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[Functional model of stationary signal formation in auditory analysis].

The model for spectrum transformation in the auditory analyser consists of three layers: that of filters whose parameters imitate the masking curves; that of non-linear transformers, the non-linearity parameters being chosen in such a way that the calculation results would correspond to the basic regularities of perception of stationary signal loudness; that of lateral inhibition. The weight function parameters of the latter were chosen according to a psychoacoustical experiment. By means of such a model the formant structure of the sound can be distinguished in a synthetic speech-like signal; at low frequencies to 1000 Hz besides formants the first harmonics are distinguished.

Hearing Tests↗

Stem cells in normal breast development and breast cancer.

The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self-renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem-cell model.

Animals↗

Molecular and endocrine biomarkers in non-involved breast: relevance to cancer chemoprevention.

The animal models for chemoprevention of breast cancer have provided important experimental systems to evaluate the efficacy of tumor suppression by dietary macro- and micronutrients. In the initiation/promotion cascade, early occurring premalignant changes constitute less extensively examined aspects of disease progression. Molecular, endocrine and cellular biomarkers may provide clinically relevant endpoints for prevention of breast cancer that focus on downregulation of preneoplastic transformation. In vitro models derived from non-involved murine and human mammary tissues are utilized to identify molecular, endocrine and cellular markers that are perturbed in response to such diverse initiators as viruses and chemical carcinogens. This upregulation was manifested as persistent Ras p21-GTP binding, altered C16 alpha/C2 hydroxylation of estradiol, and hyperplasia preceding tumorigenesis. Prototypic chemopreventive agents such as n-3 polyunsaturated fatty acids, retinoids, and indole-3-carbinol were capable of downregulating all of the preneoplastic markers perturbed by initiators. Experimental modulation of these biomarkers in murine and human mammary tissue prior to the expression of a fully transformed tumorigenic phenotype is suggestive of their potential clinical application in chemopreventive intervention for breast cancer.

Animals↗

Family bereavement and cultural diversity: a social developmental perspective.

This article offers an integrative, interdisciplinary model of bereavement as a family developmental process that unfolds in cultural context. A critique of cultural assumptions highlights the culture-bound nature of prevailing North American practices, which view grief as an isolated individual experience and emphasize detachment from the dead as a way to promote recovery. Death and grief precipitate two kinds of family change, both guided by culture yet uniquely experienced and interpreted by individual families: 1) recreating the family without a key family member, but capable of coping with both existing and new tasks; and 2) incorporating the death into an ongoing but irrevocably altered family life-cycle developmental process. In supporting family change after a death, family therapists need to collaborate with grieving families in examining the goodness of fit between their unique circumstances and the bereavement expectations of their community and culture. Four case examples are presented, two of which will apply this social developmental model to emphasize transformations of attachment to the deceased--rather than detachment--that will support the ongoing family development of grieving families.

Acculturation↗

Integral and unified model for the sewer and wastewater treatment plant focusing on transformations.

The urban drainage cycle is a very complex system with many interacting processes. Models are a great help to test different scenarios and improve the understanding of this system. At present, good models exist for the hydrodynamics of the sewer systems, for the biological conversions in the wastewater treatment plant (ASM 1 to 3) and for the receiving water (RWOM1). However, the traditional transport and conversion models for the sewer system are incompatible with the ASM definitions, making it difficult to link the models to come an integral and unified urban drainage model. In this work, a new sewer system model that is based on ASM3 has been coupled to an advanced nutrient removal model for the wastewater treatment plant. As both models are based on ASM3, they are unified in their definitions of the state variables and processes. This new combination has been used to test different scenarios and to test the influence of the sewer system on the treatment plant.

Cities↗

A mathematical model of cerebral blood flow chemical regulation--Part I: Diffusion processes.

This paper proposes a mathematical model which describes the production and diffusion of vasoactive chemical factors involved in oxygen-dependent cerebral blood flow (CBF) regulation in the rat. Partial differential equations describing the relations between input and output variables have been replaced with simpler ordinary differential equations by using mathematical approximations of the hyperbolic functions in the Laplace transform domain. This model is composed of two submodels. In the first, oxygen transport from capillary blood to cerebral tissue is analyzed to link changes in mean tissue oxygen pressure with CBF and arterial oxygen concentration changes. The second submodel presents equations describing the production of vasoactive metabolites by cerebral parenchyma, due to a lack of oxygen, and their diffusion towards pial perivascular space. These equations have been used to simulate the time dynamics of mean tissue PO2, perivascular adenosine concentration, and perivascular pH to changes in CBF. The present simulation points out that the time delay introduced by diffusion processes is negligible if compared with the other time constants of the system under study. In a subsequent work the same equations will be included in a model of the cerebral vascular bed to clarify the metabolite role in CBF regulation.

