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PubMed1983

Effects of lesions in some basal ganglia nuclei and efferent projections on tremorine-induced limb rigidity in rats.

A mechanical apparatus was used to measure in rats the effects of some unilateral basal ganglia lesions on the hind-limb rigidity produced by the cholinomimetic compound, tremorine. A globus pallidus lesion reduced the resting tone and greatly increased rigidity in the contralateral leg. Lesions in the entopeduncular, subthalamic, and accumbens nuclei had no effects on rigidity, although the entopeduncular nucleus lesion reduced resting limb tone. The role of the globus pallidus in rigidity is significant in relation to work in which striatal lesions abolished tremorine-induced rigidity. Some brain regions that receive basal ganglia efferent fibers received a lesion unilaterally. Lesions in the substantia nigra, red nucleus, or pedunculopontine nucleus had no effect on tremorine-induced rigidity. A habenular lesion significantly reduced rigidity in both hind legs. Very pronounced reductions in rigidity occurred after midbrain lesions involving the central periaqueductal grey region and the superior colliculus. The basal ganglia output pathways that may mediate tremorine rigidity are discussed, together with the possibility that the superior colliculus, which has many muscarinic receptors, may be influenced directly by tremorine.

Animals↗
PubMed1991

Interference of cephalosporins with immune response: effects of cefonicid on human T-helper cells.

To determine the immunosuppressive effect(s) of cephalosporin cefonicid (CEFO) on human T-helper cells (Th), we exposed human peripheral blood mononuclear cells (PBMC) to various concentrations of CEFO during in vitro stimulation with a panel of T-lymphocyte stimulators that activate different Th/antigen presenting cell (APC) pathways. We evaluated the proliferation and IL-2 production induced by influenza virus (FLU), allogeneic lymphocytes (ALLO), xenogeneic mouse splenocytes (XENO) or phytohemagglutinin (PHA). The proliferative responses to FLU and XENO were much more depressed by CEFO than those to ALLO or PHA. After 7 days of culture with the highest dose of CEFO tested (200 mg/l) the stimulation index (stimulated/unstimulated culture) was near to 0 in FLU and XENO treated cultures, indicating that the response against these antigens was completely abrogated. The responses to ALLO and PHA were also impaired, but not abrogated (stimulation index greater than 1). Since FLU and XENO utilize the CD4+ Th/self-APC pathway our data suggested that this pathway was extremely sensitive to CEFO-induced inhibition both when the response requires memory Th cells (FLU) and virgin Th cells (XENO). The incubation with CEFO (200 mg/l) reduced the IL-2 production by XENO, FLU and ALLO to less than 20% of control cultures, while paradoxically increases to 120% the production by PHA.

Antigens↗
PubMed1990

Pathway to carcinogenesis: the role of bacteria.

A bacterium is involved in the etiology and physiopathology of the malignant cell. It is not any bacterium, but one with specific characteristics suggestive of a plant-type metabolic and respiratory physiology. Utilizing mice growing sarcomatous lesions as an experimental model, we have been able to recover, in 100% of culture procedures, the Staphylococcus aureus coagulase positive micro-organism, provided that a modified media, as described in a later paragraph, is utilized to sustain these microbes while in transfer from in vivo to in in vitro measures. In human cancer tissue studied, the Ascomycete fungus as well as the Staphylococcus could be isolated (1). Bacteria, fungi, or viruses, isolated by the culturing of cancerous tissue or by their recognition through microscopic study, in itself do not constitute satisfactory reasons to conclude that such microbes are the causative factors in cancer etiology. There must be a definite pathway of bacterial activity to justify such a conclusion. Our experimental studies have defined such a pathway. Of extreme importance is the fact that the Staphylococcus, as a separate entity, does not and cannot produce a malignant cell. Our studies indicate that the malignant cell can only occur in a warm-blooded living animal or human, and it is dependent upon three factors. The bacterium as the first factor must possess characteristics of a plant micro-organism. Specifically, they must have a reducing factor capable of creating an oxygen free millieu in an enclosed area, must be able to convert during duress to a unicellular micro-coccus, and must remain viable within a sac or cell despite the absence of their outside cell wall.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaerobiosis↗
PubMed2003

Did a change in sensory control of skilled movements stimulate the evolution of the primate frontal cortex?

