Effects Of Transient Stimulation Research Articles

Transcriptional Bursting and Co-bursting Regulation by Steroid Hormone Release Pattern and Transcription Factor Mobility.

Genes are transcribed in a discontinuous pattern referred to as RNA bursting, but the mechanisms regulating this process are unclear. Although many physiological signals, including glucocorticoid hormones, are pulsatile, the effects of transient stimulation on bursting are unknown. Here we characterize RNA synthesis from single-copy glucocorticoid receptor (GR)-regulated transcription sites (TSs) under pulsed (ultradian) and constant hormone stimulation. In contrast to constant stimulation, pulsed stimulation induces restricted bursting centered around the hormonal pulse. Moreover, we demonstrate that transcription factor (TF) nuclear mobility determines burst duration, whereas its bound fraction determines burst frequency. Using 3D tracking of TSs, we directly correlate TF binding and RNA synthesis at a specific promoter. Finally, we uncover a striking co-bursting pattern between TSs located at proximal and distal positions in the nucleus. Together, our data reveal a dynamic interplay between TF mobility and RNA bursting that is responsive to stimuli strength, type, modality, and duration.

Cutaneous mechanisms of isometric ankle force control

The sense of force is critical in the control of movement and posture. Multiple factors influence our perception of exerted force, including inputs from cutaneous afferents, muscle afferents and central commands. Here, we studied the influence of cutaneous feedback on the control of ankle force output. We used repetitive electrical stimulation of the superficial peroneal (foot dorsum) and medial plantar nerves (foot sole) to disrupt cutaneous afferent input in 8 healthy subjects. We measured the effects of repetitive nerve stimulation on (1) tactile thresholds, (2) performance in an ankle force-matching and (3) an ankle position-matching task. Additional force-matching experiments were done to compare the effects of transient versus continuous stimulation in 6 subjects and to determine the effects of foot anesthesia using lidocaine in another 6 subjects. The results showed that stimulation decreased cutaneous sensory function as evidenced by increased touch threshold. Absolute dorsiflexion force error increased without visual feedback during peroneal nerve stimulation. This was not a general effect of stimulation because force error did not increase during plantar nerve stimulation. The effects of transient stimulation on force error were greater when compared to continuous stimulation and lidocaine injection. Position-matching performance was unaffected by peroneal nerve or plantar nerve stimulation. Our results show that cutaneous feedback plays a role in the control of force output at the ankle joint. Understanding how the nervous system normally uses cutaneous feedback in motor control will help us identify which functional aspects are impaired in aging and neurological diseases.

Response of traveling waves to transient inputs in neural fields

We analyze the effects of transient stimulation on traveling waves in neural field equations. Neural fields are modeled as integro-differential equations whose convolution term represents the synaptic connections of a spatially extended neuronal network. The adjoint of the linearized wave equation can be used to identify how a particular input will shift the location of a traveling wave. This wave response function is analogous to the phase response curve of limit cycle oscillators. For traveling fronts in an excitatory network, the sign of the shift depends solely on the sign of the transient input. A complementary estimate of the effective shift is derived using an equation for the time-dependent speed of the perturbed front. Traveling pulses are analyzed in an asymmetric lateral inhibitory network and they can be advanced or delayed, depending on the position of spatially localized transient inputs. We also develop bounds on the amplitude of transient input necessary to terminate traveling pulses, based on the global bifurcation structure of the neural field.

Gastrin release: Antrum microdialysis reveals a complex neural control

We used microdialysis to monitor local gastrin release in response to food, acid blockade and acute vagal excitation. For the first time, gastrin release has been monitored continuously in intact conscious rats in a physiologically relevant experimental setting in a fashion that minimizes confounding systemic effects. Microdialysis probes were placed in the submucosa on either side of the antrum, 3 days before the experiments. The concentration of gastrin in the antral submucosal compartment was about 20 times higher than in the microdialysate and estimated to be 5–10 times higher than in serum regardless of the prandial state. The rats were conscious during microdialysis except when subjected to electrical vagal stimulation. Acid blockade (omeprazole treatment of freely fed rats for 4 days), or bilateral sectioning of the abdominal vagal trunks (fasted, 3 days post-op.), raised the gastrin concentration in blood as well as microdialysate. The high gastrin concentration following omeprazole treatment was not affected by vagotomy. Vagal excitation stimulated the G cells: electrical vagal stimulation and pylorus ligation (fasted rats) raised the gastrin concentration transiently in both serum and microdialysate. Food intake induced a 2- to 3-fold increase in serum gastrin, while gastrin in antral microdialysate increased 10- to 15-fold. In unilaterally vagotomized rats (fasted, 3 days post-op.), food evoked a prompt peak gastrin release followed by a gradual decline on the intact side. On the vagotomized side of the antrum, the peak response seemed to be reduced while the microdialysate gastrin concentration remained elevated. Thus, unilateral vagotomy surprisingly raised the integrated gastrin response to food on the denervated side compared to the intact side, indicating that vagotomy suppresses an inhibitory as well as a stimulating effect on the G cells. While local infusion of atropine was without effect, infusion of the neuronal blocker tetrodotoxin (TTX) (which had no effect on basal gastrin) virtually abolished the food-evoked gastrin response and lowered the high microdialysate gastrin concentration in omeprazole-treated rats by 65%. We conclude that activated gastrin release, unlike basal gastrin release, is highly dependent on a neural input: 1) Vagal excitation has a transient stimulating effect on the G cells. The transient nature of the response suggests that the vagus has not only a prompt stimulatory but also a slow inhibitory effect on gastrin release. 2) Although vagal denervation did not affect the gastrin response to anacidity, the TTX experiments revealed that both food-evoked and anacidity-evoked gastrin release depends on neural input.

