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Results for “Pathway informed transformer”

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PubMed1989

Somatotopic representation in inferior area 6 of the macaque monkey.

On the basis of its cytoarchitectonic and enzymatic properties area 6 of the macaque monkey can be subdivided into two large sectors: a superior sector lying medial to the spur of the arcuate sulcus (superior area 6 or F2) and an inferior sector lying lateral to it (inferior area 6). Inferior area 6 is constituted by two enzymatic areas: F4 and F5. In this study we investigated the somatotopic organization of inferior area 6 and the adjacent area 4 combining single-neuron recording and intracortical electrical microstimulation. We found that two separate movement representations exist in this region. The caudal one corresponds to area F1 (primary motor cortex), the rostral one to inferior area 6. The two representations are mirror images one of the other with the axioproximal movements being adjacently located. In the rostral map the proximal movements are mostly located in F4, the distal movements in F5. Neuronal properties indicate that the rostral map has characteristics that are more complex than the caudal map. We propose that the rostral map is involved in transforming visual information in motor commands. F4 should be involved in the control of arm movements based on the location of the objects in respect to the body, whereas F5 should play a role in the control of grasping movements on the basis of the size of the stimuli.

Animals↗

PubMed2006

Fragmentation of singly protonated peptides via a combination of infrared and collisional activation.

The coupling of matrix-assisted laser desorption/ionization (MALDI) to Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) provides an exceptionally capable platform for peptide analysis, but an important limitation of this approach is the difficulty in obtaining informative tandem mass spectra (MS/MS) of singly protonated peptides. This difficulty is especially pronounced with peptide ions containing basic amino acid residues (for example, tryptic peptides). While such ions can be fragmented in some instrument configurations, most FTICR instruments have comparatively little facility for high-energy fragmentation. Here, a novel MS/MS approach implemented with MALDI-FTICR-MS and specifically intended for enhanced fragmentation of singly protonated peptides is described. The method involves infrared irradiation in concert with the simultaneous application of sustained off-resonance irradiation collision-induced dissociation (SORI-CID). This form of MS/MS, described as a combination of infrared and collisional activation (CIRCA), is shown to provide a greater capacity for dissociation of singly charged model peptide ions as compared to infrared multiphoton dissociation (IRMPD) or SORI-CID alone. Overall, the CIRCA approach is demonstrated to be a feasible technique for accessing useful fragmentation pathways of singly charged peptides, including those harboring basic amino acid residues--a crucial feature in the context of proteomics.

Amino Acids, Basic↗

PubMed2004

Coordinate regulation of neural tube patterning and proliferation by TGFbeta and WNT activity.

Pattern formation and growth must be tightly coupled during embryonic development. In vertebrates, however, little is known of the molecules that serve to link these two processes. Here we show that bone morphogenetic proteins (BMP) coordinate the acquisition of pattern information and the stimulation of proliferation in the embryonic spinal neural tube. We have blocked BMP and transforming growth factor-beta superfamily (TGFbeta) function in the chick embryo using Noggin, a BMP antagonist, and siRNA against Smad4. We show that BMPs/TGFbetas are necessary to regulate pattern formation and the specification of neural progenitor populations in the dorsal neural tube. BMPs also serve to establish discrete expression domains of Wnt ligands, receptors, and antagonists along the dorsal-ventral axis of the neural tube. Using the extracellular domain of Frizzled 8 to block Wnt signaling and Wnt3a ligand misexpression to activate WNT signaling, we demonstrate that the Wnt pathway acts mitogenically to expand the populations of neuronal progenitor cells specified by BMP. Thus, BMPs, acting through WNTs, couple patterning and growth to generate dorsal neuronal fates in the appropriate proportions within the neural tube.

Animals↗

PubMed1998

Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors.

