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At least 127 records · Page 7Linked to original sources
PubMed1998

Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage.

Proteases, glycosidases, and impermeant biotin derivatives were used in combination with antibodies to analyze the subcellular distribution and transmembrane disposition of the Na+/H+ exchanger NHE1. Both native human NHE1 in platelets and epitope-tagged rat NHE1 transfected into antiport-deficient cells were used for these studies. The results indicated that 1) the entire population of exchangers is present on the surface membrane of unstimulated platelets, ruling out regulation by recruitment of internal stores of NHE1; 2) the putative extracellular loops near the NH2 terminus are exposed to the medium and contain all the N- and O-linked carbohydrates; 3) by contrast, the putative extracellular loops between transmembrane domains 9-10 and 11-12 are not readily accessible from the outside and may be folded within the protein, perhaps contributing to an aqueous ion transport pathway; 4) the extreme COOH terminus of the protein was found to be inaccessible to extracellular proteases, antibodies, and other impermeant reagents, consistent with a cytosolic localization; and 5) detachment of approximately 150 amino acids from the NH2-terminal end of the protein had little effect on the transport activity of NHE1.

Amiloride↗
PubMedDate not supplied

Skin ulcers in fish: Pfiesteria and other etiologies.

Skin ulcers on fish are one of the most well-recognized indicators of polluted or otherwise stressed aquatic environments. In recent years, skin ulcer epidemics have been either experimentally or epidemiologically linked to exposure to a number of xenobiotic chemicals as well as to biotoxins. Some of these agents, such as toxins produced by the dinoflagellate alga Pfiesteria, have led to serious concerns about the health of aquatic ecosystems, such as estuaries along the east coast of the United States. However, a number of other risk factors besides Pfiesteria have been shown to damage epithelium and may also play important roles in skin ulcer pathogenesis. In addition, increasing evidence indicates that not only may skin damage occur via direct contact with toxins, but it may also be induced indirectly from physiological changes that result from exposure not only to toxins but also to other environmental stressors, such as pH and temperature extremes. The multifactorial pathways that operate at both the ecological and the organismal levels as well as the nonspecific response of the skin to insults make it very challenging to link epidemic skin ulcers to any single cause in natural aquatic populations. Consequently, using pathology to unequivocally identify the specific cause of a lesion (eg. Pfiesteria exposure) is not a valid approach. Only with an increased understanding of the basic mechanisms leading to skin damage (including development of specific biomarkers for specific toxins), along with a better understanding of ecological processes operating in these environments, will we be able to discern the relative importance of various risk factors in skin ulcer development.

Animals↗
PubMed2005

Integrin activates receptor-like protein tyrosine phosphatase alpha, Src, and Rho to increase prolactin gene expression through a final phosphatidylinositol 3-kinase/cytoskeletal pathway that is additive with insulin.

We previously showed that receptor-like protein tyrosine phosphatase (RPTP)-alpha inhibited insulin-increased prolactin gene transcription. Others suggested that RPTPalpha was a key intermediary between integrins and activation of Src. We present evidence that inhibition of insulin-increased prolactin gene transcription was secondary to RPTPalpha activation of Src, reflecting its role as mediator of integrin responses. Src kinase activity was increased in GH4 cells transiently or stably expressing RPTPalpha and cells plated on the integrin-alpha5beta1 ligand fibronectin. C-terminal Src kinase inactivated Src and blocked RPTPalpha inhibition of insulin-increased prolactin gene transcription. Expression of dominant-negative Src also prevented the RPTPalpha-mediated inhibition of insulin-increased prolactin gene expression. Low levels of a constitutively active Src mutant (SrcY/F) stimulated whereas higher expression levels of Src Y/F inhibited prolactin gene expression. Src-increased prolactin gene transcription was inhibited by expression of a blocking Rho-mutant (RhoN19), suggesting that Src acted through or required active Rho. Experiments with an activated Rho-mutant (RhoL63) demonstrated a biphasic activation/repression of prolactin gene transcription that was similar to the effect of Src. The effects of both Src and Rho were phosphatidylinositol 3-kinase dependent. Expression of SrcY/F or RhoL63 altered the actin cytoskeleton and morphology of GH4 cells. Taken together, these data suggest a physiological pathway from the cell matrix to increased prolactin gene transcription mediated by RPTPalpha/Src/Rho/phosphatidylinositol 3-kinase and cytoskeletal change that is additive with effects of insulin. Over activation of this pathway, however, caused extreme alteration of the cytoskeleton that blocked activation of the prolactin gene.

