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At least 19 recordsLinked to original sources
PubMed1978

Physiological quiescence in plasma-derived serum: influence of platelet-derived growth factor on cell growth in culture.

A platelet-derived growth factor can be shown to be the principal stimulant of DNA synthesis in whole blood serum for those cells that require serum for maintenance and growth in culture. Cell free plasma-derived serum lacks such platelet-derived material. 3T3 cells and primate arterial smooth muscle cells can be maintained in a quiescent state in culture for as long as six weeks in plasma-derived serum. Such cells can grow logarithmically after exposure to 5% whole blood serum or as little as 100 ng/ml of partially purified platelet factor. The cell cycle of smooth muscle cells has been studied in the quiescent (5% plasma-derived serum) and growing state (5% whole blood serum or 5% plasma-derived serum plus platelet factor). The generation time of smooth muscle cells is 16 to 18 hours as shown by autoradiographic frequency of labelled mitoses. The generation time is the same for cells in the growth fraction in either 5% whole blood serum or 5% plasma-derived serum. Thus, platelet factor acts by recruiting cells into the growth fraction rather than effecting a change in the duration of the cell cycle. Flow microfluorimetry studies on cells growing logarithmically in 5% whole blood serum give the following phase durations: G1 = 5.6 hours; S = 7.6 hours; and G2 + M = 3.8 hours. Based on these studies the argument is presented that cells cultured in 5% plasma-derived serum provide a more physiological base for the study of quiescence than do cells in low concentrations of whole blood serum or confluent, density inhibited cells at high (5% or greater) concentrations of whole blood serum. Furthermore, 5% plasma-derived serum represents an appropriate state to examine the perturbation of quiescent cells.

Animals↗
PubMed2023

Serine-threonine phosphoregulation by PknB and Stp contributes to quiescence and antibiotic tolerance in Staphylococcus aureus.

Staphylococcus aureus can cause infections that are often chronic and difficult to treat, even when the bacteria are not antibiotic resistant because most antibiotics act only on metabolically active cells. Subpopulations of persister cells are metabolically quiescent, a state associated with delayed growth, reduced protein synthesis, and increased tolerance to antibiotics. Serine-threonine kinases and phosphatases similar to those found in eukaryotes can fine-tune essential bacterial cellular processes, such as metabolism and stress signaling. We found that acid stress-mimicking conditions that S. aureus experiences in host tissues delayed growth, globally altered the serine and threonine phosphoproteome, and increased threonine phosphorylation of the activation loop of the serine-threonine protein kinase B (PknB). The deletion of stp, which encodes the only annotated functional serine-threonine phosphatase in S. aureus, increased the growth delay and phenotypic heterogeneity under different stress challenges, including growth in acidic conditions, the intracellular milieu of human cells, and abscesses in mice. This growth delay was associated with reduced protein translation and intracellular ATP concentrations and increased antibiotic tolerance. Using phosphopeptide enrichment and mass spectrometry-based proteomics, we identified targets of serine-threonine phosphorylation that may regulate bacterial growth and metabolism. Together, our findings highlight the importance of phosphoregulation in mediating bacterial quiescence and antibiotic tolerance and suggest that targeting PknB or Stp might offer a future therapeutic strategy to prevent persister formation during S. aureus infections.

Animals↗
PubMedDate not supplied

Quiescence and/or pathogenicity of the ascomycete micro-organism as one of three separate entities in a living animal or human host.

