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Novel small RNA-encoding genes in the intergenic regions of Escherichia coli.

BACKGROUND: Small, untranslated RNA molecules were identified initially in bacteria, but examples can be found in all kingdoms of life. These RNAs carry out diverse functions, and many of them are regulators of gene expression. Genes encoding small, untranslated RNAs are difficult to detect experimentally or to predict by traditional sequence analysis approaches. Thus, in spite of the rising recognition that such RNAs may play key roles in bacterial physiology, many of the small RNAs known to date were discovered fortuitously. RESULTS: To search the Escherichia coli genome sequence for genes encoding small RNAs, we developed a computational strategy employing transcription signals and genomic features of the known small RNA-encoding genes. The search, for which we used rather restrictive criteria, has led to the prediction of 24 putative sRNA-encoding genes, of which 23 were tested experimentally. Here we report on the discovery of 14 genes encoding novel small RNAs in E. coli and their expression patterns under a variety of physiological conditions. Most of the newly discovered RNAs are abundant. Interestingly, the expression level of a significant number of these RNAs increases upon entry into stationary phase. CONCLUSIONS: Based on our results, we conclude that small RNAs are much more widespread than previously imagined and that these versatile molecules may play important roles in the fine-tuning of cell responses to changing environments.

Blotting, Northern↗

Incorporating pathologists' criteria of malignancy into the evolutionary model for cancer development.

A wide variety of alterations in cell and tissue structure still form the basis for cancer diagnosis by pathologists. Cancer development is recognized to be an evolutionary process [Foulds, 1954; Cairns, 1975; Nowell, 1976; Sager, 1982; Tomlinson et al., 1996; Cahill et al., 1999; Tomlinson and Bodmer, 1999], but the phenotypic changes diagnostic of cancer (pathologists' "criteria of malignancy") have not been integrated into the existing evolutionary framework. Since phenotypic changes bear an important relationship to the genetic and physiologic changes underlying Darwinian evolution, we propose that diagnostic structural alterations also bear an important and predictable relation to both the cancer genes and the functional alterations active at any particular step in the development of a cancer. Cancer genes are predicted to mediate the acquisition of cellular-level diagnostic criteria and the diagnostic cellular-level structural changes should reflect in a useful manner the altered cell physiology required for the cell to achieve increased "cellular fitness" at any particular step of colonal evolution. Tissue-level criteria of malignancy should relate less directly to specific cancer genes, but tissue-level criteria should still provide essential insight into the interplay of the altered cellular fitness with the constraints imposed by the cells' microenvironment. The evolutionary framework allows tissue-level criteria of malignancy to be expressed in terms of viable hypotheses for the mechanism of clonal expansion at any particular step in cancer development. This approach to conveying the tissue-level criteria of malignancy complements pattern recognition approaches to diagnosis, and establishes common ground between pathology and cell biology. When viewed from this perspective, the functions of cancer genes appear quite different from those predicted by the "Gatekeeper, Caretaker" or "Hallmarks of Cancer" models. Finally, a full evolutionary framework incorporating the criteria of malignancy restores congruity between the histogenetic classification and the emerging molecular classification of cancer.

Cell Transformation, Neoplastic↗

Hemispheric asymmetry in visual discrimination and memory: ERP evidence for the spatial frequency hypothesis.

Event related potentials (ERPs) were recorded during delayed discrimination of simple spatial frequency gratings in the high and low frequency bands. Analyses of the waveforms N170, P220, N310, P400, and slow wave (SW) indicated significant and regionally specific interaction of spatial frequency and hemisphere for N170 amplitude. This interaction was independent of memory conditions, and appeared to be in the opposite direction of what is predicted by the spatial frequency model of hemispheric asymmetry. Additional interactions between spatial frequency and hemisphere were observed for N310 in the encoding process (reference stimulus) and for SW in the retrieval process (test stimulus). The general hypothesis of an interaction of spatial frequency and hemisphere in visual cognition is supported, but the findings indicate caution in interpreting an increase in physiological measures as an indication of more efficient brain processing. Moreover, several stages of information processing may contribute to the asymmetry observed in behavioral studies, and hemispheric balance may change dynamically during the time course of processing.

Adult↗

Applying biofluid 1H NMR-based metabonomic techniques to distinguish between HIV-1 positive/AIDS patients on antiretroviral treatment and HIV-1 negative individuals.

