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PubMed1979

Molecular clocks, molecular profiles, and optimum diets: three approaches to the problem of aging.

It has been hypothesized that the deamidation of glutaminyl and asparaginyl residues serves as a molecular clock for many biological processes including protein turnover, development, and aging. At present, this hypothesis has passed some experimental tests which are necessary but not sufficient for its acceptance. The current state of evidence about deamidation as a molecular clock is discussed. In addition, since the molecular biology of aging, especially in humans, is only partly understood, it is of value to develop quantitative, empirical measures of physiological human age and to use these measures to evaluate alternative human living conditions, especially easily adopted alternatives like variations in diet. This may allow some decrease in the suffering and loss from human aging until such time as molecular biology provides superior and more intellectually satisfying answers. An empirical system which consists of quantitative measurement of several hundred human chemical constituents followed by computerized pattern recognition is described. It is hoped that this system will eventually become an aid in the minimization of the rate of human aging through changes in diet and other factors.

Adult↗
PubMed2004

Performance in a test demanding prefrontal functions is favored by early luteal phase progesterone: an electroencephalographic study.

There are some psychological studies showing changes in intellectual efficiency before and during menstruation. Many women report that they experience a feeling of difficulty to initiate activities, confront challenging situations and lack of concentration suggesting transient changes in frontal lobe functions related with gonadal hormone levels. Therefore, performance of a task demanding prefrontal functions, the Wisconsin Card Sorting Test, with simultaneous recording of electroencephalographic (EEG) activity was assessed in 9 healthy women, in a repeated measure study, during ovulation (OVU), early luteal (EL), late luteal (LL) and menstrual (MEN) phases. Spectral power of base line and task EEG, and number of responses to reach successful and unsuccessful outcomes in the task were evaluated. Performance was impaired to a certain degree during the OVU phase and was associated with an attenuated alpha1 power and with an increase of the theta and beta2 power. Performance was better during EL phase, when progesterone level is at its highest, no significant changes were observed from BL to task. Performance was worse during LL phase when hormone levels are at its lowest and was associated with a decrease in beta1 and beta2 power together with a significant attenuation of alpha1 and alpha2 power. During MEN phase performance was also improved and was associated with a significant decrease of alpha1 and alpha2 power and no changes in beta power were observed. These findings show that performance of a task demanding internal attention and planning is modulated by physiological progesterone and estrogen levels during menstrual cycle and is associated with specific EEG profiles.

Adult↗
PubMed1994

Concurrent finger-tapping in mathematically gifted males: evidence for enhanced right hemisphere involvement during linguistic processing.

O'Boyle and Benbow (1990) have suggested that enhanced involvement of the right hemisphere (RH) during basic information processing is a neuropsychologic characteristic of the gifted brain. To provide converging evidence for this hypothesis, the present study was conducted using a concurrent finger-tapping paradigm. Specifically, 24 mathematically precocious and 16 average ability adolescent males were required to tap a key as quickly as possible while sitting silently (baseline condition), concurrently reading a paragraph aloud (verbal load), or encoding a random form into memory (spatial load). For average ability subjects, the concurrent verbal load reduced tapping rate for the right but not the left hand, reflecting a division of LH resources between linguistic processing of the paragraph and motor control of the contralateral hand. In contrast, for gifted subjects, both their left- and right-hand tapping rates were significantly reduced, suggesting that both hemispheres were engaged during verbal processing. The concurrent spatial task produced a small but reliable reduction in finger-tapping rate for both the left and right hand in each group. These findings provide additional support for the notion that enhanced reliance on RH functioning is a physiological correlate of mathematical precocity in gifted males.

Adolescent↗
PubMed1994

Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family.

