Miracle-dz/UniFAR-FTUs huggingface dataset:
Protection by dimethylthiourea against retinal light damage in rats.

The protective effect of dimethylthiourea (DMTU) against retinal light damage was determined in albino rats reared in darkness or in weak cyclic light. Rats maintained under these conditions were treated with DMTU at different concentrations and dosing schedules and then exposed for various times to intense visible light, either intermittently (1 hr light and 2 hr dark) or continuously. The extent of retinal light damage was determined 2 weeks after light exposure by comparing rhodopsin levels in experimental rats with those in unexposed control animals. To determine the effect of DMTU on rod outer segment (ROS) membrane fatty acids, ROS were isolated immediately after intermittent light exposure, and fatty acid compositions were measured. The time course for DMTU uptake and its distribution in serum, retina, and the retinal pigment epithelium (RPE)/choroid complex was determined in other rats not exposed to intense light. After intraperitoneal injection of the drug (500 mg/kg body weight), DMTU appeared rapidly in the serum, retina, and the RPE and choroid. In the ocular tissues, it was distributed 70-80% in the retina and 20-30% in the RPE and choroid. This antioxidant appears to have a long half-life because it was present in these same tissues 72 hr after a second intraperitoneal injection. For rats reared in the weak cyclic light environment, DMTU (two injections) provided complete protection against rhodopsin loss after intense light exposures of up to 16 hr. Only 15% rhodopsin loss was found in cyclic-light DMTU-treated rats after 24 hr of intermittent or continuous light. For rats reared in darkness, DMTU treatment resulted in a rhodopsin loss of less than 20% after 8-16 hr of continuous light and approximately 40% after similar exposure to intermittent light. Irrespective of the type of light exposure, rhodopsin loss in the dark-reared DMTU-treated rats was nearly identical to that found in uninjected cyclic light-reared animals. In rats from both light-rearing environments, DMTU treatment prevented the light-induced loss of docosahexaenoic acid from ROS membranes. As measured by rhodopsin levels 2 weeks later, DMTU was most effective when given as two doses administered 24 hr before and just before intense light exposure. As a single dose given during continuous light exposure, DMTU protected cyclic light-reared rats for at least 4 hr after the start of exposure but was ineffective in dark-reared animals if injected 1 hr after the start of light. It was also ineffective in both types of rats when given after light exposure. (ABSTRACT TRUNCATED AT 400 WORDS)
Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization

Mammals have genes coding for three PI5P4Ks (PtdIns5P 4-kinases), and these have different cellular localizations, tissue distributions and lipid kinase activities. We describe in the present paper a detailed molecular exploration of human PI5P4Ks α, β and γ, as well as their fly and worm homologues, to understand how and why these differences came to be. The intrinsic ATPase activities of the three isoforms are very similar, and we show that differences in their G-loop regions can account for much of their wide differences in lipid kinase activity. We have also undertaken an extensive in silico evolutionary study of the PI5P4K family, and show experimentally that the single PI5P4K homologues from Caenorhabditis elegans and Drosophila melanogaster are as widely different in activity as the most divergent mammalian isoforms. Finally we show that the close association of PI5P4Ks α and γ is a true heterodimerization, and not a higher oligomer association of homodimers. We reveal that structural modelling is consistent with this and with the apparently random heterodimerization that we had earlier observed between PI5P4Kα and PI5P4Kβ [Wang, Bond, Letcher, Richardson, Lilley, Irvine and Clarke (2010), Biochem. J. 430, 215–221]. Overall the molecular diversity of mammalian PI5P4Ks explains much of their properties and behaviour, but their physiological functionality remains elusive.
Individual/Neighborhood Social Factors and Blood Pressure in the RECORD Cohort Study: Which Risk Factors Explain the Associations?

Recent studies have started to suggest that, beyond effects of individual socioeconomic profiles, socioeconomic characteristics of residential neighborhoods are independently associated with blood pressure. However, mechanisms involved in these associations remain unknown. To distinguish between different mechanisms, we investigated whether specific risk factors of hypertension (physical inactivity, alcohol consumption, smoking, body mass index, waist circumference, and resting heart rate) intervene as mediators in the associations between individual or neighborhood socioeconomic characteristics and systolic blood pressure. We relied on data from the RECORD Cohort Study (Residential Environment and CORonary heart Disease) on 5941 participants recruited in 2007–2008, aged 30 to 79 years, residing in 1824 neighborhoods in the Paris metropolitan area. Systolic blood pressure increased independently and regularly with both decreasing individual education and decreasing residential neighborhood education. Body mass index/waist circumference and resting heart rate mediated an appreciable share of the associations between education and blood pressure and, adding validity to the finding, were the 2 most significant mediators for the effects of both individual education and neighborhood education. We found that 52% (95% CI: 25% to 79%) of the association between neighborhood education and blood pressure was mediated by body mass index/waist circumference and 20% (95% CI: 5% to 36%) by resting heart rate. Future research will have to clarify the exact mechanisms through which body weight and shape and resting heart rate intervene as mediators in the associations between individual/neighborhood education and blood pressure.
Conversion from Farnesyl Diphosphate Synthase to Geranylgeranyl Diphosphate Synthase by Random Chemical Mutagenesis (*)

