dempsey, Paula; Ma, Jinghua

2012-01-01

In this paper, an integrated approach for gear health prognostics using particle filters is presented. The presented method effectively addresses the issues in applying particle filters to gear health prognostics by integrating several new components into a particle filter: (1) data mining based techniques to effectively define the degradation state transition and measurement functions using a one-dimensional health index obtained by whitening transform; (2) an unbiased l-step ahead RUL estimator updated with measurement errors. The feasibility of the presented prognostics method is validated using data from a spiral bevel gear case study.

Unbiased metabolite profiling by liquid chromatography-quadrupole time-of-flight mass spectrometry and multivariate data analysis for herbal authentication: classification of seven Lonicera species flower buds.

PubMed

Gao, Wen; Yang, Hua; Qi, Lian-Wen; Liu, E-Hu; Ren, Mei-Ting; Yan, Yu-Ting; Chen, Jun; Li, Ping

2012-07-06

Plant-based medicines become increasingly popular over the world. Authentication of herbal raw materials is important to ensure their safety and efficacy. Some herbs belonging to closely related species but differing in medicinal properties are difficult to be identified because of similar morphological and microscopic characteristics. Chromatographic fingerprinting is an alternative method to distinguish them. Existing approaches do not allow a comprehensive analysis for herbal authentication. We have now developed a strategy consisting of (1) full metabolic profiling of herbal medicines by rapid resolution liquid chromatography (RRLC) combined with quadrupole time-of-flight mass spectrometry (QTOF MS), (2) global analysis of non-targeted compounds by molecular feature extraction algorithm, (3) multivariate statistical analysis for classification and prediction, and (4) marker compounds characterization. This approach has provided a fast and unbiased comparative multivariate analysis of the metabolite composition of 33-batch samples covering seven Lonicera species. Individual metabolic profiles are performed at the level of molecular fragments without prior structural assignment. In the entire set, the obtained classifier for seven Lonicera species flower buds showed good prediction performance and a total of 82 statistically different components were rapidly obtained by the strategy. The elemental compositions of discriminative metabolites were characterized by the accurate mass measurement of the pseudomolecular ions and their chemical types were assigned by the MS/MS spectra. The high-resolution, comprehensive and unbiased strategy for metabolite data analysis presented here is powerful and opens the new direction of authentication in herbal analysis. Copyright © 2012 Elsevier B.V. All rights reserved.

Estimating unbiased economies of scale of HIV prevention projects: a case study of Avahan.

PubMed

Lépine, Aurélia; Vassall, Anna; Chandrashekar, Sudha; Blanc, Elodie; Le Nestour, Alexis

2015-04-01

Governments and donors are investing considerable resources on HIV prevention in order to scale up these services rapidly. Given the current economic climate, providers of HIV prevention services increasingly need to demonstrate that these investments offer good 'value for money'. One of the primary routes to achieve efficiency is to take advantage of economies of scale (a reduction in the average cost of a health service as provision scales-up), yet empirical evidence on economies of scale is scarce. Methodologically, the estimation of economies of scale is hampered by several statistical issues preventing causal inference and thus making the estimation of economies of scale complex. In order to estimate unbiased economies of scale when scaling up HIV prevention services, we apply our analysis to one of the few HIV prevention programmes globally delivered at a large scale: the Indian Avahan initiative. We costed the project by collecting data from the 138 Avahan NGOs and the supporting partners in the first four years of its scale-up, between 2004 and 2007. We develop a parsimonious empirical model and apply a system Generalized Method of Moments (GMM) and fixed-effects Instrumental Variable (IV) estimators to estimate unbiased economies of scale. At the programme level, we find that, after controlling for the endogeneity of scale, the scale-up of Avahan has generated high economies of scale. Our findings suggest that average cost reductions per person reached are achievable when scaling-up HIV prevention in low and middle income countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

Forest inventory predictions from individual tree crowns: regression modeling within a sample framework

Treesearch

James W. Flewelling

2009-01-01

Remotely sensed data can be used to make digital maps showing individual tree crowns (ITC) for entire forests. Attributes of the ITCs may include area, shape, height, and color. The crown map is sampled in a way that provides an unbiased linkage between ITCs and identifiable trees measured on the ground. Methods of avoiding edge bias are given. In an example from a...

Network topological analysis reveals the functional cohesiveness for the newly discovered links by Yeast 2 Hybrid approach

NASA Astrophysics Data System (ADS)

Ghiassian, Susan; Pevzner, Sam; Rolland, Thomas; Tassan, Murat; Barabasi, Albert Laszlo; Vidal, Mark; CCNR, Northeastern University Collaboration; Dana Farber Cancer Institute Collaboration

2014-03-01

Protein-protein interaction maps and interactomes are the blueprint of Network Medicine and systems biology and are being experimentally studied by different groups. Despite the wide usage of Literature Curated Interactome (LCI), these sources are biased towards different parameters such as highly studied proteins. Yeast two hybrid method is a high throughput experimental setup which screens proteins in an unbiased fashion. Current knowledge of protein interactions is far from complete. In fact the previous offered data from Y2H method (2005), is estimated to offer only 5% of all potential protein interactions. Currently this coverage has increased to 20% of what is known as reference HI In this work we study the topological properties of Y2H protein-protein interactions network with LCI and show although they both agree on some properties, LCI shows a clear unbiased nature of interaction selections. Most importantly, we assess the properties of PPI as it evolves with increasing the coverage. We show that, the newly discovered interactions tend to connect proteins that have been closer than average in the previous PPI release. reinforcing the modular structure of PPI. Furthermore, we show, some unseen effects on PPI (as opposed to LCI) can be explained by its incompleteness.

Free energies from dynamic weighted histogram analysis using unbiased Markov state model.

PubMed

Rosta, Edina; Hummer, Gerhard

2015-01-13

The weighted histogram analysis method (WHAM) is widely used to obtain accurate free energies from biased molecular simulations. However, WHAM free energies can exhibit significant errors if some of the biasing windows are not fully equilibrated. To account for the lack of full equilibration, we develop the dynamic histogram analysis method (DHAM). DHAM uses a global Markov state model to obtain the free energy along the reaction coordinate. A maximum likelihood estimate of the Markov transition matrix is constructed by joint unbiasing of the transition counts from multiple umbrella-sampling simulations along discretized reaction coordinates. The free energy profile is the stationary distribution of the resulting Markov matrix. For this matrix, we derive an explicit approximation that does not require the usual iterative solution of WHAM. We apply DHAM to model systems, a chemical reaction in water treated using quantum-mechanics/molecular-mechanics (QM/MM) simulations, and the Na(+) ion passage through the membrane-embedded ion channel GLIC. We find that DHAM gives accurate free energies even in cases where WHAM fails. In addition, DHAM provides kinetic information, which we here use to assess the extent of convergence in each of the simulation windows. DHAM may also prove useful in the construction of Markov state models from biased simulations in phase-space regions with otherwise low population.

The density of apical cells of dark-grown protonemata of the moss Ceratodon purpureus

NASA Technical Reports Server (NTRS)

Schwuchow, J. M.; Kern, V. D.; Wagner, T.; Sack, F. D.

2000-01-01

Determinations of plant or algal cell density (cell mass divided by volume) have rarely accounted for the extracellular matrix or shrinkage during isolation. Three techniques were used to indirectly estimate the density of intact apical cells from protonemata of the moss Ceratodon purpureus. First, the volume fraction of each cell component was determined by stereology, and published values for component density were used to extrapolate to the entire cell. Second, protonemal tips were immersed in bovine serum albumin solutions of different densities, and then the equilibrium density was corrected for the mass of the cell wall. Third, apical cell protoplasts were centrifuged in low-osmolarity gradients, and values were corrected for shrinkage during protoplast isolation. Values from centrifugation (1.004 to 1.015 g/cm3) were considerably lower than from other methods (1.046 to 1.085 g/cm3). This work appears to provide the first corrected estimates of the density of any plant cell. It also documents a method for the isolation of protoplasts specifically from apical cells of protonemal filaments.

Microstructural Effects on Initiation Behavior in HMX

NASA Astrophysics Data System (ADS)

Molek, Christopher; Welle, Eric; Hardin, Barrett; Vitarelli, Jim; Wixom, Ryan; Samuels, Philip

Understanding the role microstructure plays on ignition and growth behavior has been the subject of a significant body of research within the detonation physics community. The pursuit of this understanding is important because safety and performance characteristics have been shown to strongly correlate to particle morphology. Historical studies have often correlated bulk powder characteristics to the performance or safety characteristics of pressed materials. We believe that a clearer and more relevant correlation is made between the pressed microstructure and the observed detonation behavior. This type of assessment is possible, as techniques now exist for the quantification of the pressed microstructures. Our talk will report on experimental efforts that correlate directly measured microstructural characteristics to initiation threshold behavior of HMX based materials. The internal microstructures were revealed using an argon ion cross-sectioning technique. This technique enabled the quantification of density and interface area of the pores within the pressed bed using methods of stereology. These bed characteristics are compared to the initiation threshold behavior of three HMX based materials using an electric gun based test method. Finally, a comparison of experimental threshold data to supporting theoretical efforts will be made.

Maximal Unbiased Benchmarking Data Sets for Human Chemokine Receptors and Comparative Analysis.

PubMed

Xia, Jie; Reid, Terry-Elinor; Wu, Song; Zhang, Liangren; Wang, Xiang Simon

2018-05-29

Chemokine receptors (CRs) have long been druggable targets for the treatment of inflammatory diseases and HIV-1 infection. As a powerful technique, virtual screening (VS) has been widely applied to identifying small molecule leads for modern drug targets including CRs. For rational selection of a wide variety of VS approaches, ligand enrichment assessment based on a benchmarking data set has become an indispensable practice. However, the lack of versatile benchmarking sets for the whole CRs family that are able to unbiasedly evaluate every single approach including both structure- and ligand-based VS somewhat hinders modern drug discovery efforts. To address this issue, we constructed Maximal Unbiased Benchmarking Data sets for human Chemokine Receptors (MUBD-hCRs) using our recently developed tools of MUBD-DecoyMaker. The MUBD-hCRs encompasses 13 subtypes out of 20 chemokine receptors, composed of 404 ligands and 15756 decoys so far and is readily expandable in the future. It had been thoroughly validated that MUBD-hCRs ligands are chemically diverse while its decoys are maximal unbiased in terms of "artificial enrichment", "analogue bias". In addition, we studied the performance of MUBD-hCRs, in particular CXCR4 and CCR5 data sets, in ligand enrichment assessments of both structure- and ligand-based VS approaches in comparison with other benchmarking data sets available in the public domain and demonstrated that MUBD-hCRs is very capable of designating the optimal VS approach. MUBD-hCRs is a unique and maximal unbiased benchmarking set that covers major CRs subtypes so far.

Retransformation bias in a stem profile model

Treesearch

Raymond L. Czaplewski; David Bruce

1990-01-01

An unbiased profile model, fit to diameter divided by diameter at breast height, overestimated volume of 5.3-m log sections by 0.5 to 3.5%. Another unbiased profile model, fit to squared diameter divided by squared diameter at breast height, underestimated bole diameters by 0.2 to 2.1%. These biases are caused by retransformation of the predicted dependent variable;...

Apparatus bias and place conditioning with ethanol in mice.

PubMed

Cunningham, Christopher L; Ferree, Nikole K; Howard, MacKenzie A

2003-12-01

Although the distinction between "biased" and "unbiased" is generally recognized as an important methodological issue in place conditioning, previous studies have not adequately addressed the distinction between a biased/unbiased apparatus and a biased/unbiased stimulus assignment procedure. Moreover, a review of the recent literature indicates that many reports (70% of 76 papers published in 2001) fail to provide adequate information about apparatus bias. This issue is important because the mechanisms underlying a drug's effect in the place-conditioning procedure may differ depending on whether the apparatus is biased or unbiased. The present studies were designed to assess the impact of apparatus bias and stimulus assignment procedure on ethanol-induced place conditioning in mice (DBA/2 J). A secondary goal was to compare various dependent variables commonly used to index conditioned place preference. Apparatus bias was manipulated by varying the combination of tactile (floor) cues available during preference tests. Experiment 1 used an unbiased apparatus in which the stimulus alternatives were equally preferred during a pre-test as indicated by the group average. Experiment 2 used a biased apparatus in which one of the stimuli was strongly preferred by most mice (mean % time on cue = 67%) during the pre-test. In both studies, the stimulus paired with drug (CS+) was assigned randomly (i.e., an "unbiased" stimulus assignment procedure). Experimental mice received four pairings of CS+ with ethanol (2 g/kg, i.p.) and four pairings of the alternative stimulus (CS-) with saline; control mice received saline on both types of trial. Each experiment concluded with a 60-min choice test. With the unbiased apparatus (experiment 1), significant place conditioning was obtained regardless of whether drug was paired with the subject's initially preferred or non-preferred stimulus. However, with the biased apparatus (experiment 2), place conditioning was apparent only when ethanol was paired with the initially non-preferred cue, and not when it was paired with the initially preferred cue. These conclusions held regardless of which dependent variable was used to index place conditioning, but only if the counterbalancing factor was included in statistical analyses. These studies indicate that apparatus bias plays a major role in determining whether biased assignment of an ethanol-paired stimulus affects ability to demonstrate conditioned place preference. Ethanol's ability to produce conditioned place preference in an unbiased apparatus, regardless of the direction of the initial cue bias, supports previous studies that interpret such findings as evidence of a primary rewarding drug effect. Moreover, these studies suggest that the asymmetrical outcome observed in the biased apparatus is most likely due to a measurement problem (e.g., ceiling effect) rather than to an interaction between the drug's effect and an unconditioned motivational response (e.g., "anxiety") to the initially non-preferred stimulus. More generally, these findings illustrate the importance of providing clear information on apparatus bias in all place-conditioning studies.