We completed the cDNA cloning and sequencing of gp330, the major kidney glomerular antigen for rat Heymann nephritis. The deduced 4660-aa sequence, expected to constitute a mature protein of M(r) 516,715, consists of a probable N-terminal signal peptide sequence (25 aa), an extracellular region (4400 aa), a single transmembrane domain (22 aa), and a C-terminal cytoplasmic tail (213 aa). The extracellular region contains three types of cysteine-rich repeats characteristic of the low density lipoprotein receptor (LDLR) gene family--36 LDLR ligand-binding repeats forming four clusters of putative ligand-binding domains, 16 growth factor repeats separated by 8 YWTD spacer regions, and 1 C-terminal epidermal growth factor repeat. The cytoplasmic tail contains two copies of the (FX)NPXY motif, which represents a signal for coated pitmediated internalization and an additional similar motif. The overall structure of gp330 is similar to that of the LDLR-related protein (LRP)/alpha 2-macroglobulin receptor and shows even greater similarity to the Caenorhabditis elegans protein, reported as a homologue of LRP. However, gp330 differs from these proteins in (i) the cysteine-rich repeat arrangements found in the extreme extracellular N- and C-terminal regions, (ii) the distribution pattern of cysteine residues in the YWTD spacer regions, (iii) the location of the RX(K/R)R consensus recognition sequence of furin, a precursor processing endoprotease, and (iv) the length and structure of the cytoplasmic tail. We suggest the name megalin (from Greek mega) for gp330, the largest plasma membrane protein identified so far in vertebrates. The cloned cDNA will be useful for studies on the physiological functions of gp330/megalin and for determining its role in Heymann nephritis.

Amino Acid Sequence↗
PubMed1975

Vascular anastomoses in twin placentae and their recognition.

166 placentae from multiple pregnancies (including three triplets and 17 monochorral) have been studied by injection corrosion technique, using cellulose acetate buterite in acetone, under continuous pressure within physiological limits. It has been shown that vascular anastomoses in twin placentae are usually multiple. The direct type is frequently found in monochorial twin placentae and is mostly arterial or venous in nature. The indirect type is observed more commonly in dichorial twin placentae and is mostly arteriovenous in nature. Both types are almost universally found in monochorial monoamniotic placentae. The presence of direct anastomotic channels has a highly significant association with the incidence of marginal vessels and an exaggeration of parameters of stress to an abnormal quantum--both singly and in combinations of three or more-, and is independent of the pattern of branching. In the ontogenetic time-sequence perspective, direct anastomoses, marginal vessels and parameters of stress in a twin placenta can be regarded as different phases of the sequelae of an altered vascular relationship caused by disturbances in the vicinity of the 12th week of gestation. It has been further shown that direct vascular anastomoses are a greater risk to the twins than indirect ones. The importance of early and timely recognition of such channels, by an examination of twin placentae for the presence of marginal vessels, is stressed.

Arteriovenous Anastomosis↗
PubMed2000

Solution structure of a zinc substituted eukaryotic rubredoxin from the cryptomonad alga Guillardia theta.

The rubredoxin from the cryptomonad Guillardia theta is one of the first examples of a rubredoxin encoded in a eukaryotic organism. The structure of a soluble zinc-substituted 70-residue G. theta rubredoxin lacking the membrane anchor and the thylakoid targeting sequence was determined by multidimensional heteronuclear NMR, representing the first three-dimensional (3D) structure of a eukaryotic rubredoxin. For the structure calculation a strategy was applied in which information about hydrogen bonds was directly inferred from a long-range HNCO experiment, and the dynamics of the protein was deduced from heteronuclear nuclear Overhauser effect data and exchange rates of the amide protons. The structure is well defined, exhibiting average root-mean-square deviations of 0.21 A for the backbone heavy atoms and 0.67 A for all heavy atoms of residues 7-56, and an increased flexibility toward the termini. The structure of this core fold is almost identical to that of prokaryotic rubredoxins. There are, however, significant differences with respect to the charge distribution at the protein surface, suggesting that G. theta rubredoxin exerts a different physiological function compared to the structurally characterized prokaryotic rubredoxins. The amino-terminal residues containing the putative signal peptidase recognition/cleavage site show an increased flexibility compared to the core fold, but still adopt a defined 3D orientation, which is mainly stabilized by nonlocal interactions to residues of the carboxy-terminal region. This orientation might reflect the structural elements and charge pattern necessary for correct signal peptidase recognition of the G. theta rubredoxin precursor.

