Miracle-dz/UniFAR-FTUs huggingface dataset:
Intrathecal Neostigmine, but Not Sympathectomy, Relieves Mechanical Allodynia in a Rat Model of Neuropathic Pain

Introduction Pain resulting from a usually nonpainful stimulus (allodynia) is a common characteristic of neuropathic pain. Among animal models of allodynia, tight ligature of lumbar spinal nerves has been of special interest because it has been reported to be relieved by sympathectomy. The purpose of this study was to determine whether spinal analgesic agents, which have opposite effects on sympathetic nervous system activity (clonidine decreases it and neostigmine increases it), have differing efficacy in this model. Methods Male Sprague‐Dawley rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. At least 2 weeks later, a lumbar intrathecal or jugular intravenous catheter was inserted. Withdrawal threshold to mechanical stimulation of the hind paw was determined by application of von Frey filaments before surgery; after surgery; after intrathecal injection of clonidine, neostigmine, or their combination; after intravenous injection of phentolamine or guanethidine; and after surgical sympathectomy. Results Spinal nerve ligation reduced withdrawal threshold ipsilateral to the lesion. This allodynia was relieved by clonidine (50% block of allodynia at 20 +/‐ 1.2 [micro sign]g and neostigmine (50% block of allodynia at 2 +/‐ 0.1 [micro sign]g, and they interacted synergistically to block allodynia. Neither chemical nor surgical sympathectomy altered allodynia. Discussion These results disagree with previous observations that mechanical allodynia in this animal model depends on sympathetic nervous system activity. Therefore, intrathecally administered analgesic agents, one that reduces sympathetic outflow from the spinal cord (clonidine) and one that increases it (neostigmine), were similarly effective in this model.
Reality Shock and Public Service Motivation: A Longitudinal, Qualitative Study Among Dutch Veterinary Inspectors

ABSTRACT To this day little is known about the mechanisms that help explain the mixed findings of longitudinal public service motivation (PSM) research. This study aims to deepen our understanding of post-entry PSM dynamics by focusing on the role of the often cited “reality shock” as a potential explanation for the decrease in PSM also found here. The results of this longitudinal, small-scale qualitative study of a specific cohort of newcomers who just started work as veterinary inspectors at the Dutch food safety authority suggest that a loss of PSM is not due to a generic shock effect, but is linked to having unclear job expectations and individual differences in coping behaviour.
Central Nervous System Neuropeptide Y Signaling Modulates VLDL Triglyceride Secretion

OBJECTIVE—Elevated triglyceride (TG) is the major plasma lipid abnormality in obese and diabetic patients and contributes to cardiovascular morbidity in these disorders. We sought to identify novel mechanisms leading to hypertriglyceridemia. Resistance to negative feedback signals from adipose tissue in key central nervous system (CNS) energy homeostatic circuits contributes to the development of obesity. Because triglycerides both represent the largest energy depot in the body and are elevated in both the plasma and adipose in obesity and diabetes, we hypothesized that the same neural circuits that regulate energy balance also regulate the secretion of TGs into plasma. RESEARCH DESIGN AND METHODS—In normal fasting rats, the TG secretion rate was estimated by serial blood sampling after intravascular tyloxapol pretreatment. Neuropeptide Y (NPY) signaling in the CNS was modulated by intracerebroventricular injection of NPY, receptor antagonist, and receptor agonist. RESULTS—A single intracerebroventricular injection of NPY increased TG secretion by 2.5-fold in the absence of food intake, and this was determined to be VLDL by fast performance liquid chromatography (FPLC). This effect was recapitulated by activating NPY signaling in downstream neurons with an NPY-Y5 receptor agonist. An NPY-Y1 receptor antagonist decreased the elevated TGs in the form of VLDL secretion rate by 50% compared with vehicle. Increased TG secretion was due to increased secretion of VLDL particles, rather than secretion of larger particles, because apolipoprotein B100 was elevated in FPLC fractions corresponding to VLDL. CONCLUSIONS—We find that a key neuropeptide system involved in energy homeostasis in the CNS exerts control over VLDL-TG secretion into the bloodstream.
Abnormalities of intrahepatic bile ducts in extrahepatic biliary atresia