A detailed comparison of analysis processes for MCC-IMS data in disease classification—Automated methods can replace manual peak annotations

PubMed Central

Horsch, Salome; Kopczynski, Dominik; Kuthe, Elias; Baumbach, Jörg Ingo; Rahmann, Sven

2017-01-01

Motivation Disease classification from molecular measurements typically requires an analysis pipeline from raw noisy measurements to final classification results. Multi capillary column—ion mobility spectrometry (MCC-IMS) is a promising technology for the detection of volatile organic compounds in the air of exhaled breath. From raw measurements, the peak regions representing the compounds have to be identified, quantified, and clustered across different experiments. Currently, several steps of this analysis process require manual intervention of human experts. Our goal is to identify a fully automatic pipeline that yields competitive disease classification results compared to an established but subjective and tedious semi-manual process. Method We combine a large number of modern methods for peak detection, peak clustering, and multivariate classification into analysis pipelines for raw MCC-IMS data. We evaluate all combinations on three different real datasets in an unbiased cross-validation setting. We determine which specific algorithmic combinations lead to high AUC values in disease classifications across the different medical application scenarios. Results The best fully automated analysis process achieves even better classification results than the established manual process. The best algorithms for the three analysis steps are (i) SGLTR (Savitzky-Golay Laplace-operator filter thresholding regions) and LM (Local Maxima) for automated peak identification, (ii) EM clustering (Expectation Maximization) and DBSCAN (Density-Based Spatial Clustering of Applications with Noise) for the clustering step and (iii) RF (Random Forest) for multivariate classification. Thus, automated methods can replace the manual steps in the analysis process to enable an unbiased high throughput use of the technology. PMID:28910313

The National Osteoporosis Foundation's methods and processes for developing position statements.

PubMed

Wallace, Taylor C; Bauer, Douglas C; Gagel, Robert F; Greenspan, Susan L; Lappe, Joan M; LeBoff, Meryl S; Recker, Robert R; Saag, Kenneth G; Singer, Andrea J

2016-01-01

The methods and processes described in this manuscript have been approved and adopted by the NOF Board of Trustees on November 11, 2015. This manuscript has been peer-reviewed by the NOF Research Committee and Osteoporosis International. The National Osteoporosis Foundation frequently publishes position statements for the benefit of educating healthcare professionals and the general public on a particular issue and/or concern related to preventing osteoporosis and/or promoting strong bones throughout the lifespan. This manuscript represents the official methods and processes adopted by the NOF Board of Trustees for the purpose developing future position statements in a transparent and unbiased manner.

Machine learning for autonomous crystal structure identification.

PubMed

Reinhart, Wesley F; Long, Andrew W; Howard, Michael P; Ferguson, Andrew L; Panagiotopoulos, Athanassios Z

2017-07-21

We present a machine learning technique to discover and distinguish relevant ordered structures from molecular simulation snapshots or particle tracking data. Unlike other popular methods for structural identification, our technique requires no a priori description of the target structures. Instead, we use nonlinear manifold learning to infer structural relationships between particles according to the topology of their local environment. This graph-based approach yields unbiased structural information which allows us to quantify the crystalline character of particles near defects, grain boundaries, and interfaces. We demonstrate the method by classifying particles in a simulation of colloidal crystallization, and show that our method identifies structural features that are missed by standard techniques.

Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of AβPP/Ps1 mice.

PubMed

Antequera, Desiree; Portero, Aitziber; Bolos, Marta; Orive, Gorka; Hernández, Rosa M Rm A; Pedraz, José Luis; Carro, Eva

2012-01-01

Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer's disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in AβPP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the cerebral cortex from VEGF microcapsules-treated AβPP/PS1 mice at 1, 3 and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate gyrus (DG). The number of neuronal precursors in VEGF microcapsules-treated AβPP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells also stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of AβPP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD.

Comparative stereology of the mouse and finch left ventricle.

PubMed

Bossen, E H; Sommer, J R; Waugh, R A

1978-01-01

The volume fractions and surface per unit cell volume of some subcellular components of the left ventricles of the finch and mouse were quantitated by stereologic techniques. These species were chosen for study because they have similar heart rates but differ morphologically in some respects: fiber diameter is larger in the mouse; the mouse has transverse tubules while the finch does not; and the finch has a form of junctional sarcoplasmic reticulum (JSR), extended JSR (EJSR), located in the cell interior with no direct plasmalemmal contact, while the mouse interior JSR (IJSR) abuts on transverse tubules. Our data show that the volume fraction (Vv) and surface area per unit cell volume (Sv) of total SR, and free SR (FSR) are similar. The volume fractions of mitochondria, myofibrils, and total junctional SR were also similar. The Sv of the cell surface of the finch was similar to the Sv of the cell surface of the mouse (Sv-plasmalemma plus Sv of the transverse tubules). The principal difference was in the distribution of JSR; the mouse peripheral JSR (PJSR) represents only 9% of the total JSR, while the finch PJSR accounts for 24% of the bird's JSR. The similar volume fractions of total junctional SR (PJSR + EJSR in the finch; PJSR + IJSR in the mouse) suggest that the EJSR is not an embryologic remnant, and raises the possibility that some function of JSR is independent of plasmalemmal contact.

Crataegus monogyna aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis: stereological evidences.

PubMed

Jalali, Ali Shalizar; Hasanzadeh, Shapour; Malekinejad, Hassan

2012-01-01

Cyclophosphamide (CP) is extensively used as an antineoplastic agent for the treatment of various cancers, as well as an immunosuppressive agent. However, despite its wide spectrum of clinical uses, CP is known to cause several adverse effects including reproductive toxicity. Crataegus monogyna is one of the oldest pharmaceutical plants that have been shown to be cytoprotective by scavenging free radicals. The present study was conducted to assess whether Crataegus monogyna fruits aqueous extract with anti-oxidant properties, could serve as a protective agent against reproductive toxicity during CP treatment in a rat model. Male Wistar rats were categorized into four groups. Two groups of rats were administered CP at a dose of 5 mg in 5 ml saline/kg/day for 28 days by oral gavages. One of these groups received Crataegus monogyna aqueous extract at a dose of 20 mg/kg/day orally four hours after cyclophosphamide administration. A vehicle treated control group and a Crataegus monogyna control group were also included. The CP-treated group showed significant decreases in the body, testes and epididymides weights as well as many histological alterations. Stereological parameters and spermatogenic activities (Sertoli cell, repopulation and miotic indices) were also significantly decreased by CP treatment. Notably, Crataegus coadministration caused a partial recovery in above-mentined parameters. These findings indicate that Crataegus monogyna may be partially protective against CP-induced testicular toxicity.

Degeneration and regeneration of motor and sensory nerves: a stereological study of crush lesions in rat facial and mental nerves.

PubMed

Barghash, Z; Larsen, J O; Al-Bishri, A; Kahnberg, K-E

2013-12-01

The aim of this study was to evaluate the degeneration and regeneration of a sensory nerve and a motor nerve at the histological level after a crush injury. Twenty-five female Wistar rats had their mental nerve and the buccal branch of their facial nerve compressed unilaterally against a glass rod for 30s. Specimens of the compressed nerves and the corresponding control nerves were dissected at 3, 7, and 19 days after surgery. Nerve cross-sections were stained with osmium tetroxide and toluidine blue and analysed using two-dimensional stereology. We found differences between the two nerves both in the normal anatomy and in the regenerative pattern. The mental nerve had a larger cross-sectional area including all tissue components. The mental nerve had a larger volume fraction of myelinated axons and a correspondingly smaller volume fraction of endoneurium. No differences were observed in the degenerative pattern; however, at day 19 the buccal branch had regenerated to the normal number of axons, whereas the mental nerve had only regained 50% of the normal number of axons. We conclude that the regenerative process is faster and/or more complete in the facial nerve (motor function) than it is in the mental nerve (somatosensory function). Copyright © 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Systematic, cross-cortex variation in neuron numbers in rodents and primates.

PubMed

Charvet, Christine J; Cahalane, Diarmuid J; Finlay, Barbara L

2015-01-01

Uniformity, local variability, and systematic variation in neuron numbers per unit of cortical surface area across species and cortical areas have been claimed to characterize the isocortex. Resolving these claims has been difficult, because species, techniques, and cortical areas vary across studies. We present a stereological assessment of neuron numbers in layers II-IV and V-VI per unit of cortical surface area across the isocortex in rodents (hamster, Mesocricetus auratus; agouti, Dasyprocta azarae; paca, Cuniculus paca) and primates (owl monkey, Aotus trivigratus; tamarin, Saguinus midas; capuchin, Cebus apella); these chosen to vary systematically in cortical size. The contributions of species, cortical areas, and techniques (stereology, "isotropic fractionator") to neuron estimates were assessed. Neurons per unit of cortical surface area increase across the rostro-caudal (RC) axis in primates (varying by a factor of 1.64-2.13 across the rostral and caudal poles) but less in rodents (varying by a factor of 1.15-1.54). Layer II-IV neurons account for most of this variation. When integrated into the context of species variation, and this RC gradient in neuron numbers, conflicts between studies can be accounted for. The RC variation in isocortical neurons in adulthood mirrors the gradients in neurogenesis duration in development. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A software package to improve image quality and isolation of objects of interest for quantitative stereology studies of rat hepatocarcinogenesis.

PubMed

Xu, Yihua; Pitot, Henry C

2006-03-01

In the studies of quantitative stereology of rat hepatocarcinogenesis, we have used image analysis technology (automatic particle analysis) to obtain data such as liver tissue area, size and location of altered hepatic focal lesions (AHF), and nuclei counts. These data are then used for three-dimensional estimation of AHF occurrence and nuclear labeling index analysis. These are important parameters for quantitative studies of carcinogenesis, for screening and classifying carcinogens, and for risk estimation. To take such measurements, structures or cells of interest should be separated from the other components based on the difference of color and density. Common background problems seen on the captured sample image such as uneven light illumination or color shading can cause severe problems in the measurement. Two application programs (BK_Correction and Pixel_Separator) have been developed to solve these problems. With BK_Correction, common background problems such as incorrect color temperature setting, color shading, and uneven light illumination background, can be corrected. With Pixel_Separator different types of objects can be separated from each other in relation to their color, such as seen with different colors in immunohistochemically stained slides. The resultant images of such objects separated from other components are then ready for particle analysis. Objects that have the same darkness but different colors can be accurately differentiated in a grayscale image analysis system after application of these programs.

Role of 17 beta-estradiol on type IV collagen fibers volumetric density in the basement membrane of bladder wall.

PubMed

de Fraga, Rogerio; Dambros, Miriam; Miyaoka, Ricardo; Riccetto, Cássio Luís Zanettini; Palma, Paulo César Rodrigues

2007-10-01

The authors quantified the type IV collagen fibers volumetric density in the basement membrane of bladder wall of ovariectomized rats with and without estradiol replacement. This study was conducted on 40 Wistar rats (3 months old) randomly divided in 4 groups: group 1, remained intact (control); group 2, submitted to bilateral oophorectomy and daily replacement 4 weeks later of 17 beta-estradiol for 12 weeks; group 3, sham operated and daily replacement 4 weeks later of sesame oil for 12 weeks; and group 4, submitted to bilateral oophorectomy and killed after 12 weeks. It was used in immunohistochemistry evaluation using type IV collagen polyclonal antibody to stain the fibers on paraffin rat bladder sections. The M-42 stereological grid system was used to analyze the fibers. Ovariectomy had an increase effect on the volumetric density of the type IV collagen fibers in the basement membrane of rat bladder wall. Estradiol replacement in castrated animals demonstrated a significative difference in the stereological parameters when compared to the castrated group without hormonal replacement. Surgical castration performed on rats induced an increasing volumetric density of type IV collagen fibers in the basement membrane of rats bladder wall and the estradiol treatment had a significant effect in keeping a low volumetric density of type IV collagen fibers in the basement membrane of rats bladder wall.

Unbiased and robust quantification of synchronization between spikes and local field potential.

PubMed

Li, Zhaohui; Cui, Dong; Li, Xiaoli

2016-08-30

In neuroscience, relating the spiking activity of individual neurons to the local field potential (LFP) of neural ensembles is an increasingly useful approach for studying rhythmic neuronal synchronization. Many methods have been proposed to measure the strength of the association between spikes and rhythms in the LFP recordings, and most existing measures are dependent upon the total number of spikes. In the present work, we introduce a robust approach for quantifying spike-LFP synchronization which performs reliably for limited samples of data. The measure is termed as spike-triggered correlation matrix synchronization (SCMS), which takes LFP segments centered on each spike as multi-channel signals and calculates the index of spike-LFP synchronization by constructing a correlation matrix. The simulation based on artificial data shows that the SCMS output almost does not change with the sample size. This property is of crucial importance when making comparisons between different experimental conditions. When applied to actual neuronal data recorded from the monkey primary visual cortex, it is found that the spike-LFP synchronization strength shows orientation selectivity to drifting gratings. In comparison to another unbiased method, pairwise phase consistency (PPC), the proposed SCMS behaves better for noisy spike trains by means of numerical simulations. This study demonstrates the basic idea and calculating process of the SCMS method. Considering its unbiasedness and robustness, the measure is of great advantage to characterize the synchronization between spike trains and rhythms present in LFP. Copyright © 2016 Elsevier B.V. All rights reserved.

Reply to ''Comment on 'Mutually unbiased bases, orthogonal Latin squares, and hidden-variable models'''

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

Paterek, Tomasz; Dakic, Borivoje; Brukner, Caslav

In this Reply to the preceding Comment by Hall and Rao [Phys. Rev. A 83, 036101 (2011)], we motivate terminology of our original paper and point out that further research is needed in order to (dis)prove the claimed link between every orthogonal Latin square of order being a power of a prime and a mutually unbiased basis.