Amino Acid Sequence↗
PubMed1994

Proliferative and cytolytic responses of human gamma delta T cells display a distinct specificity pattern.

The function and physiological role of gamma delta T cells are still unknown. Concerning the specificity of these cells, a proliferative response towards microbial ligands has been noted, whereas in terms of effector functions in humans a cytolytic activity against a variety of tumour targets is most prominent. Here we show data demonstrating that the cytolytic activity of activated human gamma delta T cells does not reflect the specificity of these cells in primary in vitro stimulation; moreover, we provide evidence that the recognition of target cells by gamma delta T cells can have different qualities. gamma delta T cells proliferate vigorously in primary in vitro reaction upon stimulation with various B-cell tumour lines but not with the T-cell lines Jurkat or Molt-4. However, gamma delta T cells stimulated primarily with phytohaemagglutinin or with cells from B-cell lines gain unrestricted cytolytic activity against a broad set of tumour targets, including Jurkat and Molt-4; the same set of targets is capable of inducing release of serine esterases (SE) from gamma delta T-effector cells. Whereas the cytolytic activity in the 51Cr-assay against the B-cell lines and against Molt-4 depends on the presence of Ca2+ ions in the assay, the lysis of Jurkat cells is only slightly reduced upon removal of Ca2+ from the medium; the SE release, however, is Ca2+ dependent in all cases. Taken together, these data suggest several different ways of target cell recognition by gamma delta T cells leading to either proliferation or triggering of cytolytic activity, and argue against an involvement of the gamma delta T-cell receptor in the cytotoxic activity of gamma delta T cells.

Calcium↗
PubMed2004

Discrimination of word stress in early infant perception: electrophysiological evidence.

Language acquisition crucially depends on the ability of the child to segment the incoming speech stream. Behavioral evidence supports the hypothesis that infants are sensitive to the rhythmic properties of the language input. We recorded event-related potentials (ERPs) to varying stress patterns of two syllable items in adults as well as in 4- and 5-month-old infants using a mismatch negativity (MMN) paradigm. Adult controls displayed a typical MMN to the trochaic item (stress on the first syllable) as well as to the iambic (stress on the second syllable) item. At the age of 4 months, no reliable discrimination response was seen. However, at the age of 5 months, a significant mismatch response (MMR) was observed for the trochaic item, indicating that the trochee, i.e. the most common stress pattern in German, was separated consistently from the iambic item. Hence, the present data demonstrate a clear development between 4 and 5 months with respect to the processing of different stress patterns relevant for word recognition. Moreover, possible contributions of different filter settings to the morphology of the mismatch response in infants are discussed.

Acoustic Stimulation↗
PubMed2005

Dyslexics are impaired on implicit higher-order sequence learning, but not on implicit spatial context learning.

Developmental dyslexia is characterized by poor reading ability and impairments on a range of tasks including phonological processing and processing of sensory information. Some recent studies have found deficits in implicit sequence learning using the serial reaction time task, but others have not. Other skills, such as global visuo-spatial processing may even be enhanced in dyslexics, although deficits have also been noted. The present study compared dyslexic and non-dyslexic college students on two implicit learning tasks, an alternating serial response time task in which sequential dependencies exist across non-adjacent elements and a spatial context learning task in which the global configuration of a display cues the location of a search target. Previous evidence indicates that these implicit learning tasks are based on different underlying brain systems, fronto-striatal-cerebellar circuits for sequence learning and medial temporal lobe for spatial context learning. Results revealed a double dissociation: dyslexics showed impaired sequence learning, but superior spatial context learning. Consistent with this group difference, there was a significant positive correlation between reading ability (single real and non-word reading) and sequence learning, but a significant negative correlation between these measures and spatial context learning. Tests of explicit knowledge confirmed that learning was implicit for both groups on both tasks. These findings indicate that dyslexic college students are impaired on some kinds of implicit learning, but not on others. The specific nature of their learning deficit is consistent with reports of physiological and anatomical differences for individuals with dyslexia in frontal and cerebellar structures.