The infantile cholangiopathies are a group of conditions associated with neonatal jaundice, which include extrahepatic biliary atresia, paucity of intra‐hepatic bile ducts and disorders associated with persistence of fetal biliary structures, the so‐called ductal plate malformations. Although previously regarded as distinct entities, it has recently been suggested that they may represent parts of a disease spectrum in which the principal process is one of bile duct destruction, the morphological manifestations in individual cases being influenced by the stage of intra‐uterine development at which such injury occurs and by the site within the biliary system at which there is maximum damage. To further examine this concept, we have studied liver biopsy specimens from 37 neonates with extrahepatic biliary atresia, with particular reference to abnormalities of the intrahepatic bile ducts. Paucity of intrahepatic ducts, defined as a bile duct: portal tract ratio of less than 0.9, was identified in six cases (16.2%). In eight cases (21.6%) we found concentric tubular ductal structures similar to those observed in ductal plate malformations. In one case, both abnormalities could be demonstrated. Our findings support the concept that there is overlap between the various types of infantile cholangiopathy.
Changes in biochemical composition of the cell wall of the cotton fiber during development.

The composition of the cell wall of the cotton fiber (Gossypium hirsutum L. Acala SJ-1) has been studied from the early stages of elongation (5 days postanthesis) through the period of secondary wall formation, using cell walls derived both from fibers developing on the plant and from fibers obtained from excised, cultured ovules. The cell wall of the elongating cotton fiber was shown to be a dynamic structure. Expressed as a weight per cent of the total cell wall, cellulose, neutral sugars (rhamnose, fucose, arabinose, mannose, galactose, and noncellulosic glucose), uronic acids, and total protein undergo marked changes in content during the elongation period. As a way of analyzing absolute changes in the walls with time, data have also been expressed as grams component per millimeter of fiber length. Expressed in this way for plant-grown fibers, the data show that the thickness of the cell wall is relatively constant until about 12 days postanthesis; after this time it markedly increases until secondary wall cellulose deposition is completed. Between 12 and 16 days postanthesis increases in all components contribute to total wall increase per millimeter fiber length. The deposition of secondary wall cellulose begins at about 16 days postanthesis (at least 5 days prior to the cessation of elongation) and continues until about 32 days postanthesis. At the time of the onset of secondary wall cellulose deposition, a sharp decline in protein and uronic acid content occurs. The content of some of the individual neutral sugars changes during development, the most prominent change being a large increase in noncellulosic glucose which occurs just prior to the onset of secondary wall cellulose deposition. Methylation analyses indicate that this glucose, at least in part, is 3-linked. In contrast to the neutral sugars, no significant changes in cell wall amino acid composition are observed during fiber development.Compositional analyses of cell walls derived from culture-grown fibers indicate that these walls are remarkably similar to those derived from fibers grown on the plant, both in terms of composition and in terms of relative changes in composition during development.A comparison of our results on total cell wall composition and linkages of sugars as determined by a preliminary methylation analysis of unfractionated fiber walls indicates that the primary cell wall of cotton fibers is similar to that of primary cell walls of other dicotyledons and of gymnosperms as reported in the literature.
Diallyl disulphide depletes glutathione in Candida albicans: oxidative stress‐mediated cell death studied by two‐photon microscopy