Experimental studies on I.C.R. mice with induced ascitic fluid suggest that the mold micro-organism of the ascomycete family when inoculated in a living host, with a lowered pH, may survive but only initially in a conidial phase as a distinct and separate entity. It may reside quiescently as a sexual conidium within a cell of the reticulo-endothial system or with provocation multiply as the asexual form. Because of their altered physiomorphological status these conidial bodies cannot be identified accurately either by a microscopic study on a cytobiological wet smear basis or by a stained slide, nor be readily recaptured by utilizing the conventional culture techniques. Revised culturing methods utilizing the elements carbon dioxide, sodium chloride, calcium and magnesium in Sabouraud's Agar slant aerobically may help recover the adult micro-organism for positive identification. Sometimes, however, under deteriorating or moribund status of the host the conidia may revert, in ascitic fluid, to the autonomous form spontaneously. The transformation-reformation potential of the ascomycete in vivo, the non-recognizable status of the conidial bodies, and the inability to recapture the adult autonomous form by conventional laboratory means, despite their known presence, suggests a possible relationship of this micro-organism to certain of the acute, chronic inflammatory diseases, pleomorphic tumors, granulomas, and the malignancies. These diseases despite signs of an acute or chronic inflammatory process usually give a "no growth" result. The conidial phase of the ascomycete may very well, I believe, be the malefactor in these conditions that hitherto have defied etiological explanation.

Animals↗
PubMed1977

Melatonin induction of gonadal quiescence in pinealectomized Syrian hamsters.

Pinealectomized Syrian hamsters were injected thrice daily with 25 micrograms of melatonin per injection. The injections were administered at 3-hour intervals either during the day or during the night of a photoperiodic cycle of 14 hours of light and 10 hours of darkness. After 6 weeks of treatment with melatonin during the night, both pinealectomized and intact hamsters had reduced testis weight, and pinealectomized hamsters showed decreased levels of serum gonadotropins. Injection of melatonin during the day for 7 weeks either once (75 micrograms) a day or thrice (25 micrograms per injection) daily caused a reduction in testis weight in pinealectomized hamsters. Both pinealectomized and intact females injected with melatonin thrice daily during the day became anovulatory by week 7 of treatment. These results are similar to those observed when hamsters are exposed to a short photoperiod, suggesting that melatonin may be acting as a hormone in mediating the effects of photoperiod on the reproductive system of the Syrian hamster.

Animals↗
PubMed1979

Initiation of hamster sperm motility from quiescence: effect of conditions upon flagellation and respiration.

The point within the male reproductive tract where sperm motility originates varies with mammalian species. Premotile sperm from hamster, a species whose sperm are still quiescent in the epididymis, were used here to investigate further the parameters involved in the initiation of sperm motility. Two types of motility were produced: (1) partial, weak flagellation by simple dilution; (2) strong, complete motility by inducers (calcium, cyclic adenosine 3':5'-monophosphate) in the presence of amplifiers (caffeine, spermine). Expansion of initiation conditions to test tube volumes revealed that, at high sperm dilutions, bicarbonate could also induce motility. The respiratory consequences of sperm motility induction were measured. A Large, short-term burst of oxygen consumption occurred at a time paralleling the previously reported shifts in nucleotide levels associated with this event.

Animals↗
PubMed1977

[Influence of the photoperiod on the ultrastructure of the pineal gland before and during the seasonal genital cycle in the female garden dormouse (Eliomys quercinus L.) (author's transl)].

The pinealocyte of the female garden dormouse presents ultrastructural characteristics correlated with the sexual cycle. In winter, during the period of sexual quiescence, the pinealocyte is very rich in liposomes, myelinic bodies and lysosomes; the same holds during the summer quiescence state. These organelles and a great number of intracellular vacuoles are very well developed in dormice artificially maintained in anoestrous during the normal sexual activity period by light deprivation. In spring liposomes are strongly reduced in animals that are awake and sexually active, whereas the number of "synaptic ribbons" and of densecored vesicles increases. This ultrastructural aspect can be obtained during winter quiescence in animals living at 22 degrees C, under continuous light, and showing early sexual activation. If illumination is prolonged over the seasonal sexual phase dilated cisterns of granular endoplasmic reticulum, filled with proteinaceous material, appear in the cell. It seems that light no more activates, but inhibits gonadostimulator mechanisms. The pinealocyte's ultrastructural elements which are characteristic of a definite sexual state generally develop before this state is fully established. Actually, the functional significance of these organelles is not known.