Metabonomics, the study of metabolites and their role in various physiological states, is a novel methodology arising from the post-genomics era and has extensive biomedical application. This technology has exhibited vast success in the identification and study of human diseases and may find further application in the study of HIV/AIDS. Specifically, the wide range of clinical and metabolic abnormalities associated with the use of antiretroviral (ARV) treatment may be investigated. To this end, this preliminary study evaluated whether metabonomic techniques could distinguish between HIV-1 positive/AIDS patients utilizing antiretroviral therapy and HIV-1 negative individuals. Serum metabolic profiles determined by 1H nuclear magnetic resonance (NMR) spectroscopy combined with pattern recognition analysis of the data showed that this distinction was attainable; suggesting that ARV-associated side-effects could be monitored utilizing NMR metabonomic techniques.

Acquired Immunodeficiency Syndrome↗

Flagellin-independent regulation of chemokine host defense in Campylobacter jejuni-infected intestinal epithelium.

Campylobacter jejuni is a leading cause of bacterial food-borne diarrheal disease throughout the world and the most frequent antecedent of autoimmune neuropathy Guillain-Barré syndrome. While infection is associated with immune memory, little is known regarding the role of the epithelium in targeting dendritic cells (DC) for initiating the appropriate adaptive immune response to C. jejuni. The objective of this study was to define the role for the intestinal epithelium in the induction of the adaptive immune response in C. jejuni infection by assessing the production of DC and T-cell chemoattractants. Human T84 epithelial cells were used as model intestinal epithelia. Infection of T84 cells with C. jejuni dose- and time-dependently up-regulated DC and T-cell chemokine gene transcription and secretion. Induction required live bacteria and was in the physiologically relevant direction for attraction of mucosal immunocytes. C. jejuni-activated NF-kappaB signaling was shown to be essential for proinflammatory chemokine secretion. Notably, C. jejuni secretion occurred independently of flagellin identification by Toll-like receptor 5. Secretion of a DC chemoattractant by differing clinical C. jejuni isolates suggested adherence/invasion were key virulence determinants of epithelial chemokine secretion. The regulated epithelial expression of DC and T-cell chemoattractants suggests a mechanism for the directed trafficking of immune cells required for the initiation of adaptive immunity in campylobacteriosis. Chemokine secretion occurs despite Campylobacter evasion of the flagellin pattern recognition receptor, suggesting that alternate host defense strategies limit disease pathogenesis.

Campylobacter jejuni↗

Finite state model of locomotion for functional electrical stimulation systems.

A finite state model of locomotion was developed to simplify a controller design for motor activities of handicapped humans. This paper presents a model developed for real time control of locomotion with functional electrical stimulation (FES) assistive systems. Hierarchical control of locomotion was adopted with three levels: voluntary, coordination and actuator level. This paper deals only with coordination level of control. In our previous studies we demonstrated that a skill-based expert system can be used for coordination level of control in multi-joint FES systems. Basic elements in this skill-based expert system are production rules. Production rules have the form of If-Then conditional expressions. A technique of automatic determination of these conditional expressions is presented in this paper. This technique for automatic synthesis of production rules uses fuzzy logic and artificial neural networks (ANN). The special class of fuzzy logic elements used in this research is called preferential neurons. The preferential neurons were used to estimate the relevance of each of the sensory inputs to the recognition of patterns defined as finite states. The combination of preferential neurons forms a preferential neural network. The preferential neural network belongs to a class of ANNs. The preferential neural network determined the set of finite states convenient for a skill-based expert system for different modalities of locomotion.

Ankle Joint↗

Amblyopic quasi-blindness for image structure.

Human amblyopes display reduced contrast sensitivities, suffer from perceptual distortion, and their letter acuities are worse than is predicted from grating visibility. We sought the origin of these dysfunctions by measuring normal and amblyopic sensitivities to various forms of well-defined image distortion, namely band-limited phase quantization, phase quantization with additional amplitude modulation, and grey-scale modification. Our results prove the existence of an amblyopic quasi-blindness to image structure, that cannot be explained in terms of contrast detection. We discuss these findings within the computational scheme of image decomposition into local amplitude and local phase values. they are consistent with the assumption of amblyopic eyes beings impaired in processing local phase but having the local amplitude (or "energy", possibly at reduced gain) at their disposal. Phrased in physiological terms, we propose a scheme of complex-cells-only vision in amblyopia. We also provide a demonstration of how amblyopic eyes may see the test stimuli and natural images by generating local amplitude and phase representations at limited phase resolution.