Transient β-catenin stabilization modifies lineage output from human thymic CD34+CD1a– progenitors

Increasing evidence includes Wnt proteins inside the group of master-signaling pathways that govern immune and nonimmune differentiation systems, fundamental for normal development and homeostasis. Although their precise functions in bone marrow and thymus are still controversial, numerous studies have shown that Wnt signaling is able to control the proliferation of hematopoietic stem cells and thymic progenitors and might also affect their cell-fate decisions and subsequent maturation. In the present work, we analyze the effect of transient stimulation of the canonical Wnt pathway in the differentiation potential of Lin(-)CD34(+) CD1a(-) human thymic progenitors, a multipotent and heterogeneous cell population that has the capacity to develop into T cells, NK cells, monocytes, cDC, and pDC. Our results demonstrate that giving a boost to canonical Wnt signaling, triggered by transient exposure to Wnt3a or LiCl, the differentiation capacity of thymic progenitors changes, enhancing NK cell production. On the contrary, Wnt3a- or LiCl-pretreated thymic progenitors generate a significantly lower number of myeloid lineage cells, monocytes, and cDC and exhibit a reduced capacity to differentiate into pDC lineage. As a possible mechanism for this effect, we show that Wnt3a- and LiCl-pretreated progenitors change their membrane levels of receptors for cytokines pivotal for their expansion and differentiation, such as Flt3L. Moreover, canonical Wnt pathway stimulation modifies the transcription factor profile of CD34(+)CD1(-) thymocytes, increasing Hes-1 and ID3 expression levels.

Agonistes de la GnRH versus antagonistes dans la fécondation in vitro

During in vitro fertilization (IVF) GnRH antagonists or agonists are used to optimize the control of organization of oocyte collection. The choice of stimulation protocol also takes into account the ovulatory, clinical, biological and ultrasound characteristics of the FIV candidate, as well as any stimulation measures already taken. Age appears to be the major predictive factor of oocyte response to stimulation and ultrasonography on the 3 rd day is a predictive element of the success of oocyte collection. Determination of hormonal parameters on the 3 rd day of the cycle (FSH, œstradiol, inhibin B, anti-mullerian hormone) makes it possible to refine the choice of therapy. All these elements are used to define various categories of patients in terms of response to hormonal stimulation. Agonists induce a suppression of pituitary secretion which inhibits the preovulatory LH peak and blocks natural ovulation. Nevertheless, there is an initial transient stimulating effect (flare-up) for a few days and a risk of prolonged ovarian desensitization responsible for side effects. The antagonists, administered just before the supposed ovulatory phase, provoke a rapid diminution in LH while avoiding the flare-up and prolonged ovarian desensitization. Various meta-analyses to compare both types of treatments currently suggest that agonists are superior in terms of number of oocytes produced, though the percentage of mature oocytes obtained as well as the levels of fertility are comparable whatever the type of treatment. In practice, organization of stimulation protocols using agonists is easier especially for teams working in a sequential manner. However, protocols using antagonists may be particularly useful in poor responders and are globally better tolerated.

The influence of elevated CO2 and O3 on fine roots and mycorrhizas of naturally growing young Scots pine trees during three exposure years

SummaryYoung Scots pine trees naturally established at a pine heath were exposed to two concentrations of CO2 (ambient and doubled ambient) and two O3 regimes (ambient and doubled ambient) and their combination in open‐top field chambers during growing seasons 1994, 1995 and 1996 (late May to 15 September). Filtered ozone treatment and chamberless control trees were also included in the treatment comparisons. Root ingrowth cores were inserted to the undisturbed soil below the branch projection of each tree at the beginning of the fumigation period in 1994 and were harvested at the end of the fumigation periods in 1995 and 1996. Root biomasses were determined from different soil layers in the ingrowth cores, and the infection levels of different mycorrhizal types were calculated. Elevated O3 and CO2 did not have significant effects on the biomass production of Scots pine coarse (Ø > 2 mm) or fine roots (Ø < 2 mm) and roots of grasses and dwarf shrubs. Elevated O3 caused a transient stimulation, observable in 1995, in the proportion of tuber‐like mycorrhizas, total mycorrhizas and total short roots but this stimulation disappeared during the last study year. Elevated CO2 did not enhance carbon allocation to root growth or mycorrhiza formation, although a diminishing trend in the mycorrhiza formation was observed. In the combination treatment increased CO2 inhibited the transient stimulating effect of ozone, and a significant increase of old mycorrhizas was observed. Our conclusion is that doubled CO2 is not able to increase carbon allocation to growth of fine roots or mycorrhizas in nutrient poor forest sites and realistically elevated ozone does not cause a measurable limitation to roots within a period of three exposure years.

