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A mathematical framework for describing and analysing gene regulatory networks.

This paper presents a mathematical framework for describing and analysing gene regulatory networks by autonomous differential equations. It represents an improvement on existing frameworks in that it may handle a wider range of gene regulatory mechanisms. Gene regulatory networks are frequently threshold-dominated, i.e. genes are activated only when the concentration of certain gene products lie between definite thresholds. Here, the concept of regulatory domain is introduced to describe these regions in the phase space. To each regulatory domain is associated an indicator function whose value is 1 inside and 0 outside the domain. The indicator functions thus reflect the logical structure of the network. The sharp borders between the regulatory domains may be smoothed by replacing the logical step functions by continuous sigmoids or so-called logoid functions. A logoid function coincides with the step function outside a narrow interval around the threshold, and rises continuously from 0 to 1 inside it. Using logoids, the task of finding steady states is considerably simplified. A list of regions in phase space comprising all steady states lying close to a threshold is obtained by examining a certain type of matrix called the Logoid-Jacobian. In addition, this matrix leads to the conditions necessary for stability of the steady states. External signals may be conveniently incorporated in the form of Boolean variables. Thus the framework is well suited for studying gene regulatory networks both in single cells and multicellular systems.

Animals↗

Motion processing using asymmetric shunting lateral inhibitory networks.

Asymmetrically connected inhibitory shunting networks are believed to occur in many areas of the brain, including the visual system; they can explain many peripheral visual phenomena. This paper illustrates their usefulness in motion detection, and compares details of their performance with experimental results. Two stimuli are considered: drifting gratings and jumping bars. An elementary motion detector (EMD) is defined, consisting of a pair of opposite-directed asymmetric inhibitory networks. A frequency-space expansion (equivalent to a Volterra-Wiener expansion) is used to examine the EMD's response to a drifting grating. The EMD can be tuned to independent spatial and temporal frequencies: by summing the outputs of a number of EMDs, a velocity-tuned network is obtained. This velocity-tuned network is very well suited to certain field effect transistor (FET) implementations. Since the network is nonlinear, the response to a drifting grating does not fully characterize its behaviour. The response to a jumping bar stimulus is also examined. Two animals are considered: *Cats: the work of Emerson et al on the response of directionally selective (DS) complex cells in cat visual cortex to a white noise signal. *Flies: the work of Franceschini et al on the response of the fly H1 cell to stimulation of two neighbouring receptor cells, and that of Horridge and Marcelja on the fly H1 response to various jumping bar and edge stimuli. Agreement with all three of these experiments cannot be expected, because the results for the two animals are not consistent. There are two main differences: *Time development of the velocity-tuned signal: for the fly H1 cell this generally consists of two sharp (ON and OFF) responses to the second presentation of the bar signal, while for the cat DS cell a more slowly varying signal is observed. *Response to two presentations of the bar signal in the same position (i.e., a 'jumping bar' that jumps zero distance): for the fly H1 cell there is generally no response, while the cat DS cell responds significantly. The velocity-tuned network agrees well with the results for the cat DS cells.

Journal Article↗

Cervical disk injuries in athletes.

Cervical disk injuries are defined as a cervical injury associated with neurological deficits, radicular symptoms, or radiological evidence of disk degeneration, but not with a fracture or a dislocation of the cervical spine. Thirty cases covering the period from July 1982 to June 1984 were analyzed, and the following findings are presented. Fifty percent of the injuries were sustained in American football. Sixty percent of radicular signs and symptoms were from the fourth and fifth cervical root. The roentgenographic changes were most common at the fourth and fifth intervertebral disk spaces. Most of the cases responded satisfactorily to a simple cervical collar and cervical traction. The athletes who presented radicular signs and symptoms required 5 months to return to full sports activities, and 60% of these had some residual symptoms after completion of treatment. The athletes who had a block vertebra of the cervical spine were not suited for contact sports. Recognition of the seriousness of cervical disk injuries in athletes is emphasized.

Adult↗

Derivation of extracellular fluid volume fraction and equivalent dielectric constant of the cell membrane from dielectric properties of the human body. Part 1: Incorporation of fat tissue into cell suspension model in the arm.