Using two‐photon scanning laser microscopy, we investigated the effect of an Allium sativum (garlic) constituent, diallyl disulphide (DADS), on key physiological functions of the opportunistic pathogen Candida albicans. A short 30 min exposure to 0.5 mM DADS followed by removal induced 70% cell death (50% necrotic, 20% apoptotic) within 2 h, increasing to 75% after 4 h. The early intracellular events associated with DADS‐induced cell death were monitored with two‐photon fluorescence microscopy to track mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) and NADH or reduced glutathione (GSH) under aerobic conditions. DADS treatment decreased intracellular GSH and elevated intracellular ROS levels. Additionally, DADS induced a marked decrease of Δψm and lowered respiration in cell suspensions and isolated mitochondria. In vitro kinetic experiments in cell‐free extracts suggest that glutathione‐S‐transferase (GST) is one of the intracellular targets of DADS. Additional targets were also identified, including inhibition of a site or sites between complexes II–IV in the electron transport chain, as well as the mitochondrial ATP‐synthase. The results indicate that DADS is an effective antifungal agent able to trigger cell death in Candida, most probably by eliciting oxidative stress as a consequence of thiol depletion and impaired mitochondrial function. Copyright © 2007 John Wiley & Sons, Ltd.
Forward/up directional incompatibilities during cursor placement within graphical user interfaces

Within graphical user interfaces, an indirect relationship between display and control may lead to directional incompatibilities when a forward mouse movement codes upward cursor motions. However, this should not occur for left/right movements or direct cursor controllers (e.g. touch sensitive screens). In a four-choice reaction time task, 12 participants performed movements from a central start location to a target situated at one of four cardinal points (top, bottom, left, right). A 2 × 2 × 2 design varied directness of controller (moving cursor on computer screen or pen on graphics tablet), compatibility of orientation of cursor controller with screen (horizontal or vertical) and axis of desired cursor motion (left/right or up/down). Incompatibility between orientation of controller and motion of cursor did not affect response latencies, possibly because both forward and upward movements are away from the midline and go up the visual field. However, directional incompatibilities between display and controller led to slower movement with prolonged accelerative phases. Indirect relationships between display and control led to less efficient movements with prolonged decelerative phases and a tendency to undershoot movements along the bottom/top axis. More direct cursor control devices, such as touch sensitive screens, should enhance the efficiency of aspects of cursor trajectories.
disabled-1 Functions Cell Autonomously during Radial Migration and Cortical Layering of Pyramidal Neurons

Genetic mosaics offer an excellent opportunity to analyze complex gene functions. Chimeras consisting of mutant and wild-type cells provide not only the avenue for lineage-specific gene rescue but can also distinguish cell-autonomous from non-cell-autonomous gene functions. Using an independent genetic marker for wild-type cells, we constructed Dab1+/+ ↔Dab1−/− chimeras with the aim of discovering whether or not the function of Dab1 during neuronal migration and cortical layering is cell autonomous.Dab1+/+ cells were capable of radial migration and columnar formation in aDab1−/− environment. MostDab1+/+ cells segregated to the superficial part of the mutant cortex, forming a multilayered supercortex. Neuronal birth-dating studies indicate that supercortex neurons were correctly layered, although adjacent mutant cortex neurons were in reversed order. Immunocytochemistry using Emx1, a marker for pyramidal neurons, indicates that the vast majority ofDab1+/+ neurons in the supercortex were Emx1 immunoreactive. Confirmation of the pyramidal phenotype was demonstrated by the absence of GABA immunoreactivity amongDab1+/+ cells in the supercortex. Myelin staining using 2′3′-cyclic nucleotide 3′-phosphodiesterase showed the supercortex was supported by a secondary white matter from which thick fiber tracts appear connected to the underlying mutant white matter. The presence ofDab1+/+ cells failed to rescue inversion of cortical layers and the abnormal infiltration of the marginal zone by Dab1−/− cells. Conversely, mutant cells did not impose a mutant phenotype on adjacent wild-type neurons. These results suggest that Dab1 functions cell autonomously with respect to radial migration and cortical layering of pyramidal neurons.
Multiple roles for PI 3‐kinase in the regulation of PLCγ activity and Ca2+ mobilization in antigen‐stimulated mast cells

