julilili42/papers huggingface dataset:
Systematic spatio-temporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration
2019-02-19

Abstract Calcium (Ca 2+ ) dysregulation has been linked to neuronal cell death, including in hereditary retinal degeneration. Ca 2+ dysregulation is thought to cause rod and cone photoreceptor cell death. Spatial and temporal heterogeneities in retinal disease models have hampered validation of this hypothesis. We examined the role of Ca 2+ in photoreceptor degeneration, assessing the activation pattern of Ca 2+ -dependent calpain proteases, generating spatio-temporal maps of the entire retina in the cpfl1 mouse model for primary cone degeneration, and in the rd1 and rd10 models for primary rod degeneration. We used Gaussian process models to distinguish the temporal sequences of degenerative molecular processes from other variability sources. In the rd1 and rd10 models, spatio-temporal pattern of increased calpain activity matched the progression of primary rod degeneration. High calpain activity coincided with activation of the calpain-2 isoform but not with calpain-1, suggesting differential roles for both calpain isoforms. Primary rod loss was linked to upregulation of apoptosis-inducing factor (AIF), although only a minute fraction of cells showed activity of the apoptotic marker caspase-3. After primary rod degeneration concluded, caspase-3 activation appeared in cones, suggesting apoptosis as the dominant mechanism for secondary cone loss. Gaussian process models highlighted calpain activity as a key event during primary rod photoreceptor cell death. Our data suggests a causal link between Ca 2+ dysregulation and primary, non-apoptotic degeneration of photoreceptors and a role for apoptosis in secondary degeneration of cones, highlighting the importance of the spatial and temporal location of key molecular events, which may guide the evaluation of new therapies.
Neutrophil-extracellular trap-associated RNA (naRNA) and LL37 enable self-amplifying inflammation in psoriasis
2019-02-19

Abstract Psoriasis is an inflammatory skin disease with strong immune cell infiltration and high levels of the antimicrobial peptide, LL37. LL37 was shown to complex DNA and RNA to activate plasmacytoid dendritic cells (pDC) in vitro and this has been thought to drive interferon-mediated disease exacerbation. However, the physiological source of such nucleic acids and thus an early initiating event for nucleic-acid mediated inflammation remains unknown. We hypothesized that neutrophils (PMNs), which dominate the psoriatic skin infiltrate, may be the source of DNA and LL37 as well-established components of so-called neutrophil extracellular traps (NETs). We show here that indeed primary murine and human PMNs mount a fulminant NET and cytokine response, albeit not via DNA-but rather RNA-LL37 complexes. This was dependent on TLR8/TLR13 and sensitive to TLR inhibitory oligodeoxynucleotides. Unexpectedly, copious amounts of RNA were identified as a so far unappreciated NET component in vitro and in psoriatic but not healthy skin. Importantly, RNA-LL37-triggered NETs, when transferred to naive PMNs, prompted additional de novo NET release. Our study highlights TLR-mediated RNA-LL37 sensing by PMNs as parts of a self-propagating vicious cycle that may later engulf pDC and establish chronic inflammation in psoriasis and NET-associated RNA (naRNA) as a physiologically relevant novel component. Summary Human and bacterial RNA in complex with LL37 activates neutrophils via TLR8 to release cytokines, chemokines and neutrophil extracellular traps (NETs). NETs and neutrophil-rich areas in psoriatic skin contain immunostimulatory RNA, termed here NET-associated RNA (naRNA), and LL37, which may fuel a self-sustaining inflammatory cycle in psoriasis.
Significance of pulmonary involvement in systemic sclerosis (SSc) – data form the German SSc-network
2019-02-19

Background Pulmonary involvement is the leading cause of death in SSc and can manifest as interstitial lung disease (ILD), pulmonary hypertension (PAH) or a combination (ILD-PH). Aim of this analysis was to determine prevalence, clinical characteristics and outcomes of these different forms within the German SSc Network.
Expansion of Vancomycin-Resistant Enterococcus faecium in an Academic Tertiary Hospital in Southwest Germany: a Large-Scale Whole-Genome-Based Outbreak Investigation
2019-02-20

Vancomycin-resistant Enterococcus faecium (VREfm) is a frequent cause of nosocomial outbreaks. In the second half of 2015, a sharp increase in the incidence of VREfm was observed at our university medical center.
β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer
2019-02-20

Abstract β-Arrestins are classic attenuators of G-protein–coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that β-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. β-Arrestin-1 (ARRB1) and β-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality, and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ∼80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9–mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.
Cryptic Cycling of Complexes Containing Fe(III) and Organic Matter by Phototrophic Fe(II)-Oxidizing Bacteria
2019-02-20

