Facilitation versus depression in cultured hippocampal neurons determined by targeting of Ca2+ channel Cavβ4 versus Cavβ2 subunits to synaptic terminals

Ca2+ channel β subunits determine the transport and physiological properties of high voltage–activated Ca2+ channel complexes. Our analysis of the distribution of the Cavβ subunit family members in hippocampal neurons correlates their synaptic distribution with their involvement in transmitter release. We find that exogenously expressed Cavβ4b and Cavβ2a subunits distribute in clusters and localize to synapses, whereas Cavβ1b and Cavβ3 are homogenously distributed. According to their localization, Cavβ2a and Cavβ4b subunits modulate the synaptic plasticity of autaptic hippocampal neurons (i.e., Cavβ2a induces depression, whereas Cavβ4b induces paired-pulse facilitation [PPF] followed by synaptic depression during longer stimuli trains). The induction of PPF by Cavβ4b correlates with a reduction in the release probability and cooperativity of the transmitter release. These results suggest that Cavβ subunits determine the gating properties of the presynaptic Ca2+ channels within the presynaptic terminal in a subunit-specific manner and may be involved in organization of the Ca2+ channel relative to the release machinery

A high-throughput effector screen identifies a novel small molecule scaffold for inhibition of ten-eleven translocation dioxygenase 2

Ten-eleven translocation dioxygenases (TETs) are the erasers of 5-methylcytosine (mC), the central epigenetic regulator of mammalian DNA. TETs convert mC to three oxidized derivatives with unique physicochemical properties and inherent regulatory potential, and it initializes active demethylation by the base excision repair pathway. Potent small molecule inhibitors would be useful tools to study TET functions by conditional control. To facilitate the discovery of such tools, we here report a high-throughput screening pipeline and its application to screen and validate 31.5k compounds for inhibition of TET2. Using a homogenous fluorescence assay, we discover a novel quinoline-based scaffold that we further validate with an orthogonal semi-high throughput MALDI-MS assay for direct monitoring of substrate turnover. Structure–activity relationship (SAR) studies involving >20 derivatives of this scaffold led to the identification of optimized inhibitors, and together with computational studies suggested a plausible model for its mode of action

A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours

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Invertebrate Cells as Targets for Hazardous Substances

Electron microscopy is an established diagnostic method in pathology of man as well as of vertebrate animals. During the last decade, ultrastructural studies have also been performed in invertebrates to elucidate cellular injuries caused by hazardous substances (BAYNE et al. 1985, MOORE 1985, STORCH 1988, HOPKIN 1989). The interest in invertebrates has increased due to their suitability to monitor environmental pollution. For example field and laboratory studies have been performed using the bivalve Mytilus edulis or the gastropod Littorina littorea as indicator of chemical contamination (AUFFRET 1988, CAJARAVILLE et al. 1989, CAJARAVILLE et al. 1990, MOORE 1988). Additionally, many invertebrates, such as aphids, grasshoppers, caterpillars or slugs are of significance as pest organisms in agriculture. Others, in most cases insects like the Ichneumonidae or Planipennia, are of increasing importance in biological or integrated pest control. In a series of laboratory tests we examined cellular reactions in a variety of invertebrates after exposure to environmentally relevant toxicants, like metals or pesticides. The following animals were selected for their environmental or commercial significance: -the shrimp, Penaeus monodon (Crustacea, Decapoda), as a commercially important aquaculture species which is impaired by environmental toxicants, -the flatworm, Polycelis felina (Turbellaria, Tricladida), a common inhabitant of central European brooks, which is menaced by acid rain and subsequently released aluminium, -the millipede, Cylindroiulus punctatus (Diplopoda, Julida), as an important animal of the soil macrofauna, involved in the decomposition of organic material, -the moss mite, Nothrus silvestris (Acari, Oribatida), as a representative of saprophagous soil animals occurring in high population densities, -the slug, Deroceras reticulatum (Gastropoda, Pulmonata), which is an important pest organism in European agriculture, -and Chrysoperla carnea (Insecta, Planipennia), as a beneficial species used in the biological control of aphids. It was the aim of this study to demonstrate the suitability of electron microscopy for evaluating the effects of hazardous substances on cells of invertebrate tissues

