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Results for “Pathway informed transformer”

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PubMed1989

Properties of visually driven neurons in cats pretectal region.

Properties of visually driven neurons in the cat pretectal region were studied. A detailed investigation of the receptive field (RF) structure revealed, in the majority of neurons, irregular shapes of RF contours. Dark-sensitive and bright-sensitive zones of a neuronal RF had different spatial locations. The majority of pretectal neurons were movement-sensitive and reacted weakly to stationary flashing spots. Although no clear-cut orientation sensitivity was found in the pretectal neurons, some orientations of motion were, nevertheless, more effective. In some cases a non-directional response could be transformed into a directionally-sensitive one by changing the orientation of motion. Out data confirm earlier observations that the pretectal region is involved in the central processing of visual information.

Animals↗

PubMed2004

Peaked encoding of relative luminance in macaque areas V1 and V2.

It is widely presumed that throughout the primate visual pathway neurons encode the relative luminance of objects (at a given light adaptation level) using two classes of monotonic function, one positively and the other negatively sloped. Based on computational considerations, we hypothesized that early visual cortex also contains neurons preferring intermediate relative luminance values. We tested this hypothesis by recording from single neurons in areas V1 and V2 of alert, fixating macaque monkeys during presentation of a large, spatially uniform patch oscillating slowly in luminance and surrounded by a static texture background. A substantial subset of neurons responsive to such low spatial frequency luminance stimuli in both areas exhibited prominent and statistically reliable response peaks to intermediate rather than minimal or maximal luminance values. When presented with static patches of different luminance but of the same spatial configuration, most neurons tested retained a preference for intermediate relative luminance. Control experiments using luminance modulation at multiple low temporal frequencies or reduced amplitude indicate that in the slow luminance-oscillating paradigm, responses were more strongly modulated by the luminance level than the rate of luminance change. These results strongly support our hypothesis and reveal a striking cortical transformation of luminance-related information that may contribute to the perception of surface brightness and lightness. In addition, we tested many luminance-sensitive neurons with large chromatic patches oscillating slowly in luminance. Many cells, including the gray-preferring neurons, exhibited strong color preferences, suggesting a role of luminance-sensitive cells in encoding information in three-dimensional color space.

Action Potentials↗

PubMed2006

Studies on chromosome aberration induction: what can they tell us about DNA repair?

Many, if not the majority of spontaneous or induced mutations in somatic mammalian cells associated with cancer are large chromosome level changes. For exposure to carcinogenic agents, certain specific chromosomal aberrations are likely to lie early along the pathway leading from initial molecular damage to cancer. The kinds of aberrations that occur, and the positions of breakpoints involved in their formation, can reveal not only genes and controlling elements whose expression or suppression underlie the molecular nature of the initiation of malignant transformation, but also how structural and functional features of chromatin can affect processes involved in repair or mis-repair of initial DNA damage. Thus, cytogenetics can provide information in ways that are not readily appreciated in studies requiring disruption of chromatin organization as it exists in the cell and its tissue context, and where DNA repair assays measure effects averaged over the entire genome. Examples include the fact that in contrast to a more efficient repair of single strand or base damage in transcriptionally active chromatin, after ionizing radiation exposure, the preponderance of translocation breakpoints indicating mis-repair occur in transcriptionally active or potentially active chromatin. Cytogenetic studies have led to the recognition that processing of DNA ends - both ends resulting from breaks along chromosomes and natural chromosomal termini, or telomeres - share very interesting similarities and differences. Further, direct observation of chromatin in cells during interphase can speak directly to early stages of aberration formation where processes occur within the context of intact cells, and to the role (or lack thereof) of cell cycle checkpoint responses that often accompany DNA damage. The superior resolution of many of the current molecular cytogenetics approaches, combined with immunocytochemical detection of proteins involved in DNA damage processing, and the availability of repair deficient mutants or knockdown strategies such as RNA interference, suggest that cytogenetics may still provide useful information and set certain restrictions important for rational interpretation of studies of DNA repair and associated protein interactions that can only be carried out in vitro. The intent of this paper is to focus on contributions of studies on the production of chromosomal aberrations following ionizing radiation exposure regarding important insights on associated DNA repair processes involved, and further, on guidelines or constraints they provide for the interpretation of in vitro DNA repair studies that would have been difficult to appreciate without the cytogenetics. We will first briefly summarize some early studies that serve as a reminder of the background on which current studies are based, and then carry forward to the present day certain interesting facets of these studies.

