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PubMed1999

Myogenic expression of an injectable protease-resistant growth hormone-releasing hormone augments long-term growth in pigs.

Ectopic expression of a new serum protease-resistant porcine growth hormone-releasing hormone, directed by an injectable muscle-specific synthetic promoter plasmid vector (pSP-HV-GHRH), elicits growth in pigs. A single 10 mg intramuscular injection of pSP-HV-GHRH DNA followed by electroporation in three-week-old piglets elevated serum GHRH levels by twofold to fourfold, enhanced growth hormone secretion, and increased serum insulin-like growth factor-I by threefold to sixfold over control pigs. After 65 days the average body weight of the pigs injected with pSP-HV-GHRH was approximately 37% greater than the placebo-injected controls and resulted in a significant reduction in serum urea concentration, indicating a decrease in amino acid catabolism. Evaluation of body composition indicated a uniform increase in mass, with no organomegaly or associated pathology.

Animals↗
PubMed2000

TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice.

The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.

Activating Transcription Factor 6↗
PubMed2003

Bursting into space: alterations of sympathetic control by space travel.

AIM: Astronauts return to Earth with reduced red cell masses and hypovolaemia. Not surprisingly, when they stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied autonomic function in six male astronauts (average +/- SEM age: 40 +/- 2 years) before, during, and after the 16-day Neurolab space shuttle mission. METHOD: We recorded electrocardiograms, finger photoplethysmographic arterial pressures, respiration, peroneal nerve muscle sympathetic activity, plasma noradrenaline and noradrenaline kinetics, and cardiac output, and we calculated stroke volume and total peripheral resistance. We perturbed autonomic function before and during spaceflight with graded Valsalva manoeuvres and lower body suction, and before and after the mission with passive upright tilt. RESULTS: In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33%) in three subjects, in whom noradrenaline spillover and clearance also were increased. Valsalva straining provoked greater reductions of arterial pressure, and proportionally greater sympathetic responses in space than on Earth. Lower body suction elicited greater increases of sympathetic nerve activity, plasma noradrenaline, and noradrenaline spillover in space than on Earth. After the Neurolab mission, left ventricular stroke volume was lower and heart rate was higher during tilt, than before spaceflight. No astronaut experienced orthostatic hypotension or pre-syncope during 10 min of post-flight tilting. CONCLUSION: We conclude that baseline sympathetic outflow, however measured, is higher in space than on earth, and that augmented sympathetic nerve responses to Valsalva straining, lower body suction, and post-flight upright tilt represent normal adjustments to greater haemodynamic stresses associated with hypovolaemia.

Adult↗
PubMed2000

Vasoactive neuroendocrine responses associated with tolerance to lower body negative pressure in humans.

The purpose of this investigation was to test the hypothesis that peripheral vasoconstriction and orthostatic tolerance are associated with increased circulating plasma concentrations of noradrenaline, vasopressin and renin-angiotensin. Sixteen men were categorized as having high (HT, n=9) or low (LT, n=7) tolerance to lower body negative pressure (LBNP) based on whether the endpoint of their pre-syncopal-limited LBNP (peak LBNP) exposure exceeded -60 mmHg. The two groups were matched for age, height, weight, leg volume, blood volume and maximal oxygen uptake, as well as baseline blood volume and plasma concentrations of vasoactive hormones. Peak LBNP induced similar reductions in mean arterial pressure in both groups. The reduction in leg arterial pulse volume (measured by impedance rheography), an index of peripheral vascular constriction, from baseline to peak LBNP was greater (P<0.05) in the HT group (-0.041 +/- 0.005 ml 100 ml-1) compared to the reduction in the LT group (-0. 025 +/- 0.003 ml 100 ml-1). Greater peak LBNP in the HT group was associated with higher (P<0.05) average elevations in plasma concentrations of vasopressin (pVP, Delta=+7.2 +/- 2.0 pg ml-1) and plasma renin-angiotensin (PRA, Delta=+2.9 +/- 1.3 ng Ang II ml-1 h-1) compared to average elevations of pVP (+2.2 +/- 1.0 pg ml-1) and PRA (+0.1 +/- 0.1 ng Ang II ml-1 h-1) in the LT group. Plasma noradrenaline concentrations were increased (P<0.05) from baseline to peak LBNP in both HT and LT groups, with no statistically distinguishable difference between groups. These data suggest that the renin-angiotensin and vasopressin systems may contribute to sustaining arterial pressure and orthostatic tolerance by their vasoconstrictive actions.

