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At least 451 records · Page 25Linked to original sources
PubMed1980

Variability of short-term cultures of HeLa S-3 cells: changes in DNA distributions and rates of DNA synthesis.

DNA distributions of HeLa S-3 cells in spinner culture exhibit significant time-dependent changes. The major differences appear to occur in the S-phase region. Significant changes in the rates of DNA synthesis in several S-phase subcompartments correlated well with the changes in the DNA distributions. It is proposed that fluctuations in these rates of DNA synthesis are a reflection of the inherent instability of these abnormal, heteroploid cells.

Cell Cycle↗
PubMed1984

Pluripotent stem cells do not completely maintain normal human steady-state haemopoiesis.

Since the classical work on the regulation of canine erythropoiesis by Alpen & Cranmore (1959), it has been generally accepted that recognizable bone-marrow cells are continuously replaced from sources of unrecognizable precursors. Although many features of pluripotent stem cells (PSC) and committed haemopoietic precursors have been determined, direct demonstration of a continuous influx, under normal steady-state conditions, from PSC into the recognizable bone-marrow cell compartments is still lacking. There is abundant evidence that PSC, in a number of species, including primates, resemble atypical or immature ('transitional') lymphocytes. By utilizing the technique of quantitative 14C-autoradiography, we have measured the activities of DNA and protein synthesis in individual bone-marrow cells of two healthy humans. A positive relationship was established between the protein synthesis rate and rate of movement through the cell cycle in all proliferative compartments. Lymphoid cells, considered to contain the fraction of PSC, were found in the lower range of this relationship. These low metabolic rates exclude fast growth as well as short cell-cycle times. In view of the low frequency of the potential PSC in the human bone marrow, amounting to less than 2%, these cells cannot be considered to represent a source continuously supplying the pool of rapidly proliferating, recognizable blast cells in the bone marrow under steady-state conditions. Some self-maintenance of a subcompartment within the pool of recognizable normal bone-marrow blast cells is therefore suggested.

Adult↗
PubMed1994

The requirement of matrix ATP for the import of precursor proteins into the mitochondrial matrix and intermembrane space.

The role of ATP in the matrix for the import of precursor proteins into the various mitochondrial subcompartments was investigated by studying protein translocation at experimentally defined ATP levels. Proteins targeted to the matrix were neither imported or processed when matrix ATP was depleted. Import and processing of precytochrome b2 (pb2), a precursor carrying a bipartite presequence, into the intermembrane space was also strongly dependent on matrix ATP. Preproteins, consisting of 220 or more residues of pb2 fused to dihydrofolate reductase, showed the same requirement for matrix ATP, whereas the import of shorter fusion proteins (up to 167 residues of pb2) was largely independent of matrix ATP. For those intermembrane-space-targeted proteins that did need matrix ATP, the dependence could be relieved either by unfolding these proteins prior to import or by introducing a deletion into the mature portion of the protein thereby impairing the tight folding of the cytochrome b2 domain. These results suggest the following: (a) The import of matrix-targeted preproteins, in addition to a membrane potential delta psi, requires matrix ATP [most likely to facilitate reversible binding of mitochondrial heat-shock protein 70 (mt-Hsp70) to incoming precursors], for two steps, securing the presequence on the matrix side of the inner membrane and for the completion of translocation; (b) in the case of intermembrane-space-targeted precursors with bipartite signals, the function of ATP/mt-Hsp70 is not obligatory, as components of the intermembrane-space-sorting pathway may substitute for ATP/mt-Hsp70 function (however, if a tightly folded domain is present in the precursor, ATP/mt-Hsp70 is indispensable); (c) unfolding on the mitochondrial surface of tightly folded segments of preproteins is facilitated by matrix-ATP/mt-Hsp70.

Adenosine Triphosphate↗
PubMed2004

Semaphorin 3A-mediated axon guidance regulates convergence and targeting of P2 odorant receptor axons.