The non-invasive characterisation of cell pathophysiology is clinically important. A cell suspension model is applied to derive the extracellular fluid (ECF) volume fraction and the equivalent dielectric constant of the cell membrane epsilon m from the dielectric properties of human arms. Frequency-dependent dielectric constants and electrical conductivities of arms are obtained from 35 surgical patients over a frequency range of 5-1000 kHz. The cell suspension model is applied to fit the data using a complex non-linear least-squares method. The arms show typical dielectric dispersions, although the cell suspension model yields a poor fitting in dielectric constants at lower frequencies and electrical conductivities at higher frequencies. In contrast, a new cell suspension model, taking into account the fat tissue component, remarkably improves the overall fitting performance, allowing estimation of the volume fractions of ECF (0.34 +/- 0.05) and fat tissue (0.16 +/- 0.04) and the equivalent epsilon m (23 +/- 9). The resulting estimates of the volume fraction of fat tissue are in good correlation with arm skinfold thickness (fat volume fraction of arm = 2.42 x 10(-3) x arm skinfold thickness (mm) + 0.099, R = 0.756, p < 0.0001). Therefore it is concluded that the newly derived cell suspension model is well suited for the description of the dielectric properties of human tissues and thus the derivation of the ECF volume fraction and equivalent epsilon m.

Adipose Tissue↗

Estimation of left ventricular volume and mass by magnetic resonance imaging: comparison with quantitative biplane angiocardiography.

Magnetic resonance imaging (MRI) is well suited for the delineation of cardiac anatomy. In this study an estimation of left ventricular volume and muscle mass by MRI was attempted, using an iron-shielded resistance magnet (Bruker) with 0.23 T. Images were obtained with ECG gating. For image-processing our own software program was used. Slice images were 8 mm thick and spaced 16 mm. Volumes were standardized for a "normal" LV. Muscle mass was calculated directly from the systolic image as the difference between inner and outer ventricular outline. There was a wide range of volumes and mass (100-300 ml, 200-500 g). For comparison and validation conventional biplane left ventriculography was used. Fourteen patients were studied with MRI, but satisfactory studies were obtained in only 7. Correlation of MRI and angiographic volumes was good (r = 0.84). For left ventricular mass it was excellent (r = 0.94). Ventricular walls and cavities were clearly outlined. Even minor details of anatomy were recognized. Limitations of MR study included a narrow space for the patient within the system and the long duration of data acquisition time.

Adult↗

An objective determination of +Gz acceleration tolerance.

Until recently, human +Gz acceleration tolerance has relied solely on subjective criteria relating to loss of vision. By use of newly developed noninvasive instrumentation using a transcutaneous Doppler flow system, objective end point criteria have been developed based on measured blood flow to the head. The system consists of miniature 8 MHz Doppler sensors (2 x 1 x 0.5 cm) placed on the forehead over both frontal branches of the temporal arteries to detect blood flow velocity from back scattered ultrasound. Its use has allowed for correlation of altered, decreased and actual reversal of eye level blood flow with subsequent central light loss. Over 100 subjects have now been studied during more than 2,000 centrifuge runs. Objective changes in temporal artery flow velocity consistently preceded visual degradation for each subject during all acceleration profiles. No subject has gone unconscious without first exhibiting a minimum 6 sec of total flow cessation. Retrograde flow followed by complete flow cessation always preceded central light loss. Results indicate that this method can be successfully used with a wide variety of tasks during exposure to +Gz acceleration. It is recommended for use during evaluation of protective maneuvers or devices on the centrifuge or during actual flight in high performance aircraft. It may also serve as a potential safety monitor during space Shuttle re-entry if there is doubt about a passenger's cardiovascular status.

Acceleration↗

Shock in the operating room.

