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At least 1,189 records · Page 66

Human osteoblast-like cells respond to mechanical strain with increased bone matrix protein production independent of hormonal regulation

Exposure of osteosarcoma cell lines to chronic intermittent strain increases the activity of mechano-sensitive cation (SA-cat) channels. The impact of mechano-transduction on osteoblast function has not been well studied. We analyzed the expression and production of bone matrix proteins in human osteoblast-like osteosarcoma cells, OHS-4, in response to chronic intermittent mechanical strain. The OHS-4 cells exhibit type I collagen production, 1,25-Dihydroxyvitamin D-inducible osteocalcin, and mineralization of the extracellular matrix. The matrix protein message level was determined from total RNA isolated from cells exposed to 1-4 days of chronic intermittent strain. Northern analysis for type I collagen indicated that strain increased collagen message after 48 h. Immunofluorescent labeling of type I collagen demonstrated that secretion was also enhanced with mechanical strain. Osteopontin message levels were increased several-fold by the application of mechanical load in the absence of vitamin D, and the two stimuli together produced an additive effect. Osteocalcin secretion was also increased with cyclic strain. Osteocalcin levels were not detectable in vitamin D-untreated control cells. However, after 4 days of induced load, significant levels of osteocalcin were observed in the medium. With vitamin D present, osteocalcin levels were 4 times higher in the medium of strained cells compared to nonstrained controls. We conclude that mechanical strain of osteoblast-like cells is sufficient to increase the transcription and secretion of matrix proteins via mechano-transduction without hormonal induction.

NASA Discipline Number 40-40↗

Cerebral versus systemic hemodynamics during graded orthostatic stress in humans

BACKGROUND: Orthostatic syncope is usually attributed to cerebral hypoperfusion secondary to systemic hemodynamic collapse. Recent research in patients with neurocardiogenic syncope has suggested that cerebral vasoconstriction may occur during orthostatic hypotension, compromising cerebral autoregulation and possibly contributing to the loss of consciousness. However, the regulation of cerebral blood flow (CBF) in such patients may be quite different from that of healthy individuals, particularly when assessed during the rapidly changing hemodynamic conditions associated with neurocardiogenic syncope. To be able to interpret the pathophysiological significance of these observations, a clear understanding of the normal responses of the cerebral circulation to orthostatic stress must be obtained, particularly in the context of the known changes in systemic and regional distributions of blood flow and vascular resistance during orthostasis. Therefore, the specific aim of this study was to examine the changes that occur in the cerebral circulation during graded reductions in central blood volume in the absence of systemic hypotension in healthy humans. We hypothesized that cerebral vasoconstriction would occur and CBF would decrease due to activation of the sympathetic nervous system. We further hypothesized, however, that the magnitude of this change would be small compared with changes in systemic or skeletal muscle vascular resistance in healthy subjects with intact autoregulation and would be unlikely to cause syncope without concomitant hypotension. METHODS AND RESULTS: To test this hypothesis, we studied 13 healthy men (age, 27 +/- 7 years) during progressive lower body negative pressure (LBNP). We measured systemic flow (Qc is cardiac output; C2H2 rebreathing), regional forearm flow (FBF; venous occlusion plethysmography), and blood pressure (BP; Finapres) and calculated systemic (SVR) and forearm (FVR) vascular resistances. Changes in brain blood flow were estimated from changes in the blood flow velocity in the middle cerebral artery (VMCA) using transcranial Doppler. Pulsatility (systolic minus diastolic/mean velocity) normalized for systemic arterial pressure pulsatility was used as an index of distal cerebral vascular resistance. End-tidal PACO2 was closely monitored during LBNP. From rest to maximal LBNP before the onset of symptoms or systemic hypotension, Qc and FBF decreased by 29.9% and 34.4%, respectively. VMCA decreased less, by 15.5% consistent with a smaller decrease in CBF. Similarly, SVR and FVR increased by 62.8% and 69.8%, respectively, whereas pulsatility increased by 17.2%, suggestive of a mild degree of small-vessel cerebral vasoconstriction. Seven of 13 subjects had presyncope during LBNP, all associated with a sudden drop in BP (29 +/- 9%). By comparison, hyperventilation alone caused greater changes in VMCA (42 +/- 2%) and pulsatility but never caused presyncope. In a separate group of 3 subjects, superimposition of hyperventilation during highlevel LBNP caused a further decrease in VMCA (31 +/- 7%) but no change in BP or level of consciousness. CONCLUSIONS: We conclude that cerebral vasoconstriction occurs in healthy humans during graded reductions in central blood volume caused by LBNP. However, the magnitude of this response is small compared with changes in SVR or FVR during LBNP or other stimuli known to induce cerebral vasoconstriction (hypocapnia). We speculate that this degree of cerebral vasoconstriction is not by itself sufficient to cause syncope during orthostatic stress. However, it may exacerbate the decrease in CBF associated with hypotension if hemodynamic instability develops.