Animals↗

PubMed1999

Trypanosoma cruzi epimastigotes lack ornithine decarboxylase but can express a foreign gene encoding this enzyme.

Trypanosoma cruzi, a pathogenic protozoan causing Chagas disease, lacks ornithine decarboxylase (ODC), the enzyme catalyzing the first step of polyamine biosynthetic pathway in eukaryotic cells. Our results indicate that the auxotrophy for diamines of T. cruzi epimastigotes is due to the absence of an active ODC gene in these parasites and not to the inability for the expression of this gene. The introduction of an exogenous complete coding region from Crithidia fasciculata ODC gene inserted in an expression vector specific for trypanosomatids induces the normal expression of the foreign genetic information allowing the transformed T. cruzi to overcome the exogenous polyamine requirement for growth. The enzyme expressed in the transformed parasites has shown a considerably extended metabolic stability. The loss of ODC activity in T. cruzi might be related to the parasite adaptation to the intracellular stages of its life cycle.

Animals↗

PubMed2003

Apoptosis: future perspectives.

The field of apoptosis has expanded to include research in almost all subject areas of cell biology. Despite this growth, there are still many unanswered questions, some of which are fundamental to the development of therapeutic strategies. Most importantly, the underlying mechanisms involved in conferring specificity of apoptotic signals must be determined. This will allow the development of treatments to delete injured or transformed cells and minimize damage to other tissues. Such information is also necessary to combat degenerative diseases, to prevent critical loss of cells. In addition, it would be of therapeutic benefit to selectively induce apoptosis in specific cells where removal of unwanted cells is required (e.g. tumour cells in malignant tissue or inflammatory cells responsible for tissue damage in chronic inflammatory disease). Therefore we have to understand how the full complement of signalling pathways, and survival and apoptotic proteins determine the end effect of an apoptotic signal. Apoptotic cells are known to functionally influence phagocytes that ingest them, but little is known of the effect of apoptosis on neighbouring cells or of signals generated during the apoptotic process itself. Although the processes of mitosis and apoptosis would appear to be diametrically opposed, cell-cycle proteins are involved in apoptosis, and may be able to influence cell-death mechanisms; conversely, proliferation may be caspase-dependent in some cells. Further study is necessary to discover how these pathways are interlinked since such knowledge would be particularly useful in cancer treatment. The link between pathogen-survival strategies and apoptotic mechanisms will also reward further work. Viruses, in particular, exploit cellular survival and death pathways for replication purposes and may represent a targeting approach for specific treatments.

Apoptosis↗

PubMed2003

Cadherins as modulators of cellular phenotype.

Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions. Cadherin function is critical in normal development, and alterations in cadherin function have been implicated in tumorigenesis. The strength of cadherin interactions can be regulated by a number of proteins, including the catenins, which serve to link the cadherin to the cytoskeleton. Cadherins have been implicated in a number of signaling pathways that regulate cellular behavior, and it is becoming increasingly clear that integration of information received from cell-cell signaling, cell-matrix signaling, and growth factor signaling determines ultimate cellular phenotype and behavior.

Animals↗

PubMed2002

TGF-beta signaling: positive and negative effects on tumorigenesis.

TGF-beta binding to the cell surface triggers activation of multiple signal transduction pathways that are connected in intricate ways with each other, and with other response networks involved in sensing cellular information input. Recent data indicate that changes in signal intensity and connectivity of these pathways may underlie the complex transition of the TGF-beta pathway from tumor suppressor to oncogene during tumorigenesis.

Animals↗

PubMed2004

Semisynthesis of phosphovariants of Smad2 reveals a substrate preference of the activated T beta RI kinase.

