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Biomedical subjects

J Mead

Publications and source records attributed to J Mead.

At least 19 recordsLinked to original sources
PubMed1996

The yeast alpha2 and Mcm1 proteins interact through a region similar to a motif found in homeodomain proteins of higher eukaryotes.

Homeodomain proteins are transcriptional regulatory factors that, in general, bind DNA with relatively low sequence specificity and affinity. One mechanism homeodomain proteins use to increase their biological specificity is through interactions with other DNA-binding proteins. We have examined how the yeast (Saccharomyces cerevisiae) homeodomain protein alpha2 specifically interacts with Mcm1, a MADS box protein, to bind DNA specifically and repress transcription. A patch of predominantly hydrophobic residues within a region preceding the homeodomain of alpha2 has been identified that specifies direct interaction with Mcm1 in the absence of DNA. This hydrophobic patch is required for cooperative DNA binding with Mcm1 in vitro and for transcriptional repression in vivo. We have also found that a conserved motif, termed YPWM, frequently found in homeodomain proteins of insects and mammals, partially functions in place of the patch in alpha2 to interact with Mcm1. These findings suggest that homeodomain proteins from diverse organisms may use analogous interaction motifs to associate with other proteins to achieve high levels of DNA binding affinity and specificity.

Amino Acid Sequence↗
PubMed1995

Altered DNA recognition and bending by insertions in the alpha 2 tail of the yeast a1/alpha 2 homeodomain heterodimer.

The yeast MAT alpha 2 and MATa1 homeodomain proteins bind cooperatively as a heterodimer to sites upstream of haploid-specific genes, repressing their transcription. In the crystal structure of alpha 2 and a1 bound to DNA, each homeodomain makes independent base-specific contacts with the DNA and the two proteins contact each other through an extended tail region of alpha 2 that tethers the two homeodomains to one another. Because this extended region may be flexible, the ability of the heterodimer to discriminate among DNA sites with altered spacing between alpha 2 and a1 binding sites was examined. Spacing between the half sites was critical for specific DNA binding and transcriptional repression by the complex. However, amino acid insertions in the tail region of alpha 2 suppressed the effect of altering an a1/alpha 2 site by increasing the spacing between the half sites. Insertions in the tail also decreased DNA bending by a1/alpha 2. Thus tethering the two homeodomains contributes to DNA bending by a1/alpha 2, but the precise nature of the resulting bend is not essential for repression.

Base Sequence↗
PubMed1994

The C-terminus of the B cell activator Oct-2 functions as an activation domain in yeast.

Oct-1 and Oct-2 are human transcriptional activators that bind to the same DNA element but activate distinct sets of genes. We expressed these factors in S. cerevisiae and observed greater than 5-fold stimulation of a lacZ reporter gene only with Oct-2. Transfer of the Oct-2 C-terminal domain onto either Oct-1 (Oct1.2) or a nonactivating DNA-binding domain from GAL4 created activators capable of greater than 15 and 10-fold stimulation of activity, respectively. Thus, the C-terminus of Oct-2 is sufficient to confer activation potential to nonactive DNA-binding fragments in yeast.

B-Lymphocytes↗
PubMed1992

Locomotion in men has no appreciable mechanical effect on breathing.

It has been suggested that the act of taking a stride produces substantial respiratory volume displacement and that this assists the respiratory muscles during locomotion. We measured the flow at the mouth associated with stride in walking and running humans and found it to be 1-2% of respiratory tidal volume, which is too small to make an appreciable contribution to pulmonary ventilation.

Adult↗
PubMed1991

Absence of a hemidiaphragm: mechanical implications.

Respiratory system mechanics were evaluated in a 22-year-old asymptomatic man with absence of the left hemidiaphragm. We described changes in esophageal pressure (Pes), gastric pressure (Pga), chest wall configuration, and mediastinal motion during tidal breathing, breaths to total lung capacity (TLC), and Mueller maneuvers in the upright and supine position. We predicted that contraction of the single hemidiaphragm would drive the abdominal contents caudal on the side with the intact hemidiaphragm and displace the abdominal contents cephalad on the other side. This would drive the mediastinum toward the side with the intact diaphragm, thereby reducing its effectiveness in expanding the lung on that side. When upright, this effect would be minimized to the extent that the rib cage muscles lower pleural pressure in the thorax without the diaphragm. We found that (vital capacity) VC and TLC were greater upright than supine and that Pga deflections were almost as strongly negative as Pes deflections during upright quiet breathing and breaths to TLC. Thus the rib cage muscles enhanced the inspiratory action of the right hemidiaphragm in the upright position. In the supine position, Pes became negative without change of Pga during breaths to TLC and quiet inspirations. Here, contraction of the hemidiaphragm was the dominant mechanism generating the inspiratory pressure. During maximal Mueller efforts, the mediastinum shifted toward the side with the intact diaphragm in both positions and the maximum inspiratory pressures were low. These pressures were likely to have been limited by both the finite impedance to rotation of the thoracoabdominal contents or mediastinum and a mechanical disadvantage of the remaining hemidiaphragm. We conclude that the effectiveness of the single hemidiaphragm as an inspiratory pump requires passive impedance of the abdominal viscera and mediastinum and is enhanced in the upright position by the action of the rib cage muscles.

