julilili42/papers huggingface dataset:
Noncoding RNA of Glutamine Synthetase I Modulates Antibiotic Production inStreptomyces coelicolorA3(2)
2009-12-05

ABSTRACT Overexpression of antisense chromosomal cis -encoded noncoding RNAss (ncRNAs) in glutamine synthetase I resulted in a decrease in growth, protein synthesis, and antibiotic production in Streptomyces coelicolor . In addition, we predicted 3,597 cis -encoded ncRNAs and validated 13 of them experimentally, including several ncRNAs that are differentially expressed in bacterial hormone-defective mutants.
New Architectures for Tet-On and Tet-Off Regulation in Staphylococcus aureus
2009-12-05

ABSTRACT Inducible expression is a valuable approach for the elucidation of gene functions. Here, we present new configurations of the tetracycline-dependent gene regulation ( tet ) system for Staphylococcus aureus . To provide improved and expanded modes of control, strains and plasmids were constructed for the constitutive expression of tetR or a variant allele, rev -tetR r2 . The encoded regulators respond differently to the effector anhydrotetracycline (ATc), which causes target gene expression to be induced with TetR or repressed with rev - TetR. To quantify and compare regulation mediated by episomal or chromosomal (rev-) tetR constructs, expression from a chromosomal P xyl/tet - gfpmut2 fusion was measured. Chromosomally encoded TetR showed tight repression and allowed high levels of dose-dependent gene expression in response to ATc. Regulatory abilities were further verified using a strain in which a native S. aureus gene ( zwf ) was put under tet control in its native chromosomal location. Tight repression was reflected by transcript amounts, which were barely detectable under repressed conditions and high in ATc-treated cells. In reporter gene assays, this type of control, termed Tet-on, was more efficient than Tet-off regulation, in which addition of ATc causes downregulation of a target gene. The latter was achieved and quantified by direct rev - TetR control of P xyl/tet - gfpmut2 . Additionally, TetR was used in trans to control the expression of antisense RNA for posttranscriptional gene silencing. Induction of antisense RNA expression of the fabI gene caused pronounced growth retardation lasting several hours. These results demonstrate the efficiency of the new tet systems and their flexible use for different purposes.
Misattributions of agency in schizophrenia are based on imprecise predictions about the sensory consequences of one's actions
2009-12-07

The experience of being the initiator of one's own actions seems to be infallible at first glance. Misattributions of agency of one's actions in certain neurological or psychiatric patients reveal, however, that the central mechanisms underlying this experience can go astray. In particular, delusions of influence in schizophrenia might result from deficits in an inferential mechanism that allows distinguishing whether or not a sensory event has been self-produced. This distinction is made by comparing the actual sensory information with the consequences of one's action as predicted on the basis of internal action-related signals such as efference copies. If this internal prediction matches the actual sensory event, an action is registered as self-caused; in case of a mismatch, the difference is interpreted as externally produced. We tested the hypothesis that delusions of influence are based on deficits in this comparator mechanism. In particular, we tested whether patients' impairments in action attribution tasks are caused by imprecise predictions about the sensory consequences of self-action. Schizophrenia patients and matched controls performed pointing movements in a virtual-reality setup in which the visual consequences of movements could be rotated with respect to the actual movement. Experiment 1 revealed higher thresholds for detecting experimental feedback rotations in the patient group. The size of these thresholds correlated positively with patients' delusions of influence. Experiment 2 required subjects to estimate their direction of pointing visually in the presence of constantly rotated visual feedback. When compared to controls, patients' estimates were significantly better adapted to the feedback rotation and exhibited an increased variability. In interleaved trials without visual feedback, i.e. when pointing estimates relied solely on internal action-related signals, this variability was likewise increased and correlated with both delusions of influence and the size of patients' detection thresholds as assessed in the first experiment. These findings support the notion that delusions of influence are based on imprecise internal predictions about the sensory consequences of one's actions. Moreover, we suggest that such imprecise predictions prompt patients to rely more strongly on (and thus adapt to) external agency cues, in this case vision. Such context-dependent weighted integration of imprecise internal predictions and alternative agency cues might thus reflect the common basis for the various misattributions of agency in schizophrenia patients.
Efficient and Accurate Lp-Norm Multiple Kernel Learning
2009-12-07