Semaphorins are known to play an important role in axon guidance of vertebrate olfactory sensory neurons to their targets in specific glomeruli of the olfactory bulb (OB). However, it is not clear how semaphorin-mediated guidance contributes to a systematic hierarchy of cues that govern the organization of this system. Because of the putative role that odorant receptor molecules such as P2 could play in establishing appropriate glomerular destinations for growing olfactory axons, we have also determined the spatial organization of P2 glomeruli in semaphorin 3A (Sema3A) mutant mice. First, in the postnatal OB of control and Sema3A(-/-) mice, we analysed the trajectories of olfactory axons that express the Sema3A receptor, neuropilin-1 (npn-1) and the positions of npn-1(+) glomeruli. Sema3A at the ventral OB midline guides npn-1(+) axons to targets in the lateral and medial OB. Absence of Sema3A permits many npn-1 axons to terminate aberrantly in the rostral and ventral OB. Second, in Sema3A(-/-) mice, many P2 axons are abnormally distributed throughout the ventral OB nerve layer and converge in atypical locations compared with littermate controls where P2 axons converge on stereotypically located lateral and medial glomeruli. In addition to their radically altered spatial distribution, P2 glomeruli in Sema3A(-/-) mice are significantly smaller and more numerous than in heterozygote littermates. These data show that Sema3A is an important repulsive olfactory guidance cue that establishes restricted npn-1(+) subcompartments in the olfactory bulb. Furthermore, Sema3A plays a key role in the convergence of axons expressing the odorant receptor P2 onto their appropriate targets.

Animals↗
PubMed1993

Hydrolysis of inositol trisphosphate by purified rat brain myelin.

Highly purified rat brain myelin was found to hydrolyze inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate, but subsequent hydrolysis of the latter, characteristic of whole brainstem, did not occur. Inositol 1,4,5-trisphosphate 5-phosphatase in myelin was approximately 33% of the level in microsomes and 127% that of the cytosolic fraction from brainstem. The myelin and microsomal enzymes had similar properties, as follows: activation by saponin, requirement for Mg2+ and similar Kact (0.16 and 0.13 mM), Km (8.7 +/- 2.5 and 7.0 +/- 1.0 microM), and pH optima (6.6-6.8). Vmax values were 11.2 +/- 1.0 and 26.3 +/- 2.0 nmol/mg/min for myelin and microsomes, respectively. A possible role for this enzyme in phosphoinositide-mediated signal transduction within myelin and its subcompartments is discussed.

Animals↗
PubMed1993

Effect of N,N'-dicyclohexylcarbodiimide on compartmentation and release of newly synthesized and preformed acetylcholine in Torpedo synaptosomes.

Using isolated cholinergic synaptosomes prepared from Torpedo electric organ, we studied the effects of N,N'-dicyclohexylcarbodiimide (DCCD) on acetylcholine (ACh) synthesis, compartmentation, and release after stimulation. Whereas ACh synthesis was unchanged, ACh compartmentation inside synaptosomes was affected by the presence of DCCD. In resting conditions, the uptake into the synaptic vesicle pool of newly synthesized ACh (i.e., [14C]ACh synthesized in the presence of the drug) was progressively and markedly inhibited as the duration of DCCD preincubation was increased, whereas compartmentation of endogenous ACh was unchanged in the presence of DCCD. After stimulation, the release of endogenous ACh from DCCD-treated synaptosomes was similar to that of control, in contrast to the release of [14C]ACh, which was markedly inhibited. This inhibition was observed whatever the conditions of stimulation used (gramicidin D, calcium ionophore A23187, or KCl depolarization). The study of the compartmentation of [14C]ACh during stimulation revealed a transfer of highly labeled ACh from the free to the bound ACh compartment in the presence of DCCD, suggesting the existence of several ACh subcompartments within the free and bound ACh pools. The present results are discussed in comparison with the previously reported effects of vesamicol (AH5183) on ACh compartmentation and release.