Adult↗
PubMed1991

Effects of increased end-expiratory lung volume on breathing in awake ponies.

We studied the changes in breathing and respiratory muscle electromyograms (EMG) during passively induced increases in end-expiratory lung volume (EELV) in awake normal (N), hilar nerve-denervated (HND), carotid body-denervated (CBD), and HND + CBD ponies. EELV was increased by applying continuous negative pressure (-10 and -20 cmH2O) around the torso of the standing pony. In all groups, negative pressure produced sustained increases in EELV that were linearly related to the degree of negative pressure. Elevated EELV decreased breathing frequency (f) in N and CBD ponies but increased f in HND and HND + CBD ponies. When EELV was increased, tidal volume was unchanged or above control in N ponies but was below or near control in the other groups. In all groups during elevated EELV, arterial PCO2 initially decreased but then increased relative to control with isocapnia achieved after approximately 1.5 min. In all groups, the elevated EELV was accompanied by increased stimulation of the diaphragm as indicated by increased rate of rise of the integrated EMG (P less than 0.05). During elevated EELV, the duration of diaphragm EMG was reduced, but only in HND ponies was this reduction significant (P less than 0.05). In N ponies, the major effect of elevated EELV on the expiratory transversus abdominis (TA) muscle was an increase (P less than 0.05) in duration of activity and therefore total activity. The work of breathing was thus presumably shifted more to this muscle during elevated EELV. These changes in TA timing were not observed in HND and HND + CBD ponies during elevated EELV. We conclude that elevation of EELV, which presumably places the diaphragm on a less favorable portion of its length-tension relationship, results in compensatory increased stimulation of the diaphragm that is not critically dependent on hilar and carotid chemoreceptor afferents. However, hilar afferents do contribute to the changes in diaphragm and TA duration of activity during elevated EELV.

Animals↗
PubMed1991

Airways impedance during single breaths of foreign gases.

The changes in airways resistance (Raw) and inertance (Iaw) during single inspirations of pure methane, helium, neon, and ethane at a flow of 0.1 l/s were measured in six healthy subjects by use of a forced-oscillation technique. Raw and Iaw were computed from respiratory transfer impedance obtained at a frequency of 20 Hz by applying pressure oscillations at the chest and measuring flow at the mouth with a bag-in-box system. Compared with the air data, the changes of Iaw after inhalation of 500 ml of gas averaged -41.1% with methane, -82.8% with helium, -25.8% with neon, and +4.8% with ethane. These changes were slightly less than the changes in gas density (-45%, -86%, -31%, and +5%, respectively). The inhaled volumes at which 50% of the changes had occurred (V50) did not differ significantly among gases and were approximately 100 ml. For Raw the data were more noisy than for Iaw; they were discarded in two subjects because of a strong and irreproducible volume dependence in air. Consistent differences were seen between the remaining subjects, one of whom exhibited a predominant viscosity dependence of Raw, one a predominant density dependence, and two an intermediate pattern. V50s were larger for Raw than for Iaw, indicating a more peripheral distribution of Raw. For Raw, V50s were lower with helium than with methane, in agreement with the notion that density-dependent resistance is located mainly in the large airways. The results suggest that some information on the serial distribution of Raw and Iaw may be derived from impedance measurements with foreign gases.

Adult↗
PubMed1990

Determinants of breathing frequency during walking.

Breathing frequency has been shown to depend on metabolic demand, and also to be affected by stepping frequency during walking. To assess the influence of stepping frequency on breathing frequency, we recorded the timing of breathing and stepping in ten naive subjects walking on a treadmill. Five of the subjects showed periods of breathing in rhythm with their stepping (rhythmical entrainment); five subjects never showed rhythmical entrainment. In all subjects, respiratory frequency tended to increase with increases in estimated metabolic rate (EMR) produced by increases in walking speed or treadmill inclination. Breathing frequency was also affected by stepping frequency independent of EMR, both during rhythmical entrainment and in the absence of rhythmical entrainment. The dependence of breathing frequency on stepping frequency may reflect an excitatory influence of voluntary movement on the respiratory center. We conclude that stepping importantly influences breathing frequency during walking whether or not the two are rhythmically linked. Such lability of respiratory frequency probably reflects the small metabolic cost of departure from mechanically optimal frequencies.

Adult↗
PubMed1990

Total and local impedances of the chest wall up to 10 Hz.

