julilili42/papers huggingface dataset:
N-Acetylmuramic Acid (MurNAc) Auxotrophy of the Oral Pathogen Tannerella forsythia: Characterization of a MurNAc Kinase and Analysis of Its Role in Cell Wall Metabolism
2018-01-26

<i>Tannerella forsythia</i> is an anaerobic, Gram-negative oral pathogen that thrives in multispecies gingival biofilms associated with periodontitis. The bacterium is auxotrophic for the commonly essential bacterial cell wall sugar <i>N-</i>acetylmuramic acid (MurNAc) and, thus, strictly depends on an exogenous supply of MurNAc for growth and maintenance of cell morphology. A MurNAc transporter (Tf_MurT; Tanf_08375) and an ortholog of the <i>Escherichia coli</i> etherase MurQ (Tf_MurQ; Tanf_08385) converting MurNAc-6-phosphate to GlcNAc-6-phosphate were recently described for <i>T. forsythia.</i> In between the respective genes on the <i>T. forsythia</i> genome, a putative kinase gene is located. In this study, the putative kinase (Tf_MurK; Tanf_08380) was produced as a recombinant protein and biochemically characterized. Kinetic studies revealed Tf_MurK to be a 6-kinase with stringent substrate specificity for MurNAc exhibiting a 6 × 10<sup>4</sup>-fold higher catalytic efficiency (<i>k</i><sub>cat</sub>/<i>K<sub>m</sub></i> ) for MurNAc than for <i>N-</i>acetylglucosamine (GlcNAc) with <i>k<sub>cat</sub></i> values of 10.5 s<sup>-1</sup> and 0.1 s<sup>-1</sup> and <i>K<sub>m</sub></i> values of 200 μM and 116 mM, respectively. The enzyme kinetic data suggest that Tf_MurK is subject to substrate inhibition (<i>K<sub>i[S]</sub></i> = 4.2 mM). To assess the role of Tf_MurK in the cell wall metabolism of <i>T. forsythia</i>, a kinase deletion mutant (<i>ΔTf_murK::erm</i>) was constructed. This mutant accumulated MurNAc intracellularly in the exponential phase, indicating the capability to take up MurNAc, but inability to catabolize MurNAc. In the stationary phase, the MurNAc level was reduced in the mutant, while the level of the peptidoglycan precursor UDP-MurNAc-pentapeptide was highly elevated. Further, according to scanning electron microscopy evidence, the <i>ΔTf_murK::erm</i> mutant was more tolerant toward low MurNAc concentration in the medium (below 0.5 μg/ml) before transition from healthy, rod-shaped to fusiform cells occurred, while the parent strain required > 1 μg/ml MurNAc for optimal growth. These data reveal that <i>T. forsythia</i> readily catabolizes exogenous MurNAc but simultaneously channels a proportion of the sugar into peptidoglycan biosynthesis. Deletion of <i>Tf_murK</i> blocks MurNAc catabolism and allows the direction of MurNAc solely to peptidoglycan biosynthesis, resulting in a growth advantage in MurNAc-depleted medium. This work increases our understanding of the <i>T. forsythia</i> cell wall metabolism and may pave new routes for lead finding in the treatment of periodontitis.
Bacterial Periplasmic Oxidoreductases Control the Activity of Oxidized Human Antimicrobial β-Defensin 1
2018-01-27