Epithelial ovarian cancer comprises three major histological subtypes (serous, mucinous, and endometrioid), and it is becoming clear that the developmental pathways for these subtypes are fundamentally different. In particular, endometrioid ovarian cancers probably arise by the malignant transformation of ectopic endometrial implants called endometriosis and not the ovarian surface epithelium. The PTEN/MMAC gene on chromosome 10q23 is a tumor suppressor implicated in the pathogenesis of a wide variety of malignancies, but to date, somatic mutations in PTEN have not been identified in studies of predominantly serous ovarian cancers. In endometrial cancers, PTEN mutations are very common in tumors of the endometrioid type but have rarely been found in serous types, and we hypothesized that a similar histological subtype bias might be occurring in ovarian cancer. We have analyzed 81 ovarian tumors, including 34 endometrioid, 29 serous, 10 mucinous, and 8 clear cell tumors, for loss of heterozygosity (LOH) on 10q23 and for mutations in all 9 coding exons of PTEN. LOH was common among the endometrioid (43%) and serous (28%) tumors but was infrequent among the other histological subtypes. Somatic PTEN mutations were detected in seven (21%) of the endometrioid tumors, and in all informative cases, the mutation was accompanied by loss of the wild-type allele. One mucinous tumor without 10q23 LOH was shown to harbor two somatic PTEN mutations. In this tumor, the histological appearance of the mucinous areas was atypical, and the mucinous areas contained foci of endometrioid differentiation. The majority of tumors with PTEN mutations were grade 1 and/or stage 1, suggesting that inactivation of PTEN is an early event in ovarian tumorigenesis. No PTEN mutations were found among the serous or clear cell tumors. The identification of frequent somatic PTEN mutations in endometrioid ovarian tumors indicates that it plays a significant role in the etiology of this subtype. The absence of mutations in other histological subtypes is consistent with the hypothesis that epithelial ovarian cancers arise through distinct developmental pathways.

Adenocarcinoma, Clear Cell↗

PubMed2001

cFOS and pCREB activation and maternal aggression in mice.

Lactating mice exhibit a dramatic increase in aggression, termed maternal aggression, only in association with the rearing and protection of their offspring. Previous work indicates that the neural mechanisms underlying maternal and male aggression are different in rodents. In this study, we sought to examine possible neural regions involved in the control of maternal aggression by combining behavioral testing with immunohistochemistry for both cFOS and pCREB, two indirect markers of neuronal activity. All lactating female mice were exposed to a male intruder for 20 min and those exhibiting maternal aggression were placed in one group and those that were non-aggressive were placed in a second group. Thus, the sensory stimuli were similar and the main difference between the two groups was the behavior. cFOS expression increased significantly in the claustrum, bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus, medial amygdala, and cortical amygdala in association with maternal aggression. In contrast, the number of pCREB-positive cells significantly increased only in the ventrolateral portion of the caudal periaqueductal gray and in the lateral septum in aggressive lactating mice. Due to large variance in the counts of pCREB-positive cells, the data were log transformed prior to statistical analysis. Thus, the sites of cFOS and pCREB increases do not overlap, but provide complementary indirect information on neural regions active during maternal aggression. These results complement previous studies of nitric oxide release during maternal aggression to create a possible map of the functional neural circuitry underlying maternal aggression.

Aggression↗

PubMed2002

The unexplained survival of cells in oral cancer: what is the role of p53?

In normal oral epithelium the cells divide, mature, differentiate, and die. This sequence is not normally followed in oral cancer. Instead, the death of the cells is somehow prevented, although the pathways toward cell death in normal oral epithelium and the defects in oral cancer are not well defined. However, several components in the system have been identified, and information on their interactions is becoming available. This review summarizes the evidence for cell death being due to apoptosis and the central role of the p53 gene product in its regulation. Areas for future research are also identified.

Apoptosis↗

PubMed2005

Soluble osteogenic molecular signals and the induction of bone formation.

The induction of bone formation starts by erecting scaffolds of smart biomimetic matrices acting as insoluble signals affecting the release of soluble osteogenic molecular signals. The cascade of bone differentiation by induction develops as a mosaic structure singly initiated by the osteogenic proteins of the transforming growth factor-beta (TGF-beta) supergene family. The osteogenic signals when combined with an insoluble signal or substratum initiate de novo bone formation by induction and are deployed singly, synergistically and synchronously to sculpt the architecture of the mineralized bone/bone marrow organ. The osteogenic proteins of the TGF-beta superfamily are the common molecular initiators deployed for embryonic development and the induction of bone in postnatal osteogenesis, whereby molecules exploited in embryonic development are re-deployed in postnatal tissue morphogenesis as a recapitulation of embryonic development. The pleiotropy of the osteogenic proteins of the TGF-beta superfamily is highlighted by the apparent redundancy of molecular signals initiating bone formation by induction including the TGF-beta isoforms per se, powerful inducers of endochondral bone but in the primate only. Bone induction by the TGF-beta isoforms in the primate is site and tissue specific with substantial endochondral bone induction in heterotopic sites but with absent osteoinductivity in orthotopic calvarial sites on day 30 and only limited osteogenesis pericranially on day 90. Ebaf/Lefty-A, a novel member of the TGF-beta superfamily, induces chondrogenesis in calvarial defects of Papio ursinus and bone regeneration across the defect on day 30 and 90, respectively. The strikingly pleiotropic effects of the bone morphogenetic and osteogenic proteins (BMPs/OPs) spring from amino acid sequence variations in the carboxy-terminal domain and in the transduction of distinct signalling pathways by individual Smad proteins after transmembrane serine/threonine kinase complexes of type I and II receptors. Predictable bone regeneration in clinical contexts requires information concerning the expression and cross regulation of gene products of the TGF-beta superfamily. OP-1, BMP-3, TGF-beta1 and type IV collagen mRNAs expression correlates to the morphological induction and maintenance of engineered ossicles by the hOP-1 osteogenic devices in the non-human primate P. ursinus. Amino-acid sequence variations amongst BMPs/OPs in the carboxy terminal domain confer the structure/activity profile responsible for the pleiotropic activity that controls tissue induction and morphogenesis of a variety of tissues and organs by different BMPs/OPs which are helping to engineer skeletal tissue regeneration in molecular terms.