Animals↗

A general class of Bayesian survival models with zero and nonzero cure fractions.

We propose a new class of survival models which naturally links a family of proper and improper population survival functions. The models resulting in improper survival functions are often referred to as cure rate models. This class of regression models is formulated through the Box-Cox transformation on the population hazard function and a proper density function. By adding an extra transformation parameter into the cure rate model, we are able to generate models with a zero cure rate, thus leading to a proper population survival function. A graphical illustration of the behavior and the influence of the transformation parameter on the regression model is provided. We consider a Bayesian approach which is motivated by the complexity of the model. Prior specification needs to accommodate parameter constraints due to the non-negativity of the survival function. Moreover, the likelihood function involves a complicated integral on the survival function, which may not have an analytical closed form, and thus makes the implementation of Gibbs sampling more difficult. We propose an efficient Markov chain Monte Carlo computational scheme based on Gaussian quadrature. The proposed method is illustrated with an example involving a melanoma clinical trial.

Adult↗

Wavelet variance components in image space for spatiotemporal neuroimaging data.

Neuroimaging studies place great emphasis on not only the estimation but also the standard error estimates of underlying parameters derived from a temporal model. This allows inferences to be made about the signal estimates and resulting conclusions to be drawn about the underlying data. It can often be advantageous to interrogate temporal models after spatial transformation of the data into the wavelet domain. Wavelet bases provide a multiresolution decomposition of the spatial data dimension and an ensuing reduction in spatial correlation. However, widespread acceptance of these wavelet techniques has been hampered by the limited ability to reconstruct both parametric and error estimates into the image domain after analysis of temporal models in the wavelet domain. This paper introduces a derivation and a fast implementation of a method for the calculation of the variance of the parametric images obtained from wavelet filters. The technique is proposed for a class of estimators that have been shown to be useful in neuroimaging studies. The techniques are demonstrated for both functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) data sets.

Analysis of Variance↗

Comparison of the wound-activated transformation of caulerpenyne by invasive and noninvasive Caulerpa species of the Mediterranean.

The invasive green alga, Caulerpa taxifolia, that has spread rapidly after its introduction into the Mediterranean and the North American Pacific, reacts to wounding by transforming its major metabolite caulerpenyne. This wound-activated reaction involves the transformation of the bis-enol acetate moiety of 1, releasing reactive 1,4-dialdehydes. The ability to perform this transformation is found also in both the noninvasive Mediterranean C. prolifera and the invasive C. racemosa. Trapping experiments, as well as transformation of the model substrate geranyl acetate, suggest that all three investigated Caulerpa spp. rely on esterases that act upon wounding of the algae by subsequently removing the three acetate residues of caulerpenyne. The resulting reactive 1,4-dialdehyde oxytoxin 2 can be identified by liquid chromatography-mass spectrometry and is unstable in the wounded tissue. Caulerpenyne transformation occurs rapidly, and severe tissue damage caused degradation of more than 50% of the stored caulerpenyne within 1 min in all three algae. Prevention of the enzymatic reaction before extraction, by shock freezing the tissue with liquid nitrogen, was used for the determination of the caulerpenyne content in intact algae. It gives about twofold higher values compared to an established methanol extraction protocol. The speed and mechanism of the wound-activated transformation, as well as the caulerpenyne content in intact tissue of invasive and noninvasive Caulerpa spp., are comparable. Thus, this enzymatic transformation, despite being fast and efficient, is likely not the key for the success of the investigated invasive species.

Adaptation, Physiological↗

Essence: A benchmarking-validated transformer framework for early diagnosis of Parkinson's disease using cerebrospinal fluid protein biomarkers.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The lack of objective molecular biomarkers limits early diagnosis and personalized treatment. Here, we propose Essence, a benchmarking-validated framework integrating cerebrospinal fluid (CSF) proteomics with traditional and deep learning models to identify robust protein signatures for PD. Using data from two independent cohorts, 1266 high-confidence proteins are quantified, among which 178 exhibit differential abundance between PD and healthy controls (HC). Through systematic benchmarking of ten machine learning algorithms and four neural architectures, the Transformer model consistently outperforms alternatives across multiple feature selection strategies, achieving an area under the receiver operating characteristic curve (AUC) of 1.0000 with only 35 features. Functional analyses of the top-ranked 35 proteins reveal enrichment in neuroinflammatory, synaptic, and oxidative stress-related pathways. Importantly, spatial transcriptomic profiling based on the Allen Brain Atlas shows region-specific expression of these biomarkers in PD-relevant brain structures, including the striatum, subthalamic nucleus, hippocampus, and white matter tracts. This anatomical alignment supports the functional relevance of the identified markers and highlights their potential utility in early-stage diagnosis and mechanistic understanding of PD.

