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Results for “Pathway informed transformer”

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PubMed2003

Chronic pain-autonomic interactions.

The nociceptive and the autonomic nervous systems interact at the levels of the periphery, spinal cord, brainstem, and forebrain. Spinal and visceral afferents provide converging information to spinothalamic neurons in the dorsal horn and to neurons of the nucleus tractus solitarius and parabrachial nuclei. These structures project to areas involved in reflex, homeostatic and behavioral control of autonomic outflow and nociception. Clinical and experimental observations on migraine suggest that a general hyperexcitability could develop along nociceptive trigeminal neurons allowing the activation of descending pathways that facilitate pain processing or the suppression of pathways that slow down pain transmission. Slowly progressive dysfunction of central pain systems secondary to the repetition of attacks of the originating headache has been implicated in transforming the process from an episodic to a chronic condition. This concept of an irritable focus in the central nervous system is currently known as "central sensitization" and is a characteristic feature of visceral pain. Considering primary headache as the result of the interactions between the nociceptive and autonomic systems (visceral pain) can help us to understand the complex pathophysiology of these disorders and to explore new treatments.

Animals↗

PubMed2004

Developmental neurobiology and the origin of brain tumors.

Our knowledge of the causes of brain tumors has steadily increased and is leading to a refined understanding of the signaling pathways that may be essential for tumor formation. At the same time, we are gaining insights into the developmental processes that regulate the formation of the diverse range of cell types in the normal brain. Interestingly, many of these pathways seem to overlap and suggest common mechanisms regulating tumor formation and cellular development. This overlap may also inform us about the nature of the cell of origin for different types of brain tumors. By appreciating the inter-relationship between tumor formation and development, we maybe able to design new therapeutics targeting tumors for new modes of treatment.

Animals↗

PubMed2000

Limb apraxias: higher-order disorders of sensorimotor integration.

Limb apraxia comprises a wide spectrum of higher-order motor disorders that result from acquired brain disease affecting the performance of skilled, learned movements. At present, limb apraxia is primarily classified by the nature of the errors made by the patient and the pathways through which these errors are elicited, based on a two-system model for the organization of action: a conceptual system and a production system. Dysfunction of the former would cause ideational (or conceptual) apraxia, whereas impairment of the latter would induce ideomotor and limb-kinetic apraxia. Currently, it is possible to approach several types of limb apraxia within the framework of our knowledge of the modular organization of the brain. Multiple parallel parietofrontal circuits, devoted to specific sensorimotor transformations, have been described in monkeys: visual and somatosensory transformations for reaching; transformation of information about the location of body parts necessary for the control of movements; somatosensory transformation for posture; visual transformation for grasping; and internal representation of actions. Evidence from anatomical and functional brain imaging studies suggests that the organization of the cortical motor system in humans is based on the same principles. Imitation of postures and movements also seems to be subserved by dedicated neural systems, according to the content of the gesture (meaningful versus meaningless) to be imitated. Damage to these systems would produce different types of ideomotor and limb-kinetic praxic deficits depending on the context in which the movement is performed and the cognitive demands of the action. On the other hand, ideational (or conceptual) apraxia would reflect an inability to select and use objects due to the disruption of normal integration between systems subserving the functional knowledge of actions and those involved in object knowledge.

Apraxia, Ideomotor↗

PubMed2004

Molecular footprints of human lung cancer progression.

Lung cancer is the leading cause of cancer-related death in the world. To understand the molecular processes and pathways of, and contributing factors to lung cancer progression, genetic alterations in various progression stages of lung cancer cells have been studied, since these alterations can be regarded as molecular footprints representing the individual processes of multistage lung carcinogenesis. The results indicate that defects in both the p53 and RB/p16 pathways are essential for the malignant transformation of lung epithelial cells. Several other genes, such as K-ras, PTEN and MYO18B, are genetically altered less frequently than p53 and RB/p16 in lung cancer cells, suggesting that alterations in these genes are associated with further malignant progression or unique phenotypes in a subset of lung cancer cells. However, it is still unclear what genes control the metastatic potential of lung cancer cells. Further analyses of molecular footprints in lung cancer cells, in particular in the cells of metastatic sites, will give us valuable information to fully understand the process of lung cancer progression, and to find novel ways of controlling it. Molecular footprints at the sites of p53 mutations and p16 deletions further indicate that DNA repair activities for G:C to T:A transversion and non-homologous end-joining of DNA double-strand breaks play important roles in the accumulation of genetic alterations in lung cancer cells. Thus, identification of environmental as well as genetic factors inducing or suppressing the occurrence of such alterations would be a clue to find novel ways of lung cancer prevention.