How to benchmark methods for structure-based virtual screening of large compound libraries.

PubMed

Christofferson, Andrew J; Huang, Niu

2012-01-01

Structure-based virtual screening is a useful computational technique for ligand discovery. To systematically evaluate different docking approaches, it is important to have a consistent benchmarking protocol that is both relevant and unbiased. Here, we describe the designing of a benchmarking data set for docking screen assessment, a standard docking screening process, and the analysis and presentation of the enrichment of annotated ligands among a background decoy database.

Unbiased Combinatorial Genomic Approaches to Identify Alternative Therapeutic Targets within the TSC Signaling Network

DTIC Science & Technology

2014-06-01

Specifically, we combined the CRISPR genome editing system with a novel approach allowing efficient single cell cloning of Drosophila cells with the aim of...and culture these to produce cultures completely lacking wildtype sequence at the target locus. No robust methods existed to clone single Drosophila ...targeting all kinases and phosphatases (563 genes) in the Drosophila genome . 65 samples that displayed synthetic lethality (15 genes) or synthetic

Minimizing Statistical Bias with Queries.

DTIC Science & Technology

1995-09-14

method for optimally selecting these points would o er enormous savings in time and money. An active learning system will typically attempt to select data...research in active learning assumes that the sec- ond term of Equation 2 is approximately zero, that is, that the learner is unbiased. If this is the case...outperforms the variance- minimizing algorithm and random exploration. and e ective strategy for active learning . I have given empirical evidence that, with

A sibling method for identifying vQTLs

PubMed Central

Domingue, Ben; Dawes, Christopher; Boardman, Jason; Siegal, Mark

2018-01-01

The propensity of a trait to vary within a population may have evolutionary, ecological, or clinical significance. In the present study we deploy sibling models to offer a novel and unbiased way to ascertain loci associated with the extent to which phenotypes vary (variance-controlling quantitative trait loci, or vQTLs). Previous methods for vQTL-mapping either exclude genetically related individuals or treat genetic relatedness among individuals as a complicating factor addressed by adjusting estimates for non-independence in phenotypes. The present method uses genetic relatedness as a tool to obtain unbiased estimates of variance effects rather than as a nuisance. The family-based approach, which utilizes random variation between siblings in minor allele counts at a locus, also allows controls for parental genotype, mean effects, and non-linear (dominance) effects that may spuriously appear to generate variation. Simulations show that the approach performs equally well as two existing methods (squared Z-score and DGLM) in controlling type I error rates when there is no unobserved confounding, and performs significantly better than these methods in the presence of small degrees of confounding. Using height and BMI as empirical applications, we investigate SNPs that alter within-family variation in height and BMI, as well as pathways that appear to be enriched. One significant SNP for BMI variability, in the MAST4 gene, replicated. Pathway analysis revealed one gene set, encoding members of several signaling pathways related to gap junction function, which appears significantly enriched for associations with within-family height variation in both datasets (while not enriched in analysis of mean levels). We recommend approximating laboratory random assignment of genotype using family data and more careful attention to the possible conflation of mean and variance effects. PMID:29617452

Rasch-family models are more valuable than score-based approaches for analysing longitudinal patient-reported outcomes with missing data.

PubMed

de Bock, Élodie; Hardouin, Jean-Benoit; Blanchin, Myriam; Le Neel, Tanguy; Kubis, Gildas; Bonnaud-Antignac, Angélique; Dantan, Étienne; Sébille, Véronique

2016-10-01

The objective was to compare classical test theory and Rasch-family models derived from item response theory for the analysis of longitudinal patient-reported outcomes data with possibly informative intermittent missing items. A simulation study was performed in order to assess and compare the performance of classical test theory and Rasch model in terms of bias, control of the type I error and power of the test of time effect. The type I error was controlled for classical test theory and Rasch model whether data were complete or some items were missing. Both methods were unbiased and displayed similar power with complete data. When items were missing, Rasch model remained unbiased and displayed higher power than classical test theory. Rasch model performed better than the classical test theory approach regarding the analysis of longitudinal patient-reported outcomes with possibly informative intermittent missing items mainly for power. This study highlights the interest of Rasch-based models in clinical research and epidemiology for the analysis of incomplete patient-reported outcomes data. © The Author(s) 2013.

Impurity-induced anisotropic semiconductor-semimetal transition in monolayer biased black phosphorus

NASA Astrophysics Data System (ADS)

Bui, D. H.; Yarmohammadi, Mohsen

2018-07-01

Taking into account the electron-impurity interaction within the continuum approximation of tight-binding model, the Born approximation, and the Green's function method, the main features of anisotropic electronic phase transition are investigated in monolayer biased black phosphorus (BP). To this end, we concentrated on the disordered electronic density of states (DOS), which gives useful information for electro-optical devices. Increasing the impurity concentration in both unbiased and biased impurity-infected single-layer BP, in addition to the decrease of the band gap, independent of the direction, leads to the midgap states and an extra Van Hove singularity inside and outside of the band gap, respectively. Furthermore, strong impurity scattering potentials lead to a semiconductor-semimetal transition and one more Van Hove singularity in x-direction of unbiased BP and surprisingly, this transition does not occur in biased BP. We found that there is no phase transition in y-direction. Since real applications require structures with modulated band gaps, we have studied the influence of different bias voltages on the disordered DOS in both directions, resulting in the increase of the band gap.

Optimal estimation of diffusion coefficients from single-particle trajectories

NASA Astrophysics Data System (ADS)

Vestergaard, Christian L.; Blainey, Paul C.; Flyvbjerg, Henrik

2014-02-01

How does one optimally determine the diffusion coefficient of a diffusing particle from a single-time-lapse recorded trajectory of the particle? We answer this question with an explicit, unbiased, and practically optimal covariance-based estimator (CVE). This estimator is regression-free and is far superior to commonly used methods based on measured mean squared displacements. In experimentally relevant parameter ranges, it also outperforms the analytically intractable and computationally more demanding maximum likelihood estimator (MLE). For the case of diffusion on a flexible and fluctuating substrate, the CVE is biased by substrate motion. However, given some long time series and a substrate under some tension, an extended MLE can separate particle diffusion on the substrate from substrate motion in the laboratory frame. This provides benchmarks that allow removal of bias caused by substrate fluctuations in CVE. The resulting unbiased CVE is optimal also for short time series on a fluctuating substrate. We have applied our estimators to human 8-oxoguanine DNA glycolase proteins diffusing on flow-stretched DNA, a fluctuating substrate, and found that diffusion coefficients are severely overestimated if substrate fluctuations are not accounted for.

New Approach for Investigating Reaction Dynamics and Rates with Ab Initio Calculations.

PubMed

Fleming, Kelly L; Tiwary, Pratyush; Pfaendtner, Jim

2016-01-21

Herein, we demonstrate a convenient approach to systematically investigate chemical reaction dynamics using the metadynamics (MetaD) family of enhanced sampling methods. Using a symmetric SN2 reaction as a model system, we applied infrequent metadynamics, a theoretical framework based on acceleration factors, to quantitatively estimate the rate of reaction from biased and unbiased simulations. A systematic study of the algorithm and its application to chemical reactions was performed by sampling over 5000 independent reaction events. Additionally, we quantitatively reweighed exhaustive free-energy calculations to obtain the reaction potential-energy surface and showed that infrequent metadynamics works to effectively determine Arrhenius-like activation energies. Exact agreement with unbiased high-temperature kinetics is also shown. The feasibility of using the approach on actual ab initio molecular dynamics calculations is then presented by using Car-Parrinello MD+MetaD to sample the same reaction using only 10-20 calculations of the rare event. Owing to the ease of use and comparatively low-cost of computation, the approach has extensive potential applications for catalysis, combustion, pyrolysis, and enzymology.

Gene–Environment Correlation: Difficulties and a Natural Experiment–Based Strategy

PubMed Central

Li, Jiang; Liu, Hexuan; Guo, Guang

2013-01-01

Objectives. We explored how gene–environment correlations can result in endogenous models, how natural experiments can protect against this threat, and if unbiased estimates from natural experiments are generalizable to other contexts. Methods. We compared a natural experiment, the College Roommate Study, which measured genes and behaviors of college students and their randomly assigned roommates in a southern public university, with observational data from the National Longitudinal Study of Adolescent Health in 2008. We predicted exposure to exercising peers using genetic markers and estimated environmental effects on alcohol consumption. A mixed-linear model estimated an alcohol consumption variance that was attributable to genetic markers and across peer environments. Results. Peer exercise environment was associated with respondent genotype in observational data, but not in the natural experiment. The effects of peer drinking and presence of a general gene–environment interaction were similar between data sets. Conclusions. Natural experiments, like random roommate assignment, could protect against potential bias introduced by gene–environment correlations. When combined with representative observational data, unbiased and generalizable causal effects could be estimated. PMID:23927502

The influence of SO4 and NO3 to the acidity (pH) of rainwater using minimum variance quadratic unbiased estimation (MIVQUE) and maximum likelihood methods

NASA Astrophysics Data System (ADS)

Dilla, Shintia Ulfa; Andriyana, Yudhie; Sudartianto

2017-03-01

Acid rain causes many bad effects in life. It is formed by two strong acids, sulfuric acid (H2SO4) and nitric acid (HNO3), where sulfuric acid is derived from SO2 and nitric acid from NOx {x=1,2}. The purpose of the research is to find out the influence of So4 and NO3 levels contained in the rain to the acidity (pH) of rainwater. The data are incomplete panel data with two-way error component model. The panel data is a collection of some of the observations that observed from time to time. It is said incomplete if each individual has a different amount of observation. The model used in this research is in the form of random effects model (REM). Minimum variance quadratic unbiased estimation (MIVQUE) is used to estimate the variance error components, while maximum likelihood estimation is used to estimate the parameters. As a result, we obtain the following model: Ŷ* = 0.41276446 - 0.00107302X1 + 0.00215470X2.

Response: Reading between the lines of cancer screening trials: using modeling to understand the evidence.

PubMed

Etzioni, Ruth; Gulati, Roman

2013-04-01

In our article about limitations of basing screening policy on screening trials, we offered several examples of ways in which modeling, using data from large screening trials and population trends, provided insights that differed somewhat from those based only on empirical trial results. In this editorial, we take a step back and consider the general question of whether randomized screening trials provide the strongest evidence for clinical guidelines concerning population screening programs. We argue that randomized trials provide a process that is designed to protect against certain biases but that this process does not guarantee that inferences based on empirical results from screening trials will be unbiased. Appropriate quantitative methods are key to obtaining unbiased inferences from screening trials. We highlight several studies in the statistical literature demonstrating that conventional survival analyses of screening trials can be misleading and list a number of key questions concerning screening harms and benefits that cannot be answered without modeling. Although we acknowledge the centrality of screening trials in the policy process, we maintain that modeling constitutes a powerful tool for screening trial interpretation and screening policy development.

Diabat Interpolation for Polymorph Free-Energy Differences.

PubMed

Kamat, Kartik; Peters, Baron

2017-02-02

Existing methods to compute free-energy differences between polymorphs use harmonic approximations, advanced non-Boltzmann bias sampling techniques, and/or multistage free-energy perturbations. This work demonstrates how Bennett's diabat interpolation method ( J. Comput. Phys. 1976, 22, 245 ) can be combined with energy gaps from lattice-switch Monte Carlo techniques ( Phys. Rev. E 2000, 61, 906 ) to swiftly estimate polymorph free-energy differences. The new method requires only two unbiased molecular dynamics simulations, one for each polymorph. To illustrate the new method, we compute the free-energy difference between face-centered cubic and body-centered cubic polymorphs for a Gaussian core solid. We discuss the justification for parabolic models of the free-energy diabats and similarities to methods that have been used in studies of electron transfer.

Current and efficiency of Brownian particles under oscillating forces in entropic barriers

NASA Astrophysics Data System (ADS)

Nutku, Ferhat; Aydιner, Ekrem

2015-04-01

In this study, considering the temporarily unbiased force and different forms of oscillating forces, we investigate the current and efficiency of Brownian particles in an entropic tube structure and present the numerically obtained results. We show that different force forms give rise to different current and efficiency profiles in different optimized parameter intervals. We find that an unbiased oscillating force and an unbiased temporal force lead to the current and efficiency, which are dependent on these parameters. We also observe that the current and efficiency caused by temporal and different oscillating forces have maximum and minimum values in different parameter intervals. We conclude that the current or efficiency can be controlled dynamically by adjusting the parameters of entropic barriers and applied force. Project supported by the Funds from Istanbul University (Grant No. 45662).

An Example of an Improvable Rao-Blackwell Improvement, Inefficient Maximum Likelihood Estimator, and Unbiased Generalized Bayes Estimator.

PubMed

Galili, Tal; Meilijson, Isaac

2016-01-02

The Rao-Blackwell theorem offers a procedure for converting a crude unbiased estimator of a parameter θ into a "better" one, in fact unique and optimal if the improvement is based on a minimal sufficient statistic that is complete. In contrast, behind every minimal sufficient statistic that is not complete, there is an improvable Rao-Blackwell improvement. This is illustrated via a simple example based on the uniform distribution, in which a rather natural Rao-Blackwell improvement is uniformly improvable. Furthermore, in this example the maximum likelihood estimator is inefficient, and an unbiased generalized Bayes estimator performs exceptionally well. Counterexamples of this sort can be useful didactic tools for explaining the true nature of a methodology and possible consequences when some of the assumptions are violated. [Received December 2014. Revised September 2015.].

