Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting voltage-gated sodium channels for pain therapy

Drugs inhibiting voltage-gated sodium channels have long been used as analgesics, beginning with the use of local anaesthetics for sensory blockade and then with the discovery that Nav-blocking anticonvulsants also have benefit for pain therapy. These drugs were discovered without knowledge of their molecular target, using traditional pharmacological methods, and their clinical utility is limited by relatively narrow therapeutic windows. Until recently, attempts to develop improved inhibitors using modern molecular-targeted screening approaches have met with limited success. However, in the last few years there has been renewed activity following the discovery of human Nav1.7 mutations that cause striking insensitivity to pain. Together with recent advances in the technologies required to prosecute ion channels as drug targets, this has led to significant progress being made. This article reviews these developments and summarises current findings with these emerging new Nav inhibitors, highlighting some of the unanswered questions and the challenges that remain before they can be developed for clinical use.
Enrichment for submitotic cell populations using flow cytometry.

BACKGROUND One of the most dramatic events during the course of the mammalian cell cycle is mitosis, when chromosomes condense and segregate, the nuclear envelope breaks down, and the cell divides into two daughter cells. Although cells undergoing mitosis are cytologically distinguishable from nonmitotic cells, few molecular markers are available to specifically identify mitotic cells, especially cells within different stages of mitosis. METHODS We applied the flow cytometric method of Juan et al. (Cytometry 32:71-77, 1998) to obtain cells with various levels of the molecular markers cyclin B1 and phosphorylated histone H3; fluorescence microscopy was then used to identify sorted cells in different stages of mitosis. RESULTS We observed the substantial enrichment of submitotic cell populations. CONCLUSIONS This method represents an effective approach to obtain an enriched population of submitotic cells without the use of drug treatments or prior synchronization.
Towards a Brain-inspired Information Processing System: Modelling and Analysis of Synaptic Dynamics: Towards a Brain-inspired InformationProcessing System: Modelling and Analysis ofSynaptic Dynamics

Biological neural systems in general and the central nervous system specifically exhibit a strikingly efficient computational power along with an extreme flexible and adaptive basis for acquiring and integrating new knowledge. Acquiring more insights into the actual mechanisms of information processing within the brain and their computational capabilities is a core objective of modern computer science, computational sciences and neuroscience. There is however a significant lack of knowledge regarding the basic information processing within the brain. In order to have more insights into these basic information processing methods, this book presents an approach that investigates the underlying mechanisms allowing the brain to be capable of performing such massive amounts of computational tasks with a sustainable efficiency and flexibility. A main focus of this work is the role of synapses and their involved dynamics in the brain's computational power. This work investigates, models and analyses the synaptic dynamics with integration into the level of dynamic neural networks.
An evaluation of the effects of nonselective and cardioselective β-blockers on wound healing in Sprague Dawley rats

Objectives: To investigate the effect of a nonselective β-blocker (propranolol) and cardioselective β-blocker (metoprolol) on wound healing in rats using incision and excision wound models and to compare the effect of these drugs on wound healing. Materials and Methods: Propranolol and metoprolol were given orally. Sprague Dawley rats of either sex were used. Incision and excision wound models were used to evaluate the wound-healing activity. Effects of metoprolol and propranolol on tensile strength, period of epithelialization, and hydroxyproline content were observed. Histological analysis was done to see collagen deposition and inflammatory infiltrate. Statistical Analysis Used: The data was subjected to analysis of variance (ANOVA) followed by Scheffe's test. P < 0.05 was considered to be statistically significant. Statistical analysis was done using SPSS software version 15.0. Results: Administration of propranolol or metoprolol was shown to decrease tensile strength, delay wound contraction and re-epithelialization, increase inflammatory infiltrate, and reduce collagen density and hydroxyproline levels. Conclusions: The results suggest that nonselective and cardioselective β-blockers delay wound healing and these effects are mediated by β1-receptors.
Streptococcus agalactiae Capsule Polymer Length and Attachment Is Determined by the Proteins CpsABCD