Disease Progression↗

PubMed1995

Carbohydrate molecular weight profiling, sequence, linkage, and branching data: ES-MS and CID.

This section summarizes several strategies for a more complete understanding of carbohydrate structure with a focus on glycolipids and glycoprotein glycans. The techniques include periodate oxidation to impart greater molecular specificity to isomeric glycans, methylation to improve sensitivity and the information content within CID spectra, electrospray for "soft" and efficient ionization, and CID to obtain structural detail. The lipophilicity of the products following derivatization contributes to product cleanup by solvent extraction and enhances sensitivity during ES. When combined with CID information, this yields sequence, linkage, and branching information. Oxidation and reduction preceding methylation augments CID analysis with an altered structure that can be profiled at the same sensitivity. Within the context of established motifs, these contrasting profiles corroborate glycan structure and specifically identify isobaric elements transparent in the initial profile. An earlier report indicating ring-opening fragments were essentially absent in low-energy collisions of methylated and natriated oligosaccharides contrasts our observations. However, as this report used a methylated oligomer containing an internal N-acetylhexose as an illustration, the conclusion is plausible (cf., Figure 9). The poor ionization efficiency of FAB and the high matrix background limit the dynamic range in the CID spectrum and, thereby, the ability to unambiguously identify weaker peaks. It would be expected that high-energy CID affords a broader range of fragment types, including ring-opening fragments. In terms of a structural methodology, this is ambivalent since the increase in fragmentation pathways also applies to small molecule eliminations which are usually less informative. In ES-CID-MS, the carbohydrate chemist has a powerful new tool in hand for structural elucidations that can be conducted at the low-picomole level. Parallel developments can be expected to continue for other ionization methods, in particular matrix-assisted desorption/ionization on linear and reflectron time of flight mass spectrometers, and improvement in the performance and sensitivity of high-resolution mass analyzers through the use of focal plane detectors and more sophisticated hardware and software for Fourier transform ion cyclotron resonance mass measurements. These have, as yet, only begun to be applied to carbohydrate structural analysis but should add still more versatility to experimental design in the future.

Carbohydrate Conformation↗

PubMedDate not supplied

Expression of growth factors and their receptors in human early colorectal carcinomas: immunohistochemical study.

Human colorectal carcinomas have been demonstrated to express a variety of growth factors and their cognate receptors, forming multi-autocrine, juxtacrine and/or paracrine loops. Little information, however, is available on their expression in early colorectal carcinomas in which two genetic pathways exist, i.e. adenoma-carcinoma sequence and de novo carcinoma. This study was conducted in a total of 68 early colorectal carcinomas invading the submucosa, which were subdivided into two categories by the presence of adenomatous components, namely (a) 38 carcinomas with an adenomatous component and (b) 30 carcinoma without an adenomatous component. The tumous were also classified as polypoid, flat elevated and flat depressed type. Formalin-fixed, paraffinembedded specimens were immunostained for epidermal growth factor (EGF), transforming growth factor alpha(TGFalpha), cripto, EGF-receptor(EGFR) and c-ERBB2 gene product. Of the 68 early colorectal carcinomas, EGF, TGF-alpha, cripto, EGFR and c-ERBB2 products were detected at various degrees 24(35%), 50(74%), 31(46%), 11(16%), and 34(50%), respectively. The expression was compared between 35 polypoid carcinomas with an adenoma component (suitable for adenoma-carcinoma sequence), 14 flat carcinomas without an adenoma component (possible de novo carcinomas). A significantly higher incidence (P < 0.05) of expression of the following was noted; TGF-alpha in the polypoid carcinomas with an adenoma component, and EGF and c-ERBB2 gene product in the carcinomas without an adenoma component. There was no significant difference in the incidence of cripto and EGFR, implying common events between two categories. These results indicate that two pathways exist in tumourigenesis, in which the growth factors and their receptors are expressed in different manners. TGF-alpha might play a crucial role in carcinomas arising from adenoma, while EGF and c-ERBB2 gene products are strongly indicative of de novo carcinomas.

