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PubMed2026

Development of a PCR-based technique for genotyping UGT1A1 gene and distribution of rs3064744 alleles in the Russian population.

BACKGROUND: Accurate determination of tandem thymine-adenine (TA) repeat numbers in the UGT1A1 promoter region (rs3064744) is essential for diagnosing Gilbert's syndrome and personalizing therapy with toxic agents like irinotecan and atazanavir. However, traditional polymerase chain reaction (PCR) assays face severe limitations due to the AT-rich sequence and overlapping melting temperatures (Tm) of the highly homologous 7TA and 8TA alleles. In this context, melting curve analysis (MCA) employing fluorophore-quencher systems has emerged as a promising alternative. The purpose of this study was to develop a novel genotyping approach combining optimized aPCR-MCA analysis with an automated classifier to overcome the limitations posed by the differentiation of highly homologous alleles and to demonstrate its practical application, providing the distribution of rs3064744 genotypes across four regional cohorts of the Russian population. METHODS: A specialized Dual Head 1D-convolutional neural network (1D-CNN) ensemble with Test-Time Augmentation (TTA) was developed. The model was trained and internally validated on 1,620 engineered plasmid samples, and independently evaluated on an external clinical test set of 440 unique patient genomic DNA specimens. Real-time PCR was performed on CFX96 and DTprime platforms. Additionally, population-wide screening was conducted on 997 archival clinical samples from Moscow, Sakha (Yakutia), Dagestan, and Rostov regions. RESULTS: While 5TA and 6TA alleles were easily separated, absolute Tm distributions of 7TA and 8TA alleles overlapped significantly, and non-uniform Tm shifts of 0.8 °C-1.4 °C occurred across platforms. Conventional absolute Tm thresholding was therefore inadequate. By assessing relative morphological curve divergence against co-amplified 7TA/7TA and 7TA/8TA reference anchors, the 1D-CNN ensemble neutralized instrument noise. It achieved 100% accuracy on internal validation and 100% concordance (440/440) with clinical reference pyrosequencing. Population screening revealed that Dagestan, Yakutia, and Rostov cohorts closely align with the European population. Rare 5TA and 8TA alleles were detected at low frequencies in Yakutia and Moscow. CONCLUSION: Combining LNA-modified aPCR-MCA with a comparative 1D-CNN model successfully circumvents thermodynamic limitations and eliminates human operator bias. This integrated system offers an accessible, high-throughput, and clinically valid solution for routine UGT1A1 pharmacogenetic testing.

1D-CNN↗
PubMed1998

Efficient discrimination of temporal patterns by motion-sensitive neurons in primate visual cortex.

Although motion-sensitive neurons in macaque middle temporal (MT) area are conventionally characterized using stimuli whose velocity remains constant for 1-3 s, many ecologically relevant stimuli change on a shorter time scale (30-300 ms). We compared neuronal responses to conventional (constant-velocity) and time-varying stimuli in alert primates. The responses to both stimulus ensembles were well described as rate-modulated Poisson processes but with very high precision (approximately 3 ms) modulation functions underlying the time-varying responses. Information-theoretic analysis revealed that the responses encoded only approximately 1 bit/s about constant-velocity stimuli but up to 29 bits/s about the time-varying stimuli. Analysis of local field potentials revealed that part of the residual response variability arose from "noise" sources extrinsic to the neuron. Our results demonstrate that extrastriate neurons in alert primates can encode the fine temporal structure of visual stimuli.

Action Potentials↗
PubMed2005

Neuronal correlates of movement dynamics in the dorsal and ventral premotor area in the monkey.

We investigated how neurons in the different motor areas of the frontal lobe reflect the movement dynamics, and how their neuronal activity undergoes plastic changes when monkeys adapt to perturbing forces (they learn new dynamics). Here we describe the results obtained in the dorsal premotor area (PMd) and ventral premotor area (PMv). Monkeys performed visually instructed, delayed reaching movements before, during and after exposure and adaptation to a viscous, curl force field. During movement planning (i.e., during an instructed delay that followed the cue and preceded the go signal), we found dynamics-related activity in PMd but not in PMv. A closer analysis revealed that the population of PMd reflected the dynamics of the upcoming movement increasingly over the course of the delay, starting from a kinematics-related signal. During movement execution, dynamics-related activity was present in both PMd and PMv. In this respect, the results for PMd were similar to that previously found for the supplementary motor area (SMA) whereas the results for PMv were more similar to that previously found for the primary motor cortex (M1). Plastic changes associated with the acquisition of new dynamics found in PMd and PMv were qualitatively similar to those previously observed in M1 and SMA. The ensemble of our experiments suggest a broader picture of the cortical control of movements, whereby multiple areas all contribute to the various sensorimotor processes, including "low" computations such as the movement dynamics, but also express a degree of specialization.