Prenyltransferases catalyze the consecutive condensation of isopentenyl diphosphate (IPP) with allylic diphosphates to produce prenyl diphosphates whose chain lengths are absolutely determined by each enzyme. In order to investigate the mechanisms of the consecutive reaction and of the determination of ultimate chain length, a random mutational approach was planned. The farnesyl diphosphate (FPP) synthase gene of Bacillus stearothermophilus was subjected to random mutagenesis by NaNO treatment to construct libraries of mutated FPP synthase genes on a high-copy plasmid. From the libraries, the mutants that showed the activity of geranylgeranyl diphosphate (GGPP) synthase were selected by the red-white screening method (Ohnuma, S.-i., Suzuki, M., and Nishino, T.(1994) J. Biol. Chem. 268, 14792-14797), which utilized carotenoid synthetic genes, phytoene synthase, and phytoene desaturase, to visualize the formation of GGPP in vivo. Eleven red positive clones were identified from about 24,300 mutants, and four (mutant 1, 2, 3, and 4) of them were analyzed for the enzyme activities. Results of in vitro assays demonstrated that all these mutants produced (all-E)-GGPP although the amounts were different. Each mutant was found to contain a few amino acid substitutions: mutant 1, Y81H and L275S; mutant 2, L34V and R59Q; mutant 3, V157A and H182Y; mutant 4, Y81H, P239R, and A265T. Site-directed mutagenesis showed that Y81H, L34V, or V157A was essential for the expression of the activity of GGPP synthase. Especially, the replacement of tyrosine 81 by histidine is the most effective because the production ratios of GGPP to FPP in mutant 1 and 4 are the largest. Based on prediction of the secondary structure, it is revealed that the tyrosine 81 situates on a point 11 12 Å apart from the first DDXXD motif, whose distance is similar to the length of hydrocarbon moiety of FPP. These data might suggest that the aromatic ring of tyrosine 81 blocks the chain elongation longer than FPP. Comparisons of kinetic parameters of the mutated and wild type enzymes revealed several phenomena that may relate with the change of the ultimate chain length. They are a decrease of the total reaction rate, increase of Kfor dimethylallyl diphosphate, decrease of V for dimethylallyl diphosphate, and allylic substrate dependence of K for IPP.
“Candidatus Neoehrlichia mikurensis” Infection in a Dog from Germany

ABSTRACT “Candidatus Neoehrlichia mikurensis” is a new intracellular pathogen associated with human infection and death. “Candidatus Neoehrlichia mikurensis” infection in a chronically neutropenic dog from Germany was confirmed by DNA sequencing. The same organism was previously described from ticks and two sick human beings from Germany.
Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.
Entanglement Entropy of Black Holes

The entanglement entropy is a fundamental quantity, which characterizes the correlations between sub-systems in a larger quantum-mechanical system. For two sub-systems separated by a surface the entanglement entropy is proportional to the area of the surface and depends on the UV cutoff, which regulates the short-distance correlations. The geometrical nature of entanglement-entropy calculation is particularly intriguing when applied to black holes when the entangling surface is the black-hole horizon. I review a variety of aspects of this calculation: the useful mathematical tools such as the geometry of spaces with conical singularities and the heat kernel method, the UV divergences in the entropy and their renormalization, the logarithmic terms in the entanglement entropy in four and six dimensions and their relation to the conformal anomalies. The focus in the review is on the systematic use of the conical singularity method. The relations to other known approaches such as ’t Hooft’s brick-wall model and the Euclidean path integral in the optical metric are discussed in detail. The puzzling behavior of the entanglement entropy due to fields, which non-minimally couple to gravity, is emphasized. The holographic description of the entanglement entropy of the blackhole horizon is illustrated on the two- and four-dimensional examples. Finally, I examine the possibility to interpret the Bekenstein-Hawking entropy entirely as the entanglement entropy.
Probability of Stimulus Detection in a Model Population of Rapidly Adapting Fibers