Learning linear combinations of multiple kernels is an appealing strategy when the right choice of features is unknown. Previous approaches to multiple kernel learning (MKL) promote sparse kernel combinations to support interpretability. Unfortunately, l1-norm MKL is hardly observed to outperform trivial baselines in practical applications. To allow for robust kernel mixtures, we generalize MKL to arbitrary lp-norms. We devise new insights on the connection between several existing MKL formulations and develop two efficient interleaved optimization strategies for arbitrary p > 1. Empirically, we demonstrate that the interleaved optimization strategies are much faster compared to the traditionally used wrapper approaches. Finally, we apply lp-norm MKL to real-world problems from computational biology, showing that non-sparse MKL achieves accuracies that go beyond the state-of-the-art.
Sustained dopaminergic response of parkinsonism and depression in POLG‐associated parkinsonism
2009-12-07

Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Neurometric function analysis of population codes
2009-12-07

The relative merits of different population coding schemes have mostly been analyzed\\nin the framework of stimulus reconstruction using Fisher Information. Here,\\nwe consider the case of stimulus discrimination in a two alternative forced choice\\nparadigm and compute neurometric functions in terms of the minimal discrimination\\nerror and the Jensen-Shannon information to study neural population codes.\\nWe first explore the relationship between minimum discrimination error, Jensen-\\nShannon Information and Fisher Information and show that the discrimination\\nframework is more informative about the coding accuracy than Fisher Information\\nas it defines an error for any pair of possible stimuli. In particular, it includes\\nFisher Information as a special case. Second, we use the framework to study population\\ncodes of angular variables. Specifically, we assess the impact of different\\nnoise correlations structures on coding accuracy in long versus short decoding\\ntime windows. That is, for long time window we use the common Gaussian noise\\napproximation. To address the case of short time windows we analyze the Ising\\nmodel with identical noise correlation structure. In this way, we provide a new\\nrigorous framework for assessing the functional consequences of noise correlation\\nstructures for the representational accuracy of neural population codes that is\\nin particular applicable to short-time population coding.
A joint maximum-entropy model for binary neural population patterns and continuous signals
2009-12-07

Second-order maximum-entropy models have recently gained much interest for describing the statistics of binary spike trains. Here, we extend this approach to\\ntake continuous stimuli into account as well. By constraining on the joint secondorder\\nstatistics, we obtain a joint Gaussian-Boltzmann distribution of continuous\\nstimuli and binary neural firing patterns, for which we also compute marginal and\\nconditional distributions. This model has the same computational complexity as\\npure binary models and fitting it to data is a convex problem. We show that the\\nmodel can be seen as an extension to the classical spike-triggered average and can\\nbe used as a non-linear method for extracting features which a neural population\\nis sensitive to. Further, by calculating the posterior distribution of stimuli given\\nan observed neural response, the model can be used to decode stimuli and yields\\na natural spike-train metric. Therefore, extending the framework of maximumentropy\\nmodels to continuous variables allows us to gain novel insights into the\\nrelationship between the firing patterns of neural ensembles and the stimuli they\\nare processing.
Critical Care Seizures Related to Illicit Drugs and Toxins
2009-12-07

Seizures caused by ingestion of drugs and toxins do require specific treatment aiming to terminate epileptiform activity and to eliminate the toxin. Withdrawal from regularly ingested drugs can also be accompanied by seizures requiring ICU care. This chapter discusses diagnostic and therapeutic particularities of seizures induced by illicit drugs of abuse, environmental toxins, and heavy metals.
Insulin Modulates Food-Related Activity in the Central Nervous System
2009-12-08

We demonstrate that intranasal insulin led to a reduction of activity in brain areas related to object processing and memory and may have an effect on brain activation with regard to the processing of food pictures. This effect might be part of a mechanism that terminates food intake in the postprandial state.
Cardiac awareness and autonomic cardiac reactivity during emotional picture viewing and mental stress
2009-12-08

This study investigated the relationship between autonomic cardiovascular reactivity and cardiac awareness during the following conditions: baseline, emotional picture viewing, mental stress, and heartbeat tracking. Cardiac parameters were examined by using power spectrum analysis of heart rate variability and impedance cardiography. According to their performance in a heartbeat tracking task, 38 participants were classified as good (n=19) or poor (n=19) heartbeat perceivers. Neither group differed during baseline and heartbeat tracking, but good compared to poor heartbeat perceivers demonstrated greater sympathetic reactivity during mental stress and more vagal reactivity and subjective arousal during emotional picture viewing. The results suggest that cardiac awareness is related to greater responsivity of the autonomic nervous system during situations evoking autonomic reactivity.
Evaluation of Flagella and Flagellin of Pseudomonas aeruginosa as Vaccines
2009-12-08