Adult↗
PubMed2000

Inducing jet-lag in older people: directional asymmetry.

Twenty healthy elderly subjects (12 female, 8 male; mean age 81 years, range 67-87 years) each experienced a 15-day time isolation protocol in which they lived individually in a special laboratory apartment in which sleep and circadian rhythm measures could be taken. There were two experiments: one (6 females, 4 males) involved a 6-h phase advance of the sleep/wake cycle, and the other (6 females, 4 males) a 6-h phase delay. Each started with 5 baseline days, immediately followed by the phase shift. The subject was then held to the phase shifted routine for the remainder of the study. Rectal temperatures were recorded minute-by-minute throughout the entire experiment and each night of sleep was recorded using polysomnography. A directional asymmetry in phase-shift effects was apparent, with significantly more sleep disruption and circadian rhythm amplitude disruption after the phase advance than after the phase delay. Sleep disruption was reflected in reduced time spent asleep, and in changed REM latency, which increased in the phase advance direction but decreased in the phase delay direction. Although the phase advance led to a significant increase in wakefulness in the first half of the night, the phase delay did not lead to an equivalent increase in wakefulness during the second half of the night. Examination of both raw and 'demasked' circadian rectal temperature rhythms confirmed that phase adjustment was slow in both directions, but was less slow (and more monotonic) after the phase delay than after the phase advance. Subjective alertness suffered more disruption after the phase advance than after the phase delay.

Aged↗
PubMed2003

Investigating the interaction between the homeostatic and circadian processes of sleep-wake regulation for the prediction of waking neurobehavioural performance.

The two-process model of sleep regulation has been applied successfully to describe, predict, and understand sleep-wake regulation in a variety of experimental protocols such as sleep deprivation and forced desynchrony. A non-linear interaction between the homeostatic and circadian processes was reported when the model was applied to describe alertness and performance data obtained during forced desynchrony. This non-linear interaction could also be due to intrinsic non-linearity in the metrics used to measure alertness and performance, however. Distinguishing these possibilities would be of theoretical interest, but could also have important implications for the design and interpretation of experiments placing sleep at different circadian phases or varying the duration of sleep and/or wakefulness. Although to date no resolution to this controversy has been found, here we show that the issue can be addressed with existing data sets. The interaction between the homeostatic and circadian processes of sleep-wake regulation was investigated using neurobehavioural performance data from a laboratory experiment involving total sleep deprivation. The results provided evidence of an actual non-linear interaction between the homeostatic and circadian processes of sleep-wake regulation for the prediction of waking neurobehavioural performance.

Arousal↗
PubMed2003

Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart.

INTRODUCTION: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. METHODS AND RESULTS: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. CONCLUSION: Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.

Action Potentials↗
PubMed2000

New digital measurement methods for left ventricular volume using real-time three-dimensional echocardiography: comparison with electromagnetic flow method and magnetic resonance imaging.

AIM: The aim of this study was to investigate the feasibility and accuracy of using symmetrically rotated apical long axis planes for the determination of left ventricular (LV) volumes with real-time three-dimensional echocardiography (3DE). METHODS AND RESULTS: Real-time 3DE was performed in six sheep during 24 haemodynamic conditions with electromagnetic flow measurements (EM), and in 29 patients with magnetic resonance imaging measurements (MRI). LV volumes were calculated by Simpson's rule with five 3DE methods (i.e. apical biplane, four-plane, six-plane, nine-plane (in which the angle between each long axis plane was 90 degrees, 45 degrees, 30 degrees or 20 degrees, respectively) and standard short axis views (SAX)). Real-time 3DE correlated well with EM for LV stroke volumes in animals (r=0.68-0.95) and with MRI for absolute volumes in patients (r-values=0.93-0.98). However, agreement between MRI and apical nine-plane, six-plane, and SAX methods in patients was better than those with apical four-plane and bi-plane methods (mean difference = -15, -18, -13, vs. -31 and -48 ml for end-diastolic volume, respectively, P<0.05). CONCLUSION: Apically rotated measurement methods of real-time 3DE correlated well with reference standards for calculating LV volumes. Balancing accuracy and required time for these LV volume measurements, the apical six-plane method is recommended for clinical use.

Adult↗
PubMed2000

Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.

BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

Adult↗
PubMed2000

Analysis of shape and motion of the mitral annulus in subjects with and without cardiomyopathy by echocardiographic 3-dimensional reconstruction.