Amblyopia↗

Error-related psychophysiology and negative affect.

The error-related negativity (ERN/Ne) and error positivity (Pe) have been associated with error detection and response monitoring. More recently, heart rate (HR) and skin conductance (SC) have also been shown to be sensitive to the internal detection of errors. An enhanced ERN has consistently been observed in anxious subjects and there is some suggestion that the ERN is related to general negative affective experience (NA). The ERN has been source localized to the anterior cingulate cortex-a structure implicated in the regulation of affective, response selection, and autonomic resources. Thus, the findings that autonomic measures and affective distress are related to response monitoring are consistent with anterior cingulate cortex function. In the present experiment, we sought to evaluate more comprehensively the relationship between self-reported negative affect and error-related physiology in a between-groups design. Results indicate that high NA was associated with significantly greater ERN and error-related SCR, and smaller Pe. These results are discussed in terms of anterior cingulate cortex function, psychopathology, and response monitoring.

Adult↗

The effect of disrupting the human magnocellular pathway on global motion perception.

The purpose of this study was to demonstrate the effect of human magnocellular (M)-pathway disruption on global motion perception. Coherence thresholds for global motion direction discrimination in random dot patterns were determined at slow and moderate dot speeds: (1) after adaptation to full-field sinusoidal flicker or a steady gray field, and (2) on a red or a gray background. Adaptation to flicker and a red background increased motion coherence thresholds relative to the gray baseline conditions at both dot speeds. Physiological studies have shown that M cells in the retina and LGN are inhibited by red light and are a main contributor to flicker perception in monkeys. Therefore, our results suggest that interference with processing in the subcortical M pathway disrupts higher-level motion integration.

Adolescent↗

Visual evoked responses in diabetes.

It is commonly believed that diabetic optic neuropathy is very rare and visual loss in diabetes usually is attributed to other causes. We studied the extent of optic nerve involvement in 16 diabetics with no retinopathy or ocular disease and having an almost visual acuity, using visual evoked responses produced by pattern reversal stimulation. Comparing the responses with a group of 35 healthy subjects, the latency was increased by more than one standard deviation in 13 diabetics (81%) and by more than three standard deviations in 10 diabetics (62.5%), often associated with marked reduction in amplitude. There was good correlation between conduction in the optic nerve and peripheral sensory nerve. No correlation was noted to occur with duration of diabetes or diabetic control except perhaps with juvenile onset diabetes. Normal visual acuity was noted in many cases with severely slowed conduction showing early subclinical affection of optic nerves in diabetes. The extent of central nervous system involvement in diabetes has only recently been realised because of lack of physiological techniques and study of optic nerves in diabetes has not been attempted so far. The high incidence of abnormality of visual evoked potentials in diabetes could invalidate the usefulness of this test in diagnosing multiple sclerosis.

Adolescent↗

Noninvasive physiologic monitoring of high-risk surgical patients.

OBJECTIVES: To study the feasibility of multicomponent noninvasive monitoring, consisting of a new bioimpedance method for estimating cardiac output together with routine pulse oximetry and transcutaneous oximetry, and to compare physiologic data obtained noninvasively with hemodynamic and oxygen transport data obtained by standard invasive pulmonary artery thermodilution catheter to evaluate circulatory function in high-risk surgical patients. DESIGN: Prospective descriptive analysis of the time course of physiologic patterns in surgical patients. SETTING: University-run county hospital. PATIENTS: Seventy-one consecutively monitored, high-risk critically ill surgical patients in their perioperative period. OUTCOME MEASURES: Simultaneous measurements by invasive and noninvasive methods to describe and compare the temporal physiologic patterns of survivors and nonsurvivors. RESULTS: The new impedance cardiac output estimations closely approximated those of the thermodilution method (r = 0.82, P < .001). Episodes of hypotension, tachycardia, low cardiac index, arterial hemoglobin desaturation, low transcutaneous oximetry, reduced oxygen delivery, and low oxygen consumption occurred with both groups but were more pronounced in the nonsurvivors than in the survivors. Noninvasive monitoring provided information similar to that of the thermodilution method. Both approaches indicated low flow and poor tissue perfusion (oxygenation) that was worse in the nonsurvivors. CONCLUSIONS: The multicomponent noninvasive monitoring provides continuous online, real-time displays of physiologic data that allow immediate recognition of circulatory dysfunction as well as the means to titrate therapy to appropriate predetermined therapeutic goals. The noninvasive systems are easy to apply, safe, inexpensive, reasonably accurate, and cost-effective.