The classical view of the evolution of such skilled movements as use of the hand and digits for reaching and grasping posited that these movements had their origin in the primate lineage. The hypothesis was that the permissive influence of adaptations to an arboreal environment led to the evolution and elaboration of these skills. Associated with skilled movements were increases in the size of the frontal lobe, temporal lobe, and cerebellum and the elaboration of new connections between these structures and other cortical regions, the brainstem, and spinal cord. The classical view saw rodents as phylogenetically old and relatively unrelated animals, displaying no skilled movements, and whose normal repertoire of behavior had little dependence on the frontal lobes. Here, evidence is reviewed that shows that the classical view of the origins of skilled movements is incorrect. Skilled movements are phylogenetically old, evolved in relation to food handling, and are especially well developed in rodents. Behavioral evidence also shows that the skilled movements of rodents are dependent upon the function of the frontal cortex. Nevertheless, there are difference in the sensory control of skilled movement in primates and rodents. Skilled movements are largely directed by vision in primates but are directed by hapsis/olfaction in rodents. This difference in sensory control suggests that at a dividing point between primates and rodents, there was a profound behavior/brain transformation. Primates retained the skilled movements exemplified in rodents, but brought these movements under visual control. Correspondingly, along with many other anatomical changes, the primate frontal cortex became relatively larger and move complex under visual influence.

Animals↗
PubMed2005

Column studies to investigate the fate of veterinary antibiotics in clay soils following slurry application to agricultural land.

The environment may be exposed to veterinary medicines administered to livestock due to the application of organic fertilisers to land. For other groups of substances that are applied to agricultural land (e.g. pesticides), preferential flow in underdrained clay soils has been identified as an extremely important pathway by which pollution of surface waters can occur. Three soil column leaching experiments have therefore been carried out using a clay soil to investigate the fate of a range of antibiotics from the sulphonamide, tetracycline and macrolide groups. These column studies complemented a range of other experiments at the field and semi-field scales, as well as modelling studies which are being reported in separate papers. Each column study had a different objective. The first examined the effect of pig slurry on the mobility of antibiotics in clay loam soil. The second experiment investigated changes in soil water pH due to the application of slurry. The final experiment quantified the extent to which soil tillage prior to slurry application can reduce the leaching of antibiotic residues found in slurry. It was found that slurry had no impact on the leaching of oxytetracycline although soil water pH was affected significantly by slurry application. It was also shown that pre-tillage can substantially reduce the leaching of antibiotic residues through macroporous clay soils.

Agriculture↗
PubMed1995

Macroregenerative (dysplastic) nodules and hepatocarcinogenesis: theoretical and clinical considerations.

Over the last decade or so, we have seen the development of an interesting new area of liver pathology, new because advanced imaging techniques coupled with careful screening of population at risk for HCC have focused attention on nodular hepatocellular lesions that have been previously ignored. Careful searching for these nodules has led to the acknowledgment that they are not restricted to the populations in which they were first identified and in which the association with HCC was first made, but are probably a universal phenomenon and one extremely important pathway for the development of HCC. Moving beyond these epidemiological associations, we see that careful consideration of the morphology of these lesions leads to insights into the early stages of human hepatocarcinogenesis, setting the stage for the development of a clinically useful system of nomenclature and, perhaps, new approaches to screening for early HCC. Additional important work lies ahead, as concepts from animal models of hepatocarcinogenesis are applied to these human lesions, molecular approaches to research and diagnostics are applied, and extensive prospective screening and clinicopathologic correlation studies are carried out.

Carcinoma, Hepatocellular↗
PubMed1981

Wundt's views on sensations of innervation: a reevaluation.

It is sometimes stated that Wundt believed in the primacy of 'sensations of innervation' in the control of eye and limb position, to the exclusion of afferent feedback. Wundt's own statements on the subject are traced through the six editions of the Grundzüge: he believed that sensations of innervation were a contributory factor along with peripheral feedback; but in the fourth edition he dropped the term and subsumed them under 'central sensations of senses', because increased neurophysiological knowledge made a literal interpretation of the original term impossible. In the fifth edition he developed a more precise model of central processes, described as 'sensory costimulation', and an additional idea of 'reproduced' or conditioned sensations. He mentions clinical evidence on the perception of eye and limb position of weight by paralysed and other subjects. This evidence is discussed in relation to modern theories. It is concluded that Wundt's later theories have some similarities with modern "hybrid' theories of efference-contingent afference.

Afferent Pathways↗
PubMed2000

Mutants of Arabidopsis defective in a sequence-specific mRNA degradation pathway.

