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Results for “Origin Firing”

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At least 19 recordsLinked to original sources
PubMed2025

MCM5 UFMylation regulates replication origin firing and fork progression.

Modification with UFM1 (UFMylation) is essential for cell proliferation, but its precise mechanism of action is unclear. Furthermore, the UFMylation pathway has been associated with microcephalic primordial dwarfism (MPD) disorders, and mutations causative for MPD are also identified in genes encoding components of the replicative DNA helicase complex, including the MCM hexamer. Here, we reveal that UFMylation regulates DNA replication, and that all MPD-associated mutations in UFMylation enzymes impair replication. Mechanistically, the UFM1 E3 ligase UFL1 catalyzes Lys583 UFMylation of MCM5, a critical component of the CMG replicative DNA helicase complex. Mutation of Lys583 blocking this UFMylation event destabilizes the helicase complex, delaying origin firing and slowing replication fork progression. We conclude that MCM5 UFMylation is essential for efficient origin firing and replication fork progression, both of which ensure accurate DNA replication, cell proliferation, and prevention of MPD disorders.

DNA Replication↗
PubMed2026

CDC7 and APC/CCdh1 gate distinct routes to initiate DNA replication.

Precise temporal control of DNA replication initiation is essential for faithful cell division, yet there are conflicting prevailing models for how cells trigger origin firing. Here, we demonstrate that human origins are not fired at fixed thresholds of cell cycle regulators E2F, APC/CCdh1, CDK2/1, and CDC7. Instead, origin firing is triggered at a tunable CDK2/1 threshold that is gated by either CDC7 or APC/CCdh1 activity. CDC7 phosphorylates MCM helicase, enabling Cyclin E-CDK2 to trigger origin firing at low CDK2/1 activity, independent of APC/CCdh1 inactivation. In contrast, APC/CCdh1 inactivation enables Cyclin A-CDK1 to phosphorylate MCM at distinct CDK2/1-specific sites and trigger origin firing, independent of CDC7 activity. Strikingly, this requires much higher CDK2/1 activity, which CDK2 cannot normally reach alone. Thus, having two distinct routes necessitates blocking both routes to prevent S phase: either by inhibiting CDC7 or CDK2 while also preventing APC/CCdh1 inactivation or inhibiting CDK1.

Humans↗
PubMed1975

Piribedil and apomorphine: pre- and postsynaptic effects on dopamine synthesis and neuronal activity.

Piribedil and apomorphine can cause a complete but temporary inhibition in firing of the DA-containing neurons. The cells recover to approximately 30 to 40% of the original firing rate, and with subsequent administration of the drug become more and more resistant to further inhibition. At this point they are also resistant to inhibition by other direct- or indirect-acting DA agonists that are normally able to inhibit the firing of DA cells. This effect may be due to an interaction of the DA agonists with the postsynaptic DA receptors, but apomorphine at least is able to inhibit the firing of DA cells directly when iontophoresed onto the DA cell body (Aghajanian and Bunney, 1973). These drugs can block the increase in DA synthesis observed in the absence of impulse flow, indicating a presynaptic site of acttion. Taken together, these results suggest that in interpreting the effects of drugs interacting with the DA systems several points of interaction should be considered.

Animals↗
PubMed2026

Lamin-ating the genome: quantitative gatekeeping of replication initiation.

Discovered in the 1970s, nuclear lamins control chromatin organization and are linked to many diseases. Zhang et al. now find that lamin A/C quantitatively constrains DNA replication initiation by limiting chromatin accessibility and sequestering proliferating cell nuclear antigen, extending lamin's long-known role in replication to the control of origin firing.

Journal Article↗
PubMed2026

Direct visualization of MCM helicase activation and replisome coupling in situ.