Adenoma↗

PubMed1991

Electrophysiological evidence for a direct projection of direction-sensitive retinal ganglion cells to the turtle's accessory optic system.

1. The direct retinal input pathway to the basal optic nucleus (BON), the primary nucleus of the turtle accessory optic system, was characterized physiologically. We tested the hypothesis that directional information encoded in retinal ganglion cells can influence the BON via a direct pathway. Using an in vitro whole-brain, eyes-attached preparation, we demonstrated the directness of this pathway by 1) antidromic activation of retinal ganglion cells from the contralateral BON and 2) orthodromic activation of the BON from the contralateral optic nerve. 2. Of 72 physiologically classified retinal ganglion cells, 9 could be antidromically activated from the contralateral BON with low current (less than 200 micro A). Eight of these cells were direction-sensitive (DS). The ninth cell did not respond to visual stimulus movement. The antidromic latencies ranged from 2.2 to 6.1 ms with a mean of 3.8 ms. These latencies were quite consistent for each cell, having an average SD of 0.08 ms. Moreover, consistent responses could always be recorded at stimulation rates up to 100 Hz. 3. With current stimulation of the contralateral optic nerve, the orthodromic conduction latency of 17 BON single units ranged from 2.5 to 6.6 ms with a mean of 4.6 ms. These latencies were more variable for an individual cell, having an average SD of 0.3 ms. Responses to individual current pulses could never be consistently evoked at stimulation rates greater than 40 Hz. 4. DS responses were recorded in BON single units after the removal of the dorsal midbrain, including the optic tectum and pretectum as well as the telencephalon. Three of these cells were activated orthodromically by current stimulation delivered to the contralateral optic nerve. Thus directional information reaches the BON via a direct projection from the contralateral retina. 5. Visual response properties of DS retinal ganglion cells were compared with those of BON cells to examine the transformations that take place in the brain stem. Applying a limaçon model to the responses of both DS retinal ganglion cells and BON cells revealed that both types of cells have very similar direction tuning. However, the distribution of maximally responsive directions in the retina may differ from that of the BON. 6. Because DS retinal ganglion cells project directly to the BON, and because BON cells lose their direction sensitivity after retinal application of GABA antagonists, we conclude that the BON receives essential directional information directly from DS retinal ganglion cells. This directional information in the BON may represent a retinal slip error signal necessary for retinal image stabilization.

Animals↗

PubMed2005

ETS transcription factors and their emerging roles in human cancer.

Cancer can be defined as a genetic disease, resulting as a consequence of multiple events associated with initiation, promotion and metastatic growth. Cancer results from the loss of control of cellular homeostasis. Cell homeostasis is the result of the balance between proliferation and cell death, while cellular transformation can be viewed as a loss of relationship between these events. Oncogenes and tumour suppressor genes act as modulators of cell proliferation, while the balance of apoptotic and anti-apoptotic genes controls cell death. All cancer cells acquire similar sets of functional capacities: (1) independence from mitogenic/growth signals; (2) loss of sensitivity to "anti-growth" signals; (3) evade apoptosis; (4) Neo-angiogenic conversion; (5) release from senescence; and (6) invasiveness and metastasis. One of the goals of molecular biology is to elucidate the mechanisms that contribute to the development and progression of cancer. Such understanding of the molecular basis of cancer will provide new possibilities for: (1) earlier detection as well as better diagnosis and staging of disease with detection of minimal residual disease recurrences and evaluation of response to therapy; (2) prevention; and (3) novel treatment strategies. We feel that increased understanding of ETS-regulated biological pathways will directly impact these areas. ETS proteins are transcription factors that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis. Identification of target genes that are regulated by a specific transcription factor is one of the most critical areas in understanding the molecular mechanisms that control transcription. Furthermore, identification of target gene promoters for normal and oncogenic transcription factors provides insight into the regulation of genes that are involved in control of normal cell growth, and differentiation, as well as provide information critical to understanding cancer development. This review will highlight the current understanding of ETS genes and their role in cancer.