Animals↗
PubMed1979

Calcium transport and exchange in mouse 3T3 and SV40-3T3 cells.

The kinetics of Ca++ uptake have been evaluated in 3T3 and SV40-3T3 mouse cells. The data reveal at least two exchangeable cellular compartments in the 3T3 and SV40-3T3 cell over a 50-min exposure to 45Ca++. A rapidly exchanging compartment may represent surface-membrane-localized Ca++ whereas a more slowly exchanging compartment is presumably intracellular. The transition of the 3T3 cell from exponential growth (at 3 day's incubation) to quiescence (at 7 days) is characterized by a 7.5-fold increase in the size of the fast component. Quiescence of the 3T3 cell is also characterized by a 3.2-fold increase in the unidirectional Ca++ influx into the slowly exchanging compartment and a 3.6-fold increase in its size. The increase in size of the slow compartment at quiescence may result from a redistribution of intracellular Ca++ to a more readily exchangeable compartment, possibly reflecting a release of previously bound Ca++. In contrast, no significant change in any of these parameters is observed in the proliferatively active SV40-3T3 cells after corresponding period of incubation, even though these cells attained higher growth densities and underwent postconfluence.

Animals↗
PubMed2025

Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth.

Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.

Neuropilin-2↗
PubMed1976

Anti-donor immune responses in prediction of transplant rejection.

We assessed various immune responses against donor tissue to determine their value in the diagnosis and prediction of clinical rejection episodes. Twenty-six consecutive clinical renal-transplant recipients were examined. Cell-mediated lymphocytotoxicity preceded and accompanied 41 of 45 rejection episodes (P less than 0.001). Complement-dependent antibody was present in 12 of 15 rejections (P less than 0.002)--four not accompanied by, and eight in association with, cell-mediated lymphocytotoxicity. Mixed lymphocyte reactivity or nonreactivity and inhibition by autologous serum occurred equally often in rejection and quiescence. Lymphocyte-dependent antibody occurred during both rejection episodes and quiescent phases, with a greater frequency during quiescence (P = 0.05). Cell-mediated lymphocytotoxicity was the best predictor of rejection (P less than 0.05). Cell-mediated lymphocytotoxicity was the best predictor of rejection (P less than 0.001), and was more easily suppressed by standard immunosuppressive therapy, than complement-dependent antibody. If specific cell-mediated lymphocytotoxicity, with or without antibody, recurred after rejection therapy, the graft underwent further rejection.

Antigen-Antibody Reactions↗
PubMed1977

Calcium content and distribution as a function of growth and transformation in the mouse 3T3 cell.

Total Ca content and that fraction of Ca sensitive to removal by the chelator ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetraacetate (EGTA) have been investigated in the mouse 3T3 cell as a function of growth stage, transformation with SV40 virus, and serum levels of the media. Cells were allowed to grow through several doublings in media containing (45)Ca. The cellular content of (45)Ca was used to access total cell Ca. That fraction of (45)Ca removed by EGTA was presumed to represent primarily surface-localized Ca. The data are expressed on a per cell volume basis to compensate for size differences as a function of growth stage and transformation. During exponential growth phase, the 3T3 cell contains 525pmol Ca/mul cell volume. Of this, approx. 457 pmol/mul is not removable by EGTA and, presumably, is cytoplasmically located. This value is in close agreement with previous studies on the HeLa cell (470 pmol Ca/mul cell water after the removal of the surface Ca). The low level of EGTA- removable Ca present in the 3T3 cell during early exponential growth (68 pmol Ca/mul cell volume) increases progressively with increasing cell density, and upon quiescence it is sevenfold greater. In contrast, SV40- transformed 3T3 cells growing exponentially possess total levels of Ca which are approximately two-thirds the levels of the normal 3T3 cell. However, their EGTA-sensitive Ca is not significantly different from that of exponentially growing, normal 3T3 cells. As the transformed cells continue to grow at high density, their total ca and their sensitivity to EGTA do not change, in contrast to the normal 3T3 cell. Thus, an increase in Ca associated with the cell surface appears to be correlated with growth inhibition. This has been investigated further by regulating growth of the normal and transformed cell with alterations in the serum level of the media. In 4 percent calf serum the normal cell is stopped from continued proliferation. Growth stoppage under these conditions is characterized by a nearly fourfold increase in EGTA-removable Ca, similar to the increase observed upon quiescence in depleted 10 percent serum. Similar treatment of the transformed cell does not reduce its growth rate, nor does it significantly alter Ca distribution. However, at 0.5 percent medium serum levels, the SV40 3T3 growth rate is substantially reduced and, under these conditions, EGTA-removable Ca increases twofold.