Quantum key distribution for composite dimensional finite systems

NASA Astrophysics Data System (ADS)

Shalaby, Mohamed; Kamal, Yasser

2017-06-01

The application of quantum mechanics contributes to the field of cryptography with very important advantage as it offers a mechanism for detecting the eavesdropper. The pioneering work of quantum key distribution uses mutually unbiased bases (MUBs) to prepare and measure qubits (or qudits). Weak mutually unbiased bases (WMUBs) have weaker properties than MUBs properties, however, unlike MUBs, a complete set of WMUBs can be constructed for systems with composite dimensions. In this paper, we study the use of weak mutually unbiased bases (WMUBs) in quantum key distribution for composite dimensional finite systems. We prove that the security analysis of using a complete set of WMUBs to prepare and measure the quantum states in the generalized BB84 protocol, gives better results than using the maximum number of MUBs that can be constructed, when they are analyzed against the intercept and resend attack.

Model Reduction via Principe Component Analysis and Markov Chain Monte Carlo (MCMC) Methods

NASA Astrophysics Data System (ADS)

Gong, R.; Chen, J.; Hoversten, M. G.; Luo, J.

2011-12-01

Geophysical and hydrogeological inverse problems often include a large number of unknown parameters, ranging from hundreds to millions, depending on parameterization and problems undertaking. This makes inverse estimation and uncertainty quantification very challenging, especially for those problems in two- or three-dimensional spatial domains. Model reduction technique has the potential of mitigating the curse of dimensionality by reducing total numbers of unknowns while describing the complex subsurface systems adequately. In this study, we explore the use of principal component analysis (PCA) and Markov chain Monte Carlo (MCMC) sampling methods for model reduction through the use of synthetic datasets. We compare the performances of three different but closely related model reduction approaches: (1) PCA methods with geometric sampling (referred to as 'Method 1'), (2) PCA methods with MCMC sampling (referred to as 'Method 2'), and (3) PCA methods with MCMC sampling and inclusion of random effects (referred to as 'Method 3'). We consider a simple convolution model with five unknown parameters as our goal is to understand and visualize the advantages and disadvantages of each method by comparing their inversion results with the corresponding analytical solutions. We generated synthetic data with noise added and invert them under two different situations: (1) the noised data and the covariance matrix for PCA analysis are consistent (referred to as the unbiased case), and (2) the noise data and the covariance matrix are inconsistent (referred to as biased case). In the unbiased case, comparison between the analytical solutions and the inversion results show that all three methods provide good estimates of the true values and Method 1 is computationally more efficient. In terms of uncertainty quantification, Method 1 performs poorly because of relatively small number of samples obtained, Method 2 performs best, and Method 3 overestimates uncertainty due to inclusion of random effects. However, in the biased case, only Method 3 correctly estimates all the unknown parameters, and both Methods 1 and 2 provide wrong values for the biased parameters. The synthetic case study demonstrates that if the covariance matrix for PCA analysis is inconsistent with true models, the PCA methods with geometric or MCMC sampling will provide incorrect estimates.

Markov state models from short non-equilibrium simulations—Analysis and correction of estimation bias

NASA Astrophysics Data System (ADS)

Nüske, Feliks; Wu, Hao; Prinz, Jan-Hendrik; Wehmeyer, Christoph; Clementi, Cecilia; Noé, Frank

2017-03-01

Many state-of-the-art methods for the thermodynamic and kinetic characterization of large and complex biomolecular systems by simulation rely on ensemble approaches, where data from large numbers of relatively short trajectories are integrated. In this context, Markov state models (MSMs) are extremely popular because they can be used to compute stationary quantities and long-time kinetics from ensembles of short simulations, provided that these short simulations are in "local equilibrium" within the MSM states. However, over the last 15 years since the inception of MSMs, it has been controversially discussed and not yet been answered how deviations from local equilibrium can be detected, whether these deviations induce a practical bias in MSM estimation, and how to correct for them. In this paper, we address these issues: We systematically analyze the estimation of MSMs from short non-equilibrium simulations, and we provide an expression for the error between unbiased transition probabilities and the expected estimate from many short simulations. We show that the unbiased MSM estimate can be obtained even from relatively short non-equilibrium simulations in the limit of long lag times and good discretization. Further, we exploit observable operator model (OOM) theory to derive an unbiased estimator for the MSM transition matrix that corrects for the effect of starting out of equilibrium, even when short lag times are used. Finally, we show how the OOM framework can be used to estimate the exact eigenvalues or relaxation time scales of the system without estimating an MSM transition matrix, which allows us to practically assess the discretization quality of the MSM. Applications to model systems and molecular dynamics simulation data of alanine dipeptide are included for illustration. The improved MSM estimator is implemented in PyEMMA of version 2.3.

Validation of abundance estimates from mark–recapture and removal techniques for rainbow trout captured by electrofishing in small streams

USGS Publications Warehouse

Rosenberger, Amanda E.; Dunham, Jason B.

2005-01-01

Estimation of fish abundance in streams using the removal model or the Lincoln - Peterson mark - recapture model is a common practice in fisheries. These models produce misleading results if their assumptions are violated. We evaluated the assumptions of these two models via electrofishing of rainbow trout Oncorhynchus mykiss in central Idaho streams. For one-, two-, three-, and four-pass sampling effort in closed sites, we evaluated the influences of fish size and habitat characteristics on sampling efficiency and the accuracy of removal abundance estimates. We also examined the use of models to generate unbiased estimates of fish abundance through adjustment of total catch or biased removal estimates. Our results suggested that the assumptions of the mark - recapture model were satisfied and that abundance estimates based on this approach were unbiased. In contrast, the removal model assumptions were not met. Decreasing sampling efficiencies over removal passes resulted in underestimated population sizes and overestimates of sampling efficiency. This bias decreased, but was not eliminated, with increased sampling effort. Biased removal estimates based on different levels of effort were highly correlated with each other but were less correlated with unbiased mark - recapture estimates. Stream size decreased sampling efficiency, and stream size and instream wood increased the negative bias of removal estimates. We found that reliable estimates of population abundance could be obtained from models of sampling efficiency for different levels of effort. Validation of abundance estimates requires extra attention to routine sampling considerations but can help fisheries biologists avoid pitfalls associated with biased data and facilitate standardized comparisons among studies that employ different sampling methods.

Dynamics and Instabilities of the Shastry-Sutherland Model

NASA Astrophysics Data System (ADS)

Wang, Zhentao; Batista, Cristian D.

2018-06-01

We study the excitation spectrum in the dimer phase of the Shastry-Sutherland model by using an unbiased variational method that works in the thermodynamic limit. The method outputs dynamical correlation functions in all possible channels. This output is exploited to identify the order parameters with the highest susceptibility (single or multitriplon condensation in a specific channel) upon approaching a quantum phase transition in the magnetic field versus the J'/J phase diagram. We find four different instabilities: antiferro spin nematic, plaquette spin nematic, stripe magnetic order, and plaquette order, two of which have been reported in previous studies.

Comparing least-squares and quantile regression approaches to analyzing median hospital charges.

PubMed

Olsen, Cody S; Clark, Amy E; Thomas, Andrea M; Cook, Lawrence J

2012-07-01

Emergency department (ED) and hospital charges obtained from administrative data sets are useful descriptors of injury severity and the burden to EDs and the health care system. However, charges are typically positively skewed due to costly procedures, long hospital stays, and complicated or prolonged treatment for few patients. The median is not affected by extreme observations and is useful in describing and comparing distributions of hospital charges. A least-squares analysis employing a log transformation is one approach for estimating median hospital charges, corresponding confidence intervals (CIs), and differences between groups; however, this method requires certain distributional properties. An alternate method is quantile regression, which allows estimation and inference related to the median without making distributional assumptions. The objective was to compare the log-transformation least-squares method to the quantile regression approach for estimating median hospital charges, differences in median charges between groups, and associated CIs. The authors performed simulations using repeated sampling of observed statewide ED and hospital charges and charges randomly generated from a hypothetical lognormal distribution. The median and 95% CI and the multiplicative difference between the median charges of two groups were estimated using both least-squares and quantile regression methods. Performance of the two methods was evaluated. In contrast to least squares, quantile regression produced estimates that were unbiased and had smaller mean square errors in simulations of observed ED and hospital charges. Both methods performed well in simulations of hypothetical charges that met least-squares method assumptions. When the data did not follow the assumed distribution, least-squares estimates were often biased, and the associated CIs had lower than expected coverage as sample size increased. Quantile regression analyses of hospital charges provide unbiased estimates even when lognormal and equal variance assumptions are violated. These methods may be particularly useful in describing and analyzing hospital charges from administrative data sets. © 2012 by the Society for Academic Emergency Medicine.

Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice

PubMed Central

Smeyne, Richard Jay; Breckenridge, Charles B.; Beck, Melissa; Jiao, Yun; Butt, Mark T.; Wolf, Jeffrey C.; Zadory, Dan; Minnema, Daniel J.; Sturgess, Nicholas C.; Travis, Kim Z.; Cook, Andrew R.; Smith, Lewis L.; Botham, Philip A.

2016-01-01

The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum. PMID:27788145

Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice.

PubMed

Smeyne, Richard Jay; Breckenridge, Charles B; Beck, Melissa; Jiao, Yun; Butt, Mark T; Wolf, Jeffrey C; Zadory, Dan; Minnema, Daniel J; Sturgess, Nicholas C; Travis, Kim Z; Cook, Andrew R; Smith, Lewis L; Botham, Philip A

2016-01-01

The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum.

Behavioral and Stereological Analysis of the Effects of Intermittent Feeding Diet on the Orally Administrated MDMA ("ecstasy") in Mice.

PubMed

Ebrahimian, Zeinab; Karimi, Zeinab; Khoshnoud, Mohammad Javad; Namavar, Mohammad Reza; Daraei, Bahram; Haidari, Mohsen Raza

2017-01-01

Background: 3,4-methylenedioxy-methamphetamine or MDMA (also known as "ecstasy" or "molly") is a commonly abused drug that affects behavior and can lead to neuronal damage. Intermittent feeding is an effective dietary protocol that promotes neuroprotection and improves behavioral outcomes in animal models of neurotoxicity and neurodegenerative diseases. In this study, we investigated the behavioral and histological outcomes of the effect of intermittent feeding on the orally administered MDMA in mice. Methods: The animals (male albino mice) were divided into four groups: ad libitum (AL), intermittent feeding (IF) (food given every other day), and AL and IF control groups. After five weeks, AL and IF groups were given a single oral dose of 20 or 60mg/kg MDMA. Behavior was assessed with the elevated plus-maze and the open field tests. Each of the treatment groups were then divided in to two groups: AL-AL (AL diet throughout), AL-IF (IF after MDMA administration), IF-IF (IF diet throughout), IF-AL (AL after MDMA administration). The second behavioral assessment was performed on ninth and 12th day after MDMA administration. The brains were then prepared with cresyl fast violet stain for stereology of the CA1 area of hippocampus. Results: The AL groups showed enhanced locomotion and anxiety compared to the IF ( p <0.001); however, IF groups showed significantly ( p <0.05) more locomotor activity and less anxiety recovery at ninth and 12th days compared to the AL animals. The neuronal numerical density was significantly ( p <0.05) higher in the hippocampus in the AL-IF groups compared to the AL-AL. Conclusion: IF regimen can significantly modify various behavioral characteristics induced by MDMA and promotes faster recovery from MDMA's anxiogenic effects. Additionally, IF regimen had neuroprotective effects on the neurons of the CA1 area of the hippocampus after a single oral dose of MDMA. We believe the results of our study support the need for further research examining the behavior modifying and neuroprotective potential of the IF regminen for the treatment of drug addiction in humans.

Stereological comparison of oocyte recruitment and batch fecundity estimates from paraffin and resin sections using spawning albacore (Thunnus alalunga) ovaries as a case study

NASA Astrophysics Data System (ADS)

Saber, Sámar; Macías, David; Ortiz de Urbina, Josetxu; Kjesbu, Olav Sigurd

2015-01-01

Traditional histological protocols in marine fish reproductive laboratories using paraffin as the embedding medium are now increasingly being replaced with protocols using resin instead. These procedures entail different degrees of tissue shrinkage complicating direct comparisons of measurement results across laboratories or articles. In this work we selected ovaries of spawning Mediterranean albacore (Thunnus alalunga) as the subject of our study to address the issue of structural changes, by contrasting values on oocyte recruitment and final batch fecundity given from the same tissue samples in both paraffin and resin. A modern stereological method, the oocyte packing density (OPD) theory, was used supported by initial studies on ovarian tissue sampling and measurement design. Examples of differences in the volume fraction of oocyte stages, free space and connective tissue were found between the embedding media. Mean oocyte diameters were smaller in paraffin than in resin with differences ranging between 0.5% in primary growth and 24.3% in hydration (HYD) stage oocytes. Fresh oocyte measurements showed that oocytes shrank as a consequence of the embedding process, reaching the maximal degree of shrinkage for oocytes in the HYD stage (45.8% in paraffin and 26.5% in resin). In order to assess the effect of oocyte shrinkage on the OPD result, and thereby on relative batch fecundity (Fr), oocyte diameters corrected and uncorrected for shrinkage, were used for estimations. Statistical significant differences were found (P < 0.05) between these two approaches in both embedding media. The average Fr was numerically smaller in paraffin compared to resin (86 ± 61 vs. 106 ± 54 oocytes per gram of body mass (mean ± SD)). For both embedding media statistical significant differences (P < 0.05) were seen between Fr results based on either oocytes in the germinal vesicle migration stage or HYD stage. As a valuable adjunct, the present use of the OPD theory made it possible to document that the oocyte recruitment of spawning ovaries of Mediterranean albacore followed the typical pattern of an asynchronous oocyte development and indeterminate fecundity.

Ways to improve your correlation functions

NASA Technical Reports Server (NTRS)

Hamilton, A. J. S.

1993-01-01

This paper describes a number of ways to improve on the standard method for measuring the two-point correlation function of large scale structure in the Universe. Issues addressed are: (1) the problem of the mean density, and how to solve it; (2) how to estimate the uncertainty in a measured correlation function; (3) minimum variance pair weighting; (4) unbiased estimation of the selection function when magnitudes are discrete; and (5) analytic computation of angular integrals in background pair counts.