ABSTRACT Pseudomonas aeruginosa is a serious pathogen in hospitalized, immunocompromised, and cystic fibrosis (CF) patients. P. aeruginosa is motile via a single polar flagellum made of polymerized flagellin proteins differentiated into two major serotypes: a and b. Antibodies to flagella delay onset of infection in CF patients, but whether immunity to polymeric flagella and that to monomeric flagellin are comparable has not been addressed, nor has the question of whether such antibodies might negatively impact Toll-like receptor 5 (TLR5) activation, an important component of innate immunity to P. aeruginosa . We compared immunization with flagella and that with flagellin for in vitro effects on motility, opsonic killing, and protective efficacy using a mouse pneumonia model. Antibodies to flagella were superior to antibodies to flagellin at inhibiting motility, promoting opsonic killing, and mediating protection against P. aeruginosa pneumonia in mice. Protection against the flagellar type strains PAK and PA01 was maximal, but it was only marginal against motile clinical isolates from flagellum-immunized CF patients who nonetheless became colonized with P. aeruginosa . Purified flagellin was a more potent activator of TLR5 than were flagella and also elicited higher TLR5-neutralizing antibodies than did immunization with flagella. Antibody to type a but not type b flagella or flagellin inhibited TLR5 activation by whole bacterial cells. Overall, intact flagella appear to be superior for generating immunity to P. aeruginosa , and flagellin monomers might induce antibodies capable of neutralizing innate immunity due to TLR5 activation, but solid immunity to P. aeruginosa based on flagellar antigens may require additional components beyond type a and type b proteins from prototype strains.
PRECLINICAL STUDY: Atypical development of behavioural sensitization to 3,4‐methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) in adolescent rats and its expression in adulthood: role of the MDMA chirality
2009-12-08

ABSTRACT Despite the great popularity of 3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) as a drug of abuse, not much is known about the detailed mechanisms of the acute and subchronic effects of the drug. There is especially a lack of information about the distinct behavioural effects of its optical isomers (enantiomers) R‐ and S‐MDMA compared with the racemic RS‐MDMA. For this purpose, adolescent rats were repetitively treated during two treatment stages (stage 1: days 1–10; stage 2: days 15, 17, 19) with RS‐MDMA (5 or 10 mg/kg) or each of the respective enantiomers (5 mg/kg). The repeated treatment started on postnatal day (PND) 32 and locomotor activity was measured on each day by means of a photobeam‐equipped activity box system. RS‐MDMA or S‐MDMA administration led acutely to massive hyperlocomotion and subchronically, to the development of behavioural sensitization after a short habituation period. R‐MDMA was free of hyperactivating effects and even decreased locomotor behaviour upon repeated treatment. Nevertheless, co‐administration of R‐MDMA increased the hyperactivity of S‐MDMA and made the S‐MDMA induced behavioural sensitization state‐dependent. The animals pre‐treated with R‐MDMA showed a sensitized response in adulthood when tested with RS‐MDMA. Our results indicated that even in the absence of substantial neurotoxicity, both MDMA enantiomers can lead to long‐term changes in brain circuitry and concomitant behavioural changes when repeatedly administered in adolescence. The sensitization development was most pronounced in the animals treated with S‐ and RS‐MDMA; the animals with R‐MDMA did not develop sensitization under repeated treatment but expressed a sensitized response when challenged with RS‐MDMA.
Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3
2009-12-09

Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.
Atractiellomycetes belonging to the ‘rust’ lineage (Pucciniomycotina) form mycorrhizae with terrestrial and epiphytic neotropical orchids
2009-12-09

Distinctive groups of fungi are involved in the diverse mycorrhizal associations of land plants. All previously known mycorrhiza-forming Basidiomycota associated with trees, ericads, liverworts or orchids are hosted in Agaricomycetes, Agaricomycotina. Here we demonstrate for the first time that Atractiellomycetes, members of the ‘rust’ lineage (Pucciniomycotina), are mycobionts of orchids. The mycobionts of 103 terrestrial and epiphytic orchid individuals, sampled in the tropical mountain rainforest of Southern Ecuador, were identified by sequencing the whole ITS1-5.8S-ITS2 region and part of 28S rDNA. Mycorrhizae of 13 orchid individuals were investigated by transmission electron microscopy. Simple septal pores and symplechosomes in the hyphal coils of mycorrhizae from four orchid individuals indicated members of Atractiellomycetes. Molecular phylogeny of sequences from mycobionts of 32 orchid individuals out of 103 samples confirmed Atractiellomycetes and the placement in Pucciniomycotina, previously known to comprise only parasitic and saprophytic fungi. Thus, our finding reveals these fungi, frequently associated to neotropical orchids, as the most basal living basidiomycetes involved in mycorrhizal associations of land plants.
Cytotoxic CD8+T Cell–Neuron Interactions: Perforin-Dependent Electrical Silencing Precedes But Is Not Causally Linked to Neuronal Cell Death
2009-12-09