Blood↗
PubMed2026

CIZ1 regulates G1 length and the CDK threshold for initiation of DNA replication to prevent DNA replication stress.

Eukaryotic cell division is regulated by CDK activity that must reach critical CDK threshold levels to progress through cell cycle stages. In low-mitogen, low-CDK environments, cells exit the cell cycle into a non-proliferative quiescent state, G0, that plays essential roles in stem cell maintenance and cellular homeostasis. CIZ1 regulates cell cycle and epigenetic programmes, and CIZ1 ablation promotes genomic instability after release from quiescence. Here, we show that CIZ1 contributes to mechanisms that temporally regulate cell cycle transitions in post-quiescent cells. CIZ1-/- (CIZ1 KO) fibroblasts re-entering the cell cycle from quiescence have reduced G1 phase and cell cycle length, mediated by increased intracellular CDK activity and early restriction point bypass via G1/S cyclin overexpression. In addition, CIZ1-/- cells are deficient in cyclin A chromatin binding and require increased CDK activity to initiate DNA replication, leading to DNA replication stress. Importantly, ectopic expression of CIZ1 or addition of recombinant CIZ1 reinstates the CDK threshold for initiation of DNA replication, reversing DNA replication stress and increasing replication fork rates. These data suggest that in post-quiescent cells, CIZ1 determines the threshold CDK activity required for the G1/S transition to prevent DNA replication stress.

DNA Replication↗
PubMed2025

E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility.

Quiescent cells actively repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce reentry from quiescence, but how it overcomes chromatin-mediated repression remains unclear. Here, we show that inducible E2F1 expression triggers exit from quiescence and progression through the cycle without changes in chromatin accessibility, by harnessing regulatory elements with limited, pre-existing accessibility. Using time-resolved transcriptomics, we demonstrate that E2F1 induces an accelerated transcriptional program compared to serum. Unlike serum, which triggers broad chromatin remodeling, E2F1-induced activation occurs in a context of limited accessibility. ChIP-seq reveals that E2F1 directly binds target sites in quiescent cells to upregulate canonical genes. Biochemical reconstitution shows that E2F1 binds nucleosomes and accesses internal E2F sites within histone-wrapped DNA. These findings suggest that E2F1 can engage nucleosome-associated DNA and initiate transcription without major chromatin reorganization, redefining transcription factor-chromatin dynamics during cell fate transitions and establishing E2F1 as a potent regulator of cell-cycle reentry.

Journal Article↗
PubMed2025

Chromosome duplication causes premature aging via defects in ribosome quality control.

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Ribosomes↗
PubMed1977

Migrating myoelectrical complex of the small intestine. An intrinsic activity mediated by the vagus.

