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PubMed2002

Escape from X inactivation.

Although the process of X inactivation in mammalian cells silences the majority of genes on the inactivated X chromosome, some genes escape this chromosome-wide silencing. Genes that escape X inactivation present a unique opportunity to study the process of silencing and the mechanisms that protect some genes from being turned off. In this review, we will discuss evolutionary aspects of escape from X inactivation, in relation to the divergence of the sex chromosomes. Molecular characteristics, expression, and epigenetic modifications of genes that escape will be presented, including their developmental regulation and the implications of chromatin domains along the X chromosome in modeling the escape process.

Animals↗
PubMed1988

Enhanced natriuretic effect of atrial natriuretic factor during mineralocorticoid escape in humans.

We examined the question of whether escape from the sodium-retaining effect of mineralocorticoid involves an increased natriuretic effect of atrial natriuretic factor (ANF). Seven healthy volunteers taking a 170 mmol Na/100 mmol K diet received an intravenous bolus (25 micrograms) followed by a 1-hour infusion (0.02 micrograms/kg/min) of ANF (human ANF-[99-126]) before and after 10 days of 9-fludrocortisone acetate, 0.5 mg b.i.d. Escape was accompanied by an increase in body weight (from 72.2 +/- 12.9 to 74.0 +/- 12.6 kg; p less than 0.05), mean arterial pressure (from 95 +/- 4 to 109 +/- 3 mm Hg; p less than 0.01), plasma ANF (from 9 +/- 2 to 24 +/- 4 pmol/L; p less than 0.01), and inulin clearance (from 124 +/- 9 to 137 +/- 7 ml/min; p less than 0.05). Indexes for renal sodium handling (lithium and free water clearance) were compatible with a decreased "proximal" and an increased "distal" tubular reabsorption fraction. ANF infusion raised inulin clearance comparably before and after escape to 138 +/- 10 and 152 +/- 7 ml/min, respectively, but the natriuretic effect was much larger (p less than 0.05) after escape (from 366 +/- 34 to 1294 +/- 278 mumol/min) than before (from 248 +/- 48 to 630 +/- 124 mumol/min). Indexes for tubular reabsorption were consistent with greater suppression of both "proximal" and "distal" tubular sodium reabsorption by ANF after versus before mineralocorticoid expansion. These results indicate that escape is accompanied not only by a rise in plasma ANF but also by potentiation of the natriuretic effect of ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids.

Pulmonary edema after ascent to altitude is well recognized but its pathogenesis is poorly understood. To determine whether altitude exposure increases lung vascular permeability, we exposed rats to a simulated altitude of approximately 14,500 feet (barometric pressure [Pb] 450 Torr) and measured the pulmonary transvascular escape of radiolabeled 125I-albumin corrected for lung blood content with 51Cr-tagged red blood cells (protein leak index = PLI). Exposures of 24 and 48 h caused significant increases in PLI (2.30 +/- 0.08 and 2.40 +/- 0.06) compared with normoxic controls (1.76 +/- 0.06), but brief hypoxic exposures of 1-13 h produced no increase in PLI, despite comparable increases in pulmonary artery pressure. There were associated increases in gravimetric estimates of lung water in the altitude-exposed groups and perivascular edema cuffs on histologic examination. Normobaric hypoxia (48 h; fractional inspired oxygen concentration [FIO2] = 15%) also increased lung transvascular protein escape and lung water. Dexamethasone has been used to prevent and treat altitude-induced illnesses, but its mechanism of action is unclear. Dexamethasone (0.5 or 0.05 mg/kg per 12 h) started 12 h before and continued during 48 h of altitude exposure prevented the hypoxia-induced increases in transvascular protein escape and lung water. Hemodynamic measurements (mean pulmonary artery pressure and cardiac output) were unaffected by dexamethasone, suggesting that its effect was not due to a reduction in pulmonary artery pressure or flow. The role of endogenous glucocorticoid activity was assessed in adrenalectomized rats that showed augmented hypoxia-induced increases in transvascular protein escape, which were prevented by exogenous glucocorticoid replacement. In summary, subacute hypoxic exposures increased pulmonary transvascular protein escape and lung water in rats. Dexamethasone prevented these changes independent of reductions of mean pulmonary artery pressure or flow, whereas adrenalectomy increased pulmonary vascular permeability and edema at altitude. Increases in vascular permeability in hypoxia could contribute to the development of high-altitude pulmonary edema and endogenous glucocorticoids may have an important influence on pulmonary vascular permeability in hypoxia.