Deciphering the spatial organization of molecular machines that copy the genome remains a fundamental challenge in biology. Essential for eukaryotic DNA replication, Mini-Chromosome Maintenance (MCM2-7) helicases are loaded during G1 as double hexamers (DHs) to license replication origins. Upon activation in S phase, each DH is thought to split into two single hexamers (SHs) that form the active CMG helicases and travel bidirectionally. However, the field has long been divided: biochemical and structural studies define CMG helicases as autonomous, independent motors, while genomic and cellular imaging assays suggest sister replisomes remain physically coupled within replication factories. Here, we use MINFLUX nanoscopy to localize individual MCM complexes down to nanometer precision in situ, directly resolving DHs in human cells and capturing their separation into SHs upon origin firing. We find that the resulting sister replisomes do not diffuse apart: they remain coupled at a characteristic distance of ~40 nm throughout S phase. Depletion experiments identify two distinct contributions to this coupling: local, protein-mediated tethering by the AND1 scaffold, and higher-order spatial confinement dependent on cohesin, which is dispensable for MCM loading in G1 but required to maintain coupling in S phase. By linking the nanometer-scale architecture of the replisome to the genome-wide topology of replication fountains, these findings provide direct spatial evidence that sister forks are coupled during DNA synthesis and define the molecular forces that organize replisomes within their native nuclear context.

DNA replication↗
PubMed1979

Acceleration of idioventricular rhythms by histamine in guinea pig heart: mediation by H2 receptors.

To evaluate the ability of histamine to induce ventricular arrhythmias, we studied the effects of histamine on ventricular rhythmicity in the isolated guinea pig heart with complete atrioventricular conduction block. As a function of dose (0.1-30 microgram), histamine enhanced the idioventricular rate by increasing the rate of firing of the original pacemaker and also by causing the sudden appearance of faster idioventricular rhythms that coincided with changes in pacemaker site. Anaphylaxis in the isolated guinea pig heart with complete atrioventricular conduction block caused histamine release and acceleration of idioventricular rate. The effects of histamine on idioventricular rhythmicity were not attenuated by the histamine H1 receptor antagonist chlorpheniramine, but were antagonized by the H2 receptor antagonist cimetidine. Moreover, the selective H2 agonist 4-methylhistamine (4MeH) accelerated the idioventricular rate, whereas 2-(2-thiazolyl) ethylamine (ThEA), at doses selective for H1 receptor activation, did not. The effects of histamine on idioventricular rhythmicity were not modified by the beta-adrenergic blocker pindolol. The mechanism by which histamine increases idioventricular rate probably involves two components: (1) an enhancement in automaticity of the original pacemaker, and (2) the induction of faster rhythms via reentry and/or afterdepolarizations. Whatever the mechanism, both components of the ventricular chronotropic action of histamine appear to involve exclusively histamine receptors of the H2 type. Thus, our results suggest that H2 receptor antagonists may have a role as specific antiarrhythmic agents in the treatment of cardiac dysfunctions caused by histamine release.

Anaphylaxis↗
PubMed1978

II. Effect of CO2 on afferent vagal endings in the canine lung.

We have attempted to identify the afferent endings responsible for the pulmonary-CO2 ventilatory reflex. We recorded afferent vagal impulses arising from the left lung in anesthetized dogs with separately ventilated lungs. When the left pulmonary artery was occluded, left lung PCO2 fell to 3 mm Hg and slowly-adapting pulmonary stretch receptor activity increased 46%. Firing declined to its original intensity when left lung PCO2 was raised in steps by administration of CO2, firing decreasing most between 2 and 19 mm Hg, and least between 30 and 50 mm Hg. Irritant receptor activity also increased (from 2.8 to 7.4 impulses/sec) after pulmonary arterial occlusion, the effect being reversed by administration of CO2. These procedures caused trivial changes in pulmonary and bronchial C-fiber activity. Effects on both slowly-adapting stretch receptors and irritant receptors appeared to result from a direct action of CO2 on the endings themselves, rather than from mechanical changes in the lung. Changes in slowly-adapting stretch receptor activity provide an adequate explanation for the pulmonary-CO2 ventilatory reflex, the relationship between impulse frequency and lung PCO2 suggesting that these afferents may have a role in limiting CO2 loss under conditions causing hypocapnia, but be less effective in stimulating breathing during hypercapnia.