Acetylcholine↗
PubMed2006

Age-related impairment of mesenchymal progenitor cell function.

In most mesenchymal tissues a subcompartment of multipotent progenitor cells is responsible for the maintenance and repair of the tissue following trauma. With increasing age, the ability of tissues to repair themselves is diminished, which may be due to reduced functional capacity of the progenitor cells. The purpose of this study was to investigate the effect of aging on rat mesenchymal progenitor cells. Mesenchymal progenitor cells were isolated from Wistar rats aged 3, 7, 12 and 56 weeks. Viability, capacity for differentiation and cellular aging were examined. Cells from the oldest group accumulated raised levels of oxidized proteins and lipids and showed decreased levels of antioxidative enzyme activity. This was reflected in decreased fibroblast colony-forming unit (CFU-f) numbers, increased levels of apoptosis and reduced proliferation and potential for differentiation. These data suggest that the reduced ability to maintain mesenchymal tissue homeostasis in aged mammals is not purely due to a decline in progenitor cells numbers but also to a loss of progenitor functionality due to the accumulation of oxidative damage, which may in turn be a causative factor in a number of age-related pathologies such as arthritis, tendinosis and osteoporosis.

Aging↗
PubMed1994

Morphometric approaches for evaluating pulmonary toxicity in mammals: implications for risk assessment.

Recent advances in quantitative morphology provide all the tools necessary to obtain structural information in the lung that can be quantified and interpreted in the three-dimensional world of toxicology. Structural hierarchies of conducting airways and parenchyma of the lung provide: (1) numbers of cells per airway, lobe, or lung; (2) surface areas of cells, airways, and alveoli; (3) length of airways and vessels; and (4) volumes of cells, alveoli, airways, vessels, and individual lobes or the entire lung. Unbiased sampling of these subcompartments of the lung requires fractionation of lobes or individual airways. Individual airways of proximal and distal generations are obtained by airway microdissection along one axial pathway and comparisons made between airway generations. Vertical sections of selected airways are used to sample epithelium and interstitium. Using this unbiased approach of quantitative morphology, we have shown that inhalation of low ambient concentrations of ozone ([O3]0.15 ppm) near or at the United States National Ambient Air Quality Standard (NAAQS) (0.12 ppm O3) induces significant alterations in bronchiolar epithelium and interstitium in nonhuman primates but not rats. The alterations do not appear to be concentration- or time-dependent, thereby bringing into question the current NAAQS that may be at or above the threshold for distal airway injury in primates. Unbiased morphometric methods are critical in a quantitative evaluation of toxicological injury of mammalian tracheobronchial airways.

Air Pollutants↗
PubMedDate not supplied

Electron tomographic and ultrastructural analysis of the Cryptosporidium parvum relict mitochondrion, its associated membranes, and organelles.

Sporozoites of the apicomplexan Cryptosporidium parvum possess a small, membranous organelle sandwiched between the nucleus and crystalloid body. Based upon immunolabelling data, this organelle was identified as a relict mitochondrion. Transmission electron microscopy and tomographic reconstruction reveal the complex arrangement of membranes in the vicinity of this organelle, as well as its internal organization. The mitochondrion is enveloped by multiple segments of rough endoplasmic reticulum that extend from the outer nuclear envelope. In tomographic reconstructions of the mitochondrion, there is either a single, highly-folded inner membrane or multiple internal subcompartments (which might merge outside the reconstructed volume). The infoldings of the inner membrane lack the tubular "crista junctions" found in typical metazoan, fungal, and protist mitochondria. The absence of this highly conserved structural feature is congruent with the loss, through reductive evolution, of the normal oxidative phosphorylation machinery in C. parvum. It is proposed that the retention of a relict mitochondrion in C. parvum is a strategy for compartmentalizing away from the cytosol toxic ferrous iron and sulfide, which are needed for iron sulfur cluster biosynthesis, an essential function of mitochondria in all eukaryotes.