NASA Discipline Cardiopulmonary↗

Integrating with integrins

Our central claim is that signaling by integrins provides a mechanism by which signals generated in response to adhesion, soluble hormones, and mechanical forces can interact. Such interactions permit cells to integrate these different classes of external stimuli and hence to orchestrate an efficient response. This integrating function of integrins is likely to be essential for much of development and physiology, as well as complex pathologies such as cancer. Understanding in detail how these signals are transduced and processed is likely to be an important area of research in the near future.

NASA Discipline Cell Biology↗

Neuromuscular adaptation to actual and simulated weightlessness

The chronic "unloading" of the neuromuscular system during spaceflight has detrimental functional and morphological effects. Changes in the metabolic and mechanical properties of the musculature can be attributed largely to the loss of muscle protein and the alteration in the relative proportion of the proteins in skeletal muscle, particularly in the muscles that have an antigravity function under normal loading conditions. These adaptations could result in decrements in the performance of routine or specialized motor tasks, both of which may be critical for survival in an altered gravitational field, i.e., during spaceflight and during return to 1 G. For example, the loss in extensor muscle mass requires a higher percentage of recruitment of the motor pools for any specific motor task. Thus, a faster rate of fatigue will occur in the activated muscles. These consequences emphasize the importance of developing techniques for minimizing muscle loss during spaceflight, at least in preparation for the return to 1 G after spaceflight. New insights into the complexity and the interactive elements that contribute to the neuromuscular adaptations to space have been gained from studies of the role of exercise and/or growth factors as countermeasures of atrophy. The present chapter illustrates the inevitable interactive effects of neural and muscular systems in adapting to space. It also describes the considerable progress that has been made toward the goal of minimizing the functional impact of the stimuli that induce the neuromuscular adaptations to space.

Non-NASA Center↗

A reevaluation of the vestibulo-ocular reflex: new ideas of its purpose, properties, neural substrate, and disorders

Conventional views of the vestibulo-ocular reflex (VOR) have emphasized testing with caloric stimuli and by passively rotating patients at low frequencies in a chair. The properties of the VOR tested under these conditions differ from the performance of this reflex during the natural function for which it evolved--locomotion. Only the VOR (and not visually mediated eye movements) can cope with the high-frequency angular and linear perturbations of the head that occur during locomotion; this is achieved by generating eye movements at short latency (< 16 msec). Interpretation of vestibular testing is enhanced by the realization that, although the di- and trisynaptic components of the VOR are essential for this short-latency response, the overall accuracy and plasticity of the VOR depend upon a distributed, parallel network of neurons involving the vestibular nuclei. Neurons in this network variously upon a distributed, parallel network of neurons involving the vestibular nuclei. Neurons in this network variously encode inputs from the labyrinthine semicircular canals and otoliths, as well as from the visual and somatosensory systems. The central vestibular pathways branch to contact vestibular cortex (for perception) and the spinal cord (for control of posture). Thus, the vestibular nuclei basically coordinate the stabilization of gaze and posture, and contribute to the perception of verticality and self-motion. Consequently, brainstem disorders that disrupt the VOR cause not just only nystagmus, but also instability of posture (eg, increased fore-aft sway in patients with downbeat nystagmus) and disturbance of spatial orientation (eg, tilt of the subjective visual vertical in Wallenberg's syndrome).

Review↗

Polyamines in the lateral vestibular nuclei of the squirrel monkey and their potential role in vestibular compensation

Polyamine synthesis increases in response to injurious stimuli including axotomy and denervation. Reduced eye nystagmus and head-deviation have been observed in unilateral labyrinthectomized (UL) guinea pigs treated with an inhibitor of polyamine synthesis, alpha-difluoromethylornithine (DFMO). We quantified polyamines in the lateral vestibular nuclei (LVN) of control and UL squirrel monkeys during the phase of vestibular compensation (VC) and performed an experiment to determine if DFMO reduces nystagmus previously observed in the guinea pig. Polyamines were detected in the LVN of control and UL squirrel monkeys. Putrescine and spermidine increased in the ipsilateral LVN 3 days after UL with no change in the contralateral LVN. No left-right differences were noted in the 5-day post-UL monkey. DFMO reduced nystagmus in a UL squirrel monkey. These findings suggest that polyamines are important in vestibular function and may contribute to nystagmus observed in VC.