Background: The polysaccharide capsule is a major virulence factor of Streptococcus agalactiae. Results: Mutations of the genes cpsABCD result in aberrant capsule length and localization. Conclusion: The CpsABCD proteins form a system that modulates termination of capsule elongation. Significance: This work proposes a model for the unified action of CpsABCD. The production of capsular polysaccharides (CPS) or secreted exopolysaccharides is ubiquitous in bacteria, and the Wzy pathway constitutes a prototypical mechanism to produce these structures. Despite the differences in polysaccharide composition among species, a group of proteins involved in this pathway is well conserved. Streptococcus agalactiae (group B Streptococcus; GBS) produces a CPS that represents the main virulence factor of the bacterium and is a prime target in current vaccine development. We used this human pathogen to investigate the roles and potential interdependencies of the conserved proteins CpsABCD encoded in the cps operon, by developing knock-out and functional mutant strains. The mutant strains were examined for CPS quantity, size, and attachment to the cell surface as well as CpsD phosphorylation. We observed that CpsB, -C, and -D compose a phosphoregulatory system where the CpsD autokinase phosphorylates its C-terminal tyrosines in a CpsC-dependent manner. These Tyr residues are also the target of the cognate CpsB phosphatase. An interaction between CpsD and CpsC was observed, and the phosphorylation state of CpsD influenced the subsequent action of CpsC. The CpsC extracellular domain appeared necessary for the production of high molecular weight polysaccharides by influencing CpsA-mediated attachment of the CPS to the bacterial cell surface. In conclusion, although having no impact on cps transcription or the synthesis of the basal repeating unit, we suggest that these proteins are fine-tuning the last steps of CPS biosynthesis (i.e. the balance between polymerization and attachment to the cell wall).
Effective Inhibition of Kb- and Db-Restricted Antigen Presentation in Primary Macrophages by Murine Cytomegalovirus

ABSTRACT Macrophages play an important role in murine cytomegalovirus (MCMV) infection in vivo, both in disseminating infection and in harboring latent virus. MCMV encodes three immune evasion genes (m4, m6, and m152) that interfere with the ability of cytotoxic T cells (CTL) to detect virus-infected fibroblasts, but the efficacy of immune evasion in macrophages has been controversial. Here we show that MCMV immune evasion genes function in H-2b primary bone marrow macrophages (BMMφ) in the same way that they do in fibroblasts. Metabolic labeling experiments showed that class I is retained in the endoplasmic reticulum by MCMV infection and associates with m4/gp34 to a similar extent in fibroblasts and BMMφ. We tested a series of Kb- and Db-restricted CTL clones specific for MCMV early genes against a panel of MCMV wild-type virus and mutants lacking m152, m4, or m6. MCMV immune evasion genes effectively inhibited antigen presentation. m152 appeared sufficient to abolish Db-restricted presentation in infected macrophages, as has been previously observed in infected fibroblasts. However, for inhibition of recognition of infected macrophages by Kb-restricted CTL, m4, m6, and m152 were all required. The contribution of m4 to inhibition of recognition appeared much more important in macrophages than in fibroblasts. Thus, MCMV immune evasion genes function effectively in primary macrophages to prevent CTL recognition of early antigens and show the same pattern of major histocompatibility complex class I allele discrimination as is seen in fibroblasts. Furthermore, for inhibition of Kb-restricted presentation, a strong synergistic effect was noted among m152, m4, and m6.
Effects of Propofol Sedation on Seizures and Intracranially Recorded Epileptiform Activity in Patients with Partial Epilepsy