Adult↗

Episodic memory for emotional and non-emotional words in individuals with anhedonia.

Anhedonia is a symptom that plays a significant role in theories of illness such as depression and schizophrenia. Some previous research suggests that participants who report high levels of social/physical anhedonia also show deficits in both self-report and physiological measures of emotional processing, particularly for measures of emotional valence as compared with emotional arousal. Little is known about memory for emotionally valenced information or how this might be related to emotional processing in anhedonia. Participants were 391 undergraduate students participating for course credit. We administered an incidental encoding task that required participants to rate emotional words on both valence and arousal dimensions. We then administered surprise recall and recognition tasks to all participants. Results indicated that higher levels of physical and social anhedonia were associated with attenuated valence ratings of emotional words but did not influence arousal ratings or the memory pattern for emotionally valenced information. These findings suggest that there is some reduction in emotional experience in individuals with anhedonia, but that this reduction does not appear to produce a deficit in memory performance, perhaps due to the intact experience of arousal.

Adolescent↗

The role of the rat in research on control of ingestion: a commentary and review of recent advances in understanding brain control of food intake.

The majority of data concerning the control of food intake in mammals is derived from studies of laboratory rats. Some ingestive controls, identified in rats, seem to operate identically in most farm species. Other controls, which have been identified in nonrodent species, appear to be absent in the rat. Thinking about the neural control of ingestion in agricultural species is based almost entirely on inferences drawn from experiments performed with rats. Recent studies of brain substrates of ingestive control have revealed a prominent role for the caudal hindbrain. Recognition of the caudal hindbrain's participation in the control of ingestion emphasizes the longitudinal integration of brain control of ingestion. Consequently, we must refrain from assuming that the basal forebrain is the unique site for brain control of ingestion. Progress in the investigation of the neural controls of food intake will continue to depend heavily on studies in the rat. Such studies can speed the development of understanding of ingestive controls in farm species by prescribing critical comparative studies. Lack of circumspection prior to initiation and interpretation of such comparative studies can lead, however, to costly misreading of the pattern of ingestive physiology in farm species.

Animals↗

Characterization of the mouse genes for mitochondrial transcription factors B1 and B2.

We have recently fully reconstituted the basal human mitochondrial transcription machinery in a pure in vitro system. Surprisingly, we found two different transcription factors (TFB1M and TFB2M) that each interact with mitochondrial RNA polymerase in human mitochondria, whereas there is only one such factor in budding yeast mitochondria. This unexpected finding raised important questions concerning the regulation of mitochondrial transcription in mammals in general and in other metazoans. We have now further analyzed putative homologs to TFB1M and TFB2M in different species. We mapped the mouse homologs, Tfb1m and Tfb2m, by linkage analysis to mouse Chr 17 and Chr 1, respectively. These regions display conserved linkage synteny with human Chr 6 and Chr 1, where TFB1M and TFB2M map. The intron-exon arrangements of Tfb1m and TFB1M and of Tfb2m and TFB2M were identical, and the promoter regions had similar predicted recognition elements for transcriptional factors NRF2 and Sp1. Northern blot analyses showed that Tfb1m and Tfb2m were ubiquitously expressed and had expression patterns that were very similar to the previously reported expression patterns for TFB1M and TFB2M. These findings show that Tfb1m and Tfb2m indeed are orthologs to TFB1M and TFB2M. Bioinformatic analyses indicated that most metazoans have two TFBM genes, since putative homologs to both TFB1M and TFB2M were found in D. melanogaster. Our data thus suggest that a duplication event of the TFBM gene in early metazoan evolution has permitted a more flexible regulation of mtDNA transcription, possibly in response to the complex physiological demands of multicellular organisms.

Animals↗

Mannan-binding lectin: clinical significance and applications.

