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At least 19 recordsLinked to original sources
PubMed2026

EGFR-co-amplified lncRNA ELDR drives glioblastoma tumorigenicity by enhancing BMI1 activity.

BACKGROUND: In glioblastoma (GBM), epidermal growth factor receptor (EGFR) amplification, one of the most prevalent genetic alterations, often occurs on extrachromosomal DNAs (ecDNAs) that contain amplified oncogenes and regulatory elements, driving tumor progression. Despite the central oncogenic role of EGFR amplification, therapeutic strategies targeting EGFR have demonstrated limited clinical efficacy, suggesting that additional mechanisms may underlie EGFR-driven GBM malignancy and treatment resistance. Long non-coding RNAs (lncRNAs) are critical regulators in cancer; however, the roles of EGFR-associated lncRNAs-particularly those localized on ecDNA-in GBM tumorigenicity and therapeutic resistance remain poorly understood. METHODS: Transcriptomic and genomic analyses were performed to identify lncRNAs co-amplified with EGFR. Biochemical and molecular biological studies were carried out to reveal the mechanisms. In vivo xenograft models were used to evaluate the tumorigenicity and the therapeutic efficacy of combination treatment strategies. RESULTS: The lncRNA EGFR long non-coding downstream RNA (ELDR) was co-amplified with EGFR on ecDNA and chromosomes and was associated with poor prognosis in glioma. ELDR promoted GBM tumorigenicity through a BMI1-dependent epigenetic mechanism operating in parallel with canonical EGFR signaling. Mechanistically, ELDR interacted with purine-rich element-binding protein A (PURA), disrupted the inhibitory PURA-BMI1 interaction, and thereby enhanced the activity of BMI1, a core component of Polycomb repressive complex 1 (PRC1). Therapeutically, combining a BMI1 inhibitor or ELDR-targeting antisense oligonucleotides (ASOs) with an EGFR inhibitor erlotinib significantly enhanced antitumor efficacy in preclinical models of  EGFR  -amplified GBM with high ELDR expression. CONCLUSION: EGFR co-amplified ELDR promotes GBM tumorigenicity by enhancing BMI1 activity. Targeting the ELDR-BMI1 axis in combination with EGFR inhibition represents a promising therapeutic strategy for a subset of  EGFR  -amplified GBMs with high ELDR expression.

EGFR↗
PubMed1991

Nursing skills necessary for competency in the high-tech health care system.

Neighbors, Sullivan, and Eldred tell us how schools of nursing and institutions of nursing practice conform--or fail to conform--in regard to what constitutes basic nursing procedures. Are schools leaving the new graduate unprepared for everyday practice? A survey of association degree schools is revealing.

Clinical Competence↗
PubMed1976

The mechanism of the aminoacylation of transfer ribonucleic acid: enzyme-product dissociation is not rate limiting.

It has been proposed that the rate-limiting step in the synthesis of aminoacyl-tRNA is the rate at which the product dissociates from the enzyme. The experimental evidence supporting this hypothesis comes from work at low pH and low temperature (although the reaction has been argued to have the same mechanism under physiological conditions). We have reexamined the binding assay by which M. Yarus and P. Berg (1969) (J. Mol. Biol. 42, 171-189) measured the kd for dissociation of Enz-(Ile-tRNA). We find that when overall reaction and dissociation are measured under identical conditions the two rates are not the same. Moreover, while an increase in ionic strength greatly stimulates dissociation, the same increased ionic strength slows aminoacylation. Spermine accelerates overall aminoacylation without affecting dissociation. Because any change in a rate-limiting step must, by definition, cause a parallel change in the overall reaction, these observations prove that under these conditions the synthesis of Ile-tRNA is not limited by the rate of dissociation of Enz-(Ile-tRNA). Entirely similar observations were made for the dissociation of Enz-(Val-tRNA) and the overall synthesis of Val-tRNA at 0 degrees C, PH 5.0. In addition, valine enzyme isolated by nitrocellulose filtration during the course of an aminoacylation was shown not to be saturated with recently synthesized Val-tRNA. The enzyme was in equilibrium with uncharged substrate tRNA and with product Val-tRNA. E. W. Eldred and P. R. Schimmel ((1972) Biochemistry 11, 17-23) report that the formation of Ile-tRNA proceeds at two rates: (a) k = 2 X 10(-2)S(-1) until the enzyme is saturated with the first mole of product, and (b) k = 2 X 10(-3)S(-1) for subsequent cycles. We did not observe this behavior at any pH or temperature with four different amino acid:tRNA ligases. Because aminoacylation proceeds more rapidly than "dissociation" under some conditions, we believe that the binding assay measures not only enzyme-product dissociation but also other slower reactions such as aggregation or disaggregation of Enz-(AA-tRNA). In conjunction with recent studies from other laboratories, this work makes it unlikely that enzyme-product dissociation is the rate-limiting step in the synthesis of aminoacyl-tRNA either at low temperature and pH or under more nearly physiological conditions. From the effect of salt, it would appear that the rate of aminoacylation of tRNA is largely limited by the rate or extent of formation of Enz-(tRNA) (Loftfield, R. B., and Eigner, E. A. (1967), J. Biol. Chem. 242, 5355-5359). Using the binding assay of M. Yarus ((1972) Biochemistry 11, 2050-2060), we find the Kass for Enz-(Ile-tRNA) varies linearly with the Debye-Hückel function at ionic strengths of 0.1-0.4 from 10(8) to 10(6).