Many factors may contribute to producing a shock state within the surgical environment. The classic causes of shock--hypovolemia, cardiac failure, and sepsis--occur commonly in the operating room. Additionally, concurrent surgery and anesthesia may contribute to produce clinical shock. Surgery may produce hypovolemia from "third space" loss and/or from blood loss. Some anesthetic drugs, by inhibiting the autonomic nervous system, impair the body's ability to compensate for hypovolemia, cardiac failure, or sepsis. Other entities such as tension pneumothorax, drug allergy, or mechanical factors produced by surgical exposure may contribute to hemodynamic compromise of the patient. Shock that occurs outside the surgical suite may also be produced by a variety of insults. One or more factors may contribute to inadequate tissue perfusion, thus making diagnosis of the cause(s) of shock a clinical challenge. Presented in this review is an anesthesiologist's approach to shock on a macrocirculatory level. Two important concepts are vital to this approach. First, one must act immediately to restore adequate perfusion to the brain and heart when confronted with a patient in shock. This is possible without knowing the specific cause(s) of the poor perfusion. Second, a rapid, accurate diagnosis of the cause(s) must be made if the patient is slow to respond to the initial therapy. Through the use of pulmonary artery catheterization, the factors producing any given shock state may be identified, and appropriate therapy may be instituted and monitored.

Anesthesia, General↗

Neurovascular free flaps from the foot for innervation of the hand.

Microneurovascular flaps from the first web space of the foot offer a solution to upgrade sensibility of the denervated hand. Based on the dorsalis pedis artery, it allows simple dissection and a large vessel for easy and safe anastomosis. Seven cases are presented in which combinations of the first web anatomy for a variety of denervation injuries were used. The technique is ideally suited in those cases where no areas of island flap tissue are available for transfer.

Adolescent↗

NIPALSTREE: a new hierarchical clustering approach for large compound libraries and its application to virtual screening.

A hierarchical clustering algorithm--NIPALSTREE--was developed that is able to analyze large data sets in high-dimensional space. The result can be displayed as a dendrogram. At each tree level the algorithm projects a data set via principle component analysis onto one dimension. The data set is sorted according to this one dimension and split at the median position. To avoid distortion of clusters at the median position, the algorithm identifies a potentially more suited split point left or right of the median. The procedure is recursively applied on the resulting subsets until the maximal distance between cluster members exceeds a user-defined threshold. The approach was validated in a retrospective screening study for angiotensin converting enzyme (ACE) inhibitors. The resulting clusters were assessed for their purity and enrichment in actives belonging to this ligand class. Enrichment was observed in individual branches of the dendrogram. In further retrospective virtual screening studies employing the MDL Drug Data Report (MDDR), COBRA, and the SPECS catalog, NIPALSTREE was compared with the hierarchical k-means clustering approach. Results show that both algorithms can be used in the context of virtual screening. Intersecting the result lists obtained with both algorithms improved enrichment factors while losing only few chemotypes.

Algorithms↗

A reusable perfusion supporting tissue-mimicking material for ultrasound hyperthermia phantoms.

A new ultrasonically and thermodynamically tissue-mimicking material is reported. The material is well suited for use in phantoms for testing ultrasound hyperthermia systems or related predictive models. Controlled convective heat transfer effects, mimicking to some extent perfusive heat transfer in tissues, can be instituted in the material with appropriate fluid sources and sinks. The material consists of closely packed agar spheres varying in diameters from 0.3-3.6 mm. The interstitial space between spheres is filled with 10% n-propanol solution. The material has two practical advantages over the solid-gel-type tissue-mimicking materials. The first advantage is that it allows rapid return of a hyperthermia phantom to thermal equilibrium following a heating test by rapid circulation of the perfusion fluid. The second advantage is that the material is in a "liquid" form. It can be easily siphoned in and out of phantom containers of any geometric shape for different purposes without change in its physical properties. Methods for measuring ultrasonic and thermodynamic properties of the material and the results of the measurements are reported. The physical parameters measured are the intensity attenuation and absorption coefficients, the ultrasonic speed, the thermal conductivity, specific-heat capacity and the mass density. Temperature measurements in a hyperthermia phantom made of the material are also reported.

1-Propanol↗

Distribution and immunophenotype of mononuclear phagocytes and dendritic cells in the human lung.