NASA Program Space Physiology and Countermeasures↗

Metabotropic glutamate receptors are required for the induction of long-term potentiation

Recent observations have led to the suggestion that the metabotropic glutamate receptor may play a role in the induction or maintenance of long-term potentiation (LTP). However, experimental evidence supporting a role for this receptor in the induction of LTP is still inconclusive and controversial. Here we report that, in rat dorsolateral septal nucleus (DLSN) neurons, which have the highest density of metabotropic receptors and show functional responses, the induction of LTP is not blocked by the NMDA receptor antagonist 2-amino-5-phosphonovalerate, but is blocked by two putative metabotropic glutamate receptor antagonists, L-2-amino-3-phosphonopropionic acid and L-2-amino-4-phosphonobutyrate. Furthermore, superfusion of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a selective metabotropic glutamate agonist, resulted in a long-lasting potentiation of synaptic transmission similar to that induced by tetanic stimuli. Our results demonstrated that activation of postsynaptic metabotropic receptors is both necessary and sufficient for the induction of LTP in the DLSN, and we suggest that such a mechanism may be important at other CNS synapses.

Non-NASA Center↗

Mathematical modeling of human cardiovascular system for simulation of orthostatic response

This paper deals with the short-term response of the human cardiovascular system to orthostatic stresses in the context of developing a mathematical model of the overall system. It discusses the physiological issues involved and how these issues have been handled in published cardiovascular models for simulation of orthostatic response. Most of the models are stimulus specific with no demonstrated capability for simulating the responses to orthostatic stimuli of different types. A comprehensive model incorporating all known phenomena related to cardiovascular regulation would greatly help to interpret the various orthostatic responses of the system in a consistent manner and to understand the interactions among its elements. This paper provides a framework for future efforts in mathematical modeling of the entire cardiovascular system.

NASA Discipline Cardiopulmonary↗

Mathematical modelling of flow distribution in the human cardiovascular system

The paper presents a detailed model of the entire human cardiovascular system which aims to study the changes in flow distribution caused by external stimuli, changes in internal parameters, or other factors. The arterial-venous network is represented by 325 interconnected elastic segments. The mathematical description of each segment is based on equations of hydrodynamics and those of stress/strain relationships in elastic materials. Appropriate input functions provide for the pumping of blood by the heart through the system. The analysis employs the finite-element technique which can accommodate any prescribed boundary conditions. Values of model parameters are from available data on physical and rheological properties of blood and blood vessels. As a representative example, simulation results on changes in flow distribution with changes in the elastic properties of blood vessels are discussed. They indicate that the errors in the calculated overall flow rates are not significant even in the extreme case of arteries and veins behaving as rigid tubes.

NASA Center JSC↗

Vestibular short latency responses to pulsed linear acceleration in unanesthetized animals

Linear acceleration transients were used to elicit vestibular compound action potentials in non-invasively prepared, unanesthetized animals for the first time (chicks, Gallus domesticus, n = 33). Responses were composed of a series of up to 8 dominant peaks occurring within 8 msec of the stimulus. Response amplitudes for 1.0 g stimulus ranged from 1 to 10 microV. A late, slow, triphasic, anesthesia-labile component was identified as a dominant response feature in unanesthetized animals. Amplitudes increased and latencies decreased as stimulus intensity was increased (MANOVA P less than 0.05). Linear regression slope ranges were: amplitudes = 1.0-5.0 microV/g; latencies = -300 to -1100 microseconds/g. Thresholds for single polarity stimuli (0.035 +/- 0.022 g, n = 11) were significantly lower than those of alternating polarity (0.074 +/- 0.028 g, n = 18, P less than 0.001). Bilateral labyrinthectomy eliminated responses whereas bilateral extirpation of cochleae did not significantly change response thresholds. Intense acoustic masking (100/104 dB SL) produced no effect in 2 animals, but did produce small to moderate effects on response amplitudes in 7 others. Changes were attributed to effects on vestibular end organs. Results of unilateral labyrinth blockade (tetrodotoxin) suggest that P1 and N1 preferentially reflect ipsilateral eighth nerve compound action potentials whereas components beyond approximately 2 msec reflect activity from vestibular neurons that depend on both labyrinths. The results demonstrate that short latency vestibular compound action potentials can be measured in unanesthetized, non-invasively prepared animals.