ABSTRACT The antimicrobial peptide human β-defensin 1 (hBD1) is continuously produced by epithelial cells in many tissues. Compared to other defensins, hBD1 has only minor antibiotic activity in its native state. After reduction of its disulfide bridges, however, it becomes a potent antimicrobial agent against bacteria, while the oxidized native form (hBD1ox) shows specific activity against Gram-negative bacteria. We show that the killing mechanism of hBD1ox depends on aerobic growth conditions and bacterial enzymes. We analyzed the different activities of hBD1 using mutants of Escherichia coli lacking one or more specific proteins of their outer membrane, cytosol, or redox systems. We discovered that DsbA and DsbB are essential for the antimicrobial activity of hBD1ox but not for that of reduced hBD1 (hBD1red). Furthermore, our results strongly suggest that hBD1ox uses outer membrane protein FepA to penetrate the bacterial periplasm space. In contrast, other bacterial proteins in the outer membrane and cytosol did not modify the antimicrobial activity. Using immunogold labeling, we identified the localization of hBD1ox in the periplasmic space and partly in the outer membrane of E. coli . However, in resistant mutants lacking DsbA and DsbB, hBD1ox was detected mainly in the bacterial cytosol. In summary, we discovered that hBD1ox could use FepA to enter the periplasmic space, where its activity depends on presence of DsbA and DsbB. HBD1ox concentrates in the periplasm in Gram-negative bacteria, which finally leads to bleb formation and death of the bacteria. Thus, the bacterial redox system plays an essential role in mechanisms of resistance against host-derived peptides such as hBD1.
To jump or not to jump: The Bereitschaftspotential required to jump into 192-meter abyss
2018-01-27

Abstract Self-initiated voluntary acts, such as pressing a button, are preceded by a negative electrical brain potential, the Bereitschaftspotential (BP), that can be recorded over the human scalp using electroencephalography (EEG). Up to now, the BP required to initiate voluntary acts has only been recorded under well-controlled laboratory conditions. It is thus not known if this form of brain activity also underlies motor initiation in possible life-threatening decision making, such as jumping into a 192-meter abyss, an act requiring extraordinary willpower. Here, we report BP before self-initiated 192-meter extreme bungee jumping across two semi-professional cliff divers (both male, mean age 19.3 years). We found that the spatiotemporal dynamics of the BP is comparable to that recorded under laboratory conditions. These results, possible through recent advancements in wireless and portable EEG technology, document for the first time pre-movement brain activity preceding possible life-threatening decision making.
The biogenesis of extracellular vesicles fromStaphylococcus aureusand their application as a novel vaccine platform
2018-01-28

Abstract Gram-positive bacteria secrete extracellular vesicles (EVs) that package diverse bacterial antigens and play key roles in bacterial pathogenesis. However, the mechanisms underlying EV production in Gram-positive bacteria are poorly understood. We purified and characterized EVs from a community-associated methicillin-resistant Staphylococcus aureus isolate (USA300) and investigated mechanisms underlying EV production. Native EVs contained 165 proteins, including cytosolic, surface, and secreted proteins, autolysins, and numerous cytolysins. Staphylococcal alpha-type phenol-soluble modulins (surfactant-like peptides) promoted EV biogenesis, presumably by acting at the cytoplasmic membrane, whereas peptidoglycan crosslinking and autolysin activity were found to increase EV production by altering the permeability of the staphylococcal cell wall. To address the immunogenicity of EVs, we created engineered EVs (eng-EVs) by expressing detoxified proteins Hla H35L and LukE in EVs generated from a nontoxic S. aureus ΔagrΔspa mutant. Eng-EVs exhibited no cytotoxicity in vitro, and mice immunized with the eng-EVs produced toxin-neutralizing antibodies and showed reduced lethality in a mouse sepsis model. Our study reveals novel mechanisms underlying S. aureus EV production and highlights the usefulness of EVs as a novel S. aureus vaccine platform.
Understanding and exploiting long-lived near-infrared emission of a molecular ruby
2018-01-29

Enabling strong and long-lived NIR emission from complexes with earth-abundant metal ions is exemplified by embedding chromium(III) in a very strong ligand field yielding the molecular ruby [Cr(ddpd)2]3+. This review aims at illustrating the main non-radiative decay pathways for electronically excited chromium(III) complexes, namely back-intersystem crossing, excited state distortion and multiphonon relaxation and at controlling these pathways by molecular design. The case study of [Cr(ddpd)2]3+ highlights recent successful design strategies and discusses first applications of the highly emissive 3d metal complex as optical sensor molecule and as photosensitizer.
Age, burnout and physical and psychological work ability among nurses
2018-01-29

Findings indicated physical and psychological dimensions of work ability that differed by age and occupational burnout. This emphasizes the need for interventions to reduce burnout and to address age-related strengths and vulnerabilities relating to physical and psychological work ability.
Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants
2018-01-29

Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher <i>k</i><sub>off</sub> rates compared to the <i>k</i><sub>on</sub> rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding <i>k</i><sub>on</sub> and <i>k</i><sub>off</sub> against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
The UK Centre for Astrobiology: A Virtual Astrobiology Centre. Accomplishments and Lessons Learned, 2011–2016
2018-01-29

The UK Centre for Astrobiology (UKCA) was set up in 2011 as a virtual center to contribute to astrobiology research, education, and outreach. After 5 years, we describe this center and its work in each of these areas. Its research has focused on studying life in extreme environments, the limits of life on Earth, and implications for habitability elsewhere. Among its research infrastructure projects, UKCA has assembled an underground astrobiology laboratory that has hosted a deep subsurface planetary analog program, and it has developed new flow-through systems to study extraterrestrial aqueous environments. UKCA has used this research backdrop to develop education programs in astrobiology, including a massive open online course in astrobiology that has attracted over 120,000 students, a teacher training program, and an initiative to take astrobiology into prisons. In this paper, we review these activities and others with a particular focus on providing lessons to others who may consider setting up an astrobiology center, institute, or science facility. We discuss experience in integrating astrobiology research into teaching and education activities. Key Words: Astrobiology-Centre-Education-Subsurface-Analog research. Astrobiology 18, 224-243.
Gut bacterial metabolite Urolithin A (UA) mitigates Ca2+ entry in T cells by regulating miR-10a-5p
2018-01-29

ABSTRACT The gut microbiota influences several biological functions including immune response. Inflammatory bowel disease is favourably influenced by consumption of several dietary natural plant products such as pomegranate, walnuts and berries containing polyphenolic compounds such as ellagitannins and ellagic acid. The gut microbiota metabolises ellagic acid leading to formation of bioactive urolithins A, B, C and D. Urolithin A (UA) is the most active and effective gut metabolite and acts as a potent anti-inflammatory and anti-oxidant agent. However, how gut metabolite UA affects the function of immune cells remained incompletely understood. T cell proliferation is stimulated by store operated Ca 2+ entry (SOCE) resulting from stimulation of Orai1 by STIM1/STIM2. We show here that treatment of murine CD4 + T cells with UA (10 μM, 3 days) significantly blunted SOCE in CD4 + T cells, an effect paralleled by significant downregulation of Orai1 and STIM1/2 transcript levels and protein abundance. UA treatment further increased miR-10a-5p abundance in CD4 + T cells in a dose dependent fashion. Overexpression of miR-10a-5p significantly decreased STIM1/2 and Orai1 mRNA and protein levels as well as SOCE in CD4 + T cells. UA further decreased CD4 + T cell proliferation. Thus, bacterial metabolite UA up-regulates miR-10a-5p thus interfering with Orai1/STIM1/STIM2 expression, store operated Ca 2+ entry and proliferation of murine CD4 + T cells.
IκBζ is constitutively expressed in human and murine airway epithelium
2018-01-29

ABSTRACT AIM IκBζ is a transcriptional factor induced in immune cells upon Toll-like receptor (TLR) activation. Recent studies demonstrate unconventional, constitutive expression of IκBζ in epithelium of mouse skin and eyes, possibly reflecting continuous activation of TLRs by pathogen-associated molecular patterns (PAMPs). In this context, the lung epithelium which constitutes another important barrier also expresses IκBζ but may not be as actively exposed to pathogens as skin and eyes. Our aim was to determine if IκBζ expression in the lungs is constitutive or induced. SIGNIFICANCE IκBζ is linked to lung disorders due to its role in regulating protective cytokines and antimicrobial peptides in airway epithelium and can therefore be a potential biomarker and a key therapeutic target. METHODS We evaluated IκBζ expression in airway epithelia of healthy humans and three kinds of mice: normal, gnotobiotic and Nfkbiz −/− knockout, using immunostaining and immunoblotting. RESULTS Immunohistochemistry of ciliated airway epithelial cells in healthy humans and normal mice was positive for IκBζ. The pathogen free airway cells from gnotobiotic mice also stained positive, suggesting that lung epithelial IκBζ expression does not require induction by PAMPs. Although lung epithelia from Nfkbiz −/− knockout mice also stained positive, this knockout may not have eliminated exons 3-4 and 9-14, and so did not provide the specificity control for the IκBζ antiserum. Importantly, immunoblotting tissue homogenates from gnotobiotic mouse lungs and primary human airway epithelial cells demonstrated constitutive IκBζ expression at its correct 86 kDa size. CONCLUSIONS Our data demonstrates constitutive expression of IκBζ protein in airway epithelium, indicating a potential role for this molecule in lung homeostasis.
Brain-state dependent astrocytic Ca 2+ signals are coupled to both positive and negative BOLD-fMRI signals
2018-01-30