In healthy conscious parenterally fed dogs and in sheep on their usual diet, the basic motor profile on the small intestine consists of recurring cycles of action potential activity. This cyclic pattern called the migrating myoelectrical complex comprises two distinct phases termed irregular, and regular spiking activity and is followed by a period of quiescence. The pattern persists after bilateral transthoracic vagotomy and in animals rendered diabetic by alloxan. In dogs, feeding disrupts the migrating myoelectrical complex pattern by obliterating the phases of regular spiking activity and quiescence for 6 to 12 hr, depending upon the amount of dry matter intake. After vagotomy a latency in the disruption of the migrating myoelectrical complex pattern with feeding occurs and in vagotomized dogs rendered diabetic, the duration of disruption is strongly reduced. In sheep, the duration of irregular spiking activity of a jejunal segment increased or decreased corresponding to the bulk of digesta, a phenomenon damped after vagotomy. The results indicate that the role of the vagus is limited to (1) prompting prandial disruption, which is then maintained by hormonal effect; (2) regulating the irregular spiking activity duration in relation to the bulk of digesta.

Action Potentials↗
PubMed1977

Endocrine and pharmacological factors which influence the onset of labour in rhesus monkeys.

Indomethacin administration in late pregnancy prolonged gestation in caged rhesus monkeys and inhibited premature labour and postponed delivery in chronically catheterized monkey fetuses. Chronic indomethacin treatment was associated with a reduction in the urinary excretion of a prostaglandin metabolite, a potent inhibitory effect on myometrial cyclic AMP phosphodiesterase, and severe oligohydramnios in pre-term and post-term fetuses. Experimental anencephaly (functional hypophysectomy) of the rhesus fetus results in lowered concentrations of maternal oestradiol and loss of the precise control of gestational length, with 40% of fetuses delivering beyond term. Corticotropin (ACTH) infused into the fetus results in raised concentrations of fetal and maternal cortisol, progesterone and oestrogens. Progesterone concentrations in peripheral blood apparently have little bearing on uterine quiescence in the rhesus monkey, since the concentrations of progesterone in maternal and fetal blood vary directly with uterine activity. The results of chronic infusion of corticotropin in the fetal monkey support the theory that in the monkey parturition is mediated by increased oestrogen production by the fetoplacental unit and by a rise in the concentrations of oestrone and prostaglandin in the amniotic fluid.

Adrenocorticotropic Hormone↗
PubMed1977

Serum-stimulated phosphate uptake and initiation of fibroblast proliferation.

Previous studies have shown that initiation of proliferation of density-inhibited fibroblasts by fresh serum is accompanied by a rapid increase in phosphate uptake. This increase might be a key event in the initiation of DNA synthesis. The present studies examined this possibility. Mouse 3T3, secondary chick embryo, or human diploid foreskin cultures were grown to quiescence in medium containing varying levels of serum. When proliferation of the cultures was initiated by addition of fresh serum, the changes in phosphate uptake were inversely related to the final increases in cell number. Additional experiments showed that the change in phosphate uptake following serum addition was determined by the level of phosphate uptake prior to serum addition. Addition of dexamethasone to quiescent 3T3 cultures caused them to proliferate but did not increase phosphate uptake. Similarly, trypsin or insulin stimulated proliferation of quiescent secondary chick embryo cultures, but caused little or no change in phosphate uptake. Quiescent 3T3 cultures switched to medium containing fresh serum and reduced levels of phosphate showed a decrease in both phosphate uptake and intracellular phosphate pool size. Cell proliferation in these cultures, however, was stimulated to the same degree as cultures switched to medium containing fresh serum and the normal amount of phosphate. In addition, quiescent secondary chick embryo cultures switched to medium containing fresh serum and no phosphate showed a decrease in the intracellular phosphate pool size. Thymidine incorporation and final cell number in these cultures, however, was stimulated to the same or higher degree than in cultures switched to medium containing fresh serum and the normal amount of phosphate. These results demonstrate that the rapid increase in phosphate uptake following addition of fresh serum to quiescent fibroblasts is not a necessary event for the initiation of proliferation.

Animals↗