Fast State-Space Methods for Inferring Dendritic Synaptic Connectivity

DTIC Science & Technology

2013-08-08

the results of 100 simulations with the same parameters as in Figures 4 and 5. As expected, the LARS/LARS+ results are (downward) biased and have low...with a strength slightly biased toward lower values. To measure the variability of the results across the 20 simulations , we computed for each...are downward biased and have low variance, and the OLS results are unbiased but have high variance. Note that for LARS+ the values above the median are

Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations.

PubMed

Core, Jason Q; Mehrabi, Mehrsa; Robinson, Zachery R; Ochs, Alexander R; McCarthy, Linda A; Zaragoza, Michael V; Grosberg, Anna

2017-01-01

Nuclear shape defects are a distinguishing characteristic in laminopathies, cancers, and other pathologies. Correlating these defects to the symptoms, mechanisms, and progression of disease requires unbiased, quantitative, and high-throughput means of quantifying nuclear morphology. To accomplish this, we developed a method of automatically segmenting fluorescently stained nuclei in 2D microscopy images and then classifying them as normal or dysmorphic based on three geometric features of the nucleus using a package of Matlab codes. As a test case, cultured skin-fibroblast nuclei of individuals possessing LMNA splice-site mutation (c.357-2A>G), LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4, LMNA missense mutation (c.1003C>T, pR335W) in exon 6, Hutchinson-Gilford Progeria Syndrome, and no LMNA mutations were analyzed. For each cell type, the percentage of dysmorphic nuclei, and other morphological features such as average nuclear area and average eccentricity were obtained. Compared to blind observers, our procedure implemented in Matlab codes possessed similar accuracy to manual counting of dysmorphic nuclei while being significantly more consistent. The automatic quantification of nuclear defects revealed a correlation between in vitro results and age of patients for initial symptom onset. Our results demonstrate the method's utility in experimental studies of diseases affecting nuclear shape through automated, unbiased, and accurate identification of dysmorphic nuclei.

Advances in natural stable isotope ratio analysis of human hair to determine nutritional and metabolic status.

PubMed

Petzke, Klaus J; Fuller, Benjamin T; Metges, Cornelia C

2010-09-01

We review the literature on the use of stable isotope ratios at natural abundance to reveal information about dietary habits and specific nutrient intakes in human hair protein (keratin) and amino acids. In particular, we examine whether hair isotopic compositions can be used as unbiased biomarkers to provide information about nutritional status, metabolism, and diseases. Although the majority of research on the stable isotope ratio analysis of hair has focused on bulk protein, methods have been recently employed to examine amino acid-specific isotope ratios using gas chromatography or liquid chromatography coupled to an isotope ratio mass spectrometer. The isotopic measurement of amino acids has the potential to answer research questions on amino acid nutrition, metabolism, and disease processes and can contribute to a better understanding of the variations in bulk protein isotope ratio values. First results suggest that stable isotope ratios are promising as unbiased nutritional biomarkers in epidemiological research. However, variations in stable isotope ratios of human hair are also influenced by nutrition-dependent nitrogen balance, and more controlled clinical research is needed to examine these effects in human hair. Stable isotope ratio analysis at natural abundance in human hair protein offers a noninvasive method to reveal information about long-term nutritional exposure to specific nutrients, nutritional habits, and in the diagnostics of diseases leading to nutritional stress and impaired nitrogen balance.

Enrichment assessment of multiple virtual screening strategies for Toll-like receptor 8 agonists based on a maximal unbiased benchmarking data set.

PubMed

Pei, Fen; Jin, Hongwei; Zhou, Xin; Xia, Jie; Sun, Lidan; Liu, Zhenming; Zhang, Liangren

2015-11-01

Toll-like receptor 8 agonists, which activate adaptive immune responses by inducing robust production of T-helper 1-polarizing cytokines, are promising candidates for vaccine adjuvants. As the binding site of toll-like receptor 8 is large and highly flexible, virtual screening by individual method has inevitable limitations; thus, a comprehensive comparison of different methods may provide insights into seeking effective strategy for the discovery of novel toll-like receptor 8 agonists. In this study, the performance of knowledge-based pharmacophore, shape-based 3D screening, and combined strategies was assessed against a maximum unbiased benchmarking data set containing 13 actives and 1302 decoys specialized for toll-like receptor 8 agonists. Prior structure-activity relationship knowledge was involved in knowledge-based pharmacophore generation, and a set of antagonists was innovatively used to verify the selectivity of the selected knowledge-based pharmacophore. The benchmarking data set was generated from our recently developed 'mubd-decoymaker' protocol. The enrichment assessment demonstrated a considerable performance through our selected three-layer virtual screening strategy: knowledge-based pharmacophore (Phar1) screening, shape-based 3D similarity search (Q4_combo), and then a Gold docking screening. This virtual screening strategy could be further employed to perform large-scale database screening and to discover novel toll-like receptor 8 agonists. © 2015 John Wiley & Sons A/S.

MRMC analysis of agreement studies

NASA Astrophysics Data System (ADS)

Gallas, Brandon D.; Anam, Amrita; Chen, Weijie; Wunderlich, Adam; Zhang, Zhiwei

2016-03-01

The purpose of this work is to present and evaluate methods based on U-statistics to compare intra- or inter-reader agreement across different imaging modalities. We apply these methods to multi-reader multi-case (MRMC) studies. We measure reader-averaged agreement and estimate its variance accounting for the variability from readers and cases (an MRMC analysis). In our application, pathologists (readers) evaluate patient tissue mounted on glass slides (cases) in two ways. They evaluate the slides on a microscope (reference modality) and they evaluate digital scans of the slides on a computer display (new modality). In the current work, we consider concordance as the agreement measure, but many of the concepts outlined here apply to other agreement measures. Concordance is the probability that two readers rank two cases in the same order. Concordance can be estimated with a U-statistic and thus it has some nice properties: it is unbiased, asymptotically normal, and its variance is given by an explicit formula. Another property of a U-statistic is that it is symmetric in its inputs; it doesn't matter which reader is listed first or which case is listed first, the result is the same. Using this property and a few tricks while building the U-statistic kernel for concordance, we get a mathematically tractable problem and efficient software. Simulations show that our variance and covariance estimates are unbiased.

Multifractals embedded in short time series: An unbiased estimation of probability moment

NASA Astrophysics Data System (ADS)

Qiu, Lu; Yang, Tianguang; Yin, Yanhua; Gu, Changgui; Yang, Huijie

2016-12-01

An exact estimation of probability moments is the base for several essential concepts, such as the multifractals, the Tsallis entropy, and the transfer entropy. By means of approximation theory we propose a new method called factorial-moment-based estimation of probability moments. Theoretical prediction and computational results show that it can provide us an unbiased estimation of the probability moments of continuous order. Calculations on probability redistribution model verify that it can extract exactly multifractal behaviors from several hundred recordings. Its powerfulness in monitoring evolution of scaling behaviors is exemplified by two empirical cases, i.e., the gait time series for fast, normal, and slow trials of a healthy volunteer, and the closing price series for Shanghai stock market. By using short time series with several hundred lengths, a comparison with the well-established tools displays significant advantages of its performance over the other methods. The factorial-moment-based estimation can evaluate correctly the scaling behaviors in a scale range about three generations wider than the multifractal detrended fluctuation analysis and the basic estimation. The estimation of partition function given by the wavelet transform modulus maxima has unacceptable fluctuations. Besides the scaling invariance focused in the present paper, the proposed factorial moment of continuous order can find its various uses, such as finding nonextensive behaviors of a complex system and reconstructing the causality relationship network between elements of a complex system.

STACCATO: a novel solution to supernova photometric classification with biased training sets

NASA Astrophysics Data System (ADS)

Revsbech, E. A.; Trotta, R.; van Dyk, D. A.

2018-01-01

We present a new solution to the problem of classifying Type Ia supernovae from their light curves alone given a spectroscopically confirmed but biased training set, circumventing the need to obtain an observationally expensive unbiased training set. We use Gaussian processes (GPs) to model the supernovae's (SN's) light curves, and demonstrate that the choice of covariance function has only a small influence on the GPs ability to accurately classify SNe. We extend and improve the approach of Richards et al. - a diffusion map combined with a random forest classifier - to deal specifically with the case of biased training sets. We propose a novel method called Synthetically Augmented Light Curve Classification (STACCATO) that synthetically augments a biased training set by generating additional training data from the fitted GPs. Key to the success of the method is the partitioning of the observations into subgroups based on their propensity score of being included in the training set. Using simulated light curve data, we show that STACCATO increases performance, as measured by the area under the Receiver Operating Characteristic curve (AUC), from 0.93 to 0.96, close to the AUC of 0.977 obtained using the 'gold standard' of an unbiased training set and significantly improving on the previous best result of 0.88. STACCATO also increases the true positive rate for SNIa classification by up to a factor of 50 for high-redshift/low-brightness SNe.

Developing Novel Therapeutics Targeting Undifferentiated and Castration-Resistant Prostate Cancer Stem Cells

DTIC Science & Technology

2016-10-01

identify PCSC- specific homing peptides ; and 2) To perform unbiased drug library screening to identify novel PCSC-targeting chemicals. In the past...display library (PDL) screening in PSA-/lo PCa cells to identify PCSC- specific homing peptides ; and 2) To perform unbiased drug library screening to...Goals of the Project (SOW): Aim 1: To perform phage display library (PDL) screening in PSA-/lo PCa cells to identify PCSC- specific homing peptides

Long Term Follow up of the Delayed Effects of Acute Radiation Exposure in Primates

DTIC Science & Technology

2017-10-01

66 of 94 We will then use shRNAs and/or CRISPR constructs targeting the gene of interest to knock down its expression in stem cells prior to...DLBCLs Mutational profiling identifies 150 driver genes Gene expression identifies sub- groups including cell of origin Unbiased CRISPR screen...Exome sequencing in 1,001 DLBCL patients comprehensively identifies 150 driver genes d Unbiased CRISPR screen in DLBCL cell lines identifies essential

Four photon parametric amplification. [in unbiased Josephson junction

NASA Technical Reports Server (NTRS)

Parrish, P. T.; Feldman, M. J.; Ohta, H.; Chiao, R. Y.

1974-01-01

An analysis is presented describing four-photon parametric amplification in an unbiased Josephson junction. Central to the theory is the model of the Josephson effect as a nonlinear inductance. Linear, small signal analysis is applied to the two-fluid model of the Josephson junction. The gain, gain-bandwidth product, high frequency limit, and effective noise temperature are calculated for a cavity reflection amplifier. The analysis is extended to multiple (series-connected) junctions and subharmonic pumping.

Test of mutually unbiased bases for six-dimensional photonic quantum systems

PubMed Central

D'Ambrosio, Vincenzo; Cardano, Filippo; Karimi, Ebrahim; Nagali, Eleonora; Santamato, Enrico; Marrucci, Lorenzo; Sciarrino, Fabio

2013-01-01

In quantum information, complementarity of quantum mechanical observables plays a key role. The eigenstates of two complementary observables form a pair of mutually unbiased bases (MUBs). More generally, a set of MUBs consists of bases that are all pairwise unbiased. Except for specific dimensions of the Hilbert space, the maximal sets of MUBs are unknown in general. Even for a dimension as low as six, the identification of a maximal set of MUBs remains an open problem, although there is strong numerical evidence that no more than three simultaneous MUBs do exist. Here, by exploiting a newly developed holographic technique, we implement and test different sets of three MUBs for a single photon six-dimensional quantum state (a “qusix”), encoded exploiting polarization and orbital angular momentum of photons. A close agreement is observed between theory and experiments. Our results can find applications in state tomography, quantitative wave-particle duality, quantum key distribution. PMID:24067548

Test of mutually unbiased bases for six-dimensional photonic quantum systems.

PubMed

D'Ambrosio, Vincenzo; Cardano, Filippo; Karimi, Ebrahim; Nagali, Eleonora; Santamato, Enrico; Marrucci, Lorenzo; Sciarrino, Fabio

2013-09-25

In quantum information, complementarity of quantum mechanical observables plays a key role. The eigenstates of two complementary observables form a pair of mutually unbiased bases (MUBs). More generally, a set of MUBs consists of bases that are all pairwise unbiased. Except for specific dimensions of the Hilbert space, the maximal sets of MUBs are unknown in general. Even for a dimension as low as six, the identification of a maximal set of MUBs remains an open problem, although there is strong numerical evidence that no more than three simultaneous MUBs do exist. Here, by exploiting a newly developed holographic technique, we implement and test different sets of three MUBs for a single photon six-dimensional quantum state (a "qusix"), encoded exploiting polarization and orbital angular momentum of photons. A close agreement is observed between theory and experiments. Our results can find applications in state tomography, quantitative wave-particle duality, quantum key distribution.

Mutually unbiased coarse-grained measurements of two or more phase-space variables

NASA Astrophysics Data System (ADS)

Paul, E. C.; Walborn, S. P.; Tasca, D. S.; Rudnicki, Łukasz

2018-05-01

Mutual unbiasedness of the eigenstates of phase-space operators—such as position and momentum, or their standard coarse-grained versions—exists only in the limiting case of infinite squeezing. In Phys. Rev. Lett. 120, 040403 (2018), 10.1103/PhysRevLett.120.040403, it was shown that mutual unbiasedness can be recovered for periodic coarse graining of these two operators. Here we investigate mutual unbiasedness of coarse-grained measurements for more than two phase-space variables. We show that mutual unbiasedness can be recovered between periodic coarse graining of any two nonparallel phase-space operators. We illustrate these results through optics experiments, using the fractional Fourier transform to prepare and measure mutually unbiased phase-space variables. The differences between two and three mutually unbiased measurements is discussed. Our results contribute to bridging the gap between continuous and discrete quantum mechanics, and they could be useful in quantum-information protocols.