Transforming growth factor-beta (TGF-beta) signaling regulates a wide range of cellular processes. Aberrant TGF-beta signaling has been implicated in various disease states in humans. A key element in this signaling pathway is phosphorylation of R-Smads such as Smad2 at the last two serine residues of the C-terminal sequence CSSXS (residues 463-467 in Smad2) by the TbetaRI receptor kinase. Phosphorylation results in the release of the R-Smad from the membrane-anchored protein SARA, binding to the co-mediator protein Smad4, translocation into the nucleus, and regulation of target gene expression. Expressed protein ligation was used to probe the contribution of the individual phosphate groups to Smad2 oligomerization and phosphorylation by TbetaRI. Phosphorylation at both positions was required to generate a stable homotrimer; however, the driving force for Smad2 self-association is provided by pSer465. Additionally, SARA was found to modulate the self-association of partially phosphorylated Smad2, which suggests an added role for this protein in preventing premature release of a monophosphorylated substrate from the receptor complex. In related studies, prephosphorylation of Smad2 at Ser465 was found to significantly increase the rate of phosphorylation at Ser467, suggesting that there may be specific recognition determinants within the kinase for the monophosphorylated intermediate. This information was exploited to design an improved peptide substrate for TbetaRI, which may prove valuable in the design of inhibitors of the TGF-beta pathway.

Chromatography, High Pressure Liquid↗

PubMed2004

Ion activation methods for tandem mass spectrometry.

This tutorial presents the most common ion activation techniques employed in tandem mass spectrometry. In-source fragmentation and metastable ion decompositions, as well as the general theory of unimolecular dissociations of ions, are initially discussed. This is followed by tandem mass spectrometry, which implies that the activation of ions is distinct from the ionization step, and that the precursor and product ions are both characterized independently by their mass/charge ratios. In collision-induced dissociation (CID), activation of the selected ions occurs by collision(s) with neutral gas molecules in a collision cell. This experiment can be done at high (keV) collision energies, using tandem sector and time-of-flight instruments, or at low (eV range) energies, in tandem quadrupole and ion trapping instruments. It can be performed using either single or multiple collisions with a selected gas and each of these factors influences the distribution of internal energy that the activated ion will possess. While CID remains the most common ion activation technique employed in analytical laboratories today, several new methods have become increasingly useful for specific applications. More recent techniques are examined and their differences, advantages and disadvantages are described in comparison with CID. Collisional activation upon impact of precursor ions on solid surfaces, surface-induced dissociation (SID), is gaining importance as an alternative to gas targets and has been implemented in several different types of mass spectrometers. Furthermore, unique fragmentation mechanisms of multiply-charged species can be studied by electron-capture dissociation (ECD). The ECD technique has been recognized as an efficient means to study non-covalent interactions and to gain sequence information in proteomics applications. Trapping instruments, such as quadrupole ion traps and Fourier transform ion cyclotron resonance instruments, are particularly useful for the photoactivation of ions, specifically for fragmentation of precursor ions by infrared multiphoton dissociation (IRMPD). IRMPD is a non-selective activation method and usually yields rich fragmentation spectra. Lastly, blackbody infrared radiative dissociation is presented with a focus on determining activation energies and other important parameters for the characterization of fragmentation pathways. The individual methods are presented so as to facilitate the understanding of each mechanism of activation and their particular advantages and representative applications.

Chemistry, Clinical↗

PubMedDate not supplied

Sequence seeking and counter streams: a computational model for bidirectional information flow in the visual cortex.

A computational model is proposed for some general aspects of information flow in the visual cortex. The basic process, called "sequence seeking," is a search for a sequence of mappings, or transformations, linking source and target patterns. The process has two main characteristics: it is bidirectional, bottom-up as well as top-down, and it explores in parallel a large number of alternative sequences. This operation is performed in a "counter streams" structure, in which multiple sequences are explored along two complementary pathways, an ascending and a descending one, seeking to meet. A biological embodiment of this model in cortical circuitry is proposed. The model serves to account for known aspects of cortical interconnections and to derive new predictions.

Animals↗

PubMed1993

[The erbB gene family: significance for tumor development, prognosis and new therapeutic modalities].