Amino Acyl-tRNA Synthetases↗
PubMedDate not supplied

Post-contraction variations in motor pool excitability.

Previous evidence has shown a marked increase in motoneuronal excitability during muscle contraction and decreased post-contraction excitability. This post-contraction inhibition has been shown to persist up to 800 msec following the end of contraction (Gottlieb and Agarwal, 1973) and apparently continues with gradual recovery up to one minute (Enoka, Hutton and Eldred, 1980). These effects have been attributed in part to influences of muscle receptors on the homonymous motor pool. The purpose of the present study was to observe the time course of short term post-contraction effects, following a maximum isometric contraction, on excitability of the homonymous motoneuronal pool as measured by the Hoffmann reflex. Each of five subjects lay supine on a table with shoulder blocks to prevent movement during resisted plantar flexion. The subject's preferred foot was placed in a stirrup attached to a force gauge which measured tension. Recording electrodes were applied over the soleus muscle, and M- and H-responses were evoked by percutaneous electrical stimulation of the tibial nerve at the popliteal fossa. The stimulus strength was set to elicit a control H-reflex at rest of half the magnitude of the maximum H-reflex value. For each trial the subject performed a 6 s maximum contraction of the triceps surae muscle group, beginning on one visual signal and ending on a second visual signal. The H-reflex was elicited at semi-random intervals prior to and after the visual signal to relax. Increased H-reflex excitability was observed during muscle contraction followed by a marked decrease in evoked amplitudes with gradual recovery following the end of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1978

Spinal projection to the dorsolateral nucleus of the caudal basilar pons in the cat.

In the cat, a spinal projection to a restricted area of the basilar pontine grey has been revealed with use of anterograde degeneration technique (Fink-Heimer). The area was ipsilateral to the spinal lesion, restricted to the far caudal limit of the pons, and included the dorsal and the dorsolateral subdivisions of the pontine nuclei (PN). Comparisons following high cervical, midthoracic and upper lumbar spinal lesions did not reveal any somatotopic organization. Only a few spinopontine fibers had origins below segmental level L4. Lesions of various quadrants of the cord indicated that the spinopontine fibers ascended through the dorsolateral funiculus, and not through either the dorsal or the ventral funiculi. Comparison with the degeneration effects of cerebral cortical lesions showed that the spinal projection to the PN overlapped to some extent with the projection from the first sensorimotor and second somatosensory cortices. In the rat no comparable spinopontine projection was found. It is suggested that the spinopontine pathway might forward information to the cerebellum from visceral sensory receptors or perhaps from pools of spinal interneurons.

Animals↗
PubMed1991

Localization of aspartate-like immunoreactivity in the retina of the turtle (Pseudemys scripta).

Aspartate has been reported to be a putative excitatory neurotransmitter in the retina, but little detailed information is available concerning its anatomical distribution. We used an antiserum directed against an aspartate-albumin conjugate to analyze the anatomy, dendritic stratification, and regional distribution of cell types with aspartate-like immunoreactivity in the turtle retina. The results showed dramatic differences in immunoreactivity in the peripheral versus the central retina. Strong aspartate-like immunoreactivity was shown in the peripheral retina, with many well-labeled processes in the inner plexiform layer. Many bipolar, horizontal, amacrine, and ganglion cells, some photoreceptors, and some unidentified cells were strongly immunoreactive in the peripheral retina. In contrast, although the central retina showed well-labeled horizontal cells, there was only light labeling in the inner plexiform layer with weakly immunoreactive amacrine and ganglion cells and no labeled bipolar cells. There were several strongly immunoreactive efferent nerve fibers which left the optic nerve head and arborized extensively in the retina. At the electron microscopic level, electron-dense reaction product was associated with synaptic vesicles at bipolar and amacrine cell synapses in the inner plexiform layer. These results suggest that aspartate may be involved in many diverse synaptic interactions in both the outer plexiform layer and the inner plexiform layer of the turtle retina.