Animals↗

PubMed2005

Photochemical transformations of benzo[e]pyrene in solution and adsorbed on silica gel and alumina surfaces.

The photodegradation of benzo[e]pyrene (BeP), a ubiquitous polycyclic aromatic hydrocarbon (PAH) contaminant, was investigated in solution and adsorbed on surfaces modeling the atmospheric particulate matter to provide fundamental information that could help to clarify its fate in the atmosphere. Diones, diols, and hydroxy derivatives were identified as the major photoproducts of BeP irradiated under simulated atmospheric conditions. The relative distribution of the products and the photodegradation rates of BeP were affected by the average pore size of the surface. Major photoproducts characterized in samples adsorbed on silica gel and alumina surfaces were not observed in irradiated solutions of BeP in hexane. In acetonitrile, the photodegradation rate was faster than in hexane, and one of the diones was observed. Different photoreaction pathways seem to take place in polar versus nonpolar microenvironments.

Acetonitriles↗

PubMed1994

The nephritogenic immune response.

The past year has witnessed continued advances along several fronts in understanding the initiation and effects of a nephritogenic immune response. New information on the major histocompatibility complex in autoimmunity suggests that major histocompatibility complex class I and class II expression is important in the initiation of the immune response. The complex pathways involved in the regulation of leukocyte recruitment in inflammation continue to unravel and the role of cytokines in these processes is being defined. The ability of antibodies directed against leukocyte adhesion molecules to attenuate inflammation in experimental glomerulonephritis opens up the possibility of new therapeutic agents for human disease. The need to reexamine the role of complement as an effector in immune renal disease is suggested by evidence of intrinsic renal complement component production. Recent information on the pathogenesis of renal scarring in crescentic glomerulonephritis suggests the importance of leukocyte-endothelial cell interaction and of delayed-type hypersensitivity in this process. The ability of the growth factors transforming growth factor-beta and platelet-derived growth factor to induce glomerulosclerosis has been documented in an innovative study using selective renal gene transfer. Finally, the potential importance of apoptosis of inflammatory cells as a mechanism limiting injury is a new focus of attention.

Animals↗

PubMedDate not supplied

Bioinformatics and genomic medicine.

Bioinformatics is a rapidly emerging field of biomedical research. A flood of large-scale genomic and postgenomic data means that many of the challenges in biomedical research are now challenges in computational science. Clinical informatics has long developed methodologies to improve biomedical research and clinical care by integrating experimental and clinical information systems. The informatics revolution in both bioinformatics and clinical informatics will eventually change the current practice of medicine, including diagnostics, therapeutics, and prognostics. Postgenome informatics, powered by high-throughput technologies and genomic-scale databases, is likely to transform our biomedical understanding forever, in much the same way that biochemistry did a generation ago. This paper describes how these technologies will impact biomedical research and clinical care, emphasizing recent advances in biochip-based functional genomics and proteomics. Basic data preprocessing with normalization and filtering, primary pattern analysis, and machine-learning algorithms are discussed. Use of integrative biochip informatics technologies, including multivariate data projection, gene-metabolic pathway mapping, automated biomolecular annotation, text mining of factual and literature databases, and the integrated management of biomolecular databases, are also discussed.

Computational Biology↗

PubMed1983

The radical ions and photoionization of bile pigments.