RNA and DNA viruses can be transforming and tumourigenic agents. The transformation is a consequence of the ability of viruses to integrate into the host cell's DNA and to produce transforming proteins. These proteins are mainly produced by specific integral parts of the viral genome, the oncogenes. Comparison between RNA/DNA sequence of viral oncogenes and normal human genome of non-transformed cells revealed high sequence similarities in specific genomic areas, which were named cellular proto-oncogens. They are important components of the growth regulatory pathways in normal cells. The accumulation of genetic alterations of some proto-oncogens, like the erbB-family, may be part of the mechanism, by which malignant cells can acquire a selective growth advantage. The epidermal growth factor receptor (EGF-R, c-erbB1), Her-2/neu (c-erbB2), and c-erbB3 are members of the erbB-family. The detection of increased abundance of EGF-R or Her-2/neu proteins in human tumours can provide additional information on the disease-free survival and overall survival for patients with breast, ovarian, endometrial or cervical cancer. Molecular and cell-physiological analyses have improved the understanding of tumour biology and provide the opportunity for new therapeutic approaches. Monoclonal antibody targeted therapy directed against EGF-R or Her-2/neu, the use of anti-sense oligonucleotides and oligodeoxynucleotides, and the application of tyrosine kinase and protein C-kinase inhibitors are currently being investigated.

Cell Division↗

PubMed2000

Auditory habituation in young and older adults: the verbal transformation effect.

In 3 experiments, auditory massed repetition was used to examine age-related differences in habituation by means of the verbal transformation paradigm. Participants heard 10 words (5 high frequency and 5 low frequency), each presented 180 times, and they reported perceived changes in the repeated words (verbal transformations). In these experiments, older adults reported fewer illusory percepts than young adults. Older adults' loss of auditory acuity and slowing of processing, stimulus degradation (in young adults), and instructions biasing the report of these illusory percepts did not account for the fewer illusory percepts reported by the older adults. These findings suggest that older adults' reduced susceptibility to habituation arises from centrally located declines in the transmission of information within the word-recognition pathway. The discussion focuses on the implications that these age-related declines may have on word identification during on-line speech perception.

Adolescent↗

PubMed2002

The organizing principle: microenvironmental influences in the normal and malignant breast.

The current paradigm for cancer initiation and progression rests on the groundbreaking discoveries of oncogenes and tumor suppressor genes. This framework has revealed much about the role of genetic alterations in the underlying signaling pathways central to normal cellular function and to tumor progression. However, it is clear that single gene theories or even sequential acquisition of mutations underestimate the nature of the genetic and epigenetic changes in tumors, and do not account for the observation that many cancer susceptibility genes (e.g. BRCA1, APC) show a high degree of tissue specificity in their association with neoplastic transformation. Therefore, the cellular and tissue context itself must confer additional and crucial information necessary for mutated genes to exert their influence. A considerable body of evidence now shows that cell-cell and cell-extracellular matrix (ECM) interactions are essential organizing principles that help define the nature of the tissue context, and play a crucial role in regulating homeostasis and tissue specificity. How this context determines functional integrity, and how its loss can lead to malignancy, appears to have much to do with tissue structure and polarity.

Apoptosis↗

PubMed2003

New perspectives on growth factor-sex steroid interaction in the prostate.

Many organs respond to both sex steroids and growth factors. Regulation of these pathways is integral to cell-cell communications during development and aberrant changes cause disease pathogenesis. Traditionally, paracrine and endocrine actions of growth factors and steroid hormones are considered independently. Recently, new data indicated that activin/TGFbeta and sex steroid signalling are linked; explicitly, that the pathways cross-talk intracellularly. Here we present new perspectives on these interactions, using examples predominantly from the prostate, as it is a well-characterised organ in this context. While this information provides insight to the potential mechanisms behind these interactions, it also presents a new challenge; the action of any of these factors cannot be considered exclusively without considering the impact on the other biological pathways.

Activins↗

PubMed1996

Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis.

Spatially regulated activation of the Drosophila epidermal growth factor (EGF) receptor by its ligand, Gurken, is required for establishment of the dorsal/ventral axis of the oocyte and embryo. During mid-oogenesis, Gurken is concentrated at the dorsal-anterior of the oocyte and is thought to activate the EGF receptor pathway in adjacent follicle cells. In response to this signal, dorsal follicle cell fate is determined. These cells further differentiate into either appendage-producing or midline cells, resulting in patterning in the dorsal follicle cell layer. We show here that Pointed, an ETS transcription factor, is required in dorsal follicle cells for this patterning. Loss of pointed results in the loss of midline cells and an excess of appendage-forming cells, a phenotype associated with overactivation of the EGF receptor pathway in the dorsal region. Overexpression of pointed leads to a phenotype similar to that generated by loss of the EGF receptor pathway. This suggests that Pointed normally down-regulates EGF receptor signaling in the midline to generate patterning in the dorsal region. Interestingly, pointed expression is induced by the EGF receptor pathway. These data indicate a novel antagonistic function for Pointed in oogenesis; in response to activation of the EGF receptor, pointed is expressed and negatively regulates the EGF receptor pathway, possibly by integrating information from a second pathway.