Background Case reports suggesting both pro- and anticonvulsant effect(s) of propofol have been published in recent years. The effects of sedative doses of propofol on epileptiform activities in patients suffering from intractable partial epilepsy were systematically investigated. Methods Fourteen patients suffering from complex partial seizures were studied. Electroencephalogram (EEG) was recorded from intracranial electrodes implanted in the hippocampi and temporal neocortex. Propofol was given as a computer-controlled infusion in four steps to achieve target plasma propofol concentrations of 0.3, 0.6, 0.9, and 1.2 micro gram/ml. Each concentration was maintained for 30 min, and steady-state kinetics were confirmed by blood levels drawn at 10th and 30th min at each level. Between the 15th and 30th min of each concentration of propofol, EEG was analyzed for presence of electroencephalographic seizure activity and/or number of interictal spikes (ILS). Effects of propofol on IIS frequency at different electrode sites were compared using a two-way repeated measures analysis of variance. A value of P < 0.05 was considered significant. Results None of the patients developed a seizure during the 2 h of propofol infusion. No "false spikes" (spikes developing with propofol infusion in areas where no spikes were seen in baseline EEG) were seen. Although effects of propofol on IlS frequency were highly variable across patients and at different propofol doses in the same patient, there was no statistically significant effect of propofol on any electrode site with any of the doses studied. Conclusions We were unable to demonstrate a significant change in epileptiform activity with sedative doses of propofol in patients suffering from complex partial epilepsy.
Native and Nonnative Speakers' Processing of a Miniature Version of Japanese as Revealed by ERPs

Several event-related potential (ERP) studies in second language (L2) processing have revealed a differential vulnerability of syntax-related ERP effects in contrast to purely semantic ERP effects. However, it is still debated to what extent a potential critical period for L2 acquisition, as opposed to the attained proficiency level in the L2, contributes to the pattern of results reported in previous ERP studies. We studied L2 processing within the model of a miniature version of a natural language, namely Japanese, specifically constructed to assure high proficiency of the learners. In an auditory ERP experiment, we investigated sentence processing of the Mini-Japanese in Japanese native speakers and German volunteers before and after training. By making use of three different types of violation, namely, word category, case, and classifier violations, native and nonnative ERP patterns were compared. The three types of violation elicited three characteristic ERP patterns in Japanese native speakers. The word category violation elicited an anteriorly focused, broadly distributed early negativity followed by a P600, whereas the case violation evoked a P600 which was preceded by an N400. The classifier violation led solely to a late left distributed negativity with an anterior focus. Although the P600 was similar for Japanese natives and learners, the N400 and the anterior negativities were not present in the learner group. The differences across groups suggest deviant neural processes in on-line syntactic and thematic processing in the L2 learners despite high behavioral skills.
UHF propagation in indoor hallways

A new model for UHF propagation in large buildings is presented. This model relies on knowledge of the interior arrangement of the building without requiring much detail. The guiding of radiation along hallways is the most significant propagation process at distances of more than 10 m from the transmitter. The waveguide model predicts the power loss rate along the hallways, which is affected by the coupling among the propagating modes. The coupling results from the roughness of the surfaces in the building; it is predicted in an average manner using the average deviation of the walls from perfect smoothness.
Kinetics of warfarin absorption in man

The percentage of an oral dose of warfarin absorbed has been measured by two methods. Using the urine excretion of radioactivity following oral administration of HC warfarin in 4 subjects, between 61 % and 92% of an oral dose was recovered. This variation is due to differences in the duration of urine collection. Using a comparison of the area under the plasma concentration‐time curve in 8 subjects, between 77.6% and 100% of an oral dose was apparently absorbed. The rate of warfarin absorption was rapid as ;udged by a consideration of the oral plasma concentration time curve in 8 subjects; peak drug concentrations in plasma were reached by 25 to 60 minutes after oral dosing. Rapid absorption was confirmed by measurements using two different pharmacokinetic models. Absorption was complete by 120 minutes in 4 subjects.
Nested multiplex polymerase chain reaction for the diagnosis of cutaneous herpes simplex and herpes zoster infections and a comparison with electronmicroscopy