Action Potentials↗
PubMed2001

EEG frequency and phase coupling during human information processing.

Neuronal activity during information processing is represented by oscillations within local or widespread neuronal networks. These oscillations may be recorded by the EEG (electroencephalogram). The oscillatory interaction between neuronal ensembles may be at one single frequency or at different frequencies due to non-linear coupling. The investigation of momentary coherence and phase enables the examination of synchronized oscillatory network activity during fast-changing cognitive processes. On this basis information transfer from occipital areas towards frontal areas could be described during processing of visual presented words. Non-linear phase coupling between oscillations with different frequencies during memory processing was detected by means of cross-bicoherence.

Adult↗
PubMed2026

HXMS: a standardized file format for HX-MS data.

MOTIVATION: Hydrogen/deuterium exchange-mass spectrometry (HX-MS) is a rapidly expanding technique used to investigate protein conformational ensembles. The growing popularity and utility of HX-MS has driven the development of diverse instrumentation and software, resulting in inconsistent, non-standardized data analysis and representation. Most HX-MS data formats also employ only mean deuteration representations of the data rather than full isotopic mass spectra, which reduces the information content of the data and limits downstream quantitative analysis. RESULTS: Inspired by reliable protein structure and genomics data formats, we present HXMS, a unified, lightweight, scalable, and human-readable file format for HX-MS data. The HXMS format preserves the isotopic mass envelopes for all peptides, captures the full experimental time-course including fully deuterated control samples, and contains all other key information. It supports multimodal distributions, post-translational modifications (PTMs), and experimental replicates. To promote compatibility with existing HX-MS workflows, we also developed PFLink, a Python package that converts exported data files from commonly used HX-MS software to the HXMS format. PFLink and the HXMS format will enable quantitative, higher-resolution data processing, improved data sharing and storage among HX-MS practitioners, future machine learning applications, and further developments in HX-MS analysis. AVAILABILITY AND IMPLEMENTATION: PFLink is publicly available to install locally on HuggingFace, alongside documentation, or use online at HuggingFace (https://huggingface.co/spaces/glasgow-lab/PFlink). The supplementary information includes sample input files, sample HXMS files, and a generic unfilled PFlink custom CSV file that users may populate with key experimental conditions and results, which can then be read and converted into the HXMS format.

Software↗
PubMed2006

Word concreteness and encoding effects on context-dependent discrimination.

In three experiments, we investigated the effects of word concreteness and encoding instructions on context-dependent discrimination in verbal contexts, using Murnane, Phelps, and Malmberg's (1999) ICE (item, context, ensemble) theory as the framework Word concreteness was manipulated within participants, and encoding was manipulated between participants. It was hypothesized that the magnitude of context-dependent discrimination would be affected by both concreteness and encoding instructions. Imagery instructions resulted in context-dependent discrimination for both concrete and abstract word pairs across all the experiments. Context-dependent discrimination was observed under rote instructions for concrete and abstract words, particularly when the same context word was paired multiple times with the targets. The results indicated that context-dependent discrimination is not dependent solely on the use of interactive imagery instructions or on word concreteness.

Attention↗
PubMed2006

Higher-dimensional neurons explain the tuning and dynamics of working memory cells.

Measurements of neural activity in working memory during a somatosensory discrimination task show that the content of working memory is not only stimulus dependent but also strongly time varying. We present a biologically plausible neural model that reproduces the wide variety of characteristic responses observed in those experiments. Central to our model is a heterogeneous ensemble of two-dimensional neurons that are hypothesized to simultaneously encode two distinct stimuli dimensions. We demonstrate that the spiking activity of each neuron in the population can be understood as the result of a two-dimensional state space trajectory projected onto the tuning curve of the neuron. The wide variety of observed responses is thus a natural consequence of a population of neurons with a diverse set of preferred stimulus vectors and response functions in this two-dimensional space. In addition, we propose a taxonomy of network topologies that will generate the two-dimensional trajectory necessary to exploit this population. We conclude by proposing some experimental indicators to help distinguish among these possibilities.

Action Potentials↗
PubMed2004

Layer-specific somatosensory cortical activation during active tactile discrimination.