One of the ways a cell can rapidly and tightly regulate gene expression is to target specific mRNAs for rapid decay. A number of mRNA instability sequences that mediate rapid mRNA decay have been identified, particularly from multicellular eukaryotes, but pinpointing the cellular components that play critical roles in sequence-specific decay in vivo has been more difficult. In contrast, general pathways of mRNA degradation in yeast have been well established through the analysis of mutants affecting the general mRNA decay machinery. Strategies to isolate mutants in sequence-specific mRNA decay pathways, although extremely limited so far, have the potential to be just as powerful. In the study reported here, a selection in transgenic plants allowed the isolation of rare mutants of Arabidopsis thaliana that elevate the abundance of mRNAs that contain the plant mRNA instability sequence called DST (downstream element). This instability sequence is highly conserved in unstable small auxin up RNA (SAUR) transcripts. Genetic analysis of two dst mutants isolated via this selection showed that they are incompletely dominant and represent two independent loci. In addition to affecting DST-containing transgene mRNAs, mutations at both loci increased the abundance of the endogenous DST-containing SAUR-AC1 mRNA, but not controls lacking DST sequences. That these phenotypes are caused by deficiencies in DST-mediated mRNA decay was supported by mRNA stability measurements in transgenic plants. Isolation of the dst mutants provides a means to study sequence-specific mRNA degradation in vivo and establishes a method to isolate similar mutants from other organisms.

Arabidopsis↗
PubMed1993

Signal transduction via the MAP kinases: proceed at your own RSK.

An explosion of new information linking activation of cell surface signal initiators to changes in gene expression has recently emerged. The focus of much of this information has centered around the agonist-dependent activation of the mitogen-activated protein (MAP) kinases. Although this intracellular signal transduction pathway is extremely complex, conservation of many of its components has been observed in yeast, nematodes, Drosophila, and mammals. Thus, these signaling proteins may participate in the regulation of a variety of cellular processes.

Animals↗
PubMed2006

Micromolar intracellular hydrogen peroxide disrupts metabolism by damaging iron-sulfur enzymes.

An Escherichia coli strain that cannot scavenge hydrogen peroxide has been used to identify the cell processes that are most sensitive to this oxidant. Low micromolar concentrations of H2O2 completely blocked the biosynthesis of leucine. The defect was tracked to the inactivation of isopropylmalate isomerase. This enzyme belongs to a family of [4Fe-4S] dehydratases that are notoriously sensitive to univalent oxidation, and experiments confirmed that other members were also inactivated. In vitro and in vivo analyses showed that H2O2 directly oxidized their solvent-exposed clusters in a Fenton-like reaction. The oxidized cluster then degraded to a catalytically inactive [3Fe-4S] form. Experiments indicated that H2O2 accepted two consecutive electrons during the oxidation event. As a consequence, hydroxyl radicals were not released; the polypeptide was undamaged; and the enzyme was competent for reactivation by repair processes. Strikingly, in scavenger-deficient mutants, the H2O2 that was generated as an adventitious by-product of metabolism (<1 microm) was sufficient to damage these [4Fe-4S] enzymes. This result demonstrates that aerobic organisms must synthesize H2O2 scavengers to avoid poisoning their own pathways. The extreme vulnerability of these enzymes may explain why many organisms, including mammals, deploy H2O2 to suppress microbial growth.

Catalase↗
PubMed2003

Computational approaches to motor control and their potential role for interpreting motor dysfunction.

PURPOSE OF REVIEW: Computational frameworks, notably internal models and optimal control theory, have led to rapid advances in our understanding of how the brain plans and controls movement. The purpose of this review is to provide an overview of these theoretical ideas, how they have been used to interpret motor control, as well as their potential role for interpreting motor dysfunction. RECENT FINDINGS: There are two general types of internal models, neural processes that mimic the mechanical properties of the limb (and environment). Forward internal models parallel the normal causal flow of the motor periphery and estimate limb motion from motor commands. Inverse internal models perform the reverse process by estimating motor commands from signals related to intended limb motion and/or spatial targets. This framework has led to several important behavioural observations on motor planning, control and learning, and has also been influential for interpreting neural activity in awake, behaving non-human primates. A more recent framework for interpreting motor function is optimal control theory, which recognizes that noise or errors are an inherent feature of the motor system and may influence strategies to plan and control movement. SUMMARY: Internal models and optimal feedback control both provide frameworks for interpreting motor performance, and may be of value for interpreting many motor dysfunctions associated with neurological injuries. Advanced technologies such as robots that have played a key role in these frameworks may be also of considerable value for motor assessment and rehabilitation.