Animals↗
PubMed2005

The role of the built environment in the disablement process.

The Disablement Process model explicates the transition from health conditions to disability and specifically emphasizes the role of intervening factors that speed up or slow down the pathway between pathology and disability. We used hierarchical Poisson regression analyses with data on older adults from central North Carolina to examine the role of the built environment as a modifying factor in the pathway between lower extremity functional limitations and activities of daily living. We found that, despite declining physical function, older adults report greater independence in instrumental activities when they live in environments with more land-use diversity. Independence in self-care activities is modified by housing density, in part through the effect of substandard and inadequate housing.

Activities of Daily Living↗
PubMed2006

Solved upscaling problems for implementing deammonification of rejection water.

So far, extremely efficient metabolic pathways for nitrogen removal exclusively by autotrophic organisms are well established in scientific literature but not in practice. This paper presents results from the successful implementation of rejection water deammonification in a full-scale single sludge system at the WWTP Strass, Austria. Anaerobic ammonia oxidising biomass has been accumulated during a 2.5 year start-up period when the reactor size was gradually scaled up in the steps. The pH-controlled deammonification system (DEMON) has reached a design capacity of eliminating approximately 300 kg of nitrogen per day. Energy savings outperform expectations, decreasing the mean specific demand for compressed air from 109 m3(kg N)(-1) to 29 m3(kg N)(-1). Dominance of autotrophic metabolism is confirmed by organic effluent loads topping influent loads.

Ammonia↗
PubMed2001

Overview: rational integration of agents directed at novel therapeutic targets into combination chemotherapeutic regimens.

The last decade has witnessed the introduction of a number of agents directed against novel targets into the therapeutic armamentarium for the treatment of cancer. These include agents that interrupt neoplastic cell-survival signaling or cell-cycle regulatory pathways, and differentiation-inducing agents. A common theme linking these agents is that disruption of signal-transduction-, cell-cycle-progression- or differentiation-related pathways frequently leads to mitochondrial damage and apoptosis, and loss of neoplastic cell self-renewal capacity. It has also become apparent that these novel agents may, in a dose- and sequence-dependent manner, lower the threshold for conventional cytotoxic drug-induced apoptosis, resulting in synergistic interactions. More recently, evidence has been accumulating that the judicious combination of agents that interrupt more than one signaling-, cell-cycle-regulatory- or differentiation-related pathway represents an extremely potent apoptotic stimulus for neoplastic cells. The development of rational chemotherapeutic regimens combining these novel agents with others in their class or with conventional cytotoxic drugs presents significant challenges, but offers significant opportunities for therapeutic advances in the treatment of human malignancies. A brief overview of the status of this field follows.

Animals↗
PubMed1984

[Metabolism of arachidonic acid of the skin and its significance in the pathophysiology of inflammatory dermatosis].

Arachidonic acid can be converted via the cyclo-oxygenase and lipoxygenase pathways to biologically extremely potent products. The arachidonic acid metabolites - prostaglandins, prostacyclin, thromboxane, leukotrienes and hydroxy-fatty acids - are assumed to play a major role in the pathophysiology of inflammation. The skin shows an active arachidonic acid metabolism which is believed to be involved in the pathogenesis of psoriasis and different forms of dermatitis. Research into the biochemical basis of inflammation should lead to the introduction of new, pathogenetically oriented pharmacological principles in the treatment of these dermatoses.

Arachidonic Acids↗
PubMed2001

Telomerase can inhibit the recombination-based pathway of telomere maintenance in human cells.