The semireduced, semioxidized, and OH(.)-adduct radicals of bilirubin (BR) and biliverdin (BV) have been characterized using pulse radiolysis techniques. Laser flash photolysis (265-nm) of these pigments led to monophotonic photoionization with quantum yields of 0.08 for BR and 0.03 for BV. No evidence for triplet formation or for photoisomerization was found after 265-nm laser excitation. However, 347-nm excitation of BR in chloroform led to simultaneous photoisomerization and radical formation, but the radicals are thought to have originated from a pathway other than photoionization. The relevance of these observations to BR photoreactivity is discussed. BR radical ions in alkaline solution did not react with tryptophan (TrpH), but the semioxidized TrpH radical oxidized BR with k = 4.3 X 10(8) dm3 mole-1 sec-1. When human serum albumin (HSA) was oxidized using radiolytically generated azide radicals, a radical transformation involving TrpH and TyrOH residues occurred with k = 3.8 X 10(3) sec-1. When BR was complexed with the protein the transformation rate was reduced to 1.6 X 10(3) sec-1. This was interpreted in terms of a conformational change in the protein. Identification of the probable residues involved provided information about the primary BR binding site which was consistent with an earlier report.

Bile Pigments↗

PubMed2005

Neurones associated with saccade metrics in the monkey central mesencephalic reticular formation.

Neurones in the central mesencephalic reticular formation (cMRF) begin to discharge prior to saccades. These long lead burst neurones interact with major oculomotor centres including the superior colliculus (SC) and the paramedian pontine reticular formation (PPRF). Three different functions have been proposed for neurones in the cMRF: (1) to carry eye velocity signals that provide efference copy information to the SC (feedback), (2) to provide duration signals from the omnipause neurones to the SC (feedback), or (3) to participate in the transformation from the spatial encoding of a target selection signal in the SC into the temporal pattern of discharge used to drive the excitatory burst neurones in the pons (feed-forward). According to each respective proposal, specific predictions about cMRF neuronal discharge have been formulated. Individual neurones should: (1) encode instantaneous eye velocity, (2) burst specifically in relation to saccade duration but not to other saccade metrics, or (3) have a spectrum of weak to strong correlations to saccade dynamics. To determine if cMRF neurones could subserve these multiple oculomotor roles, we examined neuronal activity in relation to a variety of saccade metrics including amplitude, velocity and duration. We found separate groups of cMRF neurones that have the characteristics predicted by each of the proposed models. We also identified a number of subgroups for which no specific model prediction had previously been established. We found that we could accurately predict the neuronal firing pattern during one type of saccade behaviour (visually guided) using the activity during an alternative behaviour with different saccade metrics (memory guided saccades). We suggest that this evidence of a close relationship of cMRF neuronal discharge to individual saccade metrics supports the hypothesis that the cMRF participates in multiple saccade control pathways carrying saccade amplitude, velocity and duration information within the brainstem.

Action Potentials↗

PubMed1996

Transforming neural computations and representing time.

Motifs of neural circuitry seem surprisingly conserved over different areas of neocortex or of paleocortex, while performing quite different sensory processing tasks. This apparent paradox may be resolved by the fact that seemingly different problems in sensory information processing are related by transformations (changes of variables) that convert one problem into another. The same basic algorithm that is appropriate to the recognition of a known odor quality, independent of the strength of the odor, can be used to recognize a vocalization (e.g., a spoken syllable), independent of whether it is spoken quickly or slowly. To convert one problem into the other, a new representation of time sequences is needed. The time that has elapsed since a recent event must be represented in neural activity. The electrophysiological hallmarks of cells that are involved in generating such a representation of time are discussed. The anatomical relationships between olfactory and auditory pathways suggest relevant experiments. The neurophysiological mechanism for the psychophysical logarithmic encoding of time duration would be of direct use for interconverting olfactory and auditory processing problems. Such reuse of old algorithms in new settings and representations is related to the way that evolution develops new biochemistry.

Action Potentials↗

PubMed2001

Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton.

Our understanding of the biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics. Among mammals, mice are the most promising animals for this experimental work. Because extensive genetic information exists, many mouse mutations are known, and cells from early mouse developmental stages are accessible, scientists have developed transgenic mice - mice in which a gene is introduced or ablated in the germ line. Thus far, we have analyzed more than 100 different transgenic and knock out models with various skeletal phenotypes, covering the major aspects of both skeletal development and skeletal maintenance. Based on these results we here present a first perspective on transgenic and gene knock out animals in skeletal research, including insights in signaling pathways controlling endochondral bone formation, in the regulation of osteoblast function, osteoclastic bone resorption and in bone tumorigenesis, as well as the central control of bone formation. The use of transgenic mice to dissect and analyze regulatory mechanisms in bone cell physiology and the pathogenesis of human bone diseases is an extremely powerful experimental tool. The data presented here demonstrate that the successful convergence of novel genetic approaches with the established and fundamental knowledge of bone biology has made a beginning.

Journal Article↗

PubMed2005

Adsorption and photodegradation of dimethyl methylphosphonate vapor at TiO(2) surfaces.