Animals↗
PubMed2006

Mitochondrial preprotein translocases as dynamic molecular machines.

Proteomic studies have demonstrated that yeast mitochondria contain roughly 1000 different proteins. Only eight of these proteins are encoded by the mitochondrial genome and are synthesized on mitochondrial ribosomes. The remaining 99% of mitochondrial precursors are encoded within the nuclear genome and after their synthesis on cytosolic ribosomes must be imported into the organelle. Targeting of these proteins to mitochondria and their import into one of the four mitochondrial subcompartments--outer membrane, intermembrane space (IMS), inner membrane and matrix--requires various membrane-embedded protein translocases, as well as numerous chaperones and cochaperones in the aqueous compartments. During the last years, several novel protein components involved in the import and assembly of mitochondrial proteins have been identified. The picture that emerges from these exciting new findings is that of highly dynamic import machineries, rather than of regulated, but static protein complexes. In this review, we will give an overview on the recent progress in our understanding of mitochondrial protein import. We will focus on the presequence translocase of the inner mitochondrial membrane, the TIM23 complex and the presequence translocase-associated motor, the PAM complex. These two molecular machineries mediate the multistep import of preproteins with cleavable N-terminal signal sequences into the matrix or inner membrane of mitochondria.

Fungal Proteins↗
PubMed1992

Segmental mean transit times of 99mtechnetium within central vascular space in liver cirrhosis.

Mean transit time (MTT) through a given vascular space is closely related to the effective blood volume in this compartment. Central vascular blood volume in liver cirrhosis is believed to be reduced, but more precise data on the location of the underfilled vascular area are lacking. 99mTechnetium first-pass angiography was performed in 15 cirrhotic patients and in 10 age-matched normals. The method of segmental analysis of MTT was validated by performing an analog study in a plastic tubing/chamber system. The mean tracer sojourn in the central circulation was described in cirrhotic patients (10.25 +/- 2.17 s vs 12.92 +/- 2.88 s; p less than 0.05); however, this finding was not observed beyond cardiopulmonary circulation (MTT between right and left heart chambers). Segmental comparative analysis between cirrhotics and normals revealed significant MTT differences in two vascular subcompartments, i.e. right chamber-pulmonary artery, and within the lung vascular bed. Analysis of time activity lung curves in patients with cirrhosis disclosed a shorter time to peak and more rapid washout of the tracer from this area, without any change in curve symmetry as compared to normals. Ascites had no apparent impact on MTT rate, and cirrhotics with most advanced disease (grade C Child-Pugh) had longer MTT through the cardiopulmonary circulation as compared to combined groups A & B (7.32 +/- 0.13 s vs 6.03 +/- 1.23 s; p less than 0.05). Our data provide further evidence for contraction of the cardiopulmonary vascular space in liver cirrhosis.

Blood Volume↗
PubMed2004

Missorting of LaCrosse virus nucleocapsid protein by the interferon-induced MxA GTPase involves smooth ER membranes.

The interferon-induced human MxA protein belongs to the class of dynamin-like, large guanosine-5'-triphosphatases that are involved in intracellular vesicle trafficking and organelle homeostasis. MxA shares many properties with the other members of this protein superfamily, including the propensity to self-assemble and to associate with lipid membranes. However, MxA is unique in that it has antiviral activity and inhibits the replication of several RNA viruses. Here, we determined the role of membranes for the antiviral function of MxA using LaCrosse-bunyavirus (LACV). We show that MxA does not affect trafficking and sorting of viral glycoproteins but binds and mislocates the viral nucleocapsid (N) protein into membrane-associated, large perinuclear complexes. We further demonstrate that MxA localizes to a subcompartment of the smooth endoplasmic reticulum where the viral N protein accumulates. In infected MxA-expressing cells, oligomeric MxA/N complexes are formed in close association with COP-I-positive vesicular-tubular membranes. Our results suggest that this membrane compartment is the preferred place where MxA and N interact, leading to efficient sequestration and missorting of an essential viral component.