Afferent Pathways↗
PubMed2025

Regulation of replication timing in Saccharomyces cerevisiae.

In order to maintain genomic integrity, DNA replication must be highly coordinated. Disruptions in this process can cause replication stress which is aberrant in many pathologies including cancer. Despite this, little is known about the mechanisms governing the temporal regulation of DNA replication initiation, thought to be related to the limited copy number of firing factors. Here, we present a high (1-kilobase) resolution stochastic model of Saccharomyces cerevisiae whole-genome replication in which origins compete to associate with limited firing factors. After developing an algorithm to fit this model to replication timing data, we validated the model by reproducing experimental inter-origin distances, origin efficiencies, and replication fork directionality. This suggests the model accurately simulates the aspects of DNA replication most important for determining its dynamics. We also use the model to predict measures of DNA replication dynamics which are yet to be determined experimentally and investigate the potential impacts of variations in firing factor concentrations on DNA replication.

Saccharomyces cerevisiae↗
PubMed1979

Lack of correlation between spontaneous fasciculations and double discharges of voluntarily activated motor units.

We have studied the possible correlation between spontaneous fasciculations and double discharges or voluntarily activated motor units in myelopathies and other proximal neuropathies. Though both these phenomena are common in these diseases, they seem to have no correlation in individual muscles. It is concluded that spontaneous fasciculations and doubling of voluntarily activated motor unit potentials have different sites of origin or different mechanism. For example, if doubling reflects a disturbance of firing in the axon hillock, spontaneous fasciculations may originate in a more peripheral part of the motor axon.

Electromyography↗
PubMed1977

Effects of 1,3-dimethyl-5-aminoadamantane hydrochloride (DMAA) on the stretch-induced reflex tension of flexor muscles and the excitability of the gamma-loop in decerebrate and spinal cats.

The effects of 10 mg/kg i.v. 1,3-dimethyl-5-aminoadamantane hydrochloride (memantine, DMAA) on the stretch-induced reflex tension of flexor muscles extensor digitorum longus and tibialis anterior (EDL/TA) and on the excitability of the neurons relaying transmission in the gamma-loop have been investigated in decerebrate and spinal cats. DMAA essentially reduced the relfex excitability of flexors EDL/TA induced by fusimotor activity in the decerebrate preparation. The drug did not stimulate the reflex activity in acute spinal cats. In the concentration used, DMAA suppressed largely the transmission of the fusimotor reflex in the decerebrate as well as in the spinal preparation, although in spinal cats DMAA increased the average firing rate of muscle spindle primaries originating from EDL/TA muscles. The possible mechanism of action of the compound on dopaminergic and serotonergic systems as well as its basic effects on neuronal membranes is discussed.

Amantadine↗
PubMed1978

Pyromania and the primal scene: a psychoanalytic comment on the work of Yukio Mishima.

In the writings of the Japanese novelist, Yukio Mishima, primal scene experiences and derivative expressions of them recur persistently. The element of fire figures prominently in connection with the wish to wreak vengeance on the persons originally observed in the act of intercourse. As a destructive, attention-compelling spectacle, fire is a particularly suitable vehicle for this purpose. In Mishima's works, revenge takes the form of retaliation in kind: parental figures, or their surrogates, are put into the position of having to observe the child, or substitutes for him, in the act of sexual infidelity. These observations as well as clinical reports in the literature suggest some insights into fantasies of pyromania. They also make possible certain speculations concerning Misima's turbulent life and dramatic suicide.

Adult↗
PubMedDate not supplied

[Optimal conditions for determing ATP of microbial origin].