Mannan-binding lectin (MBL) is a collectin (protein with both collagen-like and C-type lectin domains) synthesised in the liver and secreted into the bloodstream. Its plasma concentration is for the most part genetically determined by a series of allelic dimorphisms located both in the structural gene and in the promoter region. Genotypes made up of combinations of seven haplotypes are mainly responsible for a 1000-fold concentration variation found in human beings. MBL is a pattern recognition molecule able to bind repeating sugar arrays on many microbial surfaces, and can activate complement via associated serine proteases. A poorly defined proportion (roughly 10%) of the population with the lowest MBL concentrations is thought to be MBL insufficient and more vulnerable to a variety of infectious and noninfectious disorders. The evidence that MBL makes an important contribution to innate immunity, by increasing susceptibility to disease and/or affecting the course of disease, is discussed in detail. Preliminary results from MBL replacement therapy are encouraging, and extension of this approach to large-scale randomised clinical trials would provide solid evidence concerning the physiological significance of this protein.

Alleles↗

The relationships among risk recognition, autonomic and self-reported arousal, and posttraumatic stress symptomatology in acknowledged and unacknowledged victims of sexual assault.

OBJECTIVE: This study examined differences among acknowledged sexual assault victims, unacknowledged sexual assault victims, and nonvictims in risk recognition and its psychophysiological correlates. METHODS: Acknowledged and unacknowledged victims of sexual assault and nonvictims (n = 97) listened to a hypothetical date rape interaction and were asked to indicate the point at which the man had become sexually inappropriate. Self-report and physiological measures of emotional responding and a measure of risk recognition were used to evaluate both between- and within-subjects' differences. RESULTS: Relative to nonvictims and acknowledged victims, unacknowledged victims of sexual assault took significantly longer to recognize risk. Acknowledged victims displayed decreased heart rate activity to a portion of the hypothetical interaction, but self-reported greater arousal in response to the interaction and greater posttraumatic stress arousal symptomatology relative to nonvictims only. Posttraumatic stress symptomatology was related to self-reported emotional reactivity and response latency. CONCLUSIONS: The findings suggest that acknowledged and unacknowledged victims exhibit specific autonomic and behavioral response patterns that may perpetuate the cycle of traumatization.

Adolescent↗

Pattern identification and classification in gene expression data using an autoassociative neural network model.

The application of DNA microarray technology for analysis of gene expression creates enormous opportunities to accelerate the pace in understanding living systems and identification of target genes and pathways for drug development and therapeutic intervention. Parallel monitoring of the expression profiles of thousands of genes seems particularly promising for a deeper understanding of cancer biology and the identification of molecular signatures supporting the histological classification schemes of neoplastic specimens. However, the increasing volume of data generated by microarray experiments poses the challenge of developing equally efficient methods and analysis procedures to extract, interpret, and upgrade the information content of these databases. Herein, a computational procedure for pattern identification, feature extraction, and classification of gene expression data through the analysis of an autoassociative neural network model is described. The identified patterns and features contain critical information about gene-phenotype relationships observed during changes in cell physiology. They represent a rational and dimensionally reduced base for understanding the basic biology of the onset of diseases, defining targets of therapeutic intervention, and developing diagnostic tools for the identification and classification of pathological states. The proposed method has been tested on two different microarray datasets-Golub's analysis of acute human leukemia [Golub et al. (1999) Science 286:531-537], and the human colon adenocarcinoma study presented by Alon et al. [1999; Proc Natl Acad Sci USA 97:10101-10106]. The analysis of the neural network internal structure allows the identification of specific phenotype markers and the extraction of peculiar associations among genes and physiological states. At the same time, the neural network outputs provide assignment to multiple classes, such as different pathological conditions or tissue samples, for previously unseen instances.

Adenocarcinoma↗

Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study.

To determine the neural circuitry engaged by performance of the Wisconsin Card Sorting Test (WCST), a neuropsychological test traditionally considered to be sensitive to prefrontal lesions, regional cerebral blood flow was measured with oxygen-15 water and positron emission tomography (PET) while young normal subjects performed the test as well as while they performed a specially designed sensorimotor control task. To consider which of the various cognitive operations and other experiential phenomena involved in the WCST PET scan are critical for the pattern of physiological activation and to focus on the working memory component of the test, repeat WCST scans were also performed on nine of the subjects after instruction on the test and practice to criteria. We confirmed that performance of the WCST engages the frontal cortex and also produces activation of a complex network of regions consistently including the inferior parietal lobule but also involving the visual association and inferior temporal cortices as well as portions of the cerebellum. The WCST activation in the dorsolateral prefrontal cortex (DLPFC) remained significant even after training and practice on the test, suggesting that working memory may be largely responsible for the physiological response in DLPFC during the WCST and, conversely, that the DLPFC plays a major role in modulating working memory.

Adolescent↗