The shape and dynamics of the mitral annulus of 10 patients without heart disease (controls), 3 patients with dilated cardiomyopathy, and 5 patients with hypertrophic obstructive cardiomyopathy and normal systolic function were analyzed by transesophageal echocardiography and 3-dimensional reconstruction. Mitral annular orifice area, apico-basal motion of the annulus, and nonplanarity were calculated over time. Annular area was largest in end diastole and smallest in end systole. Mean areas were 11.8 +/- 2.5 cm(2) (controls), 15.2 +/- 4.2 cm(2) (dilated cardiomyopathy), and 10.2 +/- 2.4 cm(2) (hypertrophic cardiomyopathy) (P = not significant). After correction for body surface, annuli from patients with normal left ventricular function were smaller than annuli from patients with dilated cardiomyopathy (5.9 +/- 1.2 cm(2)/m(2) vs 7.7 +/- 1.0 cm(2)/m(2); P <.02). The change in area during the cardiac cycle showed significant differences: 23.8% +/- 5.1% (controls), 13.2% +/- 2.3% (dilated cardiomyopathy), and 32.4% +/- 7.6% (hypertrophic cardiomyopathy) (P <.001). Apico-basal motion was highest in controls, followed by those with hypertrophic obstructive and dilated cardiomyopathy (1.0 +/- 0.3 cm, 0.8 +/- 0.2 cm, 0.3 +/- 0.2 cm, respectively; P <.01). Visual inspection and Fourier analysis showed a consistent pattern of anteroseptal and posterolateral elevations of the annulus toward the left atrium. In conclusion, although area changes and apico-basal motion of the mitral annulus strongly depend on left ventricular systolic function, nonplanarity is a structural feature preserved throughout the cardiac cycle in all three groups.

Adult↗
PubMed1999

A role for cysteine 3635 of RYR1 in redox modulation and calmodulin binding.

Oxidation of the skeletal muscle Ca(2+) release channel (RYR1) increases its activity, produces intersubunit disulfide bonds, and blocks its interaction with calmodulin. Conversely, bound calmodulin protects RYR1 from the effects of oxidants (Zhang, J.-Z., Wu, Y., Williams, B. Y., Rodney, G., Mandel, F., Strasburg, G. M., and Hamilton, S. L. (1999) Am. J. Physiol. 276, Cell Physiol. C46-C53). In addition, calmodulin protects RYR1 from trypsin cleavage at amino acids 3630 and 3637 (Moore, C. P., Rodney, G., Zhang, J.-Z., Santacruz-Toloza, L., Strasburg, G. M., and Hamilton, S. L. (1999) Biochemistry 38, 8532-8537). The sequence between these two tryptic sites is AVVACFR. Alkylation of RYR1 with N-ethylmaleimide (NEM) blocks both (35)S-apocalmodulin binding and oxidation-induced intersubunit cross-linking. In the current work, we demonstrate that both cysteines needed for the oxidation-induced intersubunit cross-link are protected from alkylation with N-ethylmaleimide by bound calmodulin. We also show, using N-terminal amino acid sequencing together with analysis of the distribution of [(3)H]NEM labeling with each sequencing cycle, that cysteine 3635 of RYR1 is rapidly labeled by NEM and that this labeling is blocked by bound calmodulin. We propose that cysteine 3635 is located at an intersubunit contact site that is close to or within a calmodulin binding site. These findings suggest that calmodulin and oxidation modulate RYR1 activity by regulating intersubunit interactions in a mutually exclusive manner and that these interactions involve cysteine 3635.

Alkylation↗
PubMed2003

An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells.

Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. However, cells lacking functional ATM exhibit a prolonged G2 arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G2-checkpoint response remains unknown. We report here that the G2 checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G2 checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G2 arrest in AT cells and show that activation of this G2 checkpoint contributes to the survival of AT cells.

Alkaloids↗
PubMed2003

Modeling beta-adrenergic control of cardiac myocyte contractility in silico.

The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

Adenylyl Cyclases↗
PubMed2000

The sleep of healthy people--a diary study.