Genes, Tumor Suppressor↗

PubMed2000

The Dynamics of N(2)-O(3) and N(2)-SO(2) Probed by Microwave Spectroscopy.

The microwave spectra of N(2)-O(3) and N(2)-SO(2) have been recorded in the 6-18 GHz range using a pulsed-nozzle, Fourier transform microwave spectrometer. C-type transitions have been observed for both complexes which are slightly shifted by internal tunneling motions of the O(3) or SO(2) moieties. In addition, unshifted a-type transitions have been observed for N(2)-O(3). The nuclear hyperfine pattern is typical of equivalent nitrogen nuclei. Two sets of rotational and hyperfine constants are required to fit the symmetric and antisymmetric nuclear spin states, indicating that the equivalence arises from tunneling rotation of the nitrogen molecule. Internal tunneling motions along three tunneling pathways have been identified, although no information on the N(2) tunneling frequency is available from the spectra. From the N(2)-O(3) data the tunneling frequencies cannot be decorrelated from the rotational parameters; however, the O(3) tunneling frequency upper limit is estimated to be 2.0 MHz and the frequency of the concerted tunneling motion of both moieties is estimated to be about 8.9 MHz. For N(2)-SO(2), the SO(2) tunneling frequency is 11.5 kHz and the concerted frequency 173.9 kHz. Both complexes are roughly T shaped with the N(2) axis approximately perpendicular to the O(3) or SO(2) plane. In the equilibrium structures of both complexes, the a-c inertial plane is a plane of symmetry. The centers of mass separations are estimated from the rotational parameters to be 3.582 Å for N(2)-O(3) and 3.875 Å for N(2)-SO(2). The angle between the symmetry axes of the O(3) or SO(2) and the line joining their centers of mass have been calculated as 130.84 degrees (or 49.16 degrees ) and 119.71 degrees (or 60.29 degrees ), respectively. From the quadrupole analysis, the average angle between the N(2) axis and the a-inertial axis is 32.12 degrees for N(2)-O(3) and 27.81 degrees for N(2)-SO(2). Model electrostatic and ab initio calculations confirm these structures. Differences between the experimental and calculated structural parameters highlight the role of tunneling dynamics in these complexes. Copyright 2000 Academic Press.

Journal Article↗

PubMed2004

Neurofibromatosis with gastrointestinal stromal tumors: insights into the association.

The frequent association of stromal tumors with neurofobromatosis raises high suspicion of a possible correlation between the two entities. The aim of this study was to analyze clinicopathologic features of patients with concomitant neurofibromatosis and gastrointestinal stromal tumors and to discuss the molecular basis for their possible pathogenesis. Detailed information about clinical presentation, histology, immunostains, polymerase chain reaction amplification, and sequencing in three of our own cases was obtained. Stromal tumors presented with abdominal pain in one case and hemorrhage in another. One patient underwent surgery for malignant transformation of neurofibroma and stromal tumors were found incidentally. Stromal tumors were consistently positive for CD117, while the malignant peripheral sheath tumor was not. Mutation in the KIT juxtamembrane domain was found in one case. In this respect, some stromal tumors lack demonstrable KIT mutations but KIT remains activated. We reasoned that other mechanisms, like the Ras pathway involved in neurofibromatosis type 1, might play a role in KIT activation.

Adult↗

PubMed2006

Representation of behaviourally relevant information by blowfly motion-sensitive visual interneurons requires precise compensatory head movements.