Animals↗
PubMed1990

A peptide sequence confers retention and rapid degradation in the endoplasmic reticulum.

A nonlysosomal pathway exists for the degradation of newly synthesized proteins retained within the endoplasmic reticulum (ER). This pathway is extremely selective: whereas some proteins are rapidly degraded, others survive for long periods in the ER. The question of whether this selectivity is due to the presence within the sensitive proteins of definable peptide sequences that are sufficient to target them for degradation has been addressed. Deletion of a carboxyl-terminal sequence, comprising the transmembrane domain and short cytoplasmic tail of the alpha chain of the T cell antigen receptor (TCR-alpha), prevented the rapid degradation of this polypeptide. Fusion of this carboxyl-terminal sequence to the extracellular domain of the Tac antigen, a protein that is normally transported to the cell surface where it survives long-term, resulted in the retention and rapid degradation of the chimeric protein in the ER. Additional mutagenesis revealed that the transmembrane domain of TCR-alpha alone was sufficient to cause degradation within the ER. This degradation was not a direct consequence of retention in the ER, as blocking transport of newly synthesized proteins out of the ER with brefeldin A did not lead to degradation of the normal Tac antigen. It is proposed that a 23-amino acid sequence, comprising the transmembrane domain of TCR-alpha, contains information that determines targeting for degradation within the ER system.

Amino Acid Sequence↗
PubMed1991

Glycosylation and structure of the yeast MF alpha 1 alpha-factor precursor is important for efficient transport through the secretory pathway.

The MF alpha 1 gene encodes a precursor, prepro-alpha-factor, that undergoes several proteolytic processing steps within the classical secretory pathway to produce the mature peptide pheromone, alpha-factor. To investigate the role of structural features of the MF alpha 1 precursor in alpha-factor production, we analyzed the effect of mf alpha 1 mutations that alter precursor structure in a number of ways. These mutations resulted in decreased alpha-factor secretion and intracellular accumulation of pro-alpha-factor. With the exception of the mutant lacking all three N glycosylation sites, the pro-alpha-factor forms that accumulated were core glycosylated but had not yet undergone the addition of outer chain carbohydrate. The delay, therefore, occurred at a step prior to the first proteolytic processing step involved in maturation of the precursor and was probably due to inefficient endoplasmic reticulum-to-Golgi transport. Elimination of all three N-glycosylation sites caused a delay in disappearance of intracellular precursor, and alpha-factor secretion was also slowed. These data indicate that N glycosylation is important but not essential for transport of the precursor through the secretory pathway. The decreased alpha-factor secretion and increased precursor accumulation seen with many different structural changes of pro-alpha-factor indicate that the secretory pathway is extremely sensitive to changes in precursor structure. This sensitivity could cause inefficient secretion of heterologous proteins and hybrids between MF alpha 1 and heterologous proteins in yeast cells.

Amino Acid Sequence↗
PubMed2000

Evidence for splice site pairing via intron definition in Schizosaccharomyces pombe.

Schizosaccharomyces pombe pre-mRNAs are generally multi-intronic and share certain features with pre-mRNAs from Drosophila melanogaster, in which initial splice site pairing can occur via either exon or intron definition. Here, we present three lines of evidence suggesting that, despite these similarities, fission yeast splicing is most likely restricted to intron definition. First, mutating either or both splice sites flanking an internal exon in the S. pombe cdc2 gene produced almost exclusively intron retention, in contrast to the exon skipping observed in vertebrates. Second, we were unable to induce skipping of the internal microexon in fission yeast cgs2, whereas the default splicing pathway excludes extremely small exons in mammals. Because nearly quantitative removal of the downstream intron in cgs2 could be achieved by expanding the microexon, we propose that its retention is due to steric occlusion. Third, several cryptic 5' junctions in the second intron of fission yeast cdc2 are located within the intron, in contrast to their generally exonic locations in metazoa. The effects of expanding and contracting this intron are as predicted by intron definition; in fact, even highly deviant 5' junctions can compete effectively with the standard 5' splice site if they are closer to the 3' splicing signals. Taken together, our data suggest that pairing of splice sites in S. pombe most likely occurs exclusively across introns in a manner that favors excision of the smallest segment possible.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress.