Adolescent↗
PubMed1999

A physiological correlate of the 'spotlight' of visual attention.

Here we identify a neural correlate of the ability to precisely direct visual attention to locations other than the center of gaze. Human subjects performed a task requiring shifts of visual attention (but not of gaze) from one location to the next within a dense array of targets and distracters while functional MRI was used to map corresponding displacements of neural activation within visual cortex. The cortical topography of the purely attention-driven activity precisely matched the topography of activity evoked by the cued targets when presented in isolation. Such retinotopic mapping of attention-related activation was found in primary visual cortex, as well as in dorsomedial and ventral occipital visual areas previously implicated in processing the attended target features. These results identify a physiological basis for the effects of spatially directed visual attention.

Adult↗
PubMed2006

Automatic contour propagation in cine cardiac magnetic resonance images.

We have developed a method for automatic contour propagation in cine cardiac magnetic resonance images. The method consists of a new active contour model that tries to maintain a constant contour environment by matching gray values in profiles perpendicular to the contour. Consequently, the contours should maintain a constant position with respect to neighboring anatomical structures, such that the resulting contours reflect the preferences of the user. This is particularly important in cine cardiac magnetic resonance images because local image features do not describe the desired contours near the papillary muscle. The accuracy of the propagation result is influenced by several parameters. Because the optimal setting of these parameters is application dependent, we describe how to use full factorial experiments to optimize the parameter setting. We have applied our method to cine cardiac magnetic resonance image sequences from the long axis two-chamber view, the long axis four-chamber view, and the short axis view. We performed our optimization procedure for each contour in each view. Next, we performed an extensive clinical validation of our method on 69 short axis data sets and 38 long axis data sets. In the optimal parameter setting, our propagation method proved to be fast, robust, and accurate. The resulting cardiac contours are positioned within the interobserver ranges of manual segmentation. Consequently, the resulting contours can be used to accurately determine physiological parameters such as stroke volume and ejection fraction.

Algorithms↗
PubMed1990

Dynamic electromyography. II. Normal patterns during gait.

Human gait is a complex phenomenon. Many descriptors are needed to completely describe gait in terms of the biomechanics involved. The descriptors, when expressed as a function of the gait cycle, are complex waveforms. For each of these variables, a single "normal" pattern with bands of deviation has generally been accepted as a reference in clinical/research use to explain the abnormalities in a patient's walking pattern. In fact, one observes many "normal" patterns, and a body of research has been devoted to explaining the differences between these patterns in terms of walking speed, age, cadence, sex, etc. It would be simpler in one sense to start with the fact that different people walk with different patterns, not one pattern with bands of deviation. Numerical representation of the waveforms simplifies the analysis and interpretation of waveform data and facilitates comparison between subjects or groups of subjects. When combined with pattern recognition techniques, it also is useful for identifying subpatterns within a group. In this article, the numerical representation of electromyographic data by Karhunen-Loeve expansion are combined with cluster analysis to obtain patterns of dynamic phasic activity of 10 muscles of the lower extremity. From the 35 normal subjects walking at self-selected speed, two to four patterns are developed for each of the muscles and the physiological significance of the patterns are discussed.

Electromyography↗
PubMed1998

Characterization of late abdominal accumulation of 99Tcm-HMPAO leukocytes in a large population of children.