Iron cycling, including reduction of Fe(III) and oxidation of Fe(II), involves the formation, transformation, and dissolution of minerals and dissolved iron-organic matter compounds. It has been shown previously that Fe can be cycled so rapidly that no measurable changes in Fe(II) and Fe(III) concentrations occur, leading to a so-called cryptic cycle. Cryptic Fe cycles have been shown to be driven either abiotically by a combination of photochemical reduction of Fe(III)-OM complexes and reoxidation of Fe(II) by O 2 , or microbially by a combination of Fe(III)-reducing and Fe(II)-oxidizing bacteria. Our study demonstrates a new type of light-driven cryptic Fe cycle that is relevant for the photic zone of aquatic habitats involving abiotic photochemical reduction of Fe(III)-OM complexes and microbial phototrophic Fe(II) oxidation. This new type of cryptic Fe cycle has important implications for biogeochemical cycling of iron, carbon, nutrients, and heavy metals and can also influence the composition and activity of microbial communities.
The neurobiology of placebo effects in sports: EEG frontal alpha asymmetry increases in response to a placebo ergogenic aid
2019-02-20

Abstract The performance enhancing (ergogenic) placebo effect is elicited by an inert treatment and caused by positive affective appraisal of effort perception. Frontal alpha asymmetry (FAA) is a neurobiological correlate of positive affect. This study investigates, whether receiving an ergogenic placebo increases FAA and whether scores on the behavioral inhibition and activation system (BIS/BAS) scales affect this increase in FAA. Nineteen competitive male cyclists (37.26 ± 9.82 years) performed two maximum effort time trials. The first served as baseline for the second intervention time trial, where athletes received a placebo ergogenic aid or no treatment. We recorded FAA using EEG throughout all time trials and assessed BIS/BAS by questionnaire. There was a significant difference in change from baseline to intervention time trial in FAA during cycling in response to the placebo ergogenic aid compared to the control group. BIS, the BAS subscale Drive and the BAS-BIS difference score significantly co-varied with the change in FAA from baseline to intervention time trial in response to the placebo ergogenic aid. Administering a placebo ergogenic aid significantly influenced FAA during maximum effort cycling. Those athletes with a more pronounced goal seeking persistence and an overall dominance of the BAS over the BIS showed a significantly greater increase in FAA in response to a placebo ergogenic aid. A more pronounced BIS, however, seems to antagonize the increase in FAA associated with the ergogenic placebo response.
Superelectrophilicity of 1,2‐Azaborine: Formation of Xenon and Carbon Monoxide Adducts
2019-02-20

Abstract The BN analogue of ortho ‐benzyne, 1,2‐azaborine, is shown to bind carbon monoxide and a xenon atom under matrix isolation conditions, demonstrating its strongly Lewis acidic superelectrophilic nature. The Lewis acid–base complexes involving CO and Xe can be cleaved photochemically and reformed by mildly annealing the matrices. The interaction energy of 1,2‐azaborine with Xe is 3 kcal mol −1 according to quantum chemical computations, and is similar to that of the superelectrophilic carbene difluorovinylidene.
TMS-EEG signatures of glutamatergic neurotransmission in human cortex
2019-02-20

Abstract Neuronal activity in the brain is regulated by an excitation-inhibition balance. Glutamate is the main excitatory neurotransmitter. Transcranial magnetic stimulation (TMS) evoked electroencephalographic (EEG) potentials (TEPs) represent a novel way to quantify pharmacological effects on neuronal activity in the human cortex. Here we tested TEPs under the influence of a single oral dose of two anti-glutamatergic drugs, perampanel, an AMPA-receptor antagonist, and dextromethorphan, an NMDA-receptor antagonist, and nimodipine, an L-type voltage-gated calcium channel blocker in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled, crossover design. Single-pulse TMS was delivered to the left motor cortex and TEPs were obtained pre-and post-drug intake. Dextromethorphan specifically increased the amplitude of the N45, a negative potential around 45 ms after the TMS pulse, while perampanel reduced the P70 amplitude in the non-stimulated hemisphere. Nimodipine and placebo had no effect on TEPs. These data extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA-receptor-mediated glutamatergic excitation. In contrast, AMPA-receptor-mediated glutamatergic neurotransmission contributes to interhemispherically propagated activity reflected in the P70. These data are important to understand the physiology of TEPs as markers of excitability and propagated activity in the human cortex in health and disease.
Using a composite flow law to model deformation in the NEEM deepice core, Greenland: Part 2 the role of grain size and premelting onice deformation at high homologous temperature
2019-02-20