Adrenalectomy↗
PubMed1997

Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat.

The purpose of this study was to investigate whether escape from vasopressin-induced antidiuresis is associated with altered regulation of any of the known aquaporin water channels. After 4-d pretreatment with 1-deamino-[8-D-arginine]-vasopressin (dDAVP) by osmotic mini-pump, rats were divided into two groups: control (continued dDAVP) and water-loaded (continued dDAVP plus a daily oral water load). A significant increase in urine volume in the water-loaded rats was observed by the second day of water loading, indicating onset of vasopressin escape. The onset of escape coincided temporally with a marked decrease in renal aquaporin-2 protein (measured by semiquantitative immunoblotting), which began at day 2 and fell to 17% of control levels by day 3. In contrast, there was no decrease in the renal expression of aquaporins 1, 3, or 4. The marked suppression of whole kidney aquaporin-2 protein was accompanied by a concomitant suppression of whole kidney aquaporin-2 mRNA levels. Immunocytochemical localization and differential centrifugation studies demonstrated that trafficking of aquaporin-2 to the plasma membrane remained intact during vasopressin escape. The results suggest that escape from vasopressin-induced antidiuresis is attributable, at least in part, to a vasopressin-independent decrease in aquaporin-2 water channel expression in the renal collecting duct.

Animals↗
PubMed2004

HIV CTL escape: at what cost?

Recent data have established the HIV-1 and SIV escape CTL through epitope mutation. However, three novel studies prove that such escape comes at a "cost" to overall viral fitness. Understanding how HIV-1/SIV escape CTL and the impact of the escape mutations has tremendous importance in developing CTL based vaccines. Further, a CTL based HIV-1 vaccine is likely to have long-term protective effect against disease only if the escape virus is significantly weakened compared with wild type.

AIDS Vaccines↗
PubMed1996

Producing directed behaviour: muscle activity patterns of the cockroach escape response

The cockroach responds to wind from the front left by making an escape turn to the right, and vice versa. So far, no interneurones in the escape system are known that respond only to wind from the left or only to wind from the right. In this study, we used electromyographic recordings to determine whether motor neurones respond in this direction-selective manner during escape behaviour. In the mesothoracic coxal-femoral joint, whose movement direction is diagnostic for escape direction, the fast motor neurones of one muscle respond selectively to one wind direction, and those of the antagonistic muscle respond selectively to wind from the other direction, resulting in an appropriate turning response. This rules out an alternative hypothesis, a co-activation mechanism of specifying turn direction. These results suggest that it would be fruitful to search among the interneurones of the escape system for additional cells and circuit properties that could give rise to this sharp directional discrimination.

Journal Article↗
PubMed2005

[Effectiveness of methotrexate for the escape by salazosulfapyridine].