Animals↗
PubMed1975

Nicotine-induced reflex depression of alpha motoneuron activity in the absence of fusimotor-spindle feedback.

The effects of nicotine on the stretch reflex and on electrically induced monosynaptic and cutaneous polysynaptic reflex responses at a lumbosacral level were studied in lightly anesthetized (chloralose-urethane) cats in which the regional fusimotor-spindle loops had been interrupted by ventral rhizotomy. Doses of 15-40 mug/kg injected into the superior vena cava or the right atrium produced depression of the reflex responses in extensor and flexor alpha motoneurons after latent periods of 1-3 sec, while gamma activity was initially accelerated. The early phase of this alpha depression was abolished by bilateral vagotomy. Sebacylcholine (a nicotinic agent) and acetylcholine also caused depression of evoked alpha activity in the absence of spindle feedback. It is concluded that nicotine activates a viscerosomatic reflex by exciting sensory receptors in the cardiopulmonary region and that alpha motor depression results independent of the changes in gamma activity. However, alpha depression with delayed onset can still be elicited by nicotine after vagotomy and Renshaw blockade, and this effect is also duplicated by sebacylcholine and abolished by hexamethonium. In the doses used, spindle or skin afferents were not excited by nicotine. Thus, two more mechanisms are described by which nicotine can depress alpha activity. Both are reflex in nature, one implicating vagal, the other nonvagal peripheral receptors.

Acetylcholine↗
PubMed1991

Physiological and developmental implications of motor unit anatomy.

There is increasing evidence that the architectural design and arrangement of the fibers within a motor unit have important physiological and developmental ramifications. Limited data, however, are available to directly address this issue. In the present study the physiological properties of one motor unit in each of seven cat tibialis anterior (TA) muscles were determined. Each of these units then was repetitively stimulated to deplete the glycogen in all muscle fibers within the unit. Subsequently, the length, type of ending, and spatial distribution of fibers sampled from these physiologically and histochemically typed motor units were determined. Four fast fatigable (FF), one fast, fatigue resistant (FR), and two slow (S) motor units (MU) were studied. The samples consisted of all those glycogen-depleted fibers (9-27) contained within a single fascicle or a circumscribed area of each of the motor unit territories. The mean fiber lengths for the two slow motor units were 35.9 and 45.5 mm. The mean fiber lengths for the fast motor unit samples ranged from 8.8 to 48.5 mm. Some fibers of both the fast and slow units reached lengths of 58 mm. Most of the fibers in the slow units extended the entire distance between the proximal and distal musculotendinous planes, had relatively constant cross-sectional areas, and terminated at the tendon as blunt endings. In contrast, the majority of the fibers in the fast units terminated intrafascicularly at one end, and the cross-sectional area decreased progressively along their lengths, that is, showed a tapering pattern for a significant proportion of their lengths. Therefore, the force generated by units that end midfascicularly would appear to be transmitted to connective tissue elements and/or adjacent fibers. All fibers of a fast unit within a fascicle were located at approximately the same proximo-distal location. Thus, developmentally the selection of muscle fibers by a motoneuron would seem to be influenced by their spatial distribution. The architectural complexities of motor units also have clear implications for the mechanical interactions of active and inactive motor units. For example, the tension capabilities of a motor unit may be influenced not only by the spatial arrangement of its own fibers, but also by the level of activation of neighboring motor units.

Animals↗
PubMed1992

Immunocytochemical and biochemical studies of histamine in the retina of the turtle Pseudemys scripta.

A combination of immunocytochemical and biochemical methods was used to study histamine in the turtle retina. Histamine-like immunoreactivity was localized within paraboloids of certain cone photoreceptors by use of two different antisera directed against histamine. Preincubation of eyecups in Ringer's containing 10 microM histamine selectively increased the immunoreactivity of these photoreceptor paraboloids. The present localization of histamine in paraboloids indicated that, although histamine is in photoreceptors of the turtle retina, it may play some metabolic or neuromodulatory role, and not function as a neurotransmitter.

Animals↗
PubMed1975

Persisting changes in sensory and motor activity of a muscle following its reflex activation.