Cross‐linking the IgE‐bound Fc∊RI with polyvalent antigen leads to Ca2+‐dependent degranulation from mast cells and basophils, initiating the allergic response. This overview addresses novel roles for PI 3‐kinase in the regulation of signaling events that lie downstream of Fc∊RI‐mediated tyrosine kinase activation. The first novel role for PI 3‐kinase is in the regulation of PLCγ activity and is demonstrated by a dramatic inhibition of Fc∊RI‐induced Ins(1,4,5)P3 production after treatment of RBL‐2H3 cells with wortmannin, a PI 3‐kinase inhibitor. We show that PI 3‐kinase lipid products support Ins(1,4,5)P3 production in at least two ways: by promoting translocation and phosphorylation of PLCγ1 and by direct stimulation of both PLCγ isoforms. In vitro stimulation of PLCγ activity by PtdIns(3,4,5)P3 synergizes with activation by in vivo tyrosine phosphorylation for maximal enzymatic activity. A second novel role for PI 3‐kinase is in the regulation of antigen‐stimulated Ca2+ influx. Compared with control cells, Ca2+ responses are markedly diminished in antigen‐stimulated cells after wortmannin pretreatment. Differences include both a longer lag time to the initial elevation in Ca2+ after antigen and an inhibition of the sustained Ca2+ influx phase. However, thapsigargin challenge during the sustained phase demonstrates no difference in the state of the Ca2+ stores in antigen‐stimulated cells in the presence or absence of wortmannin. These data suggest that sufficient Ins(1,4,5)P3 is synthesized in wortmannin‐treated cells to mobilize intracellular calcium stores and, furthermore, that the affected phase of Ca2+ influx is unlikely to be attributed to capacitative mechanisms. These data are consistent with a model where at least two pathways mediate Ca2+ influx in antigen‐stimulated RBL‐2H3 cells, one that is dependent on signals from empty stores (capacitive influx) and another that is downstream of PI 3‐kinase. J. Leukoc. Biol. 65: 321–329; 1999.
A Treatment Program for Adolescents With Phenylketonuria

A treatment program for adolescents with phenylketonuria (PKU) , incorporating education, goal-setting, self-monitoring, contracts, and rewards, was evaluated by measuring knowledge of PKU, blood phenylalanine concentrations, and health locus of control (LOC) before and after participation in the program. Of the 16 subjects, seven subjects successfully completed the program by achieving behavioral goals. These subjects increased their knowledge of PKU and decreased their blood phenylalanine concentrations, but the nine nonsuccessful subjects did not. There was no significant change in LOC scores for either group. There was a significant relationship between baseline blood phenylalanine levels and success with the program. Therefore, this pilot study demonstrates that adolescents who have already achieved some measure of metabolic control can be expected to be most successful with this program and realize the greatest benefits from it in the form of increased knowledge of PKU and even better metabolic control.
Axial Length, Corneal Radius, and Age of Myopia Onset

Purpose. This study was designed to establish variations in the biometry of the ocular globe according to refractive state, and to determine the extent to which these characteristics contribute to the appearance and degree of myopia. Methods. Subjects recruited for the study were 583 university students of mean age 20.32 ± 2.82 years. Objective refraction without cycloplegia and the corneal radius (CR) of curvature were determined using an autokeratorefractometer. The axial length (AL) of the eye was measured by ultrasound biometry. The population was then characterized according to these three variables to establish relationships among them. Data were stratified by both refractive state and age of onset of myopia. Results. The prevalence of myopia (more minus than 0.50 D) was 57.78%; half the refractive defects being less minus than −3.00 D. The AL of the eye was found to be more related to the refractive error than the CR, especially in subjects with moderate myopia. In emmetropes or subjects with low myopia, the CR was directly correlated with AL, although this correlation was somewhat diminished in moderate myopias. Nonetheless, in the latter and in juvenile-onset myopia, a trend towards a shorter radius of curvature was observed. Conclusions. The AL of the eye is the main morphological variable related to myopia. The function of the cornea seems to compensate the possible myopizing effects of slight increases in AL. When increases in AL are excessive, this effect of the cornea tends to disappear.
Differential gene expression patterns in porcine nuclear transfer embryos reconstructed with fetal fibroblasts and mesenchymal stem cells