Herpes simplex virus (HSV) and varicella zoster virus (VZV) are common causes of cutaneous and mucocutaneous vesicular eruptions. Laboratory diagnostic techniques include Tzanck smears, electronmicroscopy, antigen detection and viral culture. This paper describes a nested multiplex polymerase chain reaction with respective sensitivities of 0.0001, 0.01 and 0.1 TCID50 for VZV, HSV‐1 and HSV‐2. The assay was used in (a) a salvage capacity for slides already processed for electronmicroscopy, and (b) as a front‐line assay for prospectively processed specimens. Sixty‐two glass slides with vesicle lymph/scrapings from 58 patients with suspected cutaneous herpetic lesions were examined. The clinical presentations were described as atypical/not specified (24), VZV (20) or HSV (18), and involved eruptions from diverse anatomical sites, including the genitalia. Of the 62 specimens, 6 and 38 were positive by electronmicroscopy and multiplex PCR respectively, giving a comparative sensitivity of 16% for electronmicroscopy. Nested multiplex PCR identified 15 VZV and 20 HSV‐1 infections. Where the clinical details indicated either HSV or VZV (38/62), nested multiplex PCR was statistically likely to be reactive (26/38 vs. 9/24) (χ2 P = 0.000004) whereas electronmicroscopy was not (4/38 vs. 2/24) (χ2 P = 0.77). Where the clinical details indicated VZV (20/62) or HSV (18/62), nested multiplex PCR was statistically more likely to confirm VZV (10/20 vs. 5/42) (χ2 P = 0.001) or HSV (9/18 vs. 11/44) (χ2 P = 0.05) respectively. Two suspected HSV and 6 suspected VZV infections were shown to be VZV and HSV respectively by nested multiplex PCR. J. Med. Virol. 63:52–56, 2001. © 2001 Wiley‐Liss, Inc.
Associations Between Workload and Diseases Rarely Occurring in Sickness Absence Data

This study provides rate ratios for sickness absence in relation to workload, which was accessed by means of a job exposure matrix. Emphasis is given to diseases that are seldom studied by sickness absence data either because the incidence is low or because medical treatment is not supplemented by rest from work. A total of 42,508 employees from the metal processing and retail trade were followed for 3 years. Sick leave related to hypertension, ischemic heart diseases, ulcer, neurotic disorders, or work accidents was most frequent in employees exposed to physical demands and low control. In contrast, an inverse relation was observed for psychological demands, for which rate ratios decreased with increasing exposure. This finding might be an expression of work commitment or pressure to attend rather than of coping behavior, because both hard and soft diagnoses were considered.
Alienation in Physical Education from the Perspectives of Children.

The purpose of this exploratory study was to examine the phenomenon of alienation in physical education from the perspectives of children. Of particular interest were children’s perspectives about the three constructs of alienation: (a) powerlessness, (b) meaninglessness, and (c) social isolation, as defined by Carlson (1995). A case study methodology was employed with sixth grade children (ages 10 and 11), with a total of 14 children forming the unit of analysis. Observations, field and reflective notes, drawings and semistructured interviews were used to triangulate the data. The data were analyzed by employing a continuum of inductive and deductive analysis, using categorical aggregation and direct interpretation. Three themes were identified as representative of the children’s perspectives: (a) degree of control, (b) meaning, and (c) social factors. The results are discussed in relation to their contribution to the understanding of alienation in children’s physical education and implications for practice.
Factors associated with the seroprevalence of pseudorabies virus in breeding swine from quarantined herds.

Strategies for the elimination of pseudorabies virus (PRV) from swine herds include test and removal, offspring segregation, and depopulation/repopulation. The prevalence of PRV in a herd is a major factor in selection of the most appropriate strategy. The purpose of the study reported here was to describe the prevalence of PRV in adult swine in PRV quarantined herds in Minnesota, and to determine herd factors associated with the seroprevalence. Questionnaires describing the health history of the herd, management practices, and design of the swine facilities were obtained from the owners of 142 quarantined herds. Blood was collected from 29 finishing pigs over the age of 4 months, up to 29 adult females, and all herd boars. Factors considered to be significant in a bivariate analysis were combined in a stepwise multiple logistic regression analysis. The prevalence of PRV-seropositive adults in each herd was bimodally distributed among the 142 herds. In 42 (30%) of the herds, none of the females tested was seropositive, which represented the lower mode. At least 90% of the adults tested were seropositive in 30 (21%) of the herds and represented the higher mode. The odds of the breeding swine of a given herd having a PRV seroprevalence of greater than or equal to 20% as compared with having a seroprevalence of less than 20% was 1.654 times higher per 50 adults in the herd, 13.550 times higher if the finishing pigs were seropositive, 2.378 times higher if sows were housed inside during gestation, and 1.481 times lower per number of years since the imposition of quarantine. (ABSTRACT TRUNCATED AT 250 WORDS)
Cone Beam Computed Tomography for Adaptive Radiotherapy Treatment Planning