Cytotoxic CD8 + T cells are considered important effector cells contributing to neuronal damage in inflammatory and degenerative CNS disorders. Using time-lapse video microscopy and two-photon imaging in combination with whole-cell patch-clamp recordings, we here show that major histocompatibility class I (MHC I)-restricted neuronal antigen presentation and T cell receptor specificity determine CD8 + T-cell locomotion and neuronal damage in culture and hippocampal brain slices. Two separate functional consequences result from a direct cell–cell contact between antigen-presenting neurons and antigen-specific CD8 + T cells. (1) An immediate impairment of electrical signaling in single neurons and neuronal networks occurs as a result of massive shunting of the membrane capacitance after insertion of channel-forming perforin (and probably activation of other transmembrane conductances), which is paralleled by an increase of intracellular Ca 2+ levels (within &lt;10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within ∼1 h), suggesting that extracellular effects can substitute for intracellular delivery of granzymes by perforin. Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8 + T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death.
Integrated Detection of Extended-Spectrum-Beta-Lactam Resistance by DNA Microarray-Based Genotyping of TEM, SHV, and CTX-M Genes
2009-12-10

ABSTRACT Extended-spectrum beta-lactamases (ESBL) of the TEM, SHV, or CTX-M type confer resistance to beta-lactam antibiotics in Gram-negative bacteria. The activity of these enzymes against beta-lactam antibiotics and their resistance against inhibitors can be influenced by genetic variation at the single-nucleotide level. Here, we describe the development and validation of an oligonucleotide microarray for the rapid identification of ESBLs in Gram-negative bacteria by simultaneously genotyping bla TEM , bla SHV , and bla CTX-M . The array consists of 618 probes that cover mutations responsible for 156 amino acid substitutions. As this comprises unprecedented genotyping coverage, the ESBL array has a high potential for epidemiological studies and infection control. With an assay time of 5 h, the ESBL microarray also could be an attractive option for the development of rapid antimicrobial resistance tests in the future. The validity of the DNA microarray was demonstrated with 60 blinded clinical isolates, which were collected during clinical routines. Fifty-eight of them were characterized phenotypically as ESBL producers. The chip was characterized with regard to its resolution, phenotype-genotype correlation, and ability to resolve mixed genotypes. ESBL phenotypes could be correctly ascribed to ESBL variants of bla CTX-M (76%), bla SHV (22%), or both (2%), whereas no ESBL variant of bla TEM was found. The most prevalent ESBLs identified were CTX-M-15 (57%) and SHV-12 (18%).
The Kinase Inhibitors Sunitinib and Sorafenib Differentially Affect NK Cell Antitumor Reactivity In Vitro
2009-12-10

Abstract Sunitinib and Sorafenib are protein kinase inhibitors (PKI) approved for treatment of patients with advanced renal cell cancer (RCC). However, long-term remissions of advanced RCC have only been observed after IL-2 treatment, which underlines the importance of antitumor immune responses in RCC patients. Because PKI, besides affecting tumor cells, also may inhibit signaling in immune effector cells, we determined how Sunitinib and Sorafenib influence antitumor immunity. We found that cytotoxicity and cytokine production of resting and IL-2-activated PBMC are inhibited by pharmacological concentrations of Sorafenib but not Sunitinib. Analysis of granule-mobilization within PBMC revealed that this was due to impaired reactivity of NK cells, which substantially contribute to antitumor immunity by directly killing target cells and shaping adaptive immune responses by secreting cytokines like IFN-γ. Analyses with resting and IL-2-activated NK cells revealed that both PKI concentration dependently inhibit cytotoxicity and IFN-γ production of NK cells in response to tumor targets. This was due to impaired PI3K and ERK phosphorylation which directly controls NK cell reactivity. However, while Sorafenib inhibited NK cell effector functions and signaling at levels achieved upon recommended dosing, pharmacological concentrations of Sunitinib had no effect, and this was observed upon stimulation of NK cell reactivity by tumor target cells and upon IL-2 treatment. In light of the important role of NK cells in antitumor immunity, and because multiple approaches presently aim to combine PKI treatment with immunotherapeutic strategies, our data demonstrate that choice and dosing of the most suitable PKI in cancer treatment requires careful consideration.