NASA Discipline Neuroscience↗

Extracellular matrix as a solid-state regulator in angiogenesis: identification of new targets for anti-cancer therapy

Angiogenesis, the growth of blood capillaries, is regulated by soluble growth factors and insoluble extracellular matrix (ECM) molecules. Soluble angiogenic mitogens act over large distances to initiate capillary growth whereas changes in ECM govern whether individual cells will grow, differentiate, or involute in response to these stimuli in the local tissue microenvironment. Analysis of this local control mechanism has revealed that ECM molecules switch capillary endothelial cells between differentiation and growth by both binding specific transmembrane integrin receptors and physically resisting cell-generated mechanical loads that are applied to these receptors. Control of capillary endothelial cell form and function therefore may be exerted by altering the mechanical properties of the ECM as well as its chemical composition. Understanding of this mechanochemical control mechanism has led to the development of new angiogenesis inhibitors that may be useful for the treatment of cancer.

Review↗

Blockade of 5-hydroxytryptamine3 receptors prevents cisplatin-induced but not motion- or xylazine-induced emesis in the cat

5-Hydroxytryptamine3 antagonists have been reported to prevent emesis elicited by cisplatin and radiation. This study investigated the possibility that drugs with this mechanism of action may be useful in preventing emesis elicited by other stimuli. The drugs ICS 205-930 (0.1 and 1.0 mg/kg) and MDL 72222 (0.1 and 1.0 mg/kg) were administered SC to cats before challenging them with either provocative motion or an emetic dose of xylazine. In no instance was a significant reduction in emesis evident. Zacopride was also administered before motion testing (0.01 to 10.0 mg/kg) and found to not have efficacy. To test the possibility that species or route of administration were factors in the negative results, 1.0 mg/kg of ICS 205-930 was administered SC before IV infusion of 7.5 mg/kg of cisplatin. There was a total suppression of emesis for the duration of the six-hour observation periods. This result verifies other work which found 5-hydroxytryptamine3 antagonists to be effective in preventing emesis elicited by cancer chemotherapeutic treatments. However, there is no evidence that they are effective in other syndromes, such as motion sickness and xylazine-induced emesis.

NASA Discipline Number 16-10↗

Perceived self-orientation and self-motion in microgravity, after landing and during preflight adaptation training

The research described in this paper is intended to support development and evaluation of preflight adaptation training (PAT) apparatus and procedures. Successful training depends on appropriate manipulation of visual and inertial stimuli that control perception of self-motion and self-orientation. For one part of this process, astronauts are trained to report their self-motion and self-orientation experiences. Before their space mission, they are exposed to the altered sensory environments produced by the PAT trainers. During and after the mission, they report their motion and orientation experiences. Subsequently, they are again exposed to the PAT trainers and are asked to describe relationships between their experiences in microgravity and following entry and their experiences in the trainers.

Space Flight↗

Reactions of Air Transport Flight Crews to Displays of Weather During Simulated Flight

Display of information in the cockpit has long been a challenge for aircraft designers. Given the limited space in which to present information, designers have had to be extremely selective about the types and amount of flight related information to present to pilots. The general goal of cockpit display design and implementation is to ensure that displays present information that is timely, useful, and helpful. This suggests that displays should facilitate the management of perceived workload, and should allow maximal situation awareness. The formatting of current and projected weather displays represents a unique challenge. As technologies have been developed to increase the variety and capabilities of weather information available to flight crews, factors such as conflicting weather representations and increased decision importance have increased the likelihood for errors. However, if formatted optimally, it is possible that next generation weather displays could allow for clearer indications of weather trends such as developing or decaying weather patterns. Important issues to address include the integration of weather information sources, flight crew trust of displayed weather information, and the teamed reactivity of flight crews to displays of weather. Past studies of weather display reactivity and formatting have not adequately addressed these issues; in part because experimental stimuli have not approximated the complexity of modern weather displays, and in part because they have not used realistic experimental tasks or participants. The goal of the research reported here was to investigate the influence of onboard and NEXRAD agreement, range to the simulated potential weather event, and the pilot flying on flight crew deviation decisions, perceived workload, and perceived situation awareness. Fifteen pilot-copilot teams were required to fly a simulated route while reacting to weather events presented in two graphical formats on a separate visual display. Measures of flight crew reactions included performance-based measures such as deviation decision accuracy, and judgment-based measures such as perceived decision confidence, workload, situation awareness, and display trust. Results demonstrated that pilots adopted a conservative reaction strategy, often choosing to deviate from weather rather than ride through it. When onboard and NEXRAD displays did not agree, flight crews reacted in a complex manner, trusting the onboard system more but using the NEXRAD system to augment their situation awareness. Distance to weather reduced situation awareness and heightened workload levels. Overall, flight crews tended to adopt a participative leadership style marked by open communication. These results suggest that future weather displays should exploit the existing benefits of NEXRAD presentation for situation awareness while retaining the display structure and logic inherent in the onboard system.