To understand how bical mechanical chest wall (CW) properties are related to those of the CW as a whole, we measured esophageal and gastric pressures, CW volume changes (measured with a head-out body plethysmograph), and anteroposterior and transverse CW diameter changes (measured with magnetometers attached to the surface) during sinusoidal forcing at the mouth (2.5% vital capacity, 0.5-10 Hz) in four healthy subjects. Total CW resistance decreased sharply as frequency rose to 3-4 Hz and remained relatively constant at higher frequencies. Total CW reactance became less negative with increasing frequency but showed no tendency to change sign. Above 2 Hz, diameters measured at different locations changed asynchronously between and within the rib cage and abdomen. "Local pathway impedances" (ratios of esophageal or gastric pressure to a rate of diameter change) showed frequency dependence similar to that of the total CW less than 3 Hz. Local pathway impedances increased during contraction of respiratory muscles acting on the pathway. We conclude that 1) total CW behavior is mainly a reflection of its individual local properties at less than or equal to 3 Hz, 2) local impedances within the rib cage or within the abdomen can change independently in some situations, and 3) asynchronies that develop within the CW during forcing greater than 3 Hz suggest that two compartments may be insufficient to describe CW properties from impedance measurements.

Abdominal Muscles↗
PubMed1990

Abdominal pressure transmission in humans during slow breathing maneuvers.

Pressure transmission within the abdomen was studied in four subjects standing and supine, breathing slowly and performing slow breathing maneuvers. Pressures were measured in the stomach and rectum with air-containing balloon-catheter systems Pga(air) and Prec and in the stomach with a water-filled catheter system Pga(liq). Changes in Pga(air), Pga(liq), and Prec were nearly in phase and linearly related. The changes in Pga(liq) and Prec were nearly equal in all maneuvers, whereas the changes in Pga(air) were systematically greater than those of Pga(liq) and Prec during quiet breathing and relaxation maneuvers in the upright position. During expulsive maneuvers in either posture the abdominal shape and stomach position were relatively constant, and the changes in Pga(air) were nearly equal to those of Pga(liq) and Prec. Discrepancies between changes in Pga(air) and the other pressures were consistent with presumed changes in the height of the gastric air bubble. We conclude that abdominal pressure in humans is essentially hydrostatic during quiet breathing and slow breathing maneuvers.

Abdomen↗
PubMed1989

Chest wall impedance partitioned into rib cage and diaphragm-abdominal pathways.

We measured chest wall "pathway impedances" (ratios of pressure changes to rates of volume displacement at the surface) with esophageal and gastric balloons and inductance plethysmographic belts around the rib cage and abdomen during forced volume oscillations (5% vital capacity, 0.5-4 Hz) at the mouth of five relaxed, seated subjects. Volume displacements of the total chest wall surface, measured by summing the rib cage and abdominal signals, approximated measurements using volume-displacement, body plethysmography over the entire frequency range. Resistance (R) and elastance (E) of the diaphragm-abdomen pathway were several times greater than those of the rib cage pathway, except at the highest frequencies where diaphragm-abdominal E was small. R and E of the diaphragm-abdomen pathway and of the rib cage pathway showed the same frequency dependencies as that of the total chest wall: R decreased markedly as frequency increased, and E (especially in the diaphragm-abdomen) decreased at the highest frequencies. These results suggest that the chest wall can be reasonably modeled, over the frequency range studied, as a system with two major pathways for displacement. Each pathway seems to exhibit behavior that reflects nonlinear, rate-independent dissipation as well as viscoelastic properties. Impedances of these pathways are useful indexes of changes in chest wall mechanical behavior in different situations.

Abdomen↗
PubMed1989

Impedance of the chest wall during sustained respiratory muscle contraction.

We measured total chest wall impedance (Zw), "pathway impedances" of the rib cage (Zrcpath), and diaphragm-abdomen (Zd-apath), and impedance of the belly wall including abdominal contents (Zbw+) in five subjects during sustained expiratory (change in average pleural pressure [Ppl] from relaxation = 10 and 20 cmH2O) and inspiratory (change in Ppl = -10 and -20 cmH2O) muscle contraction, using forced oscillatory techniques (0.5-4 Hz) we have previously reported for relaxation (J. Appl. Physiol. 66: 350-359, 1989). Chest wall configuration and mean lung volume were kept constant. Zw, Zrcpath, Zd-apath, and Zbw+ all increased greatly at each frequency during expiratory muscle contraction; increases were proportional to effort. Zw, Zrcpath, and Zd-apath increased greatly during inspiratory muscle contraction, but Zbw+ did not. Resistances and elastances calculated from each of the impedances showed the same changes during muscle contraction as the corresponding impedances. Each of the resistances decreased as frequency increased, independent of effort; elastances generally increased with frequency. These frequency dependencies were similar to those measured in relaxed or tetanized isolated muscle during sinusoidal stretching (P.M. Rack, J. Physiol. Lond. 183: 1-14, 1966). We conclude that during respiratory muscle contraction 1) chest wall impedance increases, 2) changes in regional chest wall impedances can be somewhat independent, depending on which muscles contract, and 3) increases in chest wall impedance are due, at least in part, to changes in the passive properties of the muscles themselves.