A semi-automatic method for positioning a femoral bone reconstruction for strict view generation.

PubMed

Milano, Federico; Ritacco, Lucas; Gomez, Adrian; Gonzalez Bernaldo de Quiros, Fernan; Risk, Marcelo

2010-01-01

In this paper we present a semi-automatic method for femoral bone positioning after 3D image reconstruction from Computed Tomography images. This serves as grounding for the definition of strict axial, longitudinal and anterior-posterior views, overcoming the problem of patient positioning biases in 2D femoral bone measuring methods. After the bone reconstruction is aligned to a standard reference frame, new tomographic slices can be generated, on which unbiased measures may be taken. This could allow not only accurate inter-patient comparisons but also intra-patient comparisons, i.e., comparisons of images of the same patient taken at different times. This method could enable medical doctors to diagnose and follow up several bone deformities more easily.

Experimental preparation and characterization of four-dimensional quantum states using polarization and time-bin modes of a single photon

NASA Astrophysics Data System (ADS)

Yoo, Jinwon; Choi, Yujun; Cho, Young-Wook; Han, Sang-Wook; Lee, Sang-Yun; Moon, Sung; Oh, Kyunghwan; Kim, Yong-Su

2018-07-01

We present a detailed method to prepare and characterize four-dimensional pure quantum states or ququarts using polarization and time-bin modes of a single-photon. In particular, we provide a simple method to generate an arbitrary pure ququart and fully characterize the state with quantum state tomography. We also verify the reliability of the recipe by showing experimental preparation and characterization of 20 ququart states in mutually unbiased bases. As qudits provide superior properties over qubits in many fundamental tests of quantum physics and applications in quantum information processing, the presented method will be useful for photonic quantum information science.

The technology and biology of single-cell RNA sequencing.

PubMed

Kolodziejczyk, Aleksandra A; Kim, Jong Kyoung; Svensson, Valentine; Marioni, John C; Teichmann, Sarah A

2015-05-21

The differences between individual cells can have profound functional consequences, in both unicellular and multicellular organisms. Recently developed single-cell mRNA-sequencing methods enable unbiased, high-throughput, and high-resolution transcriptomic analysis of individual cells. This provides an additional dimension to transcriptomic information relative to traditional methods that profile bulk populations of cells. Already, single-cell RNA-sequencing methods have revealed new biology in terms of the composition of tissues, the dynamics of transcription, and the regulatory relationships between genes. Rapid technological developments at the level of cell capture, phenotyping, molecular biology, and bioinformatics promise an exciting future with numerous biological and medical applications. Copyright © 2015 Elsevier Inc. All rights reserved.

Quantitative assessment of fibroblast growth factor receptor 1 expression in neurons and glia.

PubMed

Choubey, Lisha; Collette, Jantzen C; Smith, Karen Müller

2017-01-01

Fibroblast growth factors (FGFs) and their receptors (FGFRs) have numerous functions in the developing and adult central nervous system (CNS). For example, the FGFR1 receptor is important for proliferation and fate specification of radial glial cells in the cortex and hippocampus, oligodendrocyte proliferation and regeneration, midline glia morphology and soma translocation, Bergmann glia morphology, and cerebellar morphogenesis. In addition, FGFR1 signaling in astrocytes is required for postnatal maturation of interneurons expressing parvalbumin (PV). FGFR1 is implicated in synapse formation in the hippocampus, and alterations in the expression of Fgfr1 and its ligand, Fgf2 accompany major depression. Understanding which cell types express Fgfr1 during development may elucidate its roles in normal development of the brain as well as illuminate possible causes of certain neuropsychiatric disorders. Here, we used a BAC transgenic reporter line to trace Fgfr1 expression in the developing postnatal murine CNS. The specific transgenic line employed was created by the GENSAT project, tgFGFR1-EGFPGP338Gsat , and includes a gene encoding enhanced green fluorescent protein ( EGFP ) under the regulation of the Fgfr1 promoter, to trace Fgfr1 expression in the developing CNS. Unbiased stereological counts were performed for several cell types in the cortex and hippocampus. This model reveals that Fgfr1 is primarily expressed in glial cells, in both astrocytes and oligodendrocytes, along with some neurons. Dual labeling experiments indicate that the proportion of GFP+ ( Fgfr1 +) cells that are also GFAP+ increases from postnatal day 7 (P7) to 1 month, illuminating dynamic changes in Fgfr1 expression during postnatal development of the cortex. In postnatal neurogenic areas, GFP expression was also observed in SOX2, doublecortin (DCX), and brain lipid-binding protein (BLBP) expressing cells. Fgfr1 is also highly expressed in DCX positive cells of the dentate gyrus (DG), but not in the rostral migratory stream. Fgfr1 driven GFP was also observed in tanycytes and GFAP+ cells of the hypothalamus, as well as in Bergmann glia and astrocytes of the cerebellum. The tgFGFR1-EGFPGP338Gsat mouse model expresses GFP that is congruent with known functions of FGFR1, including hippocampal development, glial cell development, and stem cell proliferation. Understanding which cell types express Fgfr1 may elucidate its role in neuropsychiatric disorders and brain development.

Dynamic Histogram Analysis To Determine Free Energies and Rates from Biased Simulations.

PubMed

Stelzl, Lukas S; Kells, Adam; Rosta, Edina; Hummer, Gerhard

2017-12-12

We present an algorithm to calculate free energies and rates from molecular simulations on biased potential energy surfaces. As input, it uses the accumulated times spent in each state or bin of a histogram and counts of transitions between them. Optimal unbiased equilibrium free energies for each of the states/bins are then obtained by maximizing the likelihood of a master equation (i.e., first-order kinetic rate model). The resulting free energies also determine the optimal rate coefficients for transitions between the states or bins on the biased potentials. Unbiased rates can be estimated, e.g., by imposing a linear free energy condition in the likelihood maximization. The resulting "dynamic histogram analysis method extended to detailed balance" (DHAMed) builds on the DHAM method. It is also closely related to the transition-based reweighting analysis method (TRAM) and the discrete TRAM (dTRAM). However, in the continuous-time formulation of DHAMed, the detailed balance constraints are more easily accounted for, resulting in compact expressions amenable to efficient numerical treatment. DHAMed produces accurate free energies in cases where the common weighted-histogram analysis method (WHAM) for umbrella sampling fails because of slow dynamics within the windows. Even in the limit of completely uncorrelated data, where WHAM is optimal in the maximum-likelihood sense, DHAMed results are nearly indistinguishable. We illustrate DHAMed with applications to ion channel conduction, RNA duplex formation, α-helix folding, and rate calculations from accelerated molecular dynamics. DHAMed can also be used to construct Markov state models from biased or replica-exchange molecular dynamics simulations. By using binless WHAM formulated as a numerical minimization problem, the bias factors for the individual states can be determined efficiently in a preprocessing step and, if needed, optimized globally afterward.

Estimating unbiased phenological trends by adapting site-occupancy models.

PubMed

Roth, Tobias; Strebel, Nicolas; Amrhein, Valentin

2014-08-01

As a response to climate warming, many animals and plants have been found to shift phenologies, such as appearance in spring or timing of reproduction. However, traditional measures for shifts in phenology that are based on observational data likely are biased due to a large influence of population size, observational effort, starting date of a survey, or other causes that may affect the probability of detecting a species. Understanding phenological responses of species to climate change, however, requires a robust measure that could be compared among studies and study years. Here, we developed a new method for estimating arrival and departure dates based on site-occupancy models. Using simulated data, we show that our method provided virtually unbiased estimates of phenological events even if detection probability or the number of sites occupied by the species is changing over time. To illustrate the flexibility of our method, we analyzed spring arrival of two long-distance migrant songbirds and the length of the flight period of two butterfly species, using data from a long-term biodiversity monitoring program in Switzerland. In contrast to many birds that migrate short distances, the two long-distance migrant songbirds tended to postpone average spring arrival by -0.5 days per year between 1995 and 2012. Furthermore, the flight period of the short-distance-flying butterfly species apparently became even shorter over the study period, while the flight period of the longer-distance-flying butterfly species remained relatively stable. Our method could be applied to temporally and spatially extensive data from a wide range of monitoring programs and citizen science projects, to help unravel how species and communities respond to global warming.

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

Garcia-Mateo, Carlos, E-mail: cgm@cenim.csic.es

Since the major strengthening mechanisms in nanocrystalline bainitic steels arise from the exceptionally small size of the bainitc ferrite plate, accurate determination of this parameter is fundamental for quantitative relating the microstructure to the mechanical properties. In this work, the thickness of the bainitic ferrite subunits obtained by different bainitic heat treatments was determined in two steels, with carbon contents of 0.3 and 0.7 wt.%, from SEM and TEM micrographs. As these measurements were made on 2D images taken from random sections, the method includes some stereological correction factors to obtain accurate information. Finally, the determined thicknesses of bainitic ferritemore » plates were compared with the crystallite size calculated from the analysis of X-ray diffraction peak broadening. Although in some case the values obtained for crystallite size and plate thickness can be similar, this study confirms that indeed they are two different parameters. - Highlights: •Bainitic microstructure in a nanostructured and sub-micron steel •Bainitic ferrite plate thickness measured by SEM and TEM •Crystallite size determined by X-ray analysis.« less

Neurite density from magnetic resonance diffusion measurements at ultrahigh field: Comparison with light microscopy and electron microscopy

PubMed Central

Jespersen, Sune N.; Bjarkam, Carsten R.; Nyengaard, Jens R.; Chakravarty, M. Mallar; Hansen, Brian; Vosegaard, Thomas; Østergaard, Leif; Yablonskiy, Dmitriy; Nielsen, Niels Chr.; Vestergaard-Poulsen, Peter

2010-01-01

Due to its unique sensitivity to tissue microstructure, diffusion-weighted magnetic resonance imaging (MRI) has found many applications in clinical and fundamental science. With few exceptions, a more precise correspondence between physiological or biophysical properties and the obtained diffusion parameters remain uncertain due to lack of specificity. In this work, we address this problem by comparing diffusion parameters of a recently introduced model for water diffusion in brain matter to light microscopy and quantitative electron microscopy. Specifically, we compare diffusion model predictions of neurite density in rats to optical myelin staining intensity and stereological estimation of neurite volume fraction using electron microscopy. We find that the diffusion model describes data better and that its parameters show stronger correlation with optical and electron microscopy, and thus reflect myelinated neurite density better than the more frequently used diffusion tensor imaging (DTI) and cumulant expansion methods. Furthermore, the estimated neurite orientations capture dendritic architecture more faithfully than DTI diffusion ellipsoids. PMID:19732836

Is video gaming, or video game addiction, associated with depression, academic achievement, heavy episodic drinking, or conduct problems?

PubMed Central

Brunborg, Geir Scott; Mentzoni, Rune Aune; Frøyland, Lars Roar

2014-01-01

Background and aims: While the relationships between video game use and negative consequences are debated, the relationships between video game addiction and negative consequences are fairly well established. However, previous studies suffer from methodological weaknesses that may have caused biased results. There is need for further investigation that benefits from the use of methods that avoid omitted variable bias. Methods: Two wave panel data was used from two surveys of 1,928 Norwegian adolescents aged 13 to 17 years. The surveys included measures of video game use, video game addiction, depression, heavy episodic drinking, academic achievement, and conduct problems. The data was analyzed using first-differencing, a regression method that is unbiased by time invariant individual factors. Results: Video game addiction was related to depression, lower academic achievement, and conduct problems, but time spent on video games was not related to any of the studied negative outcomes. Discussion: The findings were in line with a growing number of studies that have failed to find relationships between time spent on video games and negative outcomes. The current study is also consistent with previous studies in that video game addiction was related to other negative outcomes, but it made the added contribution that the relationships are unbiased by time invariant individual effects. However, future research should aim at establishing the temporal order of the supposed causal effects. Conclusions: Spending time playing video games does not involve negative consequences, but adolescents who experience problems related to video games are likely to also experience problems in other facets of life. PMID:25215212

Characterization of background concentrations of contaminants using a mixture of normal distributions.

PubMed

Qian, Song S; Lyons, Regan E

2006-10-01

We present a Bayesian approach for characterizing background contaminant concentration distributions using data from sites that may have been contaminated. Our method, focused on estimation, resolves several technical problems of the existing methods sanctioned by the U.S. Environmental Protection Agency (USEPA) (a hypothesis testing based method), resulting in a simple and quick procedure for estimating background contaminant concentrations. The proposed Bayesian method is applied to two data sets from a federal facility regulated under the Resource Conservation and Restoration Act. The results are compared to background distributions identified using existing methods recommended by the USEPA. The two data sets represent low and moderate levels of censorship in the data. Although an unbiased estimator is elusive, we show that the proposed Bayesian estimation method will have a smaller bias than the EPA recommended method.

Anabolic effects of chrysin on the ventral male prostate and female prostate of adult gerbils (Meriones unguiculatus).