Abstract. The ice microstructure in the lower part of the North Greenland Eemian Ice Drilling (NEEM) ice core consists of relatively fine grained glacial ice with a single maximum crystallographic preferred orientation (CPO) alternated by much coarser grained Eemian ice with a partial girdle type of CPO. In this study, the grain size sensitive (GSS) composite flow law of Goldsby and Kohlstedt (2001) was used to study the effects of grain size and premelting on strain rate in the lower part of the NEEM ice core. The results show that the strain rates predicted in the fine grained glacial layers are about an order of magnitude higher than in the much coarser grained Eemian layers. The dominant deformation mechanisms between the layers is also different with basal slip accommodated by grain boundary sliding (GBS-limited creep) being the dominant deformation mechanism in the glacial layers, while GBS-limited creep and dislocation creep (basal slip accommodated by non-basal slip) contribute both roughly equally to bulk strain in the coarse grained layers. Due to the large difference in microstructure between the impurity-rich glacial ice and the impurity-depleted Eemian ice at premelting temperatures (T&gt;262 K), it is expected that the fine grained layers deform mainly by simple shear at high strain rates, while the coarse grained layers are relatively stagnant. The difference in microstructure, and consequently in viscosity, between glacial and interglacial ice at temperatures just below the melting point can have important consequences for ice dynamics close to the bedrock.
Biregular models of log Del Pezzo surfaces with rigid singularities
2019-02-20

We construct biregular models of families of log Del Pezzo surfaces with rigid cyclic quotient singularities such that a general member in each family is wellformed and quasismooth. Each biregular model consists of infinite series of such families of surfaces; parameterized by the natural numbers . Each family in these biregular models is represented by either a codimension 3 Pfaffian format modelled on the Plücker embedding of or a codimension 4 format modelled on the Segre embedding of . In particular, we show the existence of two biregular models in codimension 4 which are biparameterized, giving rise to an infinite series of models of families of log Del Pezzo surfaces. We identify those biregular models of surfaces which do not admit a -Gorenstein deformation to a toric variety.
N1-{4-[2-(Methylthio)-1H-imidazol-5-yl]pyridin-2-yl}benzene-1,4-diamine
2019-02-20

The title compound N1-{4-[2-(methylthio)-1H-imidazol-5-yl]pyridin-2-yl}benzene-1,4-diamine (2) was synthesized via nucleophilic aromatic substitution of 2-chloro-4-[2-(methylthio)-1H-imidazol-5-yl]pyridine (3) and p-phenylenediamine under acidic conditions. The synthesized compound 2 was characterized by 1H-NMR, 13C-NMR, MS HPLC, IR and UV-VIS. Additionally, the structure of 2 was confirmed by single crystal X-ray diffraction. Pyridinylimidazole 2 displays moderate affinity towards the c-Jun N-terminal kinase 3 and shows selectivity versus the closely related p38α mitogen-activated protein kinase.
The first record of Anancus (Mammalia, Proboscidea) in the late Miocene of Greece and reappraisal of the primitive anancines from Europe
2019-02-20

&amp;lt;p&amp;gt;In this article we present the tetralophodont proboscideans from the late Miocene (Turolian) locality Chomateri (Greece), near the classical locality Pikermi. The material consists of juvenile teeth, whose morphological features, such as the dislocation of the half-loph(id)s and the resultant alternate arrangement of the successive loph(id)s (anancoidy), permit the allocation to Anancus. However, the anancoidy is rather weak and the occlusal morphology simple, both regarded as primitive features within anancines. The re-examination of the late Miocene anancines from Europe reveals that they all share primitive molar features (weak anancoidy, simple morphology, thick enamel) with the material from Hohenwarth (Austria) showing further primitive skull features, such as the longer mandibular symphysis compared to other anancines. The proper name to refer to the late Miocene anancines from Europe is Anancus lehmanni (Gaziry, 1997) with type locality Dorn- D&amp;uuml;rkheim 1 (Turolian; Germany). The presence of Anancus in Chomateri consists the first late Miocene record of the genus in Greece and the first faunal element that clearly indicates that Chomateri post-dates Pikermi. We discuss the biogeography and the biostratigraphy of the late Miocene anancines of the Old World. Anancus originated possibly at ~9.0&amp;ndash;8.5 Ma in Asia and entered Europe during the second half of the Turolian, at ~7.2 Ma (Tortonian/Messinian boundary). The arrival of Anancus in Europe coincides with a faunal turnover in both the eastern and western sector of the European Mediterranean region, and in the Southern Balkans in particular, with the decline of the &amp;lsquo;Pikermian&amp;rsquo; large mammal fauna.&amp;lt;/p&amp;gt;
Whose Constitution? Constitutional Self‐Determination and Generational Change
2019-02-21

Abstract Constitutions enshrine the fundamental values of a people and they build a framework for a state’s public policy. With regard to generational change, their endurance gives rise to two interlinked concerns: the sovereignty concern and the forgone welfare concern. If constitutions are intergenerational contracts, how (in)flexible should they be? This article discusses perpetual constitutions, sunset constitutions, constitutional reform commissions, and constitutional conventions, both historically and analytically. It arrives at the conclusion that very rigid constitutions are incompatible with the principle of intergenerational justice. Recurring constitutional reform commissions at fixed intervals would give each generation of citizens a say without leaning too much on the side of flexibility.
Crucial Role of Nucleic Acid Sensing via Endosomal Toll-Like Receptors for the Defense of Streptococcus pyogenes in vitro and in vivo
2019-02-21