Although disease modifying anti-rheumatic drugs (DMARDs) are used in the treatment of rheumatoid arthritis (RA), the selection of agents in the case of relapse (escape phenomenon) lacks clear-cut standards. We compared the effectiveness in a salazosulfapyridine and then methotrexate (SASP-->MTX) group with that in the mothotrexate (SASP+MTX) group after escape phenomenon expression in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) data. Outpatients of the Matsubara Mayflower Hospital with a history of DMARD administration during the 4 years prior to May 2003 were studied. The CRP level in the SASP-->MTX group (n=8) after the escape phenomenon expression showed a decline after 3 months, but no decline was seen even after 3 months the two in the CRP level in the SASP+MTX group (n=10). However, the difference between groups was not significant. The fluctuation in ESR was similar to that in CRP. However, ESR was significantly lower in the SASP-->MTX group 20 weeks after escape phenomenon expression. In evaluating treatment effectiveness after escape phenomenon expression in each group, SASP-->MTX was effective in 10 and SASP+MTX in 7 patients. Side effects necessitated cessation of treatment in 1 patient in the SASP-->MTX group. Treatment continued in 4 patients in the SASP-->MTX group and 2 in the SASP+MTX group, even though side effects occurred. It should be borne in mind that combination therapy often has greater clinical benefit than single agent therapy but not always.

Aged↗
PubMed2005

Combined proteomics and pathways analysis of collecting duct reveals a protein regulatory network activated in vasopressin escape.

Low sensitivity is characteristic of many proteomics methods. Presented here is an approach that combines proteomics based on difference gel electrophoresis (DIGE) with bioinformatic pathways analysis to identify both abundant and relatively nonabundant proteins in inner medullary collecting duct (IMCD) altered in abundance during escape from vasopressin-induced antidiuresis. Rats received the vasopressin analog dDAVP by osmotic minipump plus either a daily water load (vasopressin escape) or only enough water to replace losses (control). Immunoblotting confirmed the hallmark of vasopressin escape, a decrease in aquaporin-2, and demonstrated a decrease in the abundance of the urea transporter UT-A3. DIGE identified 22 mostly high-abundance proteins regulated during vasopressin escape. These proteins were analyzed using pathways analysis software to reveal protein clusters incorporating the proteins identified by DIGE. A single dominant cluster emerged that included many relatively low-abundance proteins (abundances too low for DIGE identification), including several transcription factors. Immunoblotting confirmed a decrease in total and phosphorylated c-myc, a decrease in c-fos, and increases in c-jun and p53. Furthermore, immunoblotting confirmed hypothesized changes in other proteins in the proposed network: Increases in c-src, receptor for activated C kinase 1, calreticulin, and caspase 3 and decreases in steroid receptor co-activator 1, Grp78/BiP, and annexin A4. This combined approach proved capable of uncovering regulatory proteins that are altered in response to a specific physiologic perturbation without being detected directly by DIGE. The results demonstrate a dominant protein regulatory network in IMCD cells that is altered in association with vasopressin escape, providing a new framework for further studies of signaling in IMCD.

Animals↗
PubMed1992

Dentist-implemented contingent escape for management of disruptive child behavior.

We evaluated the effectiveness of a dentist-implemented intervention in which brief escape from dental treatment was provided to manage disruptive child behavior during restorative dental treatment. Within a multiple baseline design across subjects, 4 children, aged 3 to 7 years, were provided temporary escape from dental treatment contingent upon brief periods of cooperative behavior. Disruptive behavior decreased when the appropriate escape contingency was used at least 80% of the time. The escape contingency required no more time than traditional management procedures (e.g., tell-show-do, reprimands and loud commands, restraint) to bring disruptive behavior under control. Independent ratings by two dentists provided social validation of the efficacy of the escape contingency.

Child↗
PubMed1965

ESCAPE BEHAVIOR UNDER DIFFERENT FIXED RATIOS AND SHOCK INTENSITIES.

The effects of ratio length and shock intensity on bar pressing were examined in three rats in two escape-from-shock experiments. In Experiment I, shock intensity was held constant while the schedule was varied from FR 1 to FR 20. The latency of the first escape response increased with FR length while the escape rate, computed as over-all rate in shock minus latency of the first response, decreased at FR 20. In Experiment II, the schedule was held constant at FR 5 while shock intensity was manipulated. Latency decreased as intensity increased, while escape rate increased with intensity, passing through a maximum for two subjects. Responses occurring during the last 100 sec of the 2-min escape period decreased as the FR increased for all subjects, and decreased as shock intensity increased for two subjects.

