julilili42/papers huggingface dataset:
Mobile Elements, Phages, and Genomic Islands of Staphylococci and Streptococci
2014-04-08

The most important pathogenic species of the two genera, Staphylococcus aureus and Streptococcus pyogenes, have been studied more extensively than most other bacterial pathogens by microbiologists and physicians. In staphylococci, accessory genetic elements contribute to resistance to antibiotics, antiseptics, and disinfectants and are involved in genetic rearrangements and formation of virulence traits. Interestingly, the 3' region of mecA in S. sciuri also has a high homology to the corresponding region of S. aureus. The presence of one or more copies of IS431 within mec and directed repeats at the ends of mecA, as well as open reading frames within mec that may encode recombinases, suggests that mecA and its associated DNA are mobile elements. The mechanism of maintenance of genetic diversity by natural transformation of S. pneumoniae which enables intraspecies and interspecies horizontal gene transfer differs fundamentally from that described for the mecA region in staphylococci. Staphylococcal phages are also involved in the expression of virulence determinants by mediating both positive and negative lysogenic conversion. Temperate phages of Streptococcus pyogenes are of particular interest because one class of major virulence factors, the streptococcal pyrogenic toxins, reside on their genomes. Of the virulence regulators, only the vir regulon occurs in all S. pyogenes strains, which highlights its exceptional role in pathogenicity. In contrast to S. pyogenes, S. pneumoniae does develop natural competence, and it has become known as the first microorganism with the capacity to take up free DNA experimentally from the environment.
PRKAR1B mutation associated with a new neurodegenerative disorder with unique pathology
2014-04-09

Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and α-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A. Here we describe a family with a novel late-onset neurodegenerative disorder presenting with dementia and/or parkinsonism in 12 affected individuals. The disorder is characterized by a unique neuropathological phenotype displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immunoreactivity for intermediate filaments. Combining linkage analysis, exome sequencing and proteomics analysis, we identified a heterozygous c.149T>G (p.Leu50Arg) missense mutation in the gene encoding the protein kinase A type I-beta regulatory subunit (PRKAR1B). The pathogenicity of the mutation is supported by segregation in the family, absence in variant databases, and the specific accumulation of PRKAR1B in the inclusions in our cases associated with a specific biochemical pattern of PRKAR1B. Screening of PRKAR1B in 138 patients with Parkinson's disease and 56 patients with frontotemporal dementia did not identify additional novel pathogenic mutations. Our findings link a pathogenic PRKAR1B mutation to a novel hereditary neurodegenerative disorder and suggest an altered protein kinase A function through a reduced binding of the regulatory subunit to the A-kinase anchoring protein and the catalytic subunit of protein kinase A, which might result in subcellular dislocalization of the catalytic subunit and hyperphosphorylation of intermediate filaments.
Biosynthesis of the Unique Wall Teichoic Acid of Staphylococcus aureus Lineage ST395
2014-04-09