We retrospectively evaluated the incidence of late accumulation of 99Tcm-HMPAO leukocytes (99Tcm-WBC) in the right lower quadrant of a large population of children and characterized some predictive patterns that would enable differentiation of active inflammation from this late occasional accumulation of 99Tcm-WBC. We reviewed the charts of 211 children. The first group evaluated consisted of 79 controls: 30 normal children with no gastrointestinal disease, but who underwent 99Tcm-WBC scanning for other medical problems, and 49 children who had non-specific gastrointestinal (GI) complaints, but had no demonstrable inflammatory bowel disease by conventional diagnostic methods. The second group consisted of 132 children with inflammatory bowel disease: 80 children with Crohn's disease (CD), 34 with ulcerative colitis (UC) and 18 with indeterminate colitis (IC). Children were imaged at 30 min and 3 h. Fifteen (19%) of the 79 controls scanned showed accumulation of 99Tcm-WBC in the right lower quadrant at 3 h and none at 30 min. Of those 15, 8 were from the control population and 7 from the group with non-specific GI complaints and negative work-ups. There was no uptake in other segments of the bowel. The accumulation was faint, of lesser intensity than in the iliac wing, and diffuse, such that identification of a specific loop of involved bowel was not possible. Migration of the 99Tcm-WBC distal to the terminal ileum was demonstrated. The other 64 children in the control group showed no accumulation of 99Tcm-WBC at any time during their scans. All 79 scans were blindly interpreted as normal studies. There were no false-positive readings encountered in the 132 children with inflammatory bowel disease (80 CD, 34 UC, 18 IC) when the aforementioned characteristics of the late accumulation of 99Tcm were used to differentiate inflammation from this physiological excretion. In conclusion, the late accumulation of 99Tcm-WBC in the right lower quadrant is characterized by (1) accumulation at no less that 3 h, (2) no accumulation in other segments of the bowel, (3) faint accumulation of lesser intensity than in the iliac wing, (4) a diffuse accumulation pattern and (5) migration of the 99Tcm-WBC into the caecum and ascending colon over time. Recognition of this excretion pattern enables differentiation of active Crohn's disease of the small bowel from migration and accumulation of 99Tcm-WBC in the right lower quadrant of the abdomen.

Abdomen↗
PubMed1989

Molecular physiology of olfaction.

Olfactory reception is mediated by olfactory receptor cells located in the olfactory epithelium. These cells are bipolar neurons that extend a dendrite toward the nasal lumen and an axon toward the olfactory bulb in the brain. The dendrite possesses a group of apical cilia embedded in mucus. Odorant recognition and signal transduction are initiated at the membranes of these chemosensory cilia and culminate in excitation of the olfactory receptor cell. Differential activation by odorants of distinct groups of olfactory receptor cells generates patterns of neuronal activity that encode odor quality and concentration. The identities of primary odorant recognition sites at the ciliary membrane remain to be established. However, a significant body of information has become available with respect to olfactory transduction mechanisms. It is now becoming clear that olfactory transduction involves the interplay of several second messenger systems to control the responses of these exquisitely sensitive chemosensory neurons.

Animals↗
PubMed1986

Excessive binding of natural anti-alpha-galactosyl immunoglobin G to sickle erythrocytes may contribute to extravascular cell destruction.

A large proportion of sickle erythrocytes is removed from the circulation by the macrophages of the reticuloendothelial system. In view of the proposed role for natural antibodies in the destruction of normal senescent erythrocytes, we looked for a possible similarity in the antibodies that bind in situ to senescent and sickle cells. Bound IgG molecules were detected by a highly sensitive rosetting antiglobulin test, using K562 myeloid cells. After separation on Stractan density gradients, the 0.6% most dense (senescent) normal cells and the most dense 40% sickle cells displayed membrane-bound IgG as reflected by the high proportion of rosettes formed. No antibody was found on low-density cells of either type. The bound antibodies were readily eluted from both sickle and normal senescent cells by carbohydrates containing alpha-galactosyl residues. These antibodies appear identical to the recently discovered human natural anti-alpha-galactosyl IgG (anti-Gal), an IgG antibody present in high titers in normal sera. Moreover, affinity-purified anti-Gal interacted specifically with sickle and normal cells depleted of the autologous antibodies. A similar pattern of binding to the various erythrocyte subpopulations was observed when the radiolabeled lectin with anti-alpha-galactosyl specificity, Bandeiraea simplicifolia, was used. In vitro phagocytosis of normal and sickle erythrocyte subpopulations correlated with the presence of anti-Gal on these cells. The in situ binding of anti-Gal to a large proportion of sickle erythrocytes may reflect an accelerated physiologic aging process by which immune recognition of prematurely exposed alpha-galactosyl-bearing antigenic sites contributes to shortened cell survival.