PubMed

Campos, Mônica S; Ribeiro, Naiara C S; de Lima, Rodrigo F; Santos, Mariana B; Vilamaior, Patrícia S L; Regasini, Luis O; Biancardi, Manoel F; Taboga, Sebastião R; Santos, Fernanda C A

2018-03-07

Chrysin is a bioflavonoid found in fruits, flowers, tea, honey and wine, which has antioxidant, anti-inflammatory, antiallergic and anticarcinogenic properties. This flavone has also been considered as beneficial for reproduction due its testosterone-boosting potential. Thus, the aim of this study was to evaluate the effects of chrysin on the prostate and gonads of male and female adult gerbils. In addition, a comparative analysis of the effects of testosterone on these same organs was conducted. Ninety-day-old male and female gerbils were treated with chrysin (50mgkg-1day-1) or testosterone cypionate (1mgkg-1week-1) for 21 days. The ventral male prostate and female prostate were dissected out for morphological, morphometric-stereological and ultrastructural assays. Testes and ovaries were submitted to morphological and morphometric---stereological analyses. Chrysin treatment caused epithelial hyperplasia and stromal remodelling of the ventral male and female prostate. Ultrastructurally, male and female prostatic epithelial cells in the chrysin group presented marked development of the organelles involved in the biosynthetic-secretory pathway, whereas cellular toxicity was observed only in female glands. Chrysin preserved normal testicular morphology and increased the number of growing ovarian follicles. Comparatively, testosterone treatment was detrimental to the prostate and gonads, since foci of prostatic intraepithelial neoplasia and gonadal degeneration were observed in both sexes. Thus, under the experimental conditions of this study, chrysin was better tolerated than testosterone in the prostate and gonads.

A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology.

PubMed

Defres, Sylviane; Keller, Simon S; Das, Kumar; Vidyasagar, Rishma; Parkes, Laura M; Burnside, Girvan; Griffiths, Michael; Kopelman, Michael; Roberts, Neil; Solomon, Tom

2017-01-01

To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis.

Cortical orofacial motor representation in Old World monkeys, great apes, and humans. II. Stereologic analysis of chemoarchitecture.

PubMed

Sherwood, Chet C; Holloway, Ralph L; Erwin, Joseph M; Hof, Patrick R

2004-01-01

This study presents a comparative stereologic investigation of neurofilament protein- and calcium-binding protein-immunoreactive neurons within the region of orofacial representation of primary motor cortex (Brodmann's area 4) in several catarrhine primate species (Macaca fascicularis, Papio anubis, Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, and Homo sapiens). Results showed that the density of interneurons involved in vertical interlaminar processing (i.e., calbindin- and calretinin-immunoreactive neurons) as well pyramidal neurons that supply heavily-myelinated projections (i.e., neurofilament protein-immunoreactive neurons) are correlated with overall neuronal density, whereas interneurons making transcolumnar connections (i.e., parvalbumin-immunoreactive neurons) do not exhibit such a relationship. These results suggest that differential scaling rules apply to different neuronal subtypes depending on their functional role in cortical circuitry. For example, cortical columns across catarrhine species appear to involve a similar conserved network of intracolumnar inhibitory interconnections, as represented by the distribution of calbindin- and calretinin-immunoreactive neurons. The subpopulation of horizontally-oriented wide-arbor interneurons, on the other hand, increases in density relative to other interneuron subpopulations in large brains. Due to these scaling trends, the region of orofacial representation of primary motor cortex in great apes and humans is characterized by a greater proportion of neurons enriched in neurofilament protein and parvalbumin compared to the Old World monkeys examined. These modifications might contribute to the voluntary dexterous control of orofacial muscles in great ape and human communication. Copyright 2004 S. Karger AG, Basel

Stereology shows that damaged liver recovers after protein refeeding.

PubMed

Gomes, Silvio Pires; da Silva, Andréa Almeida Pinto; Crisma, Amanda Rabello; Borelli, Primavera; Hernandez-Blazquez, Francisco Javier; de Melo, Mariana P; Bacci, Barbara; Loesch, Andrzej; Coppi, A Augusto

2017-06-01

The aim of the present study was to investigate the putative effects of a low-protein diet on the three-dimensional structure of hepatocytes and determine whether this scenario could be reversed by restoring the adequate levels of protein to the diet. Using design-based stereology, the total number and volume of hepatocytes were estimated in the liver of mice in healthy and altered (by protein malnutrition) conditions and after protein renutrition. This study demonstrated a 65% decrease in the liver volume (3302 mm 3 for the control for undernourished versus 1141 mm 3 for the undernourished group) accompanied by a 46% reduction in the hepatocyte volume (8223 μm 3 for the control for undernourished versus 4475 μm 3 for the undernourished group) and a 90% increase in the total number of binucleate hepatocytes (1 549 393 for the control for undernourished versus 2 941 353 for the undernourished group). Reinstating a normoproteinic diet (12% casein) proved to be effective in restoring the size of hepatocytes, leading to an 85% increase in the total number of uninucleate hepatocytes (15 988 560 for the undernourished versus 29 600 520 for the renourished group), and partially reversed the liver atrophy. Awareness of these data will add to a better morphologic understanding of malnutrition-induced hepatopathies and will help clinicians improve the diagnosis and treatment of this condition in humans and in veterinary practice. Copyright © 2017 Elsevier Inc. All rights reserved.

The acute effect of ethanol on adrenal cortex in female rats--possible role of nitric oxide.

PubMed

Dikić, Dragoslava; Budeč, Mirela; Vranješ-Durić, Sanja; Koko, Vesna; Vignjević, Sanja; Mitrović, Olivera

2011-01-01

The present study was designed to investigate a possible role of endogenous nitric oxide (NO) in the adrenal response to an acute alcohol administration in female rats. To this end, N(ω)-nitro-L-arginine-methyl ester (L-NAME), a competitive inhibitor of all isoforms of NO synthase, was used. Adult female Wistar rats showing diestrus Day 1 were treated with: (a) ethanol (2 or 4 g/kg, intraperitoneally); (b) L-NAME (30 or 50 mg/kg, subcutaneously) followed by either ethanol or saline 3 h later. Untreated and saline-injected rats were used as controls. The animals were killed 30 min after last injection. Adrenal cortex was analyzed morphometrically, and plasma levels of adrenocorticotropic hormone (ACTH) and serum concentrations of corticosterone were determined. Acute ethanol treatment enhanced the levels of ACTH and corticosterone in a dose-dependent manner. Stereological analysis revealed that acute alcohol administration induced a significant increase in absolute volume of the cortex and the zona fasciculata (ZF). In addition, ethanol at a dose of 4 g/kg increased volume density and length of the capillaries in the ZF. However, other stereological parameters were unaffected by alcohol exposure. Pretreatment with both doses of L-NAME had no effect on ethanol-induced changes. Obtained findings indicate that acute ethanol treatment stimulates the activity of the adrenal cortex and that this effect is not mediated by endogenous NO in female rats under these experimental conditions.

Cross-Layer Resource Allocation for Wireless Visual Sensor Networks and Mobile Ad Hoc Networks

DTIC Science & Technology

2014-10-01

MMD), minimizes the maximum dis- tortion among all nodes of the network, promoting a rather unbiased treatment of the nodes. We employed the Particle...achieve the ideal tradeoff between the transmitted video quality and energy consumption. Each sensor node has a bit rate that can be used for both...Distortion (MMD), minimizes the maximum distortion among all nodes of the network, promoting a rather unbiased treatment of the nodes. For both criteria

Simulation of design-unbiased point-to-particle sampling compared to alternatives on plantation rows

Treesearch

Thomas B. Lynch; David Hamlin; Mark J. Ducey

2016-01-01

Total quantities of tree attributes can be estimated in plantations by sampling on plantation rows using several methods. At random sample points on a row, either fixed row lengths or variable row lengths with a fixed number of sample trees can be assessed. Ratio of means or mean of ratios estimators can be developed for the fixed number of trees option but are not...

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset | Office of Cancer Genomics

Cancer.gov

Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset.

Identifying chromatin readers using a SILAC-based histone peptide pull-down approach.

PubMed

Vermeulen, Michiel

2012-01-01

Posttranslational modifications (PTMs) on core histones regulate essential processes inside the nucleus such as transcription, replication, and DNA repair. An important function of histone PTMs is the recruitment or stabilization of chromatin-modifying proteins, which are also called chromatin "readers." We have developed a generic SILAC-based peptide pull-down approach to identify such readers for histone PTMs in an unbiased manner. In this chapter, the workflow behind this method will be presented in detail. Copyright © 2012 Elsevier Inc. All rights reserved.

Molecular Confirmation of the Specific Status of Anopheles halophylus (Diptera: Culicidae) and Evidence of a New Cryptic Species within An. triannulatus in Central Brazil

DTIC Science & Technology

2006-01-01

unbiased genetic dis- tances and characterized using the unweighted pair group method with arithmetic means ( UPGMA ). Re- Table 1. Gene frequencies for...0.428, and between An. halophylus and the morpho- logical variant was 0.145, supporting the observations seen with allozymes. A UPGMA dendrogram based...and R. C. Wilkerson. 2005. Anopheles tri- annulatus (Neiva and Pinto): a new Anopheles record Fig. 2. UPGMA dendrogram constructed based on RAPD

The Arms Control and Crisis Management Potential of the Proposed International Satellite Monitoring Agency (ISMA)

DTIC Science & Technology

1984-12-01

unbiased scientific method , is widespread in the West. This is particularly true of the two arms control functions to which an ISMA would contribute...Elizabeth Young (Lord and Lady Kennett), Neitber Red Nor Dead:_ The Case for Dis• aumAmjeif, Social Democratic Party (SDP), Open Forum Paper No. 2...in the national interest. The Soviet Union is not the first, and is unlikely to be the last, country to adopt a . narrow, constructionist approach to

Robertsonian translocations

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

NONE

1993-12-31

Chapter 27, describes the occurrence of Robertsonian translocations (RTs), which refer to the recombination of whole chromosome arms, in both monocentric and dicentric chromosomes. The nonrandom participation of acrocentric chromosomes in RTs is documented by various methods, including unbiased ascertainment and ascertainment through trisomy, infertility, unspecified mental retardation, and Prader-Willi syndrome. Causes of nonrandom participation of chromosomes in RTs is presented, as are the following topics: segregation in carriers of RTs and segregation in sperm cells of RT carriers, interchromosomal effects and conclusions. 48 refs., 3 figs., 2 tabs.

Follicle Detection on the USG Images to Support Determination of Polycystic Ovary Syndrome

NASA Astrophysics Data System (ADS)

Adiwijaya; Purnama, B.; Hasyim, A.; Septiani, M. D.; Wisesty, U. N.; Astuti, W.

2015-06-01

Polycystic Ovary Syndrome(PCOS) is the most common endocrine disorders affected to female in their reproductive cycle. This has gained the attention from married couple which affected by infertility. One of the diagnostic criteria considereded by the doctor is analysing manually the ovary USG image to detect the number and size of ovary's follicle. This analysis may affect low varibilites, reproducibility, and efficiency. To overcome this problems. automatic scheme is suggested to detect the follicle on USG image in supporting PCOS diagnosis. The first scheme is determining the initial homogeneous region which will be segmented into real follicle form The next scheme is selecting the appropriate regions to follicle criteria. then measuring the segmented region attribute as the follicle. The measurement remains the number and size that aimed at categorizing the image into the PCOS or non-PCOS. The method used is region growing which includes region-based and seed-based. To measure the follicle diameter. there will be the different method including stereology and euclidean distance. The most optimum system plan to detect PCO is by using region growing and by using euclidean distance on quantification of follicle.

Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys

PubMed Central

Konopaske, Glenn T.; Dorph-Petersen, Karl-Anton; Sweet, Robert A.; Pierri, Joseph N.; Zhang, Wei; Sampson, Allan R.; Lewis, David A.

2008-01-01

Background Both in vivo and post-mortem studies suggest that oligodendrocyte and myelination alterations are present in individuals with schizophrenia. However, it is unclear whether prolonged treatment with antipsychotic medications contributes to these disturbances. We recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine was associated with a 10−18% lower glial cell number in the parietal grey matter. Consequently, in this study we sought to determine whether the lower glial cell number was due to fewer oligodendrocytes as opposed to lower numbers of astrocytes. Methods Using fluorescent immunocytochemical techniques, we optimized the visualization of each cell type throughout the entire thickness of tissue sections, while minimizing final tissue shrinkage. As a result, we were able to obtain robust stereological estimates of total oligodendrocyte and astrocyte numbers in the parietal grey matter using the optical fractionator method. Results We found a significant 20.5% lower astrocyte number with a non-significant 12.9% lower oligodendrocyte number in the antipsychotic-exposed monkeys. Similar effects were seen in both the haloperidol and olanzapine groups. Conclusion These findings suggest that studies investigating glial cell alterations in schizophrenia must take into account the effect of antipsychotic treatment. PMID:17945195

Effect of Early Neonatal Exposure to Deltamethrin on the Purkinje Cell Number in Rat Cerebellum

PubMed Central

Asari, Mohd Asnizam; Abdullah, Mohammad Shukri; Abdullah, Suryati

2008-01-01

Deltamethrin is a widely used insecticide belonging to the class of pyrethroid. Although the neurotoxicity of pyrethroids including deltamethrin is well established, it is still unclear whether exposure to deltamethrin during neonatal period has any deleterious effect on the survival of the Purkinje cells in the cerebellum. In the study, we investigated the total number of Purkinje cells in experimental rats exposed to deltamethrin using a stereological method, the fractionator. Deltamethrin in a dose of 1 mg/kg/day (corresponds to 20% of LD50 ) was administered through oral gavage to male pups from 2nd to 5th postnatal day (PND). At PND 21 the animals were sacrificed and their cerebelli were removed. The cerebelli were systematically sampled using the fractionator method and stained with cresyl fast violet. The number of the Purkinje cells was counted for each cerebellum. The results showed that there was no significant difference in the total number of Purkinje cells in the deltamethrin-treated group as compared to the control animals. This suggests that deltamethrin exposure at the current dosage during the neonatal period do not have any significant effect on the survival of the Purkinje cells in the cerebellum. PMID:22570585

Testing and Validation of Computational Methods for Mass Spectrometry.