Animals↗

PubMed2001

Oscillation may play a role in time domain central auditory processing.

To study how sound intensity altered the temporal response pattern of a unit, we recorded from 92 single neurons in the inferior colliculus (IC) of the little brown bat and investigated their firing patterns in response to brief tone pulses (2 msec duration) at the characteristic frequency of the unit over a wide dynamic range (10-90 dB sound pressure level). We found two unusual response characteristics at high sound levels in approximately one-third of the IC neurons investigated. For 16 IC neurons (17%), an increase in sound level not only elicited a shorter response latency and an increase in spike count but also transformed the firing pattern of the unit from phasic to periodic; this pattern was more pronounced at higher sound levels. The firing periodicity was unit specific, ranging from 1.3 to 6.7 msec. Twenty-seven IC neurons (29%) exhibited a longer response latency at higher sound levels compared with lower sound levels [i.e., paradoxical latency shift (PLS)]. The majority of this population showed a one or more quantum increase in latency when sound level was elevated. The quantum shift was also unit specific, ranging from 1.2 to 8.2 msec. We further investigated the firing patterns of 14 IC neurons showing PLS before, during, and after iontophoretic application of bicuculline. For 12 of these neurons, drug application abolished the PLS and transformed the firing patterns of the unit at high sound levels from phasic into sustained periodic discharges. Our results suggest that neural oscillation in combination with ordinary inhibition may be responsible for the creation of PLSs shown previously to be important for temporal information processing.

Acoustic Stimulation↗

PubMed1995

Modular organization of the pontine nuclei: dendritic fields of identified pontine projection neurons in the rat respect the borders of cortical afferent fields.

Cortical afferents transferring information destined for the cerebellum terminate in the pontine nuclei (PN) in a divergent and patchy fashion. We investigated whether the form of dendritic fields of pontine projection neurons which are postsynaptic to the cortical afferents are related to this patchy pattern. To this end we used a triple combination of (1) retrograde labeling (injection of Fluorogold into the brachium pontis), (2) anterograde labeling [injection of Dil into cortical areas A17 and Sml(forelimb)], and (3) subsequent intracellular fills of identified projection neurons (Lucifer yellow) in slightly fixed slices of pontine brainstem. In 64 projection neurons whose somata were located within 160 microns of the border defined by cortical afferent fields, most of the dendritic trees were found to respect the border. Strikingly, proximal dendrites which were oriented toward the border often bent in order to avoid the boundary. This observation was supported by a quantitative analysis. It revealed that overlap areas of dendritic fields with the neighboring compartment were significantly smaller than those of hypothetical, radially organized dendritic fields of the same size, indicating that the dendritic fields are indeed confined to single compartments. In a second series of experiments, double injections of the anterograde tracers Dil and DiAsp into adjacent sites within one cortical area (A17 or Sml) were made in order to test if the topology of the cortical map is preserved within individual pontine compartments. This, however, does not seem to be the case, since the terminal fields displayed a complex pattern of overlap and nonoverlap rather than a consistent shift of terminal fields expected in the case of preserved topology. The results of the present study are consistent with the view that pontine modules independently process information from different parts of individual cortical areas. We suggest that this characteristic property of the corticopontine projection system might be the morphological basis of the well established fact that somatotopically continuous sensory maps in the cortex are transformed into maps at the level of the cerebellar cortex, showing a fractured somatotopy.

Afferent Pathways↗

PubMed2005

Sounds do-able: auditory-motor transformations and the posterior temporal plane.

Accumulating evidence in humans and non-human primates implicates the posterior superior temporal plane (STP) in the processing of both auditory spatial information and vocal sounds. Such evidence is difficult to reconcile with existing accounts of the primate auditory brain. We propose that the posteromedial STP generates sequenced auditory representations by matching incoming auditory information with stored templates. These sequenced auditory representations are subsequently used to constrain motor responses. We argue for a re-assessment of the much-debated dorsal auditory pathway in terms of its generic behavioral role as an auditory "do" pathway.

Animal Communication↗