Anemia, Sickle Cell↗
PubMed2004

Emergence of orientation-selective inhibition in the primary visual cortex: a Bayes-Markov computational model.

The recent consensus is that virtually all aspects of response selectivity exhibited by the primary visual cortex are either created or sharpened by cortical inhibitory interneurons. Experimental studies have shown that there are cortical inhibitory cells that are driven by geniculate cells and that, like their cortical excitatory counterparts, are orientation selective, though less sharply tuned. The main goal of this article is to demonstrate how orientation-selective inhibition might be created by the circuitry of the primary visual cortex (striate cortex, V1) from its nonoriented geniculate inputs. To fulfill this goal, first, a Bayes-Markov computational model is developed for the V1 area dedicated to foveal vision. The developed model consists of three parts: (i) a two-layered hierarchical Markov random field that is assumed to generate the activity patterns of the geniculate and cortical inhibitory cells, (ii) a Bayesian computational goal that is formulated based on the maximum a posteriori (MAP) estimation principle, and (iii) an iterative, deterministic, parallel algorithm that leads the cortical circuitry to achieve its assigned computational goal. The developed model is not fully LGN driven and it is not implementable by the neural machinery of V1. The model, then, is transformed into a fully LGN-driven and physiologically plausible form. Computer simulation is used to demonstrate the performance of the developed models.

Action Potentials↗
PubMed1989

Event-related potentials before and after training: chronometry and lateralization of visual N1 and N2.

Event-related potentials (ERPs) were recorded from normal right-handed males in visual-matching tasks before and after training to a high level of automaticity. The amplitude and latency of the left and right hemispheric N1 and N2 components were analyzed. While changes of N1 "after training" relative to "before training" were statistically non-significant, the N2 component appeared to be a sensitive indicator of the variability in chronometry and lateralization of cerebral processes modified by training. The N2 results suggest that with practice the physiological processes underlying performance in a visual-cognitive task become more efficient, selective and localized.

Adult↗
PubMed1994

Automatic data reduction and pattern recognition methods for analysis of 1H nuclear magnetic resonance spectra of human urine from normal and pathological states.

Multivariate data analysis techniques have been used to compare 600-MHz 1H nuclear magnetic resonance (NMR) spectra of urine obtained from patients with inborn errors of metabolism (IEM) and urine obtained from healthy subjects. These spectra are very complex; each contains many thousands of resonances with a high dynamic range. A consistent method of reducing this wealth of data to manageable proportions is presented as a two-stage process. Computer-based spectral descriptors are automatically generated and then reduced to two-dimensional maps for visualization of clustering. Data-scaling methodology has been developed to achieve complete separation between spectra from control adults and those from adult patients with independently diagnosed IEM. The methods were refined by relating IEM samples to the mean of the control samples and applying supervised learning techniques to identify descriptors contributing to class separation. This approach allowed separation of the various classes of IEM and achieved optimal separation of patients with cystinuria from those with oxalic aciduria; the principal metabolites responsible for this separation were determined as lysine and glyoxalate. The methods developed were then extended by application to the more subtle problem of classifying urine collected from healthy subjects under different physiological conditions (i.e., pre- and post-exercise and in different stages of hydration) where, unlike the IEM case, any underlying biochemical differences were not known at the outset. Fluid-loaded and fluid-deprived samples could be partially separated as well as fluid-deprived and fluid-restored samples. Partial classification of samples on the basis of subject was also observed. Therefore, intersubject differences were liable to obscure the separation by physiological state. However, by relating each sample to a mean of the normal daily urine samples for the same person and applying a form of "range scaling" to exclude data which contributed least to class separation, improved classification of the hydration states resulted, from which it was possible to deduce those biochemical substances which were altered. These novel techniques for the data reduction and classification of NMR spectra make comprehensive use of all of the NMR spectral information and have clear potential to assist in clinical diagnosis.

Adult↗