Cone beam computed tomography (CBCT) images obtained from linac-based kV imagers are typically used for image-guided radiotherapy, in particular to perform three-dimensional image matching. CBCT image sets can also be used for adaptive radiotherapy where the treatment plan is modified on the basis of periodic imaging throughout the treatment course. CBCT images provide both anatomical information and Hounsfield unit (HU) values, which are required for dose calculations. This study evaluates treatment plans based on CBCT datasets calibrated using the Catphan 504 phantom to investigate the feasibility of using CBCT for adaptive replanning. The CBCT images were acquired from a Varian On-Board Imager system. Conventional planning CT (PCT) images obtained from a Philips Brilliance Big Bore CT scanner were used as reference images. The HU-density calibration curves of CBCT were obtained using a Catphan 504 phantom and a CIRS density phantom and compared with the clinical PCT calibration curve (obtained using the CIRS density phantom). Treatment plans created using the different calibration curves were compared. Identical targets were delineated on CBCT and PCT images on four different-sized phantoms and planar dose maps were generated. The dose-volume histograms of PCT-and CBCT-based plans were compared and evaluated by gamma analysis. To extend the study to a typical clinical situation, two prostate cases were included. The dose distribution comparison between PCT-and CBCT-based plans for patients yielded similar results to those obtained using phantoms. The study also analyzed the effect of phantom dimensions on HU values and its impact on dose calculations. The isodose distributions computed based on PCT and CBCT using the Catphan calibration curve agree to within ± 1% compared to that based on CBCT using the density phantom calibration curve. However, for phantoms of larger diameter, there is a pronounced discrepancy in the 50% and 60% isodose lines, with the dose difference being about ± 3%. For phantoms whose thickness is less than the cone beam scan length (16 cm) and for phantoms whose diameter is less than that of the calibration phantom, the variation in HU values is high. The effect of a change in radial diameter has a larger impact on dose calculations. This study shows that the CIRS density phantom is not suitable for CBCT calibration and that individual calibration curves obtained using phantoms of appropriate dimensions should be used for planning individual treatment sites.
Slug, mammalian homologue gene of Drosophila escargot, promotes neuronal-differentiation through suppression of HEB/daughterless

At the neuron developmental stage, neuron-precursor cells can be differentiated into neuron or glia cells. However, precise molecular mechanism to determine the cell fate has not been clearly demonstrated. In this study, we reveal that Drosophila esgarcot and its mammalian homologue genes, Snail and Slug, play a key role in neuronal differentiation. In Drosophila model system, overexpression of Esg, like as Wingless, suppresses the bristle formation. In contrast, elimination of Esg though RNAi promotes double bristle phenotype. We can also observe the similar phenotype in Snail-overexpression system. In mammalian system, overexpression of Slug or Snail can induce neuronal differentiation. Esg and its mammalian homologue gene Slug directly interact with Daughtherless and its mammalian homologue HEB and eliminate them through siah-1 mediated protein degradation. Thus, overexpression of siah-1 can promote neuron cell differentiation, whereas si-siah-1 blocks the Slug-induced HEB suppression. In fact, Drosophila SINA, Siah-1 homologue, has been also known to be involved in bristle formation and Neuronal differentiation. In addition, it has been revealed that CK1 is involved in Esg or Snail stability and Neuronal differentiation. However, Snail is regulated only by CK1 but not by Siah. Considering the fact that Slug mutations have been found in human genetic disease, waardenberg syndrome, major symptoms of which is loss of hearing neuron and odd eye, our result implies that Slug/Snail system is required for proper neuronal differentiation, like as Esg in Drosophila.