ABSTRACT The major clonal lineages of the human pathogen Staphylococcus aureus produce cell wall-anchored anionic poly-ribitol-phosphate (RboP) wall teichoic acids (WTA) substituted with d -Alanine and N -acetyl- d -glucosamine. The phylogenetically isolated S. aureus ST395 lineage has recently been found to produce a unique poly-glycerol-phosphate (GroP) WTA glycosylated with N -acetyl- d -galactosamine (GalNAc). ST395 clones bear putative WTA biosynthesis genes on a novel genetic element probably acquired from coagulase-negative staphylococci (CoNS). We elucidated the ST395 WTA biosynthesis pathway and identified three novel WTA biosynthetic genes, including those encoding an α- O -GalNAc transferase TagN, a nucleotide sugar epimerase TagV probably required for generation of the activated sugar donor substrate for TagN, and an unusually short GroP WTA polymerase TagF. By using a panel of mutants derived from ST395, the GalNAc residues carried by GroP WTA were found to be required for infection by the ST395-specific bacteriophage Φ187 and to play a crucial role in horizontal gene transfer of S. aureus pathogenicity islands (SaPIs). Notably, ectopic expression of ST395 WTA biosynthesis genes rendered normal S. aureus susceptible to Φ187 and enabled Φ187-mediated SaPI transfer from ST395 to regular S. aureus . We provide evidence that exchange of WTA genes and their combination in variable, mosaic-like gene clusters have shaped the evolution of staphylococci and their capacities to undergo horizontal gene transfer events. IMPORTANCE The structural highly diverse wall teichoic acids (WTA) are cell wall-anchored glycopolymers produced by most Gram-positive bacteria. While most of the dominant Staphylococcus aureus lineages produce poly-ribitol-phosphate WTA, the recently described ST395 lineage produces a distinct poly-glycerol-phosphate WTA type resembling the WTA backbone of coagulase-negative staphylococci (CoNS). Here, we analyzed the ST395 WTA biosynthesis pathway and found new types of WTA biosynthesis genes along with an evolutionary link between ST395 and CoNS, from which the ST395 WTA genes probably originate. The elucidation of ST395 WTA biosynthesis will help to understand how Gram-positive bacteria produce highly variable WTA types and elucidate functional consequences of WTA variation.
The virtual observatory service TheoSSA: Establishing a database of synthetic stellar flux standards
2014-04-09

In the framework of the Virtual Observatory (VO), the German Astrophysical\\nVirtual Observatory (GAVO) developed the registered service TheoSSA\\n(Theoretical Stellar Spectra Access). It provides easy access to stellar\\nspectral energy distributions (SEDs) and is intended to ingest SEDs calculated\\nby any model-atmosphere code, generally for all effective temperature, surface\\ngravities, and elemental compositions. We will establish a database of SEDs of\\nflux standards that are easily accessible via TheoSSA's web interface.\\n The OB-type subdwarf Feige 110 is a standard star for flux calibration.\\nState-of-the-art non-local thermodynamic equilibrium (NLTE) stellar-atmosphere\\nmodels that consider opacities of species up to trans-iron elements will be\\nused to provide a reliable synthetic spectrum to compare with observations.\\n In case of Feige 110, we demonstrate that the model reproduces not only its\\noverall continuum shape from the far-ultraviolet (FUV) to the optical\\nwavelength range but also the numerous metal lines exhibited in its FUV\\nspectrum.\\n We present a state-of-the-art spectral analysis of Feige 110. We determined\\n , and\\nthe abundances of He, N, P, S, Ti, V, Cr, Mn, Fe, Co, Ni, Zn, and Ge. Ti, V,\\nMn, Co, Zn, and Ge were identified for the first time in this star. Upper\\nabundance limits were derived for C, O, Si, Ca, and Sc.\\n The TheoSSA database of theoretical SEDs of stellar flux standards guarantees\\nthat the flux calibration of astronomical data and cross-calibration between\\ndifferent instruments can be based on models and SEDs calculated with\\nstate-of-the-art model-atmosphere codes.\\n
Screening for Bioactivity
2014-04-09

The present situation in the screening for bioactive compounds is determined by the nearly unlimited capacity in the throughput of assays. The assays include classical antibacterial assays, classical antifungal assays, antitumor assays, enzyme inhibititory assays, antiparasitic assays, herbicidal assays, and algicidal assays. Alexander Fleming was one of the first scientists who used the agar plate diffusion assay to detect antibacterial activity. Most assays are focused on the inhibition of the polysaccharide network of the cell wall of many fungi, which consists of β-1,3-glucan, chitin, and mannan. One of the most promising new antifungals that were detected as glucan synthase inhibitors is the echinocandin lipopeptide group. Antitumor assays for high-throughput screening are mainly based on the specific inhibition of factors belonging to regulatory cascades. Such assays include the inhibition of protein-tyrosin phosphatases, which control the cell cycle or the inhibition of protein-tyrosin kinases. Chemical screening is focused on the chemical diversity produced by microorganisms and on the assumption that each secondary metabolite produced has or had a biological function in the producing organism. Zahner and coworkers modified the method with regard to staining reagents, sample preparation, and variation of culture conditions of the microorganisms, and his group described numerous secondary metabolites having antibacterial, antifungal, antitumor, enzyme inhibitory, or insecticidal activities.
The effects of direct and indirect speech on discourse comprehension in Dutch listeners with and without aphasia
2014-04-09