Animals↗
PubMed2001

Ontogenetic changes in mantle kinematics during escape-jet locomotion in the oval squid, Sepioteuthis lessoniana Lesson, 1830.

We investigated the kinematics of mantle movement during escape jet behavior in an ontogenetic series of Sepioteuthis lessoniana, the oval squid. Changes in mantle diameter during the jet were measured from digitized S-VHS video fields of tethered animals that ranged in age from hatchlings to 9 weeks. The amplitude of both mantle contraction and mantle hyperinflation (expressed as percent change from the resting mantle diameter) during an escape jet was significantly greater in hatchlings than in older, larger squid (P < 0.05). The maximum amplitude of mantle contraction during the escape jet decreased from an average of -40% in hatchlings to -30% in the largest animals studied. The maximum amplitude of mantle hyperinflation decreased from an average of 18% in hatchlings to 9% in the largest squid examined. In addition, the maximum rate of mantle contraction decreased significantly during ontogeny (P < 0.05), from a maximum of 8.6 mantle circumference lengths per second (L/s) in hatchlings to 3.8 L/s in the largest animals studied. The ontogenetic changes in the mantle kinematics of the escape jet occurred concomitantly with changes in the organization of collagenous connective tissue fiber networks in the mantle. The alteration in mantle kinematics during growth may result in proportionately greater mass flux during the escape jet in newly hatched squid than in larger animals.

Animals↗
PubMed1992

Effect of ruminal escape protein and fat on nitrogen utilization in lambs exposed to elevated ambient temperatures.

Eight wether lambs (mean BW = 28.8 kg) with ruminal and abomasal cannulas were assigned to either thermally neutral or high ambient temperature treatments. Within each temperature, lambs were randomly allotted to dietary treatments consisting of a basal diet (60% corn and 24% cottonseed hulls) either with (high; 11.4% CP) or without (control; 10.1% CP) added ruminal escape CP as fish meal and with (high) or without (control) 5% added ruminally inert fat in a 2 x 2 factorial treatment arrangement using a Latin square design. Lambs were fed 606 g of DM/d in each period, which consisted of a 10-d adjustment followed by 6 d of sample collection. High temperature increased (P less than .05) respiration rate, evaporative water loss, and rectal temperature. When compared with controls, lambs fed high escape CP retained more N when exposed to high temperatures (2.8 vs 3.6 g of N/d) and less N at neutral temperatures (3.3 vs 3.1 g of N/d; temperature x escape CP; P less than .05). Retention of N was greater (P less than .05) in lambs fed high than in those fed control fat (3.8 vs 2.7 g/d). Lambs fed high vs control escape CP had greater abomasal feed N flow (percentage of intake) when fed high-fat diets (77.3 vs 56.1%) but similar dietary N flow when fed control fat diets (55.8 vs 54.3%; fat x escape CP; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abomasum↗
PubMed1992

Effects of ruminally degradable and escape protein supplements on steers grazing summer native range.

One experiment was conducted during 1989 to determine whether a deficiency exists for either ruminally degradable or escape protein in steers grazing summer native range. Increasing levels of ruminally degradable (.15, .27, and .37 kg/d) and escape protein (.07, .14, and .21 kg/d) replaced a cornstarch and molasses (energy control) supplement. Supplements were isoenergetic and fed individually to steers (.88 kg/d). No response to the degradable protein supplement (P = .15) was observed; however, a linear gain response (P less than .01) was observed in steers fed escape protein in addition to ruminally degradable protein. An in vitro study indicated that more (P less than .01) microbial protein was synthesized from the energy supplement than from the degradable protein; this finding presumably relates to the numerical decrease in weight gains observed for steers fed degradable protein supplements. Analyses of esophageal extrusa samples indicated that CP was relatively constant for the 1989 growing season compared with the 1988 growing season (P less than .05). Escape protein values differed (P less than .01) between years and among months within year. Forages that were apparently grazed in 1989 were never deficient in degradable protein. Additional gain observed from feeding escape protein would indicate that microbial protein synthesis may be insufficient to satisfy the metabolizable protein requirement, which probably limited gains by steers grazing summer native range.