Animals↗
PubMed2005

The role of ARF1 and rab GTPases in polarization of the Golgi stack.

The organization and sorting of proteins within the Golgi stack to establish and maintain its cis to trans polarization remains an enigma. The function of Golgi compartments involves coat assemblages that facilitate vesicle traffic, Rab-tether-SNAP receptor (SNARE) machineries that dictate membrane identity, as well as matrix components that maintain structure. We have investigated how the Golgi complex achieves compartmentalization in response to a key component of the coat complex I (COPI) coat assembly pathway, the ARF1 GTPase, in relationship to GTPases-regulating endoplasmic reticulum (ER) exit (Sar1) and targeting fusion (Rab1). Following collapse of the Golgi into the ER in response to inhibition of activation of ARF1 by Brefeldin A, we found that Sar1- and Rab1-dependent Golgi reformation took place at multiple peripheral and perinuclear ER exit sites. These rapidly converged into immature Golgi that appeared as onion-like structures composed of multiple concentrically arrayed cisternae of mixed enzyme composition. During clustering to the perinuclear region, Golgi enzymes were sorted to achieve the degree of polarization within the stack found in mature Golgi. Surprisingly, we found that sorting of Golgi enzymes into their subcompartments was insensitive to the dominant negative GTP-restricted ARF1 mutant, a potent inhibitor of COPI coat disassembly and vesicular traffic. We suggest that a COPI-independent, Rab-dependent mechanism is involved in the rapid reorganization of resident enzymes within the Golgi stack following synchronized release from the ER, suggesting an important role for Rab hubs in directing Golgi polarization.

ADP-Ribosylation Factor 1↗
PubMed1997

Ultrastructural studies on the effect of transforming growth factor-beta 1 on rat articular cartilage.

The destruction of articular cartilage in degenerative and inflammatory joint disease reflects an imbalance between synthesis and degradation of the structural components of the tissue. In previous, mainly in vitro studies, TGF-beta has been shown not only to play a role in controlling the synthesis of matrix components such as collagen and proteoglycans but also to influence their degradation. To elucidate the effect of local administration of TGF-beta on unloaded articular cartilage in growing rats, three animals were given intraarticular injections of TGF-beta for three consecutive days and sacrificed on the fourth. Perfusion fixation was combined with qualitative and quantitative evaluation (stereology) both at the light and electron microscopic level. Local administration of TGF-beta resulted in a decrease in height of the hypertrophic zone. Furthermore, the volume density of cells decreased and cells with a distinct morphology designated stellate cells appeared in this zone. In the same compartment, TGF-beta administration resulted in decreased pericellular collagen volume density while the volume density increased in the intermediate zone. The results of our investigation support and extend previous observations: TGF-beta does not only modulate the metabolism of articular cartilage in general, but the effect is targeted to specific subcompartments of the matrix. However, the result of this acute effect on the long-term function of the tissue remains to be elucidated.

Animals↗
PubMed2005

Biogenesis of peroxisomes. Topogenesis of the peroxisomal membrane and matrix proteins.