<i>Streptococcus pyogenes</i> is a major human pathogen causing a variety of diseases ranging from common pharyngitis to life-threatening soft tissue infections and sepsis. Microbial nucleic acids, especially bacterial RNA, have recently been recognized as a major group of pathogen-associated molecular patterns (PAMPs) involved in the detection of <i>Streptococcus pyogenes</i> via endosomal Toll-like receptors (TLRs) <i>in vitro</i>. However, the individual contribution and cooperation between TLRs as well as cell-type and strain specific differences in dependency on nucleic acid detection during <i>S. pyogenes</i> infection <i>in vitro</i> have not been clarified in detail. Moreover, the role of particularly bacterial RNA for the defense of <i>S. pyogenes</i> infection <i>in vivo</i> remains poorly defined. In this study, we report that in all investigated innate immune cells involved in the resolution of bacterial infections, including murine macrophages, dendritic cells and neutrophils, recognition of <i>S. pyogenes</i> strain ATCC12344 is almost completely dependent on nucleic acid sensing via endosomal TLRs at lower MOIs, whereas at higher MOIs, detection via TLR2 plays an additional, yet redundant role. We further demonstrate that different <i>S. pyogenes</i> strains display a considerable inter-strain variability with respect to their nucleic acid dependent recognition. Moreover, TLR13-dependent recognition of <i>S. pyogenes</i> RNA is largely non-redundant in bone marrow-derived macrophages (BMDMs), but less relevant in neutrophils and bone marrow-derived myeloid dendritic cells (BMDCs) for the induction of an innate immune response <i>in vitro</i>. <i>In vivo</i>, we show that a loss of nucleic acid sensing blunts early recognition of <i>S. pyogenes</i>, leading to a reduced local containment of the bacterial infection with subsequent pronounced systemic inflammation at later time points. Thus, our results argue for a crucial role of nucleic acid sensing via endosomal TLRs in defense of <i>S. pyogenes</i> infection both <i>in vitro</i> and <i>in vivo</i>.
Wolves’ Conservation through Educational Workshops: Which Method Works Best?
2019-02-21

(1) Background: Conservation biology education is an important societal goal, targeting the worldwide promotion of biodiversity conservation. When learning about animals, direct experience poses an ideal opportunity to influence the participants’ attitudes and knowledge. However, in the case of large carnivores, direct experiences are scarcely possible, except at local zoos. School teaching should therefore rely on preserved materials, which are still originals. (2) Methods: Here, we investigated how students’ attitudes and knowledge regarding wolves can be improved in three different teaching contexts: (a) through conventional lectures, (b) through lectures combined with hands-on activities in the real classroom setting, and (c) through lectures with hands-on activities at the university. Students from general and vocational (veterinary) upper secondary school participated in the study. Attitudes and knowledge were tested before and after the teaching. (3) Results: Students displayed positive attitudes toward wolves and their prior knowledge had the highest influence on attitude ratings. Knowledge about wolves improved during teaching regardless of the teaching approach. The highest influence on attitudes and knowledge was observed in the university setting. (4) Conclusion: The university setting evidently produces the strongest effect so it is a recommended approach when designing conservational topics.
Hemostatic wound dressings: Predicting their effects by in vitro tests
2019-02-21

Background Application of controlled in vitro techniques can be used as a screening tool for the development of new hemostatic agents allowing quantitative assessment of overall hemostatic potential. Materials and methods Several tests were selected to evaluate the efficacy of cotton gauze, collagen, and oxidized regenerated cellulose for enhancing blood clotting, coagulation, and platelet activation. Results Visual inspection of dressings after blood contact proved the formation of blood clots. Scanning electron microscopy demonstrated the adsorption of blood cells and plasma proteins. Significantly enhanced blood clot formation was observed for collagen together with β-thromboglobulin increase and platelet count reduction. Oxidized regenerated cellulose demonstrated slower clotting rates not yielding any thrombin generation; yet, led to significantly increased thrombin-anti-thrombin-III complex levels compared to the other dressings. As hemostyptica ought to function without triggering any adverse events, induction of hemolysis, instigation of inflammatory reactions, and initiation of the innate complement system were also tested. Here, cotton gauze provoked high PMN elastase and elevated SC5b-9 concentrations. Conclusions A range of tests for desired and undesired effects of materials need to be combined to gain some degree of predictability of the in vivo situation. Collagen-based dressings demonstrated the highest hemostyptic properties with lowest adverse reactions whereas gauze did not induce high coagulation activation but rather activated leukocytes and complement.