Background: Research on language comprehension in aphasia has primarily focused on comprehension of isolated words and sentences. Even though previous studies have provided insights into comprehension abilities of individuals with aphasia at the word and grammatical level, our understanding of the nature and extent of their language comprehension (dis)abilities is not yet complete. In contrast to the highly restricted semantic and syntactic interpretation of sentences, discourse comprehension requires additional pragmatic and non-linguistic skills.Aims: The purpose of this study was to assess language comprehension in individuals with and without aphasia at the discourse level. In particular, it addressed the question of whether the use of direct speech, compared to indirect speech, affects comprehension of narrative discourse in Dutch aphasic and non-brain-damaged (NBD) listeners.Methods &amp; Procedures: The Direct Speech Comprehension (DISCO) test was developed to examine the effects of manipulating direct vs. indirect speech on discourse comprehension. Twenty-three individuals with aphasia and 20 NBD participants were presented with spoken narratives that contained either direct or indirect speech reports. The narratives were presented audio-visually on an iPad, and comprehension was assessed with yes/no questions.Outcomes &amp; Results: The performance of the participants with aphasia was significantly poorer than that of the NBD participants. Moreover, a main effect for condition type was found, indicating that narratives with direct speech reports were better understood than narratives with indirect speech reports by listeners with and without aphasia. There was no interaction between group and condition type indicating that this main effect held for both the aphasic and the NBD listeners. However, for the participants with aphasia, there was an interaction between condition and Token Test error score indicating that the positive effect of direct speech constructions diminishes for individuals with poorer comprehension.Conclusions: Direct speech constructions facilitate language comprehension in listeners with and without aphasia. One explanation for this finding is the occurrence of additional layers of communication, such as intonation and facial expression, often accompanying direct speech constructions. An alternative account is the degree of grammatical complexity: In Dutch, the syntactic construction of indirect speech requires embedding, whereas in direct speech the introductory sentence and the quote are both main clauses. The finding that the beneficial effect of direct speech on language comprehension diminishes for individuals with severe aphasia may indicate that the DISCO is too difficult for them to reveal an effect of a subtle manipulation such as that of condition type.
Identification and Characterization ofLegionella pneumophilaPhospholipases A
2014-04-09

The major proteins of the anion-exchange fractions with phospholipases A (PLA) activity were N-terminally sequenced. This chapter analyzes the bacterial membrane lipid composition of the Legionella pneumophila aas mutants and the 130b wild type by thin-layer chro-matography (TLC). The role of Aas during L. pneumophila intracellular infection was assessed in the three host models, U937 macrophages, A549 epithelial cells, and Acanthamoeba castellanii amoebae, and Aas was found to be dispensable, because L. pneumophila aas mutants showed the same increase in CFU in all three hosts during 72 h of infection as the wild type. The chapter presents data that show that L. pneumophila Aas contributes to the incorporation of phospholipids into the bacterial membrane, and in addition to L. pneumophila PlaA, is another enzyme involved in the detoxification of lysophospholipids. The authors examined the corresponding L. pneumophila 130b unk1 mutants for hydrolysis of diacylphospho-lipids, monoacylphospholipids, and 1-MPG and found that Unk1 did not contribute to the secreted PLA and L. pneumophila phospholipases A (LPLA) activities of L. pneumophila. The data indicate an essential role for Unk1 in infections of amoebae and macrophages by L. pneumophila. The authors identified three proteins, Aas, LvrE, and Unk1, present in the L. pneumophila culture supernatant. Aas contributes to the cell membrane integrity of L. pneumophila, but is dispensable for the infection of host cells. Since bacterial lipolytic enzymes are important bacterial tools for surviving both inside and outside of hosts, their characterization promotes one's understanding of the life cycle of L. pneumophila.
Fungal Chitin Dampens Inflammation through IL-10 Induction Mediated by NOD2 and TLR9 Activation
2014-04-10

Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10. We identified NOD2, TLR9 and the mannose receptor as essential fungal chitin-recognition receptors for the induction of this response. Chitin reduced LPS-induced inflammation in vivo and may therefore contribute to the resolution of the immune response once the pathogen has been defeated. Fungal chitin also induced eosinophilia in vivo, underpinning its ability to induce asthma. Polymorphisms in the identified chitin receptors, NOD2 and TLR9, predispose individuals to inflammatory conditions and dysregulated expression of chitinases and chitinase-like binding proteins, whose activity is essential to generate IL-10-inducing fungal chitin particles in vitro, have also been linked to inflammatory conditions and asthma. Chitin recognition is therefore critical for immune homeostasis and is likely to have a significant role in infectious and allergic disease.
Interplay of the Serine/Threonine-Kinase StkP and the Paralogs DivIVA and GpsB in Pneumococcal Cell Elongation and Division
2014-04-10

Despite years of intensive research, much remains to be discovered to understand the regulatory networks coordinating bacterial cell growth and division. The mechanisms by which Streptococcus pneumoniae achieves its characteristic ellipsoid-cell shape remain largely unknown. In this study, we analyzed the interplay of the cell division paralogs DivIVA and GpsB with the ser/thr kinase StkP. We observed that the deletion of divIVA hindered cell elongation and resulted in cell shortening and rounding. By contrast, the absence of GpsB resulted in hampered cell division and triggered cell elongation. Remarkably, ΔgpsB elongated cells exhibited a helical FtsZ pattern instead of a Z-ring, accompanied by helical patterns for DivIVA and peptidoglycan synthesis. Strikingly, divIVA deletion suppressed the elongated phenotype of ΔgpsB cells. These data suggest that DivIVA promotes cell elongation and that GpsB counteracts it. Analysis of protein-protein interactions revealed that GpsB and DivIVA do not interact with FtsZ but with the cell division protein EzrA, which itself interacts with FtsZ. In addition, GpsB interacts directly with DivIVA. These results are consistent with DivIVA and GpsB acting as a molecular switch to orchestrate peripheral and septal PG synthesis and connecting them with the Z-ring via EzrA. The cellular co-localization of the transpeptidases PBP2x and PBP2b as well as the lipid-flippases FtsW and RodA in ΔgpsB cells further suggest the existence of a single large PG assembly complex. Finally, we show that GpsB is required for septal localization and kinase activity of StkP, and therefore for StkP-dependent phosphorylation of DivIVA. Altogether, we propose that the StkP/DivIVA/GpsB triad finely tunes the two modes of peptidoglycan (peripheral and septal) synthesis responsible for the pneumococcal ellipsoid cell shape.
Triggering of Erythrocyte Cell Membrane Scrambling by Salinomycin
2014-04-10

Abstract Salinomycin, a polyether ionophore antibiotic effective against a variety of pathogens, has been shown to trigger apoptosis of cancer cells and cancer stem cells. The substance is thus considered for the treatment of malignancy. Salinomycin compromises tumour cell survival at least in part by interference with mitochondrial function. Erythrocytes lack mitochondria but may undergo apoptosis‐like suicidal cell death or eryptosis, which is characterized by scrambling of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Signalling involved in the triggering of eryptosis includes activation of oxidant‐sensitive Ca 2+ permeable cation channels with subsequent increase in cytosolic Ca 2+ activity ([Ca 2+ ] i ). This study explored whether salinomycin stimulates eryptosis. Phosphatidylserine‐exposing erythrocytes were identified by measurement of annexin‐V binding, cell volume was estimated from forward scatter, haemolysis determined from haemoglobin release, [Ca 2+ ] i quantified utilizing Fluo3‐fluorescence and oxidative stress from 2′,7′ dichlorodihydrofluorescein diacetate (DCFDA) fluorescence in flow cytometry. A 48‐hr exposure to salinomycin (5‐100 nM ) was followed by a significant increase in Fluo3‐fluorescence, DCFDA fluorescence and annexin‐V binding, as well as a significant decrease in forward scatter (at 5–10 nM , but not at 50 and 100 nM ). The annexin‐V binding after salinomycin treatment was significantly blunted but not abrogated in the nominal absence of extracellular Ca 2+ or in the presence of antioxidant n‐acetyl cysteine (1 mM ). Salinomycin triggers cell membrane scrambling, an effect at least partially due to oxidative stress and entry of extracellular Ca 2+ .
DLS 5.0 - The Biomechanical Effects of Dynamic Locking Screws
2014-04-10