Mononuclear phagocytes and dendritic cells (DC) play an important role in the immune response in the lung. DC act in the afferent phase of the immune response by presenting antigen to T cells, while macrophages play a role in the efferent phase by exerting phagocytic/cytotoxic functions. We investigated the localization and the marker pattern of these cells in the human lung. Macrophages, identified as large, rounded, acid phosphatase-positive cells, were mainly detected in the alveolar spaces, in the lumen of the bronch(iol)us, and in the bronchoalveolar lavage (BAL). They were positive for major histocompatibility complex (MHC) class II antigens (DR, DQ), CD68, RFD7, RFD9, and partly positive for RFD1. Irregularly shaped cells with a marker pattern comparable to that of blood-derived DC (positive for DR, DQ, L25, RFD1, and CD68) were predominantly observed in the epithelium and subepithelial tissue of the bronch(iol)us and in the bronchus-associated lymphoid tissue. In the epithelium, approximately 30% of these cells were positive for CD1a (OKT6). In the subepithelial tissue, these DC formed characteristic small clusters with T cells. The BAL, the alveolar spaces, and the alveolar walls contained only a small number of DC. These immunohistologic data suggest that the bronch(iol)us is well equipped to initiate immune responses. The high number of macrophages in the alveolar compartment, which have been described to suppress T cell proliferation, together with low numbers of DC, makes the alveolar compartment less suited for mounting an immune response.

Biomarkers↗

[Mechanisms of early changes in water-electrolyte metabolism in man in various ground-based models of the effects of microgravity].

Analysed was an array of data amassed in 4 series of experiments with simulated microgravity effects (HDT (-6 degrees); dry and suited immersions in horizontal and vertical position). Water-electrolyte turnover in blood and urine and hormonal controls have been under study. It was demonstrated that irrespective of the body axis position relative to the gravity vector in the immersion models, reactions of the active regulation of the water--electrolyte metabolism were noted already within the initial hours, i.e. more rapidly than in HDT. During the early phase of adaptation to the immersion models, some ostensibly similar responses were governed by different hormonal controls. Unlike the dry immersion, the suited immersion tests with various body positioning modified not only the strength but the dynamics of the water-electrolyte regulation, too. Findings also included differences in the dynamics osmo- and volumoregulation in the vertical and horizontal suited immersion tests which are, possibly, reflective of recruitment of different stimulating mechanisms and efficiency of organs-targets.

Adaptation, Physiological↗

[Effect of a combination of head-down posture and LBNP on human tracking performance and spatial orientation].

Test subjects exposed to a head-down tilt at--30 degrees for an hour participated in the experiment. The use of LBNP during tilting improved precision of arrow orientation on the round-shaped screen (during continuous tracking) but did not influence orientation relative to the gravitational axis and the long axis of the body. The selective effect of LBNP on the orientation can be attributed to the increased importance of inner coordinates due to the pressure of interior walls of the LBNP suit on the foot surface, and blood pooling in the dependent part of the body.

Animals↗

The cortical network for eye-hand coordination and its relevance to understanding motor disorders of parietal patients.

Cortical neurons in both superior (SPL) and inferior (IPL) parietal lobules are modulated by a variety of signals concerning planning and execution of eye and hand movement. Thanks to these properties, parietal neurons are ideally suited for eye-hand coordination during reaching. In SPL, a fundamental feature of neurons is the invariance of their directional tuning properties across tasks that require different forms of spatial relationships between the eye and the hand. In such conditions, the orientation of the preferred directions (PDs) of individual SPL cells cluster within a limited sector of space, the global tuning field (GTF), to be regarded as an ideal frame to dynamically match eye and hand signals on the basis of the orientation of their PDs. At the population level, the mean vectors of the GTF cover the direction continuum in a uniform fashion. These neurons are part of a parietal network richly interconnected with the premotor and motor areas of the frontal lobe. Thus, the reaching disorders of patients with optic ataxia might be interpreted as a consequence of the breakdown of the combinatorial mechanisms of the GTF of parietal neurons, and of their interplay with premotor cortex. In IPL, the main feature of eye and/or hand related neurons is the uneven distribution of their PDs, that mostly point toward the contralateral space. This anisotropy of the representation of directional motor space might explain the movement disorders that characterize directional hypokinesia in neglect patients. In conclusion, the study of the dynamic properties of parietal neurons and of their relationships with the premotor cortex via cortico-cortical connections provides a basis for an interpretation of movement disorders of parietal patients from a neurophysiological perspective.