Benchmarking↗

To split behaviour into bouts, log-transform the intervals.

Analysis of behaviour that is displayed in bouts depends crucially on quantitative estimates of bout criteria, that is, the lengths of the shortest intervals between bouts. Current methods estimate bout criteria by modelling the log-transformed (cumulative) frequency distributions of intervals between events. For analysis of feeding behaviour, these models will not result in biologically meaningful quantitative estimates (Tolkamp et al. 1998, Journal of Theoretical Biology194, 235-250). We proposed a method that models the frequency distribution of log-transformed interval lengths instead. Applying this method to a single data set showed that the log-transformed lengths of intervals between feeding events were distributed as two Gaussians. Here we test this model using a data set of 35 171 intervals between feeding that was obtained during an experiment with 38 cows in three dietary treatment groups. No meaningful bout criterion could be obtained for some individuals, which casts doubt on the general validity of the proposed model. Addition of a third log-normal improved the fit of the model and we hypothesized that this third population represents intervals including drinking. In a second experiment, we found the measurements to be consistent with this hypothesis. We obtained meaningful meal criteria for all individuals by fitting either a double, or a triple, log-normal model to the frequency distributions of the lengths of intervals between feeding. These log-normal models appear to be not only more biologically meaningful than log (cumulative) frequency models but also far more flexible. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗

Abl kinase but not PI3-kinase links to the cytoskeletal defects in Bcr-Abl transformed cells.

OBJECTIVE: The purpose of this study was to investigate the contribution of Abl kinase and phosphatidylinositol 3-kinase (PI3-kinase) to the altered adhesive properties and cytoskeletal defects in a Bcr-Abl transformed fibroblast cell model. MATERIALS ANID METHODS: Two fibroblast cell lines stably transfected with Bcr-Abl were compared to their parental counterparts for alterations in their adhesive properties in an attachment assay and for abnormalities in their cytoskeletal architecture by immunofluorescence microscopy. Cells then were treated with specific inhibitors of either the Abl kinase CGP57148 or the PI3-kinase LY294002 to determine whether these treatments would restore normal cytoarchitecture and adhesion. RESULTS: [corrected] Significant defects in cytoskeletal architecture were observed using this fibroblast model of Bcr-Abl expression. Specific changes include loss of stress fibers and focal adhesions, which correlated with an adhesive defect. [corrected] Treatment of Bcr-Abl expressing cells with CGP57148, but not LY294002, resulted in reversion of cells to a near-normal phenotype, as assessed by immunofluorescence and attachment of Bcr-Abl transformed fibroblasts. CONCLUSIONS: Our studies demonstrate that Bcr-Abl tyrosine kinase but not PI3- kinase activity is required for maintenance of cytoskeletal rearrangements resulting from Bcr-AbI expression. Further, inhibition of Abl kinase restored normal adhesive properties to the Bcr-Abl-expressing cells, demonstrating the contribution of Bcr-Abl kinase activity to abnormal cytoskeletal function.

3T3 Cells↗

Global analysis of differential gene expression after transformation with the v-H-ras oncogene in a murine tumor model.

Mouse PB-3c mast cells stably transfected with the v-H-ras oncogene induce tumor formation in vivo when implanted into mice. Such tumor cells are characterized by an autocrine IL-3 loop. DNA microarrays allow simultaneous transcript imaging of several thousand genes and the technique was applied in this tumor model to analyse gene expression following malignant transformation. Using three independent tumor lines derived from the same precursor the expression of about 400 out of 11 000 genes was modulated in each tumor. A subset of only 75 genes (0.68%) is shared and up- or downregulated in all three lines. A significant portion of this gene pool possesses functions related to tumorigenesis such as cell adhesion, signaling or transcriptional regulation. Apart from a number of expressed sequence tags (EST's) we find downregulation of four interferon-inducible genes in the tumor lines. Finally, when we extrapolate our data to the complete mouse genome, we estimate that about 500 genes are differentially expressed in tumor cells compared to the precursor cell PB-3c.

Animals↗

Prediction of resource utilization and case cost for acute nonvariceal upper gastrointestinal hemorrhage at a Canadian community hospital.