Flying blowflies shift their gaze by saccadic turns of body and head, keeping their gaze basically fixed between saccades. For the head, this results in almost pure translational optic flow between saccades, enabling visual interneurons in the fly motion pathway to extract information about translation of the animal and thereby about the spatial layout of the environment. There are noticeable differences between head and body movements during flight. Head saccades are faster and shorter than body saccades, and the head orientation is more stable between saccades than the body orientation. Here, we analyse the functional importance of these differences by probing visual interneurons of the blowfly motion pathway with optic flow based on either head movements or body movements, as recorded accurately with a magnetic search coil technique. We find that the precise head-body coordination is essential for the visual system to separate the translational from the rotational optic flow. If the head were tightly coupled to the body, the resulting optic flow would not contain the behaviourally important information on translation. Since it is difficult to resolve head orientation in many experimental paradigms, even when employing state-of-the-art digital video techniques, we introduce a 'headifying algorithm', which transforms the time-dependent body orientation in free flight into an estimate of head orientation. We show that application of this algorithm leads to an estimated head orientation between saccades that is sufficiently stable to enable recovering information on translation. The algorithm may therefore be of practical use when head orientation is needed but cannot be measured.

Algorithms↗

PubMed1995

The specificity of the transforming growth factor beta receptor kinases determined by a spatially addressable peptide library.

Type I and II receptors for the transforming growth factor beta (TGF-beta) are transmembrane serine/threonine kinases that are essential for TGF-beta signaling. However, little is known about their in vivo substrates or signal transduction pathways. To determine the substrate specificity of these kinases, we developed combinatorial peptide libraries synthesized on a hydrophilic matrix that is easily accessible to proteins in aqueous solutions. When we subjected these libraries to phosphorylation by the cAMP-dependent protein kinase, we obtained the optimal peptide sequence RRXS (I/L/V), in perfect agreement with the substrate sequence deduced from mutagenesis and crystal structure analyses. By using the same libraries, we showed that the optimal substrate peptide for both the type I and II TGF-beta receptors was KKKKKK(S/T)XXX. Since the two kinases are thought to play different roles in intracellular signal transduction, it was a surprise to find that they have almost identical substrate specificity. Our method is direct, sensitive, and simple and provides information about the kinase specificity for all the amino acid residues at each position.

Activin Receptors, Type I↗

PubMed2001

Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare but informative syndrome for endocrine tumorigenesis. Since its isolation, several groups have begun to determine the role of menin, the protein product of MEN1, in sporadic endocrine tumors as well as tumors of the MEN1 syndrome. Mutations of menin have been reported in more than 400 families and tumors, most of which are truncating mutations, thus supporting the function of menin as a tumor suppressor. The exact function of menin is unknown, but overexpression of menin inhibits proliferation of Ras-transformed NIH3T3 cells. Since menin interacts with proteins from both the TGF beta and AP-1 signaling pathways, perhaps its tumor suppressor function is related to these key cell growth pathways. In this review we will discuss the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors.

Amino Acid Sequence↗

PubMedDate not supplied

Monitoring of hemispheric or brainstem functions with neurophysiologic methods during interventional neuroradiology.

Interventional neuroradiology, sometimes requiring full anesthesia, is now performed in high-risk patients. The neurologic state of an anesthetized patient cannot always be sufficiently evaluated during the neuroradiologic examination. In such cases neurophysiological methods provide information about some aspects of the patient's cerebral condition. Three useful neurophysiological methods for monitoring hemispheric or brainstem functions during the neuroradiologic procedure are on-line or Fourier-transformed electroencephalographic (EEG) analysis; the monitoring of somatosensory-evoked potentials; and the monitoring of brainstem acoustic-evoked potentials. All methods can be done in the operating room with small, mobile equipment.

Afferent Pathways↗

PubMed2006

CpG island hypermethylation in progression of esophageal and gastric cancer.