The goal of this study is to establish a link between somatosensory physiology and psychophysics at the probabilistic level. The model for a population of monkey rapidly adapting (RA) mechanoreceptive fibers by Gl and Bolanowski (2002) was used to study the probability of stimulus detection when a 40 Hz sinusoidal stimulation is applied with a constant contactor size (2 mm radius) on the terminal phalanx. In the model, the detection was assumed to be mediated by one or more active fibers. Two hypothetical receptive field organizations (uniformly random and gaussian) with varying average innervation densities were considered. At a given stimulus-contactor location, changing the stimulus amplitude generates sigmoid probability-of-detection curves for both receptive field organizations. The psychophysical results superimposed on these probability curves suggest that 5 to 10 active fibers may be required for detection. The effects of the contactor location on the probability of detection reflect the pattern of innervation in the model. However, the psychophysical data do not match with the predictions from the populations with uniform or gaussian distributed receptive field centers. This result may be due to some unknown mechanical factors along the terminal phalanx, or simply because a different receptive field organization is present. It has been reported that human observers can detect one single spike in an RA fiber. By considering the probability of stimulus detection across subjects and RA populations, this article proves that more than one active fiber is indeed required for detection.
Effect of eye position within the orbit on electrically elicited saccadic eye movements: a comparison of the macaque monkey's frontal and supplementary eye fields.

1. We quantitatively compared the effects of eye position within the orbit on saccadic eye movements electrically elicited from two oculomotor areas of the macaque monkey's frontal lobe cortex: the frontal eye field (FEF) and the supplementary eye field (SEF). 2. The effect of eye position on electrically elicited saccades was studied by delivering 70-ms trains of intracortical microstimulation while the monkeys fixated a spot of light. Tests of different fixation points located across a rectangular array were randomly intermixed. Complete experiments were carried out on 38 sites in three FEFs of two monkeys and 59 sites from three SEFs of the same two monkeys. Stimulation currents for the array experiments were usually 10-20 microA above the site threshold; the average current used was 36 microA for FEF and 49 microA for SEF. 3. The magnitude of effect of the initial eye position on the elicited saccade's dimensions was quantified at each site by computing the linear regression of saccadic eye movement displacement on the eye position within the orbit when stimulation was applied. This computation was done separately for the horizontal and vertical axes. We call the resulting pair of regression coefficients "orbital perturbation indexes. " Indexes of 0.0 represent elicited saccades that do not change their trajectory with different initial eye positions (constant-vector saccades), whereas indexes of -1.0 represent elicited saccades that end at the same orbital position regardless of initial eye position (goal-directed saccades). 4. The effect of eye position varied across sites. In both FEF and SEF, the orbital perturbation indexes were distributed between approximately 0.0 and -0.5, with the horizontal and vertical indexes highly correlated across sites. 5. The average orbital perturbation indexes were small for both eye fields and were not significantly different. The mean horizontal indexes were -0.13 and -0.16 for SEF and FEF, respectively. The mean vertical indexes were -0.16 and -0.13. Neither SEF versus FEF difference was statistically significant. 6. In both SEF and FEF, sites yielding larger-amplitude saccades generally had larger orbital effects than sites yielding smaller saccades. This relationship accounted for the majority of the variability of the orbital perturbation indexes across sites in both SEF and FEF. 7. These results indicate that SEF and FEF are not distinguished from each other by the orbital dependence of their electrically elicited saccades. Thus they do not confirm the previously hypothesized dichotomy that FEF codes constant-vector saccades and SEF codes goal-directed saccades. (ABSTRACT TRUNCATED AT 400 WORDS)
i-Sitosterolemia and Xanthomatosis A NEWLY DESCRIBED LIPID STORAGE DISEASE IN TWO SISTERS

This work was presented in part at the 65th Annual Meeting of the American Society for Clinical Investigation, Atlantic City, N. J., 30 April 1973 (J. Clin. Invest. 52, 9a). Received for publication 24 September 1973 and in revised form 26 November 1973. (0.2 mg/g wet wt) and in skin surface lipids (3.2 mg/g of lipid). The intestinal absorption of 8-sitosterol in both the patients, measured by two techniques, indicated greatly increased absorption of this sterol (about 24 and 28% in the patients L. H. and R. H., respectively, normal absorption being < 5%). We suggest that increased absorption of P-sitosterol must be considered as one cause of this disease. The reason for the extensive xanthomatosis in these two patients remains unknown. Perhaps in some way plant sterols initiated the development of xanthomas with otherwise normal plasma cholesterol levels. Clinical atherosclerosis has not yet occurred. The occurrence of f-sitosterolemia in these two sisters with unaffected parents suggests an inherited recessive trait.
Fuzzy Diffusion Analysis: Decision Significance and Applicable Scenarios