The DLS may ultimately be an improvement over the angular stable plate osteosynthesis. The advantages of the angular stability are not only preserved but even supplemented by a dynamic element which leads to homogenous fracture movement and to a potentially uniform callus distribution.
Immune recognition ofOnchocerca volvulusproteins in the human host and animal models of onchocerciasis
2014-04-10

Abstract Onchocerca volvulus is a tissue-dwelling, vector-borne nematode parasite of humans and is the causative agent of onchocerciasis or river blindness. Natural infections of BALB/c mice with Litomosoides sigmodontis and of cattle with Onchocerca ochengi were used as models to study the immune responses to O. volvulus -derived recombinant proteins ( Ov ALT-2, Ov NLT-1, Ov 103 and Ov 7). The humoral immune response of O. volvulus -infected humans against Ov ALT-2, Ov NLT-1 and Ov 7 revealed pronounced immunoglobulin G (IgG) titres which were, however, significantly lower than against the lysate of O. volvulus adult female worms. Sera derived from patients displaying the hyperreactive form of onchocerciasis showed a uniform trend of higher IgG reactivity both to the single proteins and the O. volvulus lysate. Sera derived from L. sigmodontis- infected mice and from calves exposed to O. ochengi transmission in a hyperendemic area also contained IgM and IgG1 specific for O. volvulus -derived recombinant proteins. These results strongly suggest that L. sigmodontis- specific and O. ochengi -specific immunoglobulins elicited during natural infection of mice and cattle cross-reacted with O. volvulus -derived recombinant antigens. Monitoring O. ochengi- infected calves over a 26-month period, provided a comprehensive kinetic of the humoral response to infection that was strictly correlated with parasite load and occurrence of microfilariae.
Human dignity in late-medieval spiritual and political conflicts
2014-04-10

Recently, medievalists have started to address the question of individuality in the Middle Ages. They broadly agree that Leopold von Ranke, Jakob Burkhardt and others were misguided in understanding the Renaissance as a break with the dark medieval collectivism. The same holds – to an extent that is yet to be determined – for the understanding and justification of human dignity. In the Middle Ages, a number of perspectives arise that break ground for the idea of dignity and equality between humans. At the same time, though, there are numerous medieval approaches that vigorously challenge such ideas.
THE KNICKKOPF DOMON DOMAIN IS ESSENTIAL FOR CUTICLE DIFFERENTIATION IN Drosophila melanogaster
2014-04-10

The dopamine monoxygenase N‐terminal (DOMON) domain is found in extracellular proteins across several eukaryotic and prokaryotic taxa. It has been proposed that this domain binds to heme or sugar moieties. Here, we have analyzed the role of four highly conserved amino acids in the DOMON domain of the Drosophila melanogaster Knickkopf protein that is inserted into the apical plasma membrane and assists extracellular chitin organization. In principal, we generated Knickkopf versions with exchanged residues tryptophan 299, methionine 333 , arginine 401 , or histidine 437 , and scored for the ability of the respective engineered protein to normalize the knickkopf mutant phenotype. Our results confirm the absolute necessity of tryptophan 299, methionine 333 , and histidine 437 for Knickkopf function and stability, the latter two being predicted to be critical for heme binding. In contrast, arginine 401 is required for full efficiency of Knickkopf activity. Taken together, our genetic data support the prediction of these residues to mediate the function of Knickkopf during cuticle differentiation in insects. Hence, the DOMON domain is apparently an essential factor contributing to the construction of polysaccharide‐based extracellular matrices.