Genetic and proteomic approaches have led to the identification of 32 proteins, collectively called peroxins, which are required for the biogenesis of peroxisomes. Some are responsible for the division and inheritance of peroxisomes; however, most peroxins have been implicated in the topogenesis of peroxisomal proteins. Peroxisomal membrane and matrix proteins are synthesized on free ribosomes in the cytosol and are imported post-translationally into pre-existing organelles (Lazarow PB & Fujiki Y (1985) Annu Rev Cell Biol1, 489-530). Progress has been made in the elucidation of how these proteins are targeted to the organelle. In addition, the understanding of the composition of the peroxisomal import apparatus and the order of events taking place during the cascade of peroxisomal protein import has increased significantly. However, our knowledge on the basic principles of peroxisomal membrane protein insertion or translocation of peroxisomal matrix proteins across the peroxisomal membrane is rather limited. The latter is of particular interest as the peroxisomal import machinery accommodates folded, even oligomeric, proteins, which distinguishes this apparatus from the well characterized translocons of other organelles. Furthermore, the origin of the peroxisomal membrane is still enigmatic. Recent observations suggest the existence of two classes of peroxisomal membrane proteins. Newly synthesized class I proteins are directly targeted to and inserted into the peroxisomal membrane, while class II proteins reach their final destination via the endoplasmic reticulum or a subcompartment thereof, which would be in accord with the idea that the peroxisomal membrane might be derived from the endoplasmic reticulum.

Endoplasmic Reticulum↗
PubMed1986

Update on the concept of the cell cycle: the contribution of flow cytometry.

Flow cytometry has been extensively used to provide accurate estimates of the relative amounts of various cellular constituents (DNA, RNA, proteins) for cell kinetic studies. Multiparametric analysis also supports the recent concept that cell growth and the DNA division cycle may be under distinct regulatory mechanisms. Moreover, metabolic subcompartments of the cell cycle, distinguished by flow cytometry, have offered a highly sensitive cell classification in comparison with the conventional distinction of the four main phases of the cell cycle. Finally, a new sensitive and powerful technology, BrdU/DNA analysis, represents a remarkable maturing of a very useful alternative for the study of DNA synthesis and cell cycle traverse.

Animals↗
PubMed2004

Comparison of pulmonary/nasal CYP2F expression levels in rodents and rhesus macaque.

Naphthalene is a ubiquitous environmental contaminant that results in dose-dependent and tissue-, species-, and cell-selective necrosis of murine Clara cells upon exposure. Naphthalene is metabolized by CYP2F to a 1,2-epoxide, the first and obligate step in events leading to cytotoxicity. The studies reported here examine the relationship between levels of transcript (mRNA) and CYP2F protein in the respiratory tract of rodents with tissue susceptibility to injury. In both mice and rats, the lung contains more CYP2F transcript than liver; levels in kidney were undetectable. Mice expressed 4- and 8-fold greater CYP2F transcript in lung and liver tissue, respectively, than rats. Quantitative immunoblot blot analysis of CYP2F in airway subcompartments revealed mice to have 30- (minor daughters/terminal bronchioles), 20- (major daughter), 40- (trachea), and 6- (parenchyma) fold higher levels of CYP2F protein than rats. Within the lungs of both rodent species, the highest CYP2F expression was found in the distal airways. The kidney contained undetectable amounts of CYP2F; multiple immunoreactive bands in liver precluded quantification. The olfactory epithelium contains the greatest amount of cytochrome P450 protein of all tissues studied in the rat, consistent with the observed pattern of in vivo injury. Overall, these studies in rodents demonstrate a strong association between CYP2F expression levels and susceptibility to naphthalene-induced cytotoxicity. Of all primate tissues studied, only the nasal ethmoturbinates contain quantifiable amounts of CYP2F, roughly 10- and 20-fold less than the corresponding tissues in rats and mice, respectively. These results suggest that rhesus macaques may be refractory to naphthalene-induced pulmonary injury.

Animals↗
PubMed1990

Protein sorting to mitochondria: evolutionary conservations of folding and assembly.

According to the endosymbiont hypothesis, mitochondria have lost the autonomy of their prokaryotic ancestors. They have to import most of their proteins from the cytosol because the mitochondrial genome codes for only a small percentage of the polypeptides that reside in the organelle. Recent findings show that the sorting of proteins into the mitochondrial subcompartments and their folding and assembly follow principles already developed in prokaryotes. The components involved may have structural and functional equivalents in bacteria.

Amino Acid Sequence↗