OBJECTIVE: Upper gastrointestinal hemorrhage (UGIH) is common, and thus imposes a substantial burden on health care resources. We describe resource utilization and cost for management of acute nonvariceal UGIH, and studied their variation among population subgroups. METHODS: Resource utilization and direct medical case costs were extracted for consecutive admissions for nonvariceal UGIH at a large community hospital in southern Ontario through chart review and adaptation of an administrative case cost database. Univariate and multiple regression models were then developed to identify independent demographic predictors of case cost and length of stay. RESULTS: Among 116 eligible admissions the average length of stay and case cost were 4.26 days and Can$2690, respectively (Can$1 = US$0.70). Both cost and length of stay demonstrated significant univariate relationships with age, comorbid illness, prior peptic ulcer disease (PUD), and prior UGIH. Age and prior PUD persisted as independent predictors in multiple regression models. An inverse transformation of total case cost allowed these variables to explain 26% of the total variance. CONCLUSIONS: Resource utilization for management of acute nonvariceal UGIH at a Canadian community hospital varies substantially among population subgroups, but correlates independently with age and prior ulcer history. Careful attention must be paid to practice environments and demographic profiles before economic models of strategies to prevent or treat UGIH are applied to specific subpopulations.

Acute Disease↗

Biological and epistemological models of localization in the nineteenth century: from Gall to Charcot.

In the latter half of the nineteenth century, the localizationist doctrines became closely associated with the memory trace paradigm. The analysis of the texts dealing with the localization and the nature of 'the loss of articulated speech' (motor aphasia) by Bouillaud, Lordat, Dax, Broca, Trousseau, Baillarger, Charcot and Wernicke shows how the biological paradigm of localization presented by Gall and based on the notion of organ-function correspondence was transformed into a model based on localizable memory traces. This change resulted in the theoretical unification of the mechanisms of motor and non-motor forms of aphasia. These forms, which the earlier authors tended to separate in their analyses of the underlying mechanisms, were now regarded as involving similar mechanisms related to the loss of mnestic images. The crucial step in this development was taken by Broca who presented the hypothesis that the faculty of coordination of speech movements, which according to his predecessors was the faculty lost in motor aphasia, was actually an intellectual faculty and a specific form of memory, and motor aphasia consequently a selective kind of amnesia. Theorists like Charcot and Wernicke generalized this idea into a comprehensive theory of the nature of localization based on the notion of memory traces. Thus, the localization of function was reduced to the localization of representations. Instead of biological paradigms, this model of localization is rooted in the epistemological tradition of psychology represented by Locke and Condillac, who were primarily interested in the problem of representation. In physiology, this approach usually resulted in attempts at localizing representations instead of functions.

Amnesia↗

Phenotypic variance among cells isolated from spontaneous mouse mammary tumors in primary suspension culture.

A method is given for selecting epithelial cells directly from primary mammary tumors in Methocel suspension culture. The frequency of colony-forming units in primary tumors was approximately 10(-4). Colonies grew by cell division; formation and growth of colonies was cell density dependent. Five Methocel isolates were established in monolayer culture and characterized. Two were epithelial, evidenced by functional occluding junctions. The other three were not typed in vitro, although they formed carcinomas in vivo. All were subtetraploid by passage 10. There were variations in ability of the five Methocel isolates to reclone in suspension that appeared to be due to the evolution of anchorage-dependent variants during their growth in monolayer culture. These variants could be purified by limiting dilution plating on solid substrates. The five Methocel isolates and their derivative variants were used to determine correlations between transformation markers and tumorigenicity. Only three Methocel-derived sublines of nine tested, including two recloned in Methocel, were tumorigenic at all when inoculated in two sites of three syngeneic hosts, one athymic. The other six were nontumorigenic. The tumorigenic sublines were less tumorigenic than uncultured cells of parent tumors or parent tumor cells grown in primary monolayer culture. Thus, anchorage-independent growth is not a reliable marker for the tumorigenic mammary phenotype. No correlation was found between two other "contact-related" transformation markers, rapid growth rate and monolayer overgrowth, and tumorigenicity. The three transformation markers were expressed independently. Both tumorigenic and nontumorigenic sublines expressed mammary tumor virus antigens M.W. 28,000 protein and M.W. 52,000 glycoprotein, although only a minor fraction of cells contained the M.W. 52,000 glycoprotein. These data emphasize the heterogeneity of phenotypes in mammary tumors as well as differences between fibroblasts and mammary epithelium in models of neoplastic transformation.

Animals↗

Transient modifications of respiratory capacity in thymic cells during murine radioleukemogenesis.

The evolution of mitochondrial oxidative phosphorylation was studied during cancer induction in a model of thymic radiolymphomagenesis in C57BL/Ka mice. During the preneoplastic period, thymuses displayed an increase of the cytochrome c oxidase activity and oxygen consumption together with oxidative DNA damage assessed by the presence of the 8-hydroxydeoxyguanine DNA base modification. These transient changes in mitochondrial functional activity were not observed in thymuses of mice rescued from lymphoma development by a bone marrow graft, suggesting an important role of mitochondria for neoplastic transformation in this model, which might therefore be of interest to test the utilization of antioxidants for the prevention of radiation-induced malignancies.

8-Hydroxy-2'-Deoxyguanosine↗