Signal transduction in fibroblasts stably transformed by [Val12]Ras--the activities of extracellular-signal-regulated kinase and Jun N-terminal kinase are only moderately increased, and the activity of the delta-inhibitor of c-Jun is not alleviated.

Ras-transformed cells often show high levels of expression of activating protein-1 and Ets and of genes regulated by these transcription factors. In analogy with the effects of transient stimulation of Ras, it is assumed that the increase in transcription-factor transactivation in stably transformed cells is due to Ras-induced constitutive activation of mitogen-activated protein kinases. However, this has not been extensively studied. Using specific substrate peptides, we have examined here the activities of two types of mitogen-activated protein kinase, extracellular-signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK), in [Val12]Ras-transformed rat embryo fibroblast cell lines. These activities were elevated 2-3-fold in Ras-transformed cells compared with non-transformed cells with a similar growth rate. Increased ERK activity was not necessarily accompanied by a similar increase in JNK activity. In transformed cells, ERK and JNK activities could be stimulated fourfold and ninefold by phorbol ester and ultraviolet-light treatment, respectively, indicating that only a fraction of these enzymes were constitutively activated in these cells. It has been suggested that inactive JNK downregulates c-Jun transcriptional activity by binding to the c-Jun delta-domain. No decrease in delta-inhibitor activity could be demonstrated in Ras-transformed cells compared with control cells, consistent with the presence of mainly inactive JNK in transformed cells. Treatment of transformed cells wih benzodiazepine 5B, an inhibitor of Ras farnesylation, decreased ERK and JNK activities, and concomitantly caused morphological reversion, reduced growth rate, and normalization of transformation-related gene expression. We conclude that in stably Ras-transformed cells the moderately increased ERK/JNK activities are not coregulated, and that ERK rather than JNK activity correlated with transformation-related gene expression.

Effect of cisapride on the isolated guinea pig gall bladder and common bile duct

1. 1. In this study, the effect of cisapride on the isolated guinea pig gall bladder (GB) and common bile duct (CBD) motility was investigated. 2. 2. Cisapride, up to a certain concentration, produced an increase in tone of the GB (EC 50 1.35 × 10 −8 M) and the CBD (EC 50 2.75 × 10 −9 M), whereas, at concentrations higher than 3 × 10 −5M for the GB and 5 × 10 −6M for the CBD, it produced a transient increase in tone followed by a sustained decrease in tone or in the contraction amplitude or in both. 3. 3. The cisapride-induced increase in tone was antagonized by atropine on both the GB and the CBD. 4. 4. Cisapride up to 2 × 10 −5M for the GB and 3 × 10 −6M for the CBD did not modify, whereas, at concentrations higher than 2.8 × 10 −5M for the GB and 4 × 10 −6M for the CBD, it antagonized, noncompetitively, the concentration-response curve to exogenously applied acetylcholine. The IC 50 values for cisapride on the EC 50 of acetylcholine on the GB and the CBD were 9.4 × 10 −5M and 8.2 × 10 −6 M, respectively. 5. 5. In conclusion, on the guinea pig GB and CBD, low concentrations of cisapride produce a stimulating effect, probably of cholinergic origin, whereas higher concentrations produce a transient stimulating effect, probably of cholinergic origin, followed by a sustained relaxing effect, which may involve both cholinergic and noncholinergic pathways.

The effect of transient stimulation of lung irritant receptors on the pattern of breathing in rabbits.

1. 100 ms pulses of inflation and deflation were applied to the lungs of anaesthetized rabbits before and during inactivation of pulmonary stretch receptors. 2. Pulses of either sign given in inspiration often produced augmented breaths, whether or not stretch receptors were inactivated. Inflation pulses were more effective than deflation pulses. 3. After an augmented breath it was impossible to produce another for at least 1 min (refractoriness). 4. Pulses of deflation always shortened expiration. Pulses of inflation early in expiration shortened expiration. Later in expiration they lengthened expiration when stretch receptors were active and shortened expiration when stretch receptors were blocked. No refractoriness was observed for the effects on expiratory time. 5. Pulses in paralysed animals caused a burst of phrenic activity of fixed duration, usually with brief latency. There was no refractoriness. 6. We suggest that the duration of inspiration is governed by the activity of pulmonary stretch receptors, except during an augmented breath, and that the duration of expiration is governed by a balance of stretch and irritant receptor activity.

Satiation of the transient stimulating effect of erotic films.

Satiation of the transient stimulating effect of erotic films.