Moral Reasoning in Psychopaths

Patienten mit der psychischen Störung „Psychopathie“ zeigen ein Muster von emotionaler Abgestumpftheit, Impulsivität und unmoralischem Verhalten. Zur Untersuchung moralischen Urteilens wurden in der vorliegenden Studie alltagsrelevante Konflikte mit moralischem bzw. neutralem Inhalt entwickelt und 12 „psychopathischen“ forensischen Patienten sowie 12 nicht-psychopathischen forensischen Patienten präsentiert. „Psychopathische“ im Vergleich zu nicht-psychopathischen Patienten berichteten signifikant positivere Gefühle bei unmoralischen Entscheidungen als Nicht-Psychopathen. Außerdem wurden in der Gruppe der „Psychopathen“ im Vergleich zu den Nicht-Psychopathen signifikant häufiger unmoralische Entscheidungen auf moralische Konflikte getroffen. Diese Befunde deuten darauf hin, dass eine Störung der Emotionsverarbeitung ursächlich für dissoziales Verhalten bei „Psychopathen“ sein könnte.Psychopathic patients show a behavioral pattern that is characterized by indifference, impulsivity and antisocial behavior. To investigate moral reasoning we developed conflicts of everyday life with either moral or neutral content. These conflicts were then presented to a group of 12 psychopathic forensic patients as well as to a group of 12 non-psychopathic forensic patients.Psychopathic compared to non-psychopathic patients reported significantly higher positive feelings when choosing an immoral response alternative than non-psychopaths. Furthermore, psychopaths picked significantly more often an immoral response alternative in the conflicts with moral content than did the non-psychopaths. These results indicate that impairment in emotional processing abilities may be at the core of antisocial behavior in psychopathy

Typing and Species Identification of Clinical Klebsiella Isolates by Fourier Transform Infrared Spectroscopy and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry

Klebsiella pneumoniae and related species are frequent causes of nosocomial infections and outbreaks. Therefore, quick and reliable strain typing is crucial for the detection of transmission routes in the hospital. The aim of this study was to evaluate Fourier transform infrared spectroscopy (FTIR) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) as rapid methods for typing clinical Klebsiella isolates in comparison to whole-genome sequencing (WGS), which was considered the gold standard for typing and identification. Here, 68 clinical Klebsiella strains were analyzed by WGS, FTIR, and MALDI-TOF MS. FTIR showed high discriminatory power in comparison to the WGS reference, whereas MALDI-TOF MS exhibited a low ability to type the isolates. MALDI-TOF mass spectra were further analyzed for peaks that showed high specificity for different Klebsiella species. Phylogenetic analysis revealed that the Klebsiella isolates comprised three different species: K. pneumoniae, K. variicola, and K. quasipneumoniae. Genome analysis showed that MALDI-TOF MS can be used to distinguish K. pneumoniae from K. variicola due to shifts of certain mass peaks. The peaks were tentatively identified as three ribosomal proteins (S15p, L28p, L31p) and one stress response protein (YjbJ), which exhibit amino acid differences between the two species. Overall, FTIR has high discriminatory power to recognize the clonal relationship of isolates, thus representing a valuable tool for rapid outbreak analysis and for the detection of transmission events due to fast turnaround times and low costs per sample. Furthermore, specific amino acid substitutions allow the discrimination of K. pneumoniae and K. variicola by MALDI-TOF MS

Sustainability in a changing world: integrating human health and wellbeing, urbanisation, and ecosystem services

There is an urgent need to address interlinked sustainability issues in a world challenged by inequality, finite resources and unprecedented changes across Earth’s systems. As Future Earth Fellows, based on our collective expertise in a diverse range of sustainability issues, here we identify a specific need to recognise and respond appropriately to the nexus between human health and wellbeing, urbanisation, and ecosystem services (the ‘WUE nexus’). This nexus is a priority area for research, policy and practice. In particular, it provides a useful pathway to meet the challenges of successful implementation of the Sustainable Development Goals (SDGs). In this brief, we present the following policy recommendations:1. By emphasising urban-rural linkages, foster an integrated approach to ensure food security, food safety, and health promotion;2. Secure resilient livelihoods for all, in particular for vulnerable groups; and3. Integrate co-production of knowledge in science for decision-making, including the co-design of implementation frameworks, and the adoption of a nexus approach.<br/

Article Developmental Control of Nuclear Size and Shape by kugelkern and kurzkern

Summary Background: The shape of a nucleus depends on the nuclear lamina, which is tightly associated with the inner nuclear membrane and on the interaction with the cytoskeleton. However, the mechanism connecting the differentiation state of a cell to the shape changes of its nucleus are not well understood. We investigated this question in early Drosophila embryos, where the nuclear shape changes from spherical to ellipsoidal together with a 2.5-fold increase in nuclear length during cellularization. Results: We identified two genes, kugelkern and kurzkern, required for nuclear elongation. In kugelkern-and kurzkern-depleted embryos, the nuclei reach only hal

Towards plant-odor-related olfactory neuroethology in Drosophila

Drosophila melanogaster is today one of the three foremost models in olfactory research, paralleled only by the mouse and the nematode. In the last years, immense progress has been achieved by combining neurogenetic tools with neurophysiology, anatomy, chemistry, and behavioral assays. One of the most important tasks for a fruit fly is to find a substrate for eating and laying eggs. To perform this task the fly is dependent on olfactory cues emitted by suitable substrates as e.g. decaying fruit. In addition, in this area, considerable progress has been made during the last years, and more and more natural and behaviorally active ligands have been identified. The future challenge is to tie the progress in different fields together to give us a better understanding of how a fly really behaves. Not in a test tube, but in nature. Here, we review our present state of knowledge regarding Drosophila plant-odor-related olfactory neuroethology to provide a basis for new progress