Telomere length can be maintained by telomerase or by a recombination-based pathway. Because individual telomeres in cells using the recombination-based pathway of telomere maintenance appear to periodically become extremely short, cells using this pathway to maintain telomeres may be faced with a continuous state of crisis. We expressed telomerase in a human cell line that uses the recombination-based pathway of telomere maintenance to test whether telomerase would prevent telomeres from becoming critically short and examine the effects that this might have on the recombination-based pathway of telomere maintenance. In these cells, telomerase maintains the length of the shortest telomeres. In some cases, the long heterogeneous telomeres are completely lost, and the cells now permanently contain short telomeres after only 40 population doublings. This corresponds to a telomere reduction rate of 500 base pairs/population doubling, a rate that is much faster than expected for normal telomere shortening but is consistent with the rapid telomere deletion events observed in cells using the recombination-based pathway of telomere maintenance (Murnane, J. P., Sabatier, L., Marder, B. A., and Morgan, W. F. (1994) EMBO J. 13, 4953-4962). We also observed reductions in the fraction of cells containing alternative lengthening of telomere-associated promyelocytic leukemia bodies and extrachromosomal telomere repeats; however, no alterations in the rate of sister chromatid exchange were observed. Our results demonstrate that human cells using the recombination-based pathway of telomere maintenance retain factors required for telomerase to maintain telomeres and that once the telomerase-based pathway of telomere length regulation is engaged, recombination-based elongation of telomeres can be functionally inhibited.

Chromosome Aberrations↗
PubMed2006

Biochemical and regulatory properties of a respiratory island encoded by a conjugative plasmid in the extreme thermophile Thermus thermophilus.

In the present paper, we summarize the current knowledge on the first step of the denitrification pathway in the ancestral extreme thermophilic bacterium Thermus thermophilus. In this organism, nitrate respiration is performed by a mobilizable respiratory island that encodes a new type of respiratory NADH dehydrogenase as electron donor, a tetrameric membrane nitrate reductase as final electron acceptor, two nitrate/nitrite transporters and the transcription factors required for their expression in response to nitrate and anoxia.

Bacterial Proteins↗
PubMed1999

Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways.

Hyperglycemia can cause vascular dysfunctions by multiple factors including hyperosmolarity, oxidant formation, and protein kinase C (PKC) activation. We have characterized the effect of hyperglycemia on p38 mitogen-activated protein (p38) kinase activation, which can be induced by oxidants, hyperosmolarity, and proinflammatory cytokines, leading to apoptosis, cell growth, and gene regulation. Glucose at 16.5 mM increased p38 kinase activity in a time-dependent manner compared with 5.5 mM in rat aortic smooth muscle cells (SMC). Mannitol activated p38 kinase only at or greater than 22 mM. High glucose levels and a PKC agonist activated p38 kinase, and a PKC inhibitor, GF109203X, prevented its activation. However, p38 kinase activation by mannitol or tumor necrosis factor-alpha was not inhibited by GF109203X. Changes in PKC isoform distribution after exposure to 16.5 mM glucose in SMC suggested that both PKC-beta2 and PKC-delta isoforms were increased. Activities of p38 kinase in PKC-delta- but not PKC-beta1-overexpressed SMC were increased compared with control cells. Activation of p38 kinase was also observed and characterized in various vascular cells in culture and aorta from diabetic rats. Thus, moderate hyperglycemia can activate p38 kinase by a PKC-delta isoform-dependent pathway, but glucose at extremely elevated levels can also activate p38 kinase by hyperosmolarity via a PKC-independent pathway.

Adenoviridae↗
PubMed1984

Topographic organization of somatosensory corticotectal influences in cat.