Ensemble neuronal activity was recorded in each layer of the whisker area of the primary somatosensory cortex (SI) while rats performed a whisker-dependent tactile discrimination task. Comparison of this activity with SI activity evoked by similar passive whisker stimulation revealed fundamental differences in tactile signal processing during active and passive stimulation. Moreover, significant layer-specific functional differences in SI activity were observed during active discrimination. These differences could not be explained solely by variations in ascending thalamocortical input to SI. Instead, these results suggest that top-down influences during active discrimination may alter the overall functional nature of SI as well as layer-specific mechanisms of tactile processing.

Afferent Pathways↗
PubMed2005

Genomics and variation of ionotropic glutamate receptors: implications for neuroplasticity.

We used two approaches to identify sequence variants in ionotropic glutamate receptor (IGR) genes: high-throughput screening and resequencing techniques, and "information mining" of public (e.g. dbSNP, ENSEMBL) and private (i.e. Celera Discovery System) sequence databases. Each of the 16 known IGRs is represented in these databases, their positions on a canonical physical map are established. Comparisons of mouse, rat, and human sequences revealed substantial conservation among these genes, which are located on different chromosomes but found within syntenic groups of genes. The IGRs are members of a phylogenetically ancient gene family, sharing similarities with glutamate-like receptors in plants. Parsimony analysis of amino acid sequences groups the IGRs into three distinct clades based on ligand-binding specificity and structural features, such as the channel pore and membrane spanning domains. A collection of 38 variants with amino acid changes was obtained by combining screening, resequencing, and informatics approaches for several of the IGR genes. This represents only a fraction of the sequence variation across these genes, but in fact these may constitute a large fraction of the common polymorphisms at these genes and these polymorphisms are a starting point for understanding the role of these variants in function. Genetically influenced human neurobehavioral phenotypes are likely to be linked to IGR genetic variants. Because ionotropic glutamate receptor activation leads to calcium entry, which is fundamental in brain development and in forms of synaptic plasticity essential for learning and memory and is essential for neuronal survival, it is likely that sequence variants in IGR genes may have profound functional roles in neuronal activation and survival mechanisms.

Amino Acid Substitution↗
PubMed2002

Concordant and discordant coding of spatial location in populations of hippocampal CA1 pyramidal cells.

Pyramidal cells in the rat hippocampus commonly show place-related activity, but it has been difficult to understand the factors that govern them. A particularly important question is whether individual cells have identifiable correlates that can be manipulated independently of the correlates of other cells. Recently Tanila et al. examined the activity of small ensembles of hippocampal cells in rats running on a plus-maze with distinct intra- and extramaze cues. When the two sets of cues were rotated 90 degrees in opposite directions, some cells followed the intramaze cues, others followed the extramaze cues, and others "remapped" unpredictably; moreover, all possible combinations were seen within simultaneously recorded ensembles. In the current study, CA1 pyramidal cell population activity was recorded from four rats in a similar paradigm, using a recording system that permitted the analysis of ensembles of 4-70 simultaneously recorded units. The results were consistent with the data from the earlier study in showing an increase in remapping over time and in showing some place fields following one of the defined sets of cues while others remapped. When the possibility of random remapping was controlled for, however, the analysis did not show significant numbers of place fields following both sets of cues simultaneously. Furthermore, all rats initially showed fully concordant responses with all place fields following the local cues. For two rats, this pattern continued until a new configuration was introduced at which time all fields switched to follow the distal cues. Taken together, the results are difficult to reconcile with the hypothesis that individual hippocampal cells encode information about different subsets of cues in the environment.

Animals↗
PubMed2004

Coding and transmission of information by neural ensembles.

The brain processes information about sensory stimuli and motor intentions using a massive ensemble of neurons arrayed in parallel. Individual neurons receive convergent inputs from thousands of other neurons, leading to the possibility that patterns of spikes across the input neurons might be crucial components of the neural code. Recently, advances in multielectrode recording techniques have allowed several laboratories to investigate the nature of the interactions between neurons, and their potential role in information coding. Several recent studies have found that the amount of information coded by correlated activity about sensory and motor variables is small, casting doubt on the hypothesis that correlations between pairs of neurons are important for information coding. However, other studies have documented the appearance of coherent oscillations, during particular task epochs and conditions that require selective processing of sensory information, supporting the hypothesis that coherent oscillations between neurons might reflect the dynamic flow of information in the brain.

Animals↗
PubMed2001

Slow cortical potentials during retention of object, spatial, and verbal information.