Animal Feed↗
PubMed2002

Apparent ruminal degradation and rumen escape of soluble nitrogen fractions in grass and grass silage administered intraruminally to lactating dairy cows.

The main objective of this study was to investigate in vivo ruminal degradation and rumen escape of soluble N fractions in grass and grass silage. Soluble protein and long-chain peptides (PLP), small peptides (SP) and free AA (FAA) were obtained from fresh grass and grass silages fertilized with different levels of N. Soluble extracts from the forages were pulse dosed into the rumen of three cannulated lactating dairy cows, and a simple or complex model was used to examine the kinetics of the soluble N fractions in the rumen. When soluble extracts from silage were investigated, pulse dosages of total nonammonia N (NAN) were 21, 27, and 32 g, while for fresh grass only dosages of 20 g were ruminally administered. In the silage extracts, mean proportions of PLP-N, SP-N, and FAA-N in the NAN were 30, 52, and 18%, respectively, whereas in the fresh grass the corresponding values were 67, 20, and 13%. From silage extracts, all three soluble N fractions showed a linear decrease (P < 0.05) in degradation rate and an increase (P < 0.05) in ruminal escape with increasing dosage. In silage, mean degradation rates, parameterized from the complex model, were 230, 214, and 334%/h for PLP-N, SP-N, and FAA-N, respectively, and the ruminal escape was highest (P < 0.05) for SP-N (11.2% of dose) and lowest (P < 0.05) for FAA-N (5.0% of dose). No differences in degradation rate and ruminal escape between fresh grass and silage were observed. However, the proportion of N dose converted to ammonia was only 24% in the fresh grass, whereas for the silages a mean value of 76% was found. From this study, it is concluded that a significant amount of dietary soluble N escapes ruminal degradation, and thus contributes to the intestinal AA supply. Moreover, if the main aim is to study degradation kinetics of individual N fractions, a complex model should be used in the evaluation. This model can also be used to study ruminal synchronization of N and energy for microbial growth.

Animal Feed↗
PubMed2003

Viremia control despite escape from a rapid and potent autologous neutralizing antibody response after therapy cessation in an HIV-1-infected individual.

The neutralizing Ab response after primary HIV-1 infection is delayed relative to the virus-specific CD8(+) T cell response and the initial decline in plasma viremia. Because nearly all HIV-1 infections result in AIDS, it would be instructive to study cases where neutralizing Ab production commenced sooner. This was done in subject AC10, an individual treated during early infection and in whom a rapid autologous neutralizing Ab response was detected after therapy cessation as rebound viremia declined and remained below 1000 RNA copies/ml of blood for over 2.5 years. This subject's Abs were capable of reducing the infectivity of his rebound virus by >4 logs in vitro at a time when rebound viremia was down-regulated and virus-specific CD8(+) T cells were minimal, suggesting that neutralizing Abs played an important role in the early control of viremia. The rebound virus did not exhibit an unusual phenotype that might explain its high sensitivity to neutralization by autologous sera. Neutralization escape occurred within 75 days and was proceeded by neutralizing Ab production to the escape variant and subsequent escape. Notably, escape was not associated with a significant rise in plasma viremia, perhaps due to increasing CD8(+) T cell responses. Sequence analysis of gp160 revealed a growing number of mutations over time, suggesting ongoing viral evolution in the face of potent antiviral immune responses. We postulate that an early effective neutralizing Ab response can provide long-term clinical benefits despite neutralization escape.

Adult↗
PubMed2003

Epitope escape mutation and decay of human immunodeficiency virus type 1-specific CTL responses.