All cells adapt to hypertonic stress by regulating their volume after shrinkage, by accumulating organic osmolytes, and by activating mechanisms that protect against and repair hypertonicity-induced damage. In mammals and nematodes, inhibition of signaling from the DAF-2/IGF-1 insulin receptor activates the DAF-16/FOXO transcription factor, resulting in increased life span and resistance to some types of stress. We tested the hypothesis that inhibition of insulin signaling in Caenorhabditis elegans also increases hypertonic stress resistance. Genetic inhibition of DAF-2 or its downstream target, the AGE-1 phosphatidylinositol 3-kinase, confers striking resistance to a normally lethal hypertonic shock in a DAF-16-dependent manner. However, insulin signaling is not inhibited by or required for adaptation to hypertonic conditions. Microarray studies have identified 263 genes that are transcriptionally upregulated by DAF-16 activation. We identified 14 DAF-16-upregulated genes by RNA interference screening that are required for age-1 hypertonic stress resistance. These genes encode heat shock proteins, proteins of unknown function, and trehalose synthesis enzymes. Trehalose levels were elevated approximately twofold in age-1 mutants, but this increase was insufficient to prevent rapid hypertonic shrinkage. However, age-1 animals unable to synthesize trehalose survive poorly under hypertonic conditions. We conclude that increased expression of proteins that protect eukaryotic cells against environmental stress and/or repair stress-induced molecular damage confers hypertonic stress resistance in C. elegans daf-2/age-1 mutants. Elevated levels of solutes such as trehalose may also function in a cytoprotective manner. Our studies provide novel insights into stress resistance in animal cells and a foundation for new studies aimed at defining molecular mechanisms underlying these essential processes.

Animals↗
PubMed2005

Multi-joint dynamics and the development of movement control.

The movement control of articulated limbs in humans has been explained in terms of equilibrium points and moving equilibrium points or virtual trajectories. One hypothesis is that the nervous system controls multi-segment limbs by simply planning in terms of these equilibrium points and trajectories. The present paper describes a planar computer simulation of an articulated three-segment limb, controlled by pairs of muscles. The shape of the virtual trajectory is analyzed when the limb is required to make fast movements with endpoint movements along a straight line with bell-shaped velocity profiles. Apparently, the faster the movement, the more the virtual trajectory deviates from the real trajectory and becomes up to eight times longer. The complexity of the shape of the virtual trajectories and its length in these fast movements makes it unlikely that the nervous system plans using these trajectories. It seems simpler to set up the required bursts of muscle activation, coupled in the nervous system to the direction of movement, the speed, and the place in workspace. Finally, it is argued that the two types of explanation do not contradict each other: when a relation is established in the nervous system between muscle activation and movements, equilibrium points and virtual trajectories are necessarily part of that relation.

Animals↗
PubMed2024

A case of Ph+ acute lymphoblastic leukemia and EGFR mutant lung adenocarcinoma synchronous overlap: may one TKI drug solve two diseases?

BACKGROUND: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare. CASE PRESENTATION: An 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases. CONCLUSION: As far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

Humans↗
PubMed1995

Different neural pathways coordinate Drosophila flight initiations evoked by visual and olfactory stimuli.

To determine the role played by the giant fiber interneurons (GFs) in coordinating the jumping stages of visually elicited and olfactory-induced fight initiation we have recorded extracellularly from the cervical connective nerve during flight initiation. A spike is recorded from the cervical connective upon brain stimulation that has the same threshold as does activation of the tergotrochanteral muscle (TTM) and dorsal longitudinal muscles (DLMs). A consistent time interval occurs between the spike and activation of the TTM. Thus, the spike probably results from activity in the GFs. The time intervals between the spike and activation of the TTM during GF stimulation and visually elicited flight initiation are similar. These results suggest that the GFs coordinate the activation of the TTM and DLMs during the jumping stage of visually elicited flight initiation. A spike is also recorded from the cervical connective during olfactory-induced flight initiations, but its shape and the time interval between it and activation of the TTM is different from that observed during GF stimulation. Although some olfactory-induced flight initiations exhibit a pattern of muscle activation, olfactory-induced flight initiations exhibit a pattern of muscle activation indistinguishable from that evoked by GF stimulation, our results indicate that regardless of the pattern of muscle activation, olfactory-induced flight initiations are not coordinated by the GF circuit. The sterotypic sequence and timing of activation of TTM and DLMs characteristic of the GF pathway can, therefore, be evoked by neurons other than those constituting the GF pathway.

Action Potentials↗