The present study compared the developmental ability and gene expression pattern at 4‐cell, 8‐cell, morula, and blastocyst stages of porcine nuclear transfer (NT) embryos from fetal fibroblasts (FFs) and mesenchymal stem cells (MSCs), in vitro fertilized (IVF), and in vivo derived embryos. MSC‐NT embryos showed enhanced blastocyst formation, higher total cell number, and a low incidence of apoptosis compared to FF‐NT embryos. Alterations in the expression pattern of genes implicated in transcription and pluripotency (Oct4, Stat3, Nanog), DNA methylation (Dnmt1, Dnmt3a), histone deacetylation (Hdac2), growth factor signaling, and imprinting (Igf2, Igf2r) and apoptosis (Bax, Bcl2) regulation were observed in NT embryos. The expression of transcripts in MSC‐NT embryos more closely followed that of the in vivo derived embryos compared with FF‐NT embryos. In conclusion, MSCs with a relatively undifferentiated genome might serve as suitable donors that could be more efficiently reprogrammed to re‐activate expression of early embryonic genes in porcine NT. Developmental Dynamics 236:435–446, 2007. © 2006 Wiley‐Liss, Inc.
The Effect of Infrastructure on Worker Mobility: Evidence from High-Speed Rail Expansion in Germany

We use the expansion of the high-speed rail (HSR) network in Germany as a natural experiment to examine the causal effect of reductions in commuting time between regions on the commuting decisions of workers and their choices regarding where to live and where to work. We exploit three key features in this setting: (i) investment in HSR has, in some cases dramatically, reduced travel times between regions, (ii) several small towns were connected to the HSR network only for political reasons, and (iii) high-speed trains have left the transportation of goods unaffected. Combining novel information on train schedules and the opening of HSR stations with panel data on all workers in Germany, we show that a reduction in travel time by 1% raises the number of commuters between regions by 0.25%. This effect is mainly driven by workers changing jobs to smaller cities while keeping their place of residence in larger ones. Our findings support the notion that benefits from infrastructure investments accrue in particular to peripheral regions, which gain access to a large pool of qualified workers with a preference for urban life. We find that the introduction of high-speed trains led to a modal shift toward rail transportation in particular on medium distances between 150 and 400 km.
Determinants of Human Immunodeficiency Virus Type 1 Baseline Susceptibility to the Fusion Inhibitors Enfuvirtide and T-649 Reside outside the Peptide Interaction Site

ABSTRACT The peptide fusion inhibitor (PFI) enfuvirtide is the first of a new class of entry inhibitors to receive FDA approval. We previously determined the susceptibility of 55 PFI-naïve-patient isolates to enfuvirtide and a second peptide inhibitor, T-649. Seven of the 55 viral isolates were insusceptible to enfuvirtide, T-649, or both inhibitors in the absence of prior exposure. To determine the molecular basis of the insusceptible phenotypes, we PCR amplified and cloned five PFI-insusceptible and one PFI-susceptible, full-length, biologically functional env genes and characterized viruses pseudotyped with the Env proteins in a single-round drug sensitivity assay. Overall, the mean 50% inhibitory concentrations of enfuvirtide and T-649 for the PFI-insusceptible Env pseudotypes were 1.4 to 1.7 log10 and 1.2 to 1.8 log10 greater, respectively, than those for a PFI-susceptible lab strain, NLHX; however, all of the PFI-insusceptible Env proteins conserved the sequence of a critical enfuvirtide interaction site (residues 36 to 38 of gp41, GIV) in HR-1. In contrast, multiple amino acid changes were observed C-terminal to HR-1, many of which were located in regions of HR-2 corresponding to the PFI. Nevertheless, peptides based on patient-derived HR-2 sequences were not more potent inhibitors than enfuvirtide or T-649, arguing that the basis of PFI susceptibility is not a higher-affinity, competitive HR-1/HR-2 interaction. These results demonstrate that regions of Env outside the enfuvirtide interaction site can significantly impact the PFI susceptibility of patient-derived Env, even prior to drug exposure. We hypothesize that both gp120 gene- and gp41 gene-encoded determinants that minimize the window of opportunity for PFI to bind provide a growth advantage and possibly a predisposition to resistance to this new class of drugs in vivo.