We used event related potentials (ERPs) to examine both the specificity and the timing of slow cortical scalp potentials (SPs) elicited by the retention of object, spatial, and verbal information in working memory (WM). Participants performed a modified delayed matching task in which a task cue presented in the middle of the delay interval indicated what type of information had to be retained for a subsequent comparison with the test stimulus. The first experiment used nameable objects and spatial locations as stimuli. The retrieval mode (visual vs. verbal) was manipulated by presenting either figural information or printed words as test stimuli. Transient ensembles of frontal and parieto-occipital slow waves with different scalp topographies for object and spatial information were evoked as a function of task cues. When words rather than objects were used as test stimuli highly similar, though more pronounced, fronto-parietal slow wave patterns were obtained. The second experiment using unfamiliar objects and non-nameable spatial locations indicated that neither the left frontal negative SP nor the posterior SPs are exclusively related to verbal working memory operations. The results indicate that a parietal negative SP reflects processes of spatial selective attention whereas a parieto-occipital positive SP indexes the retention of visual object information. Left frontal negative SPs are generated by a compound of higher order frontal control processes and vary as a function of information type.

Adult↗
PubMed2006

fMRI models of dendritic and astrocytic networks.

In order to elucidate the relationships between hierarchical structures within the neocortical neuropil and the information carried by an ensemble of neurons encompassing a single voxel, it is essential to predict through volume conductor modeling LFPs representing average extracellular potentials, which are expressed in terms of interstitial potentials of individual cells in networks of gap-junctionally connected astrocytes and synaptically connected neurons. These relationships have been provided and can then be used to investigate how the underlying neuronal population activity can be inferred from the measurement of the BOLD signal through electrovascular coupling mechanisms across the blood-brain barrier. The importance of both synaptic and extrasynaptic transmission as the basis of electrophysiological indices triggering vascular responses between dendritic and astrocytic networks, and sequential configurations of firing patterns in composite neural networks is emphasized. The purpose of this review is to show how fMRI data may be used to draw conclusions about the information transmitted by individual neurons in populations generating the BOLD signal.

Animals↗
PubMed1993

The bilateral field advantage on a letter-matching task.

A series of studies have reported that responding is faster when letter pairs to be matched are projected to two hemispheres rather than one. Four experiments described here tested this bilateral field advantage and identified factors that influence its extent. Subjects were shown letter pairs drawn from the ensemble "AaBb", and classified the letter pairs as "Match" if the letters had the same name (regardless of case) and "No Match" if they did not. In the first two experiments the letter pairs were presented unilaterally (both letters in one visual field), bilaterally (one letter in each visual field), or centrally (both letters on the vertical midline, above and below fixation), in order to investigate how the bilateral field advantage is influenced by screen location. The third experiment added a bilateral-diagonal position (to check for artefacts related to horizontal scanning strategies), and the fourth experiment added distractor digits (to equate initial processing demands in the bilateral and unilateral conditions). Results indicate that the bilateral field advantage is a robust phenomenon, although several manipulations reduced its magnitude. Implications of these findings for models of hemispheric collaboration and interhemispheric processing are discussed.

Adolescent↗
PubMed1983

An unexpected interactive pattern of visual field asymmetries revealed by faster/slower response partitioning.

Subjects were presented with unilaterally-exposed schematic, outline faces in one condition, and three-letter single-syllable first names in another. In either case there was an ensemble of four items which were to be partitioned, by the subjects making a manual choice-reaction-time response, into two subsets. No easy rule permitted the partitioning either of the faces or of the names (DEN, LES versus LEN, DES). While no clear pattern of asymmetries emerged from an overall analysis, or from a simple comparison of the two types of response, when the subjects' individual responses were instead partitioned into faster and slower, a striking pattern of interactive asymmetries emerged which was consistent for both sexes and both tasks. Thus the slower of the two responses was associated with a left field superiority, and the faster with a right. These findings were discussed in the context of perceived or covert task demands, which are not always immediately recognizable from a superficial or conventional analysis of response data, and the effect of positive (target) and negative (nontarget) processing upon behavioral asymmetries.

Discrimination Learning↗
PubMed1997

Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles.