The adsorption and degradation of the nerve agent simulant dimethyl methylphosphonate (DMMP) over UV-irradiated TiO(2) powders and thin films has been investigated. Adsorption of vapor-phase DMMP on TiO(2) powder is characterized by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). Photochemically assisted oxidation of adsorbed DMMP is carried out in situ by irradiation of samples in the DRIFTS accessory, giving kinetic data and information on specific site binding of DMMP and catalyst poisoning. Gas-phase intermediates from a static vapor phase reaction are identified by gas chromatography-mass spectrometry analysis, and surface-bound intermediates and products are analyzed by high-performance liquid chromatography-mass spectrometry, and ion chromatography of both aqueous and organic extractions from the TiO(2). Adsorbed DMMP is photodegraded in a stepwise fashion to give methylphosphonic acid, PO(4)(3-), H(2)O, and CO(2) as products. A proposed reaction pathway is consistent with a rapid degradation of DMMP but with extensive poisoning of the catalyst by surface-bound phosphonate products.

Journal Article↗

PubMed1998

Assessing the cancer risk from environmental PCBs.

A new approach to assessing the cancer risk from environmental polychlorinated biphenyls (PCBs) considers both toxicity and environmental processes to make distinctions among environmental mixtures. New toxicity information from a 1996 cancer study of four commercial mixtures strengthens the case that all PCB mixtures can cause cancer, although different mixtures have different potencies. Environmental processes alter PCB mixtures through partitioning, chemical transformation, and preferential bioaccumulation; these processes can increase or decrease toxicity considerably. Bioaccumulated PCBs are of greatest concern because they appear to be more toxic than commercial PCBs and more persistent in the body. The new approach uses toxicity studies of commercial mixtures to develop a range of cancer potency estimates and then considers the effect of environmental processes to choose appropriate values for representative classes of environmental mixtures. Guidance is given for assessing risks from different exposure pathways, less-than-lifetime and early-life exposures, and mixtures containing dioxinlike compounds.

Environmental Exposure↗

PubMed2005

Coordinate processing during the left-to-right hand transfer investigated by EEG.

Information about visuomotor tasks is coded in extrinsic, object-centered and intrinsic, body-related coordinates. For the reproduction of a trained task in mirror orientation with the opposite untrained hand, acquired extrinsic coordinates must be transformed. In contrast, intrinsic coordinates have to be modified during the execution of the originally oriented task. As shown recently, processes of coordinate transformations during the right-to-left hand transfer are associated with movement preparation and occur preferentially in the left hemisphere. Here, movement-related potentials, EEG power, and EEG coherence were recorded during the repetition of a drawing task previously trained by the nondominant left hand (Learned-task) and its execution in original and mirror orientation by the right hand (Normal- and Mirror-task). To identify EEG correlates of coordinate processing during intermanual transfer rather than effects due to the use of the right versus left hand, only those EEG data were analyzed which differed between the Normal- and Mirror-tasks. Whereas the Normal-task did not differ from the Learned-task in any of these predefined EEG parameters, beta coherence increased in the Mirror-task in the period ranging from 1 to 2 s after movement onset. These increases were especially prominent between hemispheres but were also observed symmetrically in the parieto-frontal electrode pairs of both hemispheres. Behavioral data revealed that the performance in the Learned- and both transfer tasks improved after left-hand training. Results of the present study indicate that coordinate transformation during the left-to-right hand transfer occurs in the phase of movement execution and affects predominantly extrinsic coordinates. Intrinsic coordinates are presumably mainly used in their original form. The modification of extrinsic coordinates is accompanied by increased information flow between both hemispheres; thereby inter-hemispheric connections--as mediated via the corpus callosum--seem to play a central role.

Adult↗

PubMed1998

Silent glutamatergic synapses and nociception in mammalian spinal cord.

Neurons in the superficial dorsal horn of the spinal cord are important for conveying sensory information from the periphery to the central nervous system. Some synapses between primary afferent fibres and spinal dorsal horn neurons may be inefficient or silent. Ineffective sensory transmission could result from a small postsynaptic current that fails to depolarize the cell to threshold for an action potential or from a cell with a normal postsynaptic current but an increased threshold for action potentials. Here we show that some cells in the superficial dorsal horn of the lumbar spinal cord have silent synapses: they do not respond unless the holding potential is moved from -70 mV to +40 mV. Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter of the raphe-spinal projecting pathway, transforms silent glutamatergic synapses into functional ones. Therefore, transformation of silent glutamatergic synapses may serve as a cellular mechanism for central plasticity in the spinal cord.

Animals↗