A study was made to see if contractions induced by reflex action were followed by an elevation in muscle afferent activity comparable to the post-contraction sensory discharge (PCSD) that occurs after stimulation of the ventral roots. In lightly anesthetized cats, extension reflexes of the triceps surae muscle in the otherwise denervated leg were induced by contralateral stimulation of the popliteal nerve or footpad. The reflex response was followed by an elevated afferent discharge, which disappeared after a brief stretch, as is characteristic also of the PCSD. Crossed-extension responses in fusimotor activity unaccompanied by contraction of the gross muscle were also succeeded by an elevation in sensory discharge and an increased sensitivity to a vibratory stimulus applied to the tendon. Pinna reflexes had a similar effect. In the presence of the elevated discharge, alpha-motoneurons demonstrated increased sensitivity to vibration stimuli. It is suggested that the increase in spindle sensitivity may help stabilize the muscle against minor pertubations in length, at least when background fusimotor activity is relatively quiet.

Animals↗
PubMed1990

Synaptic analysis of amacrine cells in the turtle retina which contain tyrosine hydroxylase-like immunoreactivity.

This study examined amacrine cells in the retina of the turtle Pseudemys scripta elegans, which were labelled using an antiserum directed against tyrosine hydroxylase (an enzyme participating in catecholamine synthesis). These cells were investigated using both light and electron microscopy. Labelled somata were located in the inner nuclear layer near the border of the inner plexiform layer. The dendritic arborizations of these neurons were tristratified and arborized in strata 1 and 3 and near the border between strata 4 and 5. Serial tangential sections taken through the entire inner plexiform layer of a 1 mm-2 region in mid-peripheral retina were examined. All of the synapses associated with labelled profiles were counted and classified. The majority (84%) of the synapses involving labelled processes represented output, while the remaining 16% represented synaptic input. The synaptic output of the labelled processes was as follows: 87% onto unlabelled amacrine cells, 4% onto ganglion cells, 9% onto unidentified cell processes. None of the synaptic output from labelled processes was onto bipolar cells. The synaptic input to these labelled cells was from bipolar cells (29%) and from unlabelled amacrine cells (71%). A well labelled amacrine cell was serially sectioned and examined at the ultrastructural level to analyze its synaptic connectivity. Immunoreaction product was located diffusely throughout the cytoplasm and in large vesicles. The synaptic organization of the cell was directed primarily toward output. The labelled processes were postsynaptic and presynaptic to unlabelled amacrine cell processes in strata 1 and 3 and at the border between strata 4 and 5. Synaptic input from bipolar cells was seen exclusively near the border between strata 4 and 5. Labelled processes were presynaptic to ganglion cell processes in stratum 1 and at the border between strata 4 and 5, but not in stratum 3. Quantitative studies suggested that amacrine cell inputs and outputs were evenly distributed across the dendritic arborization, while bipolar cell inputs and outputs to ganglion cells were concentrated on the distal parts of the dendritic arborization. No labelled processes were seen in the outer plexiform layer, indicating that the cells with tyrosine hydroxylase-like immunoreactivity in the turtle retina were true amacrine cells and not interplexiform cells.

Animals↗
PubMed1992

Colocalization of enkephalin-, glucagon-, and corticotropin-releasing factor-like immunoreactivity in GABAergic amacrine cells in turtle retina.

The large number of amacrine cells which contain gamma-aminobutyric acid (GABA) in the turtle retina makes it difficult to examine specific GABAergic cell types. In order to selectively label subpopulations of GABAergic neurons, we have used fluorescent double-labeling immunocytochemical techniques to examine the localization of GABA-like immunoreactivity (LI) in amacrine cells which contain antigens resembling the neuropeptides glucagon (GLUC), corticotropin-releasing factor (CRF) or enkephalin (ENK). GABA-LI was found in 41% of the cells with GLUC-, 100% of the cells with CRF-, and 69% of the cells with ENK-LI. There were regional differences in the presence of GABA-LI in amacrine cell populations with ENK-LI. GABA-LI was present in about 80% of the cells with ENK-LI outside of the visual streak, while only 37% of the cells within the streak had GABA-LI. Based on the distinct morphologies and regional distributions of these peptidergic amacrine cells, we conclude that they represent different subpopulations of GABAergic amacrine cells in the turtle retina. Future studies can now utilize existing information regarding the synaptic connectivity of these peptidergic amacrine cells to help delineate the functions of GABAergic amacrine cells in the turtle retina.

Animals↗