Adult↗
PubMed1989

Transition from dynamically maintained to relaxed end-expiratory volume in human infants.

Newborn infants, in contrast to adults, dynamically maintain end-expiratory lung volume (EEV) above relaxation volume. The purpose of this study was to determine at what age children develop a breathing strategy that is relaxed, i.e., determined by the mechanical characteristics of the lung and chest wall. Forty studies were performed in 27 healthy infants and children aged 1 mo to 8 yr during natural sleep. Volume changes were recorded with the use of respiratory inductance plethysmography (RIP). The volume signal was differentiated to yield flow. Flow-volume representations were generated for a random sample of the recorded breaths to determine the predominant breathing strategy utilized, i.e., relaxed, interrupted, or indeterminate. The respiratory pattern was predominantly interrupted below 6 mo of age and predominantly relaxed over 1 yr of age. Mixed patterns were observed in children 6-12 mo of age. The number of breaths that could not be classified (indeterminate) decreased with age. Respiratory frequency measured from the sample of breaths decreased with age and was accompanied by an increase in expiratory time. We conclude that a relaxed EEV develops at the end of the first year of life and may be related to changes in the mechanical properties of the chest wall associated with growth as well as changes in respiratory timing.

Analog-Digital Conversion↗
PubMed1989

Changes of time constants during infancy and early childhood.

We used respiratory inductance plethysmography to record tidal respiration in 27 healthy unsedated infants and children 1 mo to 8 yr of age during sleep. Rib cage and abdominal outputs were present at approximately equal gains and summed to obtain an estimate of volume. Flow-volume curves were generated from the uncalibrated volume signal and its flow derivative. Expiratory time constants (tau) were obtained by visually drawing a line through the linear portion of the expiratory flow-volume relationship. tau increased significantly during the first 10 mo of life. After 10 mo, the estimated rate of increase of tau for older children was less than 5% of the estimated initial rate and not significantly different from zero. Prolongation of tau was paralleled by an increase in expiratory time (Te), and no changes in Te/tau were observed in the first 2 yr of life. These changes in tau likely reflect the increase in lung compliance induced by rapid alveolar growth during infancy. After the first year, expiratory time constants appear to remain relatively constant and may be consistent with balanced changes in compliance and resistance beyond infancy.

Aging↗
PubMed1989

Dyspnea on immersion: mechanisms in patients with bilateral diaphragm paralysis.

Patients with bilateral diaphragm paralysis are able to inflate their lungs by two mechanisms: relaxing the abdominal wall or expanding the rib cage. Each maneuver promotes lung expansion by shifting support of the abdominal contents from the abdominal wall to the diaphragm. We describe a patient with bilateral diaphragm paralysis who experienced acute dyspnea when immersed in water to the level of the abdomen and discuss the precipitation of dyspnea in the context of the strategies available to these patients for lung inflation.

Abdominal Muscles↗
PubMed1989

Action of the inspiratory muscles of the rib cage during breathing in newborns.

To determine whether the rib cage muscles actively contribute to tidal volume change in infancy, we measured tidal volume (VT), using a pneumotachograph, respiratory gastric pressure swings (Pga), using a liquid-filled gastric catheter, and rib cage and abdominal volume, using respiratory inductive plethysmography in 15 newborns, both before and during 2% CO2-induced hyperventilation. Active rib cage expansion produced by phasic contraction of the inspiratory muscles of the rib cage should reduce respiratory abdominal pressure fluctuations by moving the anterior abdominal wall outward and cephalad, thereby having an expanding influence on the abdominal cavity. During quiet sleep (n = 13), CO2-induced hyperventilation was associated with significant increases in VT, Pga, rib cage volume (Vrc), and abdominal volume (Vab). Increments in Pga were small relative to VT, as shown by an increase in the slope of the VT versus Pga respiratory loop (VT/Pga) in all subjects (p less than 0.001, paired t test). CO2 breathing was associated with an increase in the contribution of the rib cage compartment to total volume change (Vrc/Vrc + Vab) in all infants studied (p less than 0.001, paired t test), and the total volume response to hyperventilation was more strongly related to changes in rib cage volume (slope = 0.62, r = 0.90) than to abdominal volume (slope = 0.31, r = 0.60). During REM sleep (n = 6), mean VT/Pga did not change significantly, and the rib cage contribution to tidal breathing decreased in three of six infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