Hippocampal cells that fire together during behaviour exhibit enhanced activity correlations during subsequent sleep, with some preservation of temporal order information. Thus, information reflecting experiences during behaviour is re-expressed in hippocampal circuits during subsequent 'offline' periods, as postulated by some theories of memory consolidation. If the hippocampus orchestrates the reinstatement of experience-specific activity patterns in the neocortex, as also postulated by such theories, then correlation patterns both within the neocortex and between hippocampus and neocortex should also re-emerge during sleep. Ensemble recordings were made in the posterior parietal neocortex, in CA1, and simultaneously in both areas, in seven rats. Each session involved an initial sleep episode (S1), behaviour on a simple maze (M), and subsequent sleep (S2). The ensemble activity-correlation structure within and between areas during S2 resembled that of M more closely than did the correlation pattern of S1. Temporal order (i.e. the asymmetry of the cross-correlogram) was also preserved within, but not between, structures. Thus, traces of recent experience are re-expressed in both hippocampal and neocortical circuits during sleep, and the representations in the two areas tend to correspond to the same experience. The poorer preservation of temporal firing biases between neurons in the different regions may reflect the less direct synaptic coupling between regions than within them. Alternatively, it could result from a shift, between behavioural states, in the relative dominance relations in the corticohippocampal dialogue. Between-structure order will be disrupted, for example, if, during behaviour, neocortical patterns tend to drive corresponding hippocampal patterns, whereas during sleep the reverse occurs. This possibility remains to be investigated.

Animals↗
PubMed1997

Failure of centrally placed objects to control the firing fields of hippocampal place cells.

Previous work has shown that the angular position of hippocampal place cell firing fields is accurately controlled by the position of a single white cue card attached to the wall of a recording cylinder: when the card is rotated, fields rotate equally. In this study, we asked whether similar control could be exerted by three-dimensional objects placed directly in the recording arena. In each of several conditions, the locations of the objects relative to each other and their distances from the cylinder wall were fixed. In Experiment 1, the objects were all near the center of the cylinder. In this condition, the angular position of firing fields could, in general, not be predicted from the angular position of the object set. When a white wall card was added to the object arrangement, the stimulus ensemble exerted nearly ideal control over angular firing position. Nevertheless, when the card was withdrawn, the objects still did not control field position. In Experiment 2, place cells were recorded in the presence of two new arrangements of the same objects used in Experiment 1. In the "clustered objects" condition, the objects were placed next to each other, 10 cm from the wall. In the "objects-at-periphery" condition, the objects were put against the cylinder wall by equally increasing the distances among the objects. In both conditions, we found virtually ideal control by the objects over angular field position. These results indicate that the failure of stimulus control in Experiment 1 must be attributable to the arrangement of the objects and not to the nature of the objects themselves. Overall, the results are in line with behavioral studies that show that it is very difficult to teach rats to locate food relative to landmarks inside the behavioral arena.

Animals↗
PubMed1999

A working memory "theory of relativity": elasticity in temporal, spatial, and modality dimensions conserves item capacity in radial maze, verbal tasks, and other cognition.

It is remarkable that working memory (WM) capacity for numbers of items remains modest, at approximately 7+/-2 (the so-called "magical number"), across a wide variety of kinds of material. Indeed, consideration of radial maze studies together with more traditional memory research shows that WM capacity remains fairly constant whether the items are verbal or visuospatial, and that this same capacity is true of other species as of humans. In contrast to their limited numerousness, WM items are extremely flexible in ways that are here brought under the heading of "dimensionality." Therefore, the physical items represented in WM, can vary widely in any quantitative characteristic and in the temporal pace at which they are encountered. Combinatorial considerations suggest that WM numerousness results from evolution of a middle ground between a sterile parsimony and an overwhelming excess, for organizing neurocognitive associations. Such natural selection seems likely to have worked opportunistically to yield diverse characteristics of neuronal tissue, from subcellular components to properties of ensembles, which converge on the required cognitive properties of WM. Priming and implicit memory may play supporting roles with WM. These intermediate-term memory phenomena allow certain kinds of background information to be accumulated at higher volume than seems possible from the textbook, "modal model" of memory. By expediting attentional focus on subsets of information already in long-term memory, priming may help WM chunks to emerge in limited number as appropriately scaled "figures" from the primed "ground." The larger neuronal dynamic patterns that embody these cognitive phenomena must regulate their microscopic component systems, automatically selecting those having parameters of temporal persistence, rhythm, and connectivity patterns that are pertinent to the current task. Relevant neural phenomena may include "Hebbian" associativity and persistence of firing patterns in prefrontal or hippocampal neurons. A conceivable basis for scaling and normalizing WM representations, along arbitrarily long or short ranges of any cognitive dimension, involves harmonic multiplier relationships among brain electrical rhythms and/or among topographical spatial periodic representations.

Animals↗