The upper gastrointestinal (GI) cancers have various carcinogenic pathways and precursor lesions, such as dysplasia for esophageal squamous cell carcinoma, Barrett esophagus for esophageal adenocarcinoma, and intestinal metaplasia for the intestinal-type of gastric cancer. Recently, many epigenetic events in carcinogenic pathways have been revealed, along with genomic and genetic alterations. This information has provided deeper insight into an understanding of the mechanisms of upper GI carcinogenesis. Moreover, detection methods of aberrant methylation have been applied to clinical fields to stratify high-risk groups, detect early cancer, and to predict clinical outcomes. In this review, a variety of information is summarized regarding gene hypermethylation in esophageal and gastric cancer.

Adenocarcinoma↗

PubMed1995

A field theory of saccade generation: temporal-to-spatial transform in the superior colliculus.

Recent models have placed the superior colliculus inside the local feedback loop that generates the pulse of innervation needed to make a saccade. Such closed-loop models need to take into account the different coordinate systems of visual and motor signals. This paper presents a computational model showing how the superior colliculus can bring the visual and motor information together in a common reference frame.

Animals↗

PubMed2003

Mechanisms of guanine nucleotide exchange and Rac-mediated signaling revealed by a dominant negative trio mutant.

Rho family GTPases play important roles in a variety of cellular processes, including actin cytoskeleton reorganization, transcription activation, and DNA synthesis. Dominant negative mutants of Rho GTPases, such as T17NRac1, that block the endogenous Rho protein activation by sequestering upstream guanine nucleotide exchange factors (GEFs) have been widely used to implicate specific members of the Rho family in various signaling pathways. We show here that such an approach could produce potentially misleading results since many Rho GEFs can interact with multiple Rho proteins promiscuously, and overexpression of one dominant negative Rho protein mutant may affect the activity of other members of the Rho family. Based on the available structural information, we have identified the highly conserved amino acid pairing of Asn(1406)Trio-Asp(65)Rac1 of the GEF-Rho GTPase interaction as the critical catalytic machinery required for the Rac1 GDP/GTP exchange reaction. The N1406A/D1407A mutant of Trio acted dominant negatively in vitro by retaining Rac1 binding activity but losing GEF catalytic activity and competitively inhibited Rac1 activation by wild type Trio. It readily blocked the platelet-derived growth factor (PDGF)-induced lamellipodia formation and inhibited the wild type Trio-induced serum response factor activation. Moreover the mutant was able to selectively inhibit Dbl-induced Rac1 activation without affecting RhoA activity in cells. In contrast to the non-discriminative inhibitory effect displayed by T17NRac1, the Trio mutant was ineffective in inhibiting PDGF-stimulated DNA synthesis and Dbl-induced transformation, revealing the Rac-independent functions of PDGF and Dbl. These studies identify a conserved pair of amino acid residues of the Trio-Rac interaction that is likely to be essential to the GEF catalysis of Rho family GTPases and demonstrate that a dominant negative mutant derived from a Rho GTPase regulator constitutes a new generation of specific inhibitors of Rho GTPase signaling pathways.

Actins↗

PubMed2003

Expression of dengue ApoptoM sequence results in disruption of mitochondrial potential and caspase activation.

Apoptotic cell death has been involved as a cytopathologic mechanism in response to dengue (DEN) virus infection. Little information exists about how DEN virus replication triggers apoptosis in infected cells. We reported that a nine-residue sequence of the DEN M protein referred to as ApoptoM has proapoptotic properties in transformed and tumor cells of various origins. The aim of the present study was to investigate whether ApoptoM-induced apoptosis is associated to mitochondrial dysfunction and requires caspase activation. Intracellular expression of ApoptoM provokes the disruption of the mitochondrial transmembrane potential without subsequent generation of reactive oxygen species. We showed that ApoptoM-induced apoptosis involves the activation of a caspase-like protease pathway. Caspase-3 like activity was detected in ApoptoM-expressing cells. However, there was no role for caspase-9 in ApoptoM-mediated cell death. Our data suggest that a particular mitochondrion-dependent apoptotic pathway may be involved in induction of apoptosis by ApoptoM.

Amino Acid Chloromethyl Ketones↗