Distributed wireless sensor networks (WSNs) operate under severe energy constraints and are largely characterized by short-range multi-hop radio communications, which signify the role of energy-efficient routing schemes for such networks. Fuzzy diffusion, an energy optimization on the general diffusion schemes for application-aware sensor networks, has been shown to offer substantial improvement in WSN lifetime and connectivity. The initial exploration depicted the advantages of extreme conservative routing in dense WSNs. However, a progressive investigation of fuzzy diffusion is needed to address several important aspects of the protocol mechanism and to quantify its applicability. Fuzzy diffusion is primarily based upon energy-aware routing decisions, and so an analysis of the impact of decision-making strategies on the protocol performance is required to substantiate the use of any specific tool. The purpose of this work is to quantify the contribution of fuzzy logic in computing efficient forwarding decisions as compared to simpler, straightforward crisp decision-making strategies. Further, this paper aims at exploring the network and traffic scenarios under which fuzzy diffusion scheme would be efficient, through a series of simulation experiments
Production of Phosphatidylinositol 5-Phosphate by the Phosphoinositide 3-Phosphatase Myotubularin in Mammalian Cells*

MTM1, the gene encoding myotubularin (MTM1), is mutated in the X-linked myotubular myopathy (XLMTM), a severe genetic muscular disorder. MTM1 is a phosphoinositide phosphatase hydrolyzing phosphatidylinositol 3-phosphate (PtdIns(3)P) in yeast and in vitro. Because this lipid is implicated in the regulation of vesicular trafficking, we used established cell lines from XLMTM patients to evaluate whether the lack of endogenous MTM1 expression could affect PtdIns(3)P labeling patterns. Our results showed that the vesicular trafficking related to early endosomes was not significantly affected in the XLMTM cell lines compared with control cells. However, in addition to PtdIns(3)P, we found that MTM1 can hydrolyze phosphatidylinositol 3,5-bisphosphate both in vitro and in mammalian cells. Using a mass assay, we demonstrated that the product generated is phosphatidylinositol 5-phosphate (PtdIns(5)P), a recently discovered phosphoinositide, the function of which is still unknown. In L6 myotubes overexpressing MTM1, hyperosmotic shock induced an increase in the mass level of PtdIns(5)P that was reduced by 50% upon overexpression of the MTM1 inactive mutant D278A. These data demonstrate for the first time a role for MTM1 in the production of PtdIns(5)P in mammalian cells, suggesting that the lack of transformation of phosphatidylinositol 3,5-bisphosphate into PtdIns(5)P might be an important component in the etiology of myotubular myopathy.
Microglial secreted cathepsin B induces neuronal apoptosis

Activated microglia release a number of substances that can influence neuronal signalling and survival. Here we report that microglia stimulated with the peptide chromogranin A (CGA), secreted the cysteine protease, cathepsin B. Conditioned medium from CGA exposed microglia was neurotoxic to the HT22 hippocampal cell line and to primary cultures of cerebellar granule neurones. In both neuronal cell types, the neurotoxicity could be significantly attenuated with z‐FA‐fmk or by depletion of microglial conditioned medium with cathepsin B antibody. Conditioned medium from activated microglia or cathepsin B alone induced neuronal apoptosis and caspase 3 activation. Our data indicate that CGA‐activated microglia can trigger neuronal apoptosis and that this may be mediated through the secretion of cathepsin B. Since cathepsins may also play a role in the amyloidogenic processing of amyloid precursor protein, these results may have significance for tissue damage and neuronal loss in the neuropathology of Alzheimer's disease.
A heuristic algorithm for RNA secondary structure based on genetic algorithm

Ribonucleic acid (RNA) has an essential and an important role in cellular life. Their functions are directly related to their secondary and tertiary structures. For this reason, RNA structure prediction is one of the most important topics in bioinformatics. X-Ray, Crystallography, and Nuclear Magnetic Resonance are the current physics methods used to determinate the RNA structures. These methods are very efficient but they are very expensive, they require a lot of efforts and extremely time consuming. Therefore, the use of bioinformatics methods to predict the RNA structure is highly desirable and several methods have been proposed. In this paper, we propose a new algorithm that combines between the Greedy Randomized Adaptive Search Procedure (GRASP) and the Genetic Algorithm principle (GA). To assess the efficacy of our algorithm, we have compared it with some of the well-known algorithms for RNA secondary structure prediction such as RNAstructure, IPknot, TT2NE and CyloFold, by using four tests cases TMV, CcTMV, CGMMV and Hs_PrP. The obtained results show clearly the effectiveness of the proposed algorithm.