Using electrophysiological techniques, the present study demonstrated that substantial direct somatosensory cortical influences on the superior colliculus (SC) originate from three areas: a) SIV, b) para-SIV (the cortex adjacent to SIV but deeper in the anterior ectosylvian sulcus (AES) and for which no topography has yet been described), and c) the rostral suprasylvian sulcus. Influences also appeared to originate from SI and SII, but these may have been indirect. Detailed examination of the AES revealed that these corticotectal projections are topographically organized, and stimulation of a given cortical locus was observed to affect only those cells in the SC whose receptive fields overlapped those of cells at the stimulation site. A similar receptive-field register was found between the suprasylvian sulcus and the SC. Within this topographic pattern, considerable convergence was evident and an individual SC cell could be influenced from a surprisingly large cortical area. This was particularly evident within the representation of the forelimb. Thus, an SC cell with a receptive field covering the forelimb and paw could receive convergent input from many cortical cells with receptive fields covering all or restricted portions of this body region. Considerable corticotectal divergence also was observed within this general topographic scheme. For example, a given corticotectal site representing the digits sent projections to many different SC cells that included the digits within their receptive fields. These data are more consistent with a block-to-block than a point-to-point corticotectal projection. Somatosensory corticotectal projections excited only those SC cells that could also be activated by peripheral somatosensory stimuli. Similarly, the caudal AES, which contains auditory cells, excited only those SC cells activated also by peripheral auditory stimuli. Yet convergent influences from both auditory and somatosensory regions of the AES were observed in the SC cells that could be activated by both auditory and somatosensory stimuli. These data indicate that the AES is a major source of excitatory input to cells of the deep laminae of the SC. Since it is these deep laminae cells that project to premotor regions of the brain stem and the spinal cord, it is reasonable to suppose that the AES has a significant impact on the output signals of the SC that initiate the orientation responses to peripheral sensory stimulation.

Animals↗
PubMed1975

[Substitute pathways of the arterial system of the lower extremities].

Some ideas emphazied by RENARD and his collaborators were rediscovered.--Anastomosis doesnt always signify compensation and it is often difficult to appreciate the functional importance of the anastomoses shown by arteriographies.--The most valuable compensations are made by short ways. Long ways only come into action when the shorter are obliterated. Finally a certain number of arteries play an important role in the compensatory circulation, that is:--the system of lumbar arteries--the hypogastric artery--the origin of the deep femoral artery.

Arteries↗
PubMed1985

[Ultrasonic test of key zones and collateral pathways in cases of arteriopathies of the lower extremities].

Justification is provided for the use of maximal methodology of the Doppler arterial examination of lower limbs by an improved approach to the collateral and distal networks and the detection of possibly dangerous lesions in key zones such as the femoral fork. Details are given of the method used for examination of iliac artery axes, the femoral artery intersection, the deep femoral and popliteal arteries and the popliteal supply network, as well as for rating of the distal tibial circulation.

Arterial Occlusive Diseases↗
PubMed1995

Insulin-like growth factor I receptor activated by a transmembrane mutation.

We constructed mutant receptors by mutating transmembrane Val922 of the human insulin-like growth factor I receptor (IGF-IR). Assays of receptor kinase and autophosphorylation revealed constitutively augmented tyrosine kinase activity of V922E IGF-IR in both transient and stable expression. The constitutively active tyrosine kinase of this mutant was verified by promoted tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the absence of IGF-I. In CHO cells stably increasing V922E IGF-IR, both IRS-1 phosphorylation and the IRS-1 associated phosphoinositide 3-kinase activity were stimulated in the absence of IGF-I to the level attained by 1 nM IGF-I stimulation of wild-type IGF-IR, whereas the Ras-mitogen-activated protein kinase pathway was not activated under the same condition. In these CHO cells, V922E IGF-IR significantly stimulated glucose uptake but did not promote mitogenesis in the absence of IGF-I. We thus conclude that the V922E mutation of IGF-IR switches on the intrinsic tyrosine kinase and differentially activates the downstream pathways. This mutant is extremely useful in clarifying the turning-on mechanism of IGF-IR as well as the differential roles of individual downstream pathways of receptor tyrosine kinases.

Animals↗
PubMed1990

Magnetic transcranial brain stimulation: painless evaluation of central motor pathways. Normal values and clinical application in spinal cord diagnostics: upper extremities.