Significance The role of astrocytes on brain function is controversial in many aspects. It remains challenging to specify the in vivo functional impact of astrocytic calcium signal when mediating vasodilation/constriction at varied physiological or pathophysiological conditions. Here, we applied simultaneous fMRI and GCaMP-mediated Ca 2+ optical fiber recording to detect distinct astrocytic Ca 2+ signals (evoked vs. intrinsic) coupled to positive and negative blood-oxygen-level-dependent signals, respectively and concurrently, with unique spatial and temporal patterns. Not only did we demonstrate the distinct neurovascular coupling events coupled to the evoked and intrinsic astrocytic calcium signals, but also revealed the thalamic regulation mechanism underlying the astrocytic calcium-mediated brain state switch. This astrocytic-relevant regulatory mechanism could underlie numerous brain disorder and injury models relevant to gliovascular disruption.
Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review
2018-01-30

In recent years, a vast quantity of clinical data has been accumulated on the pathophysiology of symptomatic vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in peri- and postmenopausal women and on the treatment options for these conditions. Guidelines from several societies have recently been updated in favor of VVA/GSM vaginal therapy with the lowest possible doses of estrogens. The combination of a vaginal ultra-low dose of 0.03 mg of estriol (E3) and lyophilized, viable Lactobacillus acidophilus KS400 (0.03 mg-E3/L) is a unique product with a dual mechanism of action supporting not only the proliferation and maturation of the vaginal epithelium, but also restoration of the lactobacillary microflora. It has been demonstrated efficiently to establish and maintain a healthy vaginal ecosystem. Use of this combination considerably improves the clinical signs and symptoms as well as the quality of life of menopausal women suffering from vaginal atrophy. This combination therapy is well tolerated with a low overall incidence of side-effects and negligible estriol absorption. Based on recent scientific evidence and current treatment guidelines, the 0.03 mg-E3/L combination could be considered one of the options for the treatment of symptomatic vaginal atrophy in aging menopausal women.
Norms and validation of the online and paper-and-pencil versions of the Abbreviated Math Anxiety Scale (AMAS) for Polish adolescents and adults
2018-01-30

The Abbreviated Math Anxiety Scale (AMAS) is one of the most popular instruments measuring math anxiety (MA). It has been validated across several linguistic and cultural contexts. In this study, we investigated the extent of administration method invariance of the AMAS by comparing results (average scores, reliabilities, factorial structure) obtained online with those from paper-and-pencil. We administered the online version of the AMAS to Polish students. Results indicate that psychometric properties of the AMAS do not differ between online and paper-and-pencil administration. Additionally, average scores of the AMAS did not differ considerably between administration forms, contrary to previous results showing that computerized measurement of MA leads to higher scores. Therefore, our results provide evidence for the usefulness of the AMAS as a reliable and valid MA measurement tool for online research and online screening purposes across cultures and also large similarity between administration forms outside an American-English linguistic and cultural context. Finally, we provide percentile and standard norms for the AMAS for adolescents and adults (in the latter case for both online and paper-and-pencil administration) as well as critical differences for the comparison of both subscales in an individual participant for practical diagnostic purposes.
Photosensitizers for Photogalvanic Cells in the Chemistry Classroom
2018-01-30

Alternative solar cells on the basis of titanium dioxide are subject of intense research. For the integration of this topic into the chemistry curriculum a set of experiments with photogalvanic cells has been developed. Titania phototelectrodes need to be irradiated with UV light, but the spectrum of solar light contains only little UV radiation. Thus photosensitizers are needed that harvest visible light. Here we present a series of experiments with different dye solutions that can serve as an alternative to the priorly used anthocyanins in the chemistry classroom. The dyes presented are more stable and also work as sensitizers in titania-based photogalvanic cells.
Measuring Microtubule Supertwist and Defects by Three-Dimensional-Force-Clamp Tracking of Single Kinesin-1 Motors
2018-01-30