Animals↗

Release of a mitogenic factor by adult rat lung slices in culture.

In an effort to develop a suitable bioassay for testing lung growth factors that might be operative during compensatory lung growth following partial pneumonectomy, a simple and inexpensive lung organ culture system was characterized. The culture employs lung tissue slices obtained by means of a device allowing thicknesses of 500 microns to be cut reproducibly. To avoid the collapse of the organ, the alveolar spaces were filled prior to culture with Noble agar-containing Eagle's-Dulbecco's modified medium. Lung tissue sections could be maintained ultrastructurally intact for at least one week. The results showed that upon culture, a part of the type II pneumocytes undergo differentiation into type I pneumocytes, thus demonstrating that the culture system may be suited for differentiation studies. One surprising feature of this culture system was the mitogenic impulse associated with culture. Radioactively labeled thymidine incorporation was strongly stimulated in the culture, mainly affecting the epithelial cells, as could be established by "back-to-back" autoradiography. With a reconstruction experiment, it was possible to demonstrate the local release of a mitogenic factor following slicing, mincing, or dissection of the lung tissue, which could be assayed by its ability to induce serum-starved Balb/c 3T3 cells to synthesize DNA in culture.

3T3 Cells↗

Mammoscopy and endoscopic implant and breast tissue evaluation.

Mammoscopy seems to be a very promising technique that allows evaluation of implant integrity and documentation of the condition of breast implants in situ. It is a useful tool in the evaluation of intercapsular conditions in the augmented and reconstructed breast. Because of the limitations of capsular space, however, there is a greater possibility of implant disruption when multiple manipulations are attempted through separate ports of entry. It is best to use the endoscope for visualization and documentation and to minimize the amount of manipulation that has to be done through other ports for fear of rupturing the implant. Endoscopy is a limited procedure best suited for documentation and evaluation rather than endoscopic surgical procedures, particularly when capsulotomy and capsulectomy can be done more readily under direct vision through a slightly larger incision.

Breast↗

Eye use in search is determined by the nature of task in the domestic chick (Gallus gallus).

In Experiments 1-3 chicks were trained to find, using both eyes, food covered by a cap, using wide-angle search so as to involve lateral and frontal visual fields, with either local or positional cues, or both, identifying the baited site. At test they used right, left or both eyes (RE, LE, Bin). When both types of cue were relevant, LE made greater use of positional cues than the other two groups, as has been previously found, whereas RE made greater use of local (colour) cues. However, when only one type of cue was relevant, RE and LE were equally able to use positional or local cues. Right/left differences emerge when RE and LE can be used in different ways during training. In Experiments 4-5 Bin chicks were shown to turn preferentially to the right during wide-angle search, when relying on local, and to the left when relying on positional cues. In search, parallel processing of RE and LE inputs appears to allow competition which is usually won by the eye system more suited to the task, which then initiates targeting to objects which are visible to its eye.

Analysis of Variance↗

Image processing for improved eye-tracking accuracy.

Video cameras provide a simple, noninvasive method for monitoring a subject's eye movements. An important concept is that of the resolution of the system, which is the smallest eye movement that can be reliably detected. While hardware systems are available that estimate direction of gaze in real-time from a video image of the pupil, such systems must limit image processing to attain real-time performance and are limited to a resolution of about 10 arc minutes. Two ways to improve resolution are discussed. The first is to improve the image processing algorithms that are used to derive an estimate. Off-line analysis of the data can improve resolution by at least one order of magnitude for images of the pupil. A second avenue by which to improve resolution is to increase the optical gain of the imaging setup (i.e., the amount of image motion produced by a given eye rotation). Ophthalmoscopic imaging of retinal blood vessels provides increased optical gain and improved immunity to small head movements but requires a highly sensitive camera. The large number of images involved in a typical experiment imposes great demands on the storage, handling, and processing of data. A major bottleneck had been the real-time digitization and storage of large amounts of video imagery, but recent developments in video compression hardware have made this problem tractable at a reasonable cost. Images of both the retina and the pupil can be analyzed successfully using a basic toolbox of image-processing routines (filtering, correlation, thresholding, etc.), which are, for the most part, well suited to implementation on vectorizing supercomputers.

Algorithms↗