Painless transcranial magnetic stimulation has been performed on 53 healthy adults in order to obtain normal values of central motor pathway conduction times to cervical segments innervating upper limb muscles. Central motor latency was 5.1 msec when recording from the biceps brachii and 5.2 msec when recording from the abductor pollicis brevis or abductor digiti minimi muscles. The plexus motor latency as the conduction time between the cervical motor root and the proximal nerve trunks in the axillary region was 2.2 msec and 2.6 msec when recorded from the abductor pollicis brevis and abductor digiti minimi muscles, respectively. Conduction times higher than mean latency + 2 standard deviation may indicate a pathologic conduction slowing. Magnetic stimulation of the motor system is a new painless neurophysiologic technique enabling examination of the central motor pathways in awake subjects. With respect to spinal cord diagnostics, this method is useful in conditions such as compression of the spinal cord or of the motor root in the intervertebral foramen or canal.

Adult↗
PubMed1999

Posteroventral pallidotomy for midbrain tremor after a pontine hemorrhage. Case report.

This 49-year-old man gradually developed a disabling action tremor in the proximal right upper extremity 8 months after suffering a pontine tegmental hemorrhage. The intraoperative microrecording in the nucleus ventralis intermedius (VIM) of the left thalamus revealed tremor-synchronous grouped discharges with a vigorous (2.7 Hz) action tremor predominantly in the shoulder and upper arm. High frequency electrical stimulation in the VIM did not affect the tremor. A posteroventral pallidotomy (PVP) was performed and resulted in the successful alleviation of all tremor activity. Posteroventral pallidotomy is known to alleviate parkinsonian tremors, especially those occurring in the contralateral lower extremity, trunk, and proximal segment of the contralateral upper extremity. The authors consider the pallidoreticular pathway to be an important tremor-mediating pathway for the proximal segment of the upper extremities and believe it can be controlled more effectively by PVP than by VIM thalamotomy, as demonstrated by the PVP-induced resolution of the midbrain tremor observed in this case.

Cerebral Hemorrhage↗
PubMed1987

CT detection of intrapelvic origin of lower extremity infections in traumatized limbs.

Late appearing, lower extremity infections in previously traumatized limbs may originate from occult intrapelvic sources. Computerized tomography can accurately document the intrapelvic source and trace its pathway into the lower extremity. In this paper, we describe two cases of thigh infections originating from pelvic abscesses in limbs that were previously operated on following trauma. Computerized tomography was instrumental in making the diagnosis and directing the appropriate surgical treatment.

Abscess↗
PubMed2006

Antitumor enediyne chromoprotein C-1027: mechanistic investigation of the chromophore-mediated self-decomposition pathway.

C-1027 is an extremely potent antitumor agent that causes double-stranded DNA cleavages. It is a unique small molecule-protein complex composed of a highly reactive enediyne chromophore, which upon binding reacts with its target molecule DNA through radical-mediated hydrogen abstraction and an apoprotein that encapsulates the chromophore serving as its carrier to reach DNA. Although C-1027 has favorable properties as an effective drug delivery system, it slowly self-decomposes due to the reactivity of the chromophore toward the apoprotein. Understanding how the C-1027 destroys itself may enable design of its analogues that overcome this limitation. In this paper, mechanistic insights into the self-reactivity of C-1027 that facilitates its own decomposition are described. We provide evidence that the formation of the Gly96 radical, which promotes the oxidative protein scission and the subsequent chromophore release, is the major pathway for the self-decomposition of C-1027. On the basis of the newly isolated products of the self-decomposition, we propose that the apoprotein effectively protects two different structural elements of the chromophore that are essential for its biological activity: the nine-membered enediyne moiety (necessary for DNA cleavage) and the benzoxazine moiety (necessary for DNA intercalation). Using an engineered apoprotein analogue kinetically more stable toward the chromophore radical, we show that enhanced overall properties can be achieved for the natural C-1027 with respect to stability and antitumor activities. The results present the first example of a rationally designed C-1027 analogue reported to display superior in vitro antitumor activity to the natural C-1027. Our findings may have implications for design of proteins that can stably encapsulate highly reactive small molecules.

Aminoglycosides↗