To provide baseline data for various research studies at the University of Pittsburgh over a 10-year period, 266 healthy subjects (144 male, 122 female, aged 20-50 years) meeting certain criteria each completed a 14-night sleep diary. For each night, the diary allowed the subjective measurement of bedtime, wake time, time in bed (TIB), sleep efficiency, number of minutes of wake after sleep onset (WASO), alertness on awakening, and percentage of morning needing an alarm (or a person functioning as one). Weeknight versus weekend night differences in TIB (TIBdiff), weekday altertness, and reliance on alarms were examined as possible indicators of sleep debt. In addition, general descriptive data were tabulated. On average, bedtimes were at 23:48 and wake times at 07:23, yielding a mean TIB of 7 hours 35 minutes. As expected, bedtimes and wake times were later on weekend nights than on weeknights. Bedtimes were 26 minutes later, wake times 53 minutes later, yielding a mean weekend TIB increase of 27 minutes. Overall, subjects perceived their sleep latency to be 10.5 minutes, reported an average of one awakening during the night (with an average of 6.4 minutes of WASO), had a diary sleep efficiency of 96.3%, and awoke with an alterness rating of 69.5%. These variables differed little between weeknight and weekend nights. Subjects used an alarm (or a person functioning as an alarm) on 60.9% nights overall, 68.3% on weeknights, 42.5% on weekends. When TIBdiff was used as an estimate of sleep debt (comparing subjects with TIBdiff > 75 minutes with those with a TIBdiff < 30 minutes), the group with more "catch-up sleep" on weekends had shorter weeknight TIB durations (by about 24 minutes) and relied more on an alarm for weekday waking (by about 22%), indicating the possible utility of these variables as sleep debt indices.

Adult↗
PubMed2000

Circadian rhythms in healthy aging--effects downstream from the pacemaker.

Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms "downstream" from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24 h routine, sleeping at night) and unmasking (36 h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men).

Adult↗
PubMed2003

The relationship between lifestyle regularity and subjective sleep quality.

In previous work we have developed a diary instrument-the Social Rhythm Metric (SRM), which allows the assessment of lifestyle regularity-and a questionnaire instrument--the Pittsburgh Sleep Quality Index (PSQI), which allows the assessment of subjective sleep quality. The aim of the present study was to explore the relationship between lifestyle regularity and subjective sleep quality. Lifestyle regularity was assessed by both standard (SRM-17) and shortened (SRM-5) metrics; subjective sleep quality was assessed by the PSQI. We hypothesized that high lifestyle regularity would be conducive to better sleep. Both instruments were given to a sample of 100 healthy subjects who were studied as part of a variety of different experiments spanning a 9-yr time frame. Ages ranged from 19 to 49 yr (mean age: 31.2 yr, s.d.: 7.8 yr); there were 48 women and 52 men. SRM scores were derived from a two-week diary. The hypothesis was confirmed. There was a significant (rho = -0.4, p < 0.001) correlation between SRM (both metrics) and PSQI, indicating that subjects with higher levels of lifestyle regularity reported fewer sleep problems. This relationship was also supported by a categorical analysis, where the proportion of "poor sleepers" was doubled in the "irregular types" group as compared with the "non-irregular types" group. Thus, there appears to be an association between lifestyle regularity and good sleep, though the direction of causality remains to be tested.

Adult↗
PubMed2000

Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease.

The RNA and DNA tumor viruses have made fundamental contributions to two major areas of cancer research. Viruses were vital, first, to the discovery and analysis of cellular growth control pathways and the synthesis of current concepts of cancer biology and, second, to the recognition of the etiology of some human cancers. Transforming retroviruses carry oncogenes derived from cellular genes that are involved in mitogenic signalling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events. Viruses are now accepted as bona fide etiologic factors of human cancer; these include hepatitis B virus, Epstein-Barr virus, human papillomaviruses, human T-cell leukemia virus type I and hepatitis C virus, plus several candidate human cancer viruses. It is estimated that 15% of all human tumors worldwide are caused by viruses. The infectious nature of viruses distinguishes them from all other cancer-causing factors; tumor viruses establish long-term persistent infections in humans, with cancer an accidental side effect of viral replication strategies. Viruses are usually not complete carcinogens, and the known human cancer viruses display different roles in transformation. Many years may pass between initial infection and tumor appearance and most infected individuals do not develop cancer, although immunocompromised individuals are at elevated risk of viral-associated cancers. Variable factors that influence viral carcinogenesis are reviewed, including possible synergy between viruses and environmental cofactors. The difficulties in establishing an etiologic role for a virus in human cancer are discussed, as well as the different approaches that proved viral links to cancer. Future directions for tumor virus studies are considered.

Cell Transformation, Viral↗