Bliss, James P.↗

Formal Consistency Verification of Deliberative Agents with Respect to Communication Protocols

The aim of this paper is to show a method that is able to detect inconsistencies in the reasoning carried out by a deliberative agent. The agent is supposed to be provided with a hybrid Knowledge Base expressed in a language called CCR-2, based on production rules and hierarchies of frames, which permits the representation of non-monotonic reasoning, uncertain reasoning and arithmetic constraints in the rules. The method can give a specification of the scenarios in which the agent would deduce an inconsistency. We define a scenario to be a description of the initial agent s state (in the agent life cycle), a deductive tree of rule firings, and a partially ordered set of messages and/or stimuli that the agent must receive from other agents and/or the environment. Moreover, the method will make sure that the scenarios will be valid w.r.t. the communication protocols in which the agent is involved.

Ramirez, Jaime↗

Expansion of direction space around the cardinal axes revealed by smooth pursuit eye movements

It is well established that perceptual direction discrimination shows an oblique effect; thresholds are higher for motion along diagonal directions than for motion along cardinal directions. Here, we compare simultaneous direction judgments and pursuit responses for the same motion stimuli and find that both pursuit and perceptual thresholds show similar anisotropies. The pursuit oblique effect is robust under a wide range of experimental manipulations, being largely resistant to changes in trajectory (radial versus tangential motion), speed (10 versus 25 deg/s), directional uncertainty (blocked versus randomly interleaved), and cognitive state (tracking alone versus concurrent tracking and perceptual tasks). Our data show that the pursuit oblique effect is caused by an effective expansion of direction space surrounding the cardinal directions and the requisite compression of space for other directions. This expansion suggests that the directions around the cardinal directions are in some way overrepresented in the visual cortical pathways that drive both smooth pursuit and perception.

Visual Pathways/physiology↗

Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo

Ex vivo human immunodeficiency virus type 1 (HIV-1) infection of human lymphoid tissue recapitulates some aspects of in vivo HIV-1 infection, including a severe depletion of CD4(+) T cells and suppression of humoral immune responses to recall antigens or to polyclonal stimuli. These effects are induced by infection with X4 HIV-1 variants, whereas infection with R5 variants results in only mild depletion of CD4(+) T cells and no suppression of immune responses. To study the mechanisms of suppression of immune responses in this ex vivo system, we used aldrithiol-2 (AT-2)-inactivated virions that have functional envelope glycoproteins but are not infectious and do not deplete CD4(+) T cells in human lymphoid tissues ex vivo. Nevertheless, AT-2-inactivated X4 (but not R5) HIV-1 virions, even with only a brief exposure, inhibit antibody responses in human lymphoid tissue ex vivo, similarly to infectious virus. This phenomenon is mediated by soluble immunosuppressive factor(s) secreted by tissue exposed to virus.

2,2'-Dipyridyl/analogs & derivatives/pharmacology↗

Motion Cueing Algorithm Development: Human-Centered Linear and Nonlinear Approaches

While the performance of flight simulator motion system hardware has advanced substantially, the development of the motion cueing algorithm, the software that transforms simulated aircraft dynamics into realizable motion commands, has not kept pace. Prior research identified viable features from two algorithms: the nonlinear "adaptive algorithm", and the "optimal algorithm" that incorporates human vestibular models. A novel approach to motion cueing, the "nonlinear algorithm" is introduced that combines features from both approaches. This algorithm is formulated by optimal control, and incorporates a new integrated perception model that includes both visual and vestibular sensation and the interaction between the stimuli. Using a time-varying control law, the matrix Riccati equation is updated in real time by a neurocomputing approach. Preliminary pilot testing resulted in the optimal algorithm incorporating a new otolith model, producing improved motion cues. The nonlinear algorithm vertical mode produced a motion cue with a time-varying washout, sustaining small cues for longer durations and washing out large cues more quickly compared to the optimal algorithm. The inclusion of the integrated perception model improved the responses to longitudinal and lateral cues. False cues observed with the NASA adaptive algorithm were absent. The neurocomputing approach was crucial in that the number of presentations of an input vector could be reduced to meet the real time requirement without degrading the quality of the motion cues.

Houck, Jacob A.↗