Endogenous luminescence of the luciferin-luciferase extract from firely tails was studied in determing low concentrations of ATP. The optimum concentration of the the extract, corresponding to the minumum effect of endogenous luminescence, was found in the reaction medium. The solution of luciferin-luciferase was unstable at room temperature and upon dilution. The activity of luciferin-luciferse solutions did not change after freezing in liquid nitrogen with following thawing. The content of ATP was assayed in the cells of Sarcina flava disintegrated with ultrasound.

Adenosine Triphosphate↗
PubMed1979

Firing behaviour in a stochastic nerve membrane model based upon the Hodgkin-Huxley equations.

A nerve membrane model with a two-state pore system was investigated by computer simulation in the uniform (space-clamped) case. Both sodium and potassium conducting pores were modelled, each pore having four independent gates which switched randomly between the open and the closed position, governed by the assumed rate constants. Each pore conducted only when all the gates were open. The model was based upon the Hodgkin-Huxley equations for the giant axon in squid, and in the limit of an infinite number of pores it was identical to these. The firing behaviour of this model as a function of the number of pores and the injected current were investigated. The mean firing frequency and the distribution of interspike intervals were mainly used in the presentation of the results. It was found that for pore numbers less than about 20 000 the main effects due to a finite number of pores were a lowering of the current threshold for firing and a more linear frequency current relationship relative to that of the original H-H equations. For higher pore numbers an increase in the current threshold and a pronounced burst firing close to the threshold were found.

Animals↗
PubMed1976

Ascending spinal tracts of the spino-bulbo-spinal reflex in cats.

Twenty-six chloralosed cats were employed in order to determine spinal ascending pathways of the spino-bulbo-spinal (SBS) reflex evoked by stimulation of the sural nerve. 1. Partial spinal transection of the dorsal part of the lateral funiculus abolished the SBS reflex ipsilateral to sural nerve stimulation. 2. By recording spinal cord potentials in response to sural nerve stimulation two pathways were established in the dorsolateral funiculus as the spinal ascending tracts of the SBS reflex; one is the direct pathway to the bulbar reticular-formation (direct spino-reticular tract) and the other one (indirect spino-reticular tract) is the relayed by the lateral cervical nucleus. Direct stimulation of the dorsolateral funiculus at the lumbar level elicited the SBS reflex. 3. Short-latency unit discharges were recorded from axons of the direct spino-reticular tract by sural nerve stimulation. These axons were discharged antidromically by stimulation of the bulbar reticular formation. 4. Intracellular recordings from the neurons of the lateral cervical nucleus revealed that spike potentials, riding on EPSPs, were induced by sural nerve stimulation and antidromic firings were obtained by stimulation of the bulbar reticular formation. 5. Neurons originating the spino-reticular tract, direct and indirect, were located in the Rexed V-VII laminae in the lower lumbar segments. They were fired monosynaptically by sural nerve stimulation and antidromically by stimulating the dorsolateral funiculus of the lumbar segments. Among them, some were activated antidromically by stimulating the bulbar reticular formation.

Animals↗
PubMed1978

Role of primate flocculus during rapid behavioral modification of vestibuloocular reflex. II. Mossy fiber firing patterns during horizontal head rotation and eye movement.