Three-dimensional (3D) nanometer tracking of single biomolecules provides important information about their biological function. However, existing microscopy approaches often have only limited spatial or temporal precision and do not allow the application of defined loads. Here, we developed and applied a high-precision 3D-optical-tweezers force clamp to track in vitro the 3D motion of single kinesin-1 motor proteins along microtubules. To provide the motors with unimpeded access to the whole microtubule lattice, we mounted the microtubules on topographic surface features generated by UV-nanoimprint lithography. Because kinesin-1 motors processively move along individual protofilaments, we could determine the number of protofilaments the microtubules were composed of by measuring the helical pitches of motor movement on supertwisted microtubules. Moreover, we were able to identify defects in microtubules, most likely arising from local changes in the protofilament number. While it is hypothesized that microtubule supertwist and defects can severely influence the function of motors and other microtubule-associated proteins, the presented method allows for the first time to fully map the microtubule lattice in situ. This mapping allows the correlation of motor-filament interactions with the microtubule fine-structure. With the additional ability to apply loads, we expect our 3D-optical-tweezers force clamp to become a valuable tool for obtaining a wide range of information from other biological systems, inaccessible by two-dimensional and/or ensemble measurements.
Linking Teacher and Parent Ratings of Teacher-Nominated Gifted Elementary School Students to Each Other and to School Grades
2018-01-30

This study investigated teacher and parent ratings of teacher-nominated gifted elementary school students’ verbal abilities, mathematical abilities, deductive reasoning, creative thinking, and engagement, and connected these ratings to school grades. Teacher and parent ratings were compared with regard to accuracy levels and halo effects. Furthermore, this study explored the correlations between teacher and parent ratings and how they are related to school grades. The study was based on data from 572 elementary school students participating in an enrichment program. The results indicated the same accuracy levels for teachers and parents. However, teacher ratings were more strongly affected by halo effects than parent ratings. The correlations between teacher and parent ratings were small to medium. Both raters’ ratings were independently and positively associated with German grades when controlling for each other. Positive teacher or parent ratings of mathematical abilities and engagement buffered the relation between the other rater’s ratings and math grades.
CERA Attenuates Kidney Fibrogenesis in the db/db Mouse by Influencing the Renal Myofibroblast Generation
2018-01-30

Tubulointerstitial fibrosis (TIF) is a pivotal pathophysiological process in patients with diabetic nephropathy (DN). Multiple profibrotic factors and cell types, including transforming growth factor beta 1 (TGF-β1) and interstitial myofibroblasts, respectively, are responsible for the accumulation of extracellular matrix in the kidney. Matrix-producing myofibroblasts can originate from different sources and different mechanisms are involved in the activation process of the myofibroblasts in the fibrotic kidney. In this study, 16-week-old db/db mice, a model for type 2 DN, were treated for two weeks with continuous erythropoietin receptor activator (CERA), a synthetic erythropoietin variant with possible non-hematopoietic, tissue-protective effects. Non-diabetic and diabetic mice treated with placebo were used as controls. The effects of CERA on tubulointerstitial fibrosis (TIF) as well as on the generation of the matrix-producing myofibroblasts were evaluated by morphological, immunohistochemical, and molecular biological methods. The placebo-treated diabetic mice showed significant signs of beginning renal TIF (shown by picrosirius red staining; increased connective tissue growth factor (CTGF), fibronectin and collagen I deposition; upregulated KIM1 expression) together with an increased number of interstitial myofibroblasts (shown by different mesenchymal markers), while kidneys from diabetic mice treated with CERA revealed less TIF and fewer myofibroblasts. The mechanisms, in which CERA acts as an anti-fibrotic agent/drug, seem to be multifaceted: first, CERA inhibits the generation of matrix-producing myofibroblasts and second, CERA increases the ability for tissue repair. Many of these CERA effects can be explained by the finding that CERA inhibits the renal expression of the cytokine TGF-β1.