To investigate possible mechanisms behind HIV-1 escape from CTL, we performed detailed longitudinal analysis of Gag (SLYNTVATL)- and RT (ILKEPVHGV)-specific CTL responses and plasma epitope sequences in five individuals. Among those with CTL against consensus epitope sequences, epitope mutations developed over several years, invariably followed by decay of the CTL targeting the consensus epitopes. The maturation state of the CTL varied among individuals and appeared to affect the rate of epitope mutation and CTL decay, despite similar IFN-gamma production. Escape mutations were oligoclonal, suggesting fitness constraints. The timing of escape indicated that the net selective advantage of escape mutants was slight, further underscoring the importance of understanding factors determining selective pressure and viral fitness in vivo. Our data show surprisingly consistent decay of CTL responses after epitope escape mutation and provide insight into potential mechanisms for both immune failure and shifting CTL specificities.

Adult↗
PubMed2003

Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages.

Listeria monocytogenes (Lm) evades being killed after phagocytosis by macrophages by escaping from vacuoles into cytoplasm. Activated macrophages are listericidal, in part because they can retain Lm in vacuoles. This study examined the contribution of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) to the inhibition of Lm escape from vacuoles. Lm escaped from vacuoles of nonactivated macrophages within 30 min of infection. Macrophages activated with IFN-gamma, LPS, IL-6, and a neutralizing Ab against IL-10 retained Lm within the vacuoles, and inhibitors of ROI and RNI blocked inhibition of vacuolar escape to varying degrees. Measurements of Lm escape in macrophages from gp91(phox-/-) and NO synthase 2(-/-) mice showed that vacuolar retention required ROI and was augmented by RNI. Live cell imaging with the fluorogenic probe dihydro-2',4,5,6,7,7'-hexafluorofluorescein coupled to BSA (DHFF-BSA) indicated that oxidative chemistries were generated rapidly and were localized to Lm vacuoles. Chemistries that oxidized DHFF-BSA were similar to those that retained Lm in phagosomes. Fluorescent conversion of DHFF-BSA occurred more efficiently in smaller vacuoles, indicating that higher concentrations of ROI or RNI were generated in more confining volumes. Thus, activated macrophages retained Lm within phagosomes by the localization of ROI and RNI to vacuoles, and by their combined actions in a small space

Animals↗
PubMed2000

Water penetration and escape in proteins.

The kinetics of water penetration and escape in cytochrome c (cyt c) is studied by molecular dynamics (MD) simulations at various temperatures. Water molecules that penetrate the protein interior during the course of an MD simulation are identified by monitoring the number of water molecules in the first coordination shell (within 3.5 A) of each water molecule in the system. Water molecules in the interior of cyt c have 0-3 water molecules in their first hydration shell and this coordination number persists for extended periods of time. At T = 300 K we identify over 200 events in which water molecules penetrate the protein and reside inside for at least 5 picoseconds (ps) within a 1.5 nanoseconds (ns) time period. Twenty-seven (27) water molecules reside for at least 300 ps, 17 water molecules reside in the protein interior for times longer than 500 ps, and two interior water molecules do not escape; at T = 360 K one water molecule does not escape; at 430 K all water molecules exchange. Some of the internal water molecules show mean square displacements (MSD) of 1 A2 characteristic of structural waters. Others show MSD as large as 12 A2, suggesting that some of these water molecules occupy transient cavities and diffuse extensively within the protein. Motions of protein-bound water molecules are rotationally hindred, but show large librations. Analysis of the kinetics of water escape in terms of a survival time correlation function shows a power law behavior in time that can be interpreted in terms of a broad distribution of energy barriers, relative to kappa BT, for water exchange. At T = 300 K estimates of the roughness of the activation energy distribution is 4-10 kJ/mol (2-4 kappa BT). Activation enthalpies for water escape are 6-23 kJ/mol. The difference in activation entropies between fast exchanging (0.01 ns) and slow exchanging (0.1-1 ns) water molecules is -27 J/K/mol. Dunitz (Science 1997;264:670.) has estimated the maximum entropy loss of a water molecule due to binding to be 28 J/K/mol. Therefore, our results suggest that the entropy of interior water molecules is similar to entropy of bulk water.

Animals↗