1. Extracellular recordings were obtained from 113 mossu fibers (MFs) in the flocculus of alert monkeys trained to perform a visual tracking task during sinusoidal, horizontal head rotation. The analysis of MF discharge patterns was designed to allow quantitative comparison of the discharge properties of flocculus MFs with brain stem cell populations from which the MFs might originate and with flocculus Purkinje cells (P-cells). Based on their firing patterns, MFs were divided into two classes. Vestibular MFs discharged in relation to head velocity and, in some cases, also in relation to eye movement. Eye movement MFs discharged only in relation to one or more components of eye movement. 2. Vestibular MFs were subdivided into three classes. Vestibular-only MFs (n = 15) displayed a modulation in firing rate during head rotation but exhibited no relationship to spontaneous eye movements. Vestibular-plus-saccade MFs (n = 14) displayed a modulation in firing rate during head rotation that quantitatively resembled the modulation in vestibular-only MFs. In addition, a pause in firing rate interrupted the vestibular modulation during saccades in one or more directions. Vestibular-plus-position MFs (n = 4) exhibited steady firing rates that were linearly related to horizontal eye position in the absence of vestibular stimulation. Sinusoidal head rotation evoked a modulation ofiring rate above and below the firing rate set by the eye position. 3. during sinusoidal head rotation, vestibular MF firing rate led head velocity by an average of 24 degrees. The amplitude of MF firing-rate modulation increased as a function of the frequency of head rotation and, hence, maximum head velocity. Since these characteristics are similar to those displayed by P-cells during suppression of the VOR, vestibular MFs probably transmit the head velocity component of P-cell firing rate to the flocculus. Based on evidence from other mammals and a quantitative comparison of population discharge characteristics, it is likely that vestibular MFs originate from the vestibular nerve and from cells in the medial vestibular nucleus. 4. Based on their discharge patterns, eye movement MFs were also subdivided into three classes. Burst MFs (n = 14) emitted a high-frequency burst of spikes prior to and during saccades in one or more direction, but were silent during steady fixation. Burst-tonic MFs (n = 53) emitted a burst of spikes prior to saccades in a preferred ("on") direction, ceased firing during saccades in the opposite ("off") direction, and exhibited steady firing rates that increased as steady gaze shifted in the on direction. Tonic MFs (n = 13) displayed steady firing rates that increased as the position of steady gaze shifted in the on direction, and either paused or exhibited step changes in firing rate during saccades. 5. During steady fixation, 64% of tonic and burst-tonic MFs were recruited into maintained firing within +/- 10 degrees of the primary direction of gaze...

Animals↗
PubMed1979

The central control of the lumbar sympathetic pathway to the large intestine of the cat.

1. The origin of the lumbar sympathetic inhibitory outflow to the large intestine was studied by recording simultaneously changes in colonic motility and efferent firing in the lumbar colonic nerves (l.c.n.) following lesions at various levels of the neuraxis. 2. Multiunit recordings from the l.c.n. usually consisted of irregular grouped discharges which were unrelated to spontaneous colonic contractions or to respiratory or cardiac cycles. The firing was depressed by the administration of ganglionic blocking agents or by decentralization of the inferior mesenteric ganglion, indicating that it was post-ganglionic and primarily central in origin. 3. In the majority of experiments colonic motility and l.c.n. firing were not altered by transection of the cervical (C2-C3) or thoracic (T10-T13) spinal cord. However, in these acute spinal animals destruction of the lumbar ventral roots or the lumbar spinal cord markedly enhanced colonic motility and depressed l.c.n. firing. These findings indicate supraspinal mechanisms are not essential for the generation of the lumbar inhibitory outflow to the colon. 4. Transection of the l.c.n. enhanced colonic motility in animals with an intact neuraxis, in acute spinal animals and in animals where the thoracolumbar sympathetic outflow was blocked. It is concluded that peripheral ganglionic as well as spinal pathways can sustain an inhibitory input to the colon. 5. L.c.n. firing was enchanced by stretching or pinching the proximal colon or small intestine or by electrical stimulation of intestinal afferent fibres (Adelta and C fibres) in the l.c.m. and mesenteric branches of the splanchnic nerves. The reflexes occurred via spinal pathways and were blocked by transection of the lumbar dorsal roots. Spontaneous firing in the l.c.n. was also generated by isolated segments of the lumbar spinal cord; however, this firing occurred independently of traditional reflex pathways since it was uanffected by transection of the lumbar dorsal roots. It is concluded that the spontaneous firing must be generated via ventral root afferent pathways or via endogenous oscillator circuits in the lumbar spinal cord.

Animals↗