PubMed

Gatto, Laurent; Hansen, Kasper D; Hoopmann, Michael R; Hermjakob, Henning; Kohlbacher, Oliver; Beyer, Andreas

2016-03-04

High-throughput methods based on mass spectrometry (proteomics, metabolomics, lipidomics, etc.) produce a wealth of data that cannot be analyzed without computational methods. The impact of the choice of method on the overall result of a biological study is often underappreciated, but different methods can result in very different biological findings. It is thus essential to evaluate and compare the correctness and relative performance of computational methods. The volume of the data as well as the complexity of the algorithms render unbiased comparisons challenging. This paper discusses some problems and challenges in testing and validation of computational methods. We discuss the different types of data (simulated and experimental validation data) as well as different metrics to compare methods. We also introduce a new public repository for mass spectrometric reference data sets ( http://compms.org/RefData ) that contains a collection of publicly available data sets for performance evaluation for a wide range of different methods.

Rapid System to Quantitatively Characterize the Airborne Microbial Community

NASA Technical Reports Server (NTRS)

Macnaughton, Sarah J.

1998-01-01

Bioaerosols have been linked to a wide range of different allergies and respiratory illnesses. Currently, microorganism culture is the most commonly used method for exposure assessment. Such culture techniques, however, generally fail to detect between 90-99% of the actual viable biomass. Consequently, an unbiased technique for detecting airborne microorganisms is essential. In this Phase II proposal, a portable air sampling device his been developed for the collection of airborne microbial biomass from indoor (and outdoor) environments. Methods were evaluated for extracting and identifying lipids that provide information on indoor air microbial biomass, and automation of these procedures was investigated. Also, techniques to automate the extraction of DNA were explored.

Population annealing with weighted averages: A Monte Carlo method for rough free-energy landscapes

NASA Astrophysics Data System (ADS)

Machta, J.

2010-08-01

The population annealing algorithm introduced by Hukushima and Iba is described. Population annealing combines simulated annealing and Boltzmann weighted differential reproduction within a population of replicas to sample equilibrium states. Population annealing gives direct access to the free energy. It is shown that unbiased measurements of observables can be obtained by weighted averages over many runs with weight factors related to the free-energy estimate from the run. Population annealing is well suited to parallelization and may be a useful alternative to parallel tempering for systems with rough free-energy landscapes such as spin glasses. The method is demonstrated for spin glasses.

Orbital debris: A technical assessment

NASA Technical Reports Server (NTRS)

Gleghorn, George; Asay, James; Atkinson, Dale; Flury, Walter; Johnson, Nicholas; Kessler, Donald; Knowles, Stephen; Rex, Dietrich; Toda, Susumu; Veniaminov, Stanislav

1995-01-01

To acquire an unbiased technical assessment of (1) the research needed to better understand the debris environment, (2) the necessity and means of protecting spacecraft against the debris environment, and (3) potential methods of reducing the future debris hazard, NASA asked the National Research Council to form an international committee to examine the orbital debris issue. The committee was asked to draw upon available data and analyses to: characterize the current debris environment, project how this environment might change in the absence of new measures to alleviate debris proliferation, examine ongoing alleviation activities, explore measures to address the problem, and develop recommendations on technical methods to address the problems of debris proliferation.

The Evolution of 3D Microimaging Techniques in Geosciences

NASA Astrophysics Data System (ADS)

Sahagian, D.; Proussevitch, A.

2009-05-01

In the analysis of geomaterials, it is essential to be able to analyze internal structures on a quantitative basis. Techniques have evolved from rough qualitative methods to highly accurate quantitative methods coupled with 3-D numerical analysis. The earliest primitive method for "seeing'" what was inside a rock was multiple sectioning to produce a series of image slices. This technique typically completely destroyed the sample being analyzed. Another destructive method was developed to give more detailed quantitative information by forming plastic casts of internal voids in sedimentary and volcanic rocks. For this, void were filled with plastic and the rock dissolved away with HF to reveal plastic casts of internal vesicles. Later, new approaches to stereology were developed to extract 3D information from 2D cross-sectional images. This has long been possible for spheres because the probability distribution for cutting a sphere along any small circle is known analytically (greatest probability is near the equator). However, large numbers of objects are required for statistical validity, and geomaterials are seldom spherical, so crystals, vesicles, and other inclusions would need a more sophisticated approach. Consequently, probability distributions were developed using numerical techniques for rectangular solids and various ellipsoids so that stereological techniques could be applied to these. The "holy grail" has always been to obtain 3D quantitative images non-destructively. A key method is Computed X-ray Tomography (CXT), in which attenuation of X-rays is recorded as a function of angular position in a cylindrical sample, providing a 2D "slice" of the interior. When a series of these "slices" is stacked (in increments equivalent with the resolution of the X-ray to make cubic voxels), a 3D image results with quantitative information regarding internal structure, particle/void volumes, nearest neighbors, coordination numbers, preferred orientations, etc. CXT can be done at three basic levels of resolution, with "normal" x-rays providing tens of microns resolution, synchrotron sources providing single to few microns, and emerging XuM techniques providing a practical 300 nm and theoretical 60 nm. The main challenges in CXT imaging have been in segmentation, which delineates material boundaries, and object recognition (registration), in which the individual objects within a material are identified. The former is critical in quantifying object volume, while the latter is essential for preventing the false appearance of individual objects as a continuous structure. Additional, new techniques are now being developed to enhance resolution and provide more detailed analysis without the complex infrastructure needed for CXT. One such method is Laser Scanning Confocal Microscopy, in which a laser is reflected from individual interior surfaces of a fluorescing material, providing a series of sharp images of internal slices with quantitative information available, just as in x-ray tomography, after "z-stacking" of planes of pixels. Another novel approach is the use of Stereo Scanning Electron Microscopy to create digital elevation models of 3D surficial features such as partial bubble margins on the surfaces of fine volcanic ash particles. As other novel techniques emerge, new opportunities will be presented to the geological research community to obtain ever more detailed and accurate information regarding the interior structure of geomaterials.

Unbiased contaminant removal for 3D galaxy power spectrum measurements

NASA Astrophysics Data System (ADS)

Kalus, B.; Percival, W. J.; Bacon, D. J.; Samushia, L.

2016-11-01

We assess and develop techniques to remove contaminants when calculating the 3D galaxy power spectrum. We separate the process into three separate stages: (I) removing the contaminant signal, (II) estimating the uncontaminated cosmological power spectrum and (III) debiasing the resulting estimates. For (I), we show that removing the best-fitting contaminant (mode subtraction) and setting the contaminated components of the covariance to be infinite (mode deprojection) are mathematically equivalent. For (II), performing a quadratic maximum likelihood (QML) estimate after mode deprojection gives an optimal unbiased solution, although it requires the manipulation of large N_mode^2 matrices (Nmode being the total number of modes), which is unfeasible for recent 3D galaxy surveys. Measuring a binned average of the modes for (II) as proposed by Feldman, Kaiser & Peacock (FKP) is faster and simpler, but is sub-optimal and gives rise to a biased solution. We present a method to debias the resulting FKP measurements that does not require any large matrix calculations. We argue that the sub-optimality of the FKP estimator compared with the QML estimator, caused by contaminants, is less severe than that commonly ignored due to the survey window.

Cluster Masses Derived from X-ray and Sunyaev-Zeldovich Effect Measurements

NASA Technical Reports Server (NTRS)

Laroque, S.; Joy, Marshall; Bonamente, M.; Carlstrom, J.; Dawson, K.

2003-01-01

We infer the gas mass and total gravitational mass of 11 clusters using two different methods; analysis of X-ray data from the Chandra X-ray Observatory and analysis of centimeter-wave Sunyaev-Zel'dovich Effect (SZE) data from the BIMA and OVRO interferometers. This flux-limited sample of clusters from the BCS cluster catalogue was chosen so as to be well above the surface brightness limit of the ROSAT All Sky Survey; this is therefore an orientation unbiased sample. The gas mass fraction, f_g, is calculated for each cluster using both X-ray and SZE data, and the results are compared at a fiducial radius of r_500. Comparison of the X-ray and SZE results for this orientation unbiased sample allows us to constrain cluster systematics, such as clumping of the intracluster medium. We derive an upper limit on Omega_M assuming that the mass composition of clusters within r_500 reflects the universal mass composition Omega_M h_100 is greater than Omega _B / f-g. We also demonstrate how the mean f_g derived from the sample can be used to estimate the masses of clusters discovered by upcoming deep SZE surveys.

Evaluation of the procedure 1A component of the 1980 US/Canada wheat and barley exploratory experiment

NASA Technical Reports Server (NTRS)

Chapman, G. M. (Principal Investigator); Carnes, J. G.

1981-01-01

Several techniques which use clusters generated by a new clustering algorithm, CLASSY, are proposed as alternatives to random sampling to obtain greater precision in crop proportion estimation: (1) Proportional Allocation/relative count estimator (PA/RCE) uses proportional allocation of dots to clusters on the basis of cluster size and a relative count cluster level estimate; (2) Proportional Allocation/Bayes Estimator (PA/BE) uses proportional allocation of dots to clusters and a Bayesian cluster-level estimate; and (3) Bayes Sequential Allocation/Bayesian Estimator (BSA/BE) uses sequential allocation of dots to clusters and a Bayesian cluster level estimate. Clustering in an effective method in making proportion estimates. It is estimated that, to obtain the same precision with random sampling as obtained by the proportional sampling of 50 dots with an unbiased estimator, samples of 85 or 166 would need to be taken if dot sets with AI labels (integrated procedure) or ground truth labels, respectively were input. Dot reallocation provides dot sets that are unbiased. It is recommended that these proportion estimation techniques are maintained, particularly the PA/BE because it provides the greatest precision.

Empirical Bayes Estimation of Semi-parametric Hierarchical Mixture Models for Unbiased Characterization of Polygenic Disease Architectures

PubMed Central

Nishino, Jo; Kochi, Yuta; Shigemizu, Daichi; Kato, Mamoru; Ikari, Katsunori; Ochi, Hidenori; Noma, Hisashi; Matsui, Kota; Morizono, Takashi; Boroevich, Keith A.; Tsunoda, Tatsuhiko; Matsui, Shigeyuki

2018-01-01

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic [~40% of independent genome-wide SNPs are risk variants, most within odds ratio (OR = 1.03)], whereas rheumatoid arthritis was less polygenic (~4 to 8% risk variants, significant portion reaching OR = 1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutations. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases. PMID:29740473

Unbiased Metabolite Profiling of Schizophrenia Fibroblasts under Stressful Perturbations Reveals Dysregulation of Plasmalogens and Phosphatidylcholines.

PubMed

Huang, Joanne H; Park, Hyoungjun; Iaconelli, Jonathan; Berkovitch, Shaunna S; Watmuff, Bradley; McPhie, Donna; Öngür, Dost; Cohen, Bruce M; Clish, Clary B; Karmacharya, Rakesh

2017-02-03

We undertook an unbiased metabolite profiling of fibroblasts from schizophrenia patients and healthy controls to identify metabolites and pathways that are dysregulated in disease, seeking to gain new insights into the disease biology of schizophrenia and to discover potential disease-related biomarkers. We measured polar and nonpolar metabolites in the fibroblasts under normal conditions and under two stressful physiological perturbations: growth in low-glucose media and exposure to the steroid hormone dexamethasone. We found that metabolites that were significantly different between schizophrenia and control subjects showed separation of the two groups by partial least-squares discriminant analysis methods. This separation between schizophrenia and healthy controls was more robust with metabolites identified under the perturbation conditions. The most significant individual metabolite differences were also found in the perturbation experiments. Metabolites that were significantly different between schizophrenia and healthy controls included a number of plasmalogens and phosphatidylcholines. We present these results in the context of previous reports of metabolic profiling of brain tissue and plasma in schizophrenia. These results show the applicability of metabolite profiling under stressful perturbations to reveal cellular pathways that may be involved in disease biology.

Should multiple imputation be the method of choice for handling missing data in randomized trials?

PubMed Central

Sullivan, Thomas R; White, Ian R; Salter, Amy B; Ryan, Philip; Lee, Katherine J

2016-01-01

The use of multiple imputation has increased markedly in recent years, and journal reviewers may expect to see multiple imputation used to handle missing data. However in randomized trials, where treatment group is always observed and independent of baseline covariates, other approaches may be preferable. Using data simulation we evaluated multiple imputation, performed both overall and separately by randomized group, across a range of commonly encountered scenarios. We considered both missing outcome and missing baseline data, with missing outcome data induced under missing at random mechanisms. Provided the analysis model was correctly specified, multiple imputation produced unbiased treatment effect estimates, but alternative unbiased approaches were often more efficient. When the analysis model overlooked an interaction effect involving randomized group, multiple imputation produced biased estimates of the average treatment effect when applied to missing outcome data, unless imputation was performed separately by randomized group. Based on these results, we conclude that multiple imputation should not be seen as the only acceptable way to handle missing data in randomized trials. In settings where multiple imputation is adopted, we recommend that imputation is carried out separately by randomized group. PMID:28034175

Should multiple imputation be the method of choice for handling missing data in randomized trials?

PubMed

Sullivan, Thomas R; White, Ian R; Salter, Amy B; Ryan, Philip; Lee, Katherine J

2016-01-01

The use of multiple imputation has increased markedly in recent years, and journal reviewers may expect to see multiple imputation used to handle missing data. However in randomized trials, where treatment group is always observed and independent of baseline covariates, other approaches may be preferable. Using data simulation we evaluated multiple imputation, performed both overall and separately by randomized group, across a range of commonly encountered scenarios. We considered both missing outcome and missing baseline data, with missing outcome data induced under missing at random mechanisms. Provided the analysis model was correctly specified, multiple imputation produced unbiased treatment effect estimates, but alternative unbiased approaches were often more efficient. When the analysis model overlooked an interaction effect involving randomized group, multiple imputation produced biased estimates of the average treatment effect when applied to missing outcome data, unless imputation was performed separately by randomized group. Based on these results, we conclude that multiple imputation should not be seen as the only acceptable way to handle missing data in randomized trials. In settings where multiple imputation is adopted, we recommend that imputation is carried out separately by randomized group.