Refine
Has Fulltext
- yes (11246) (remove)
Year of publication
- 2024 (196)
- 2023 (725)
- 2022 (1060)
- 2021 (1230)
- 2020 (801)
- 2019 (779)
- 2018 (685)
- 2017 (511)
- 2016 (643)
- 2015 (582)
- 2014 (587)
- 2013 (503)
- 2012 (506)
- 2011 (344)
- 2010 (206)
- 2009 (104)
- 2008 (106)
- 2007 (83)
- 2006 (71)
- 2005 (75)
- 2004 (52)
- 2003 (41)
- 2002 (40)
- 2001 (30)
- 2000 (15)
- 1999 (8)
- 1998 (1)
- 1995 (1)
- 1994 (140)
- 1993 (159)
- 1992 (118)
- 1991 (121)
- 1990 (98)
- 1989 (94)
- 1988 (83)
- 1987 (70)
- 1986 (63)
- 1985 (39)
- 1984 (38)
- 1983 (25)
- 1982 (30)
- 1981 (20)
- 1980 (16)
- 1979 (21)
- 1978 (19)
- 1977 (13)
- 1976 (12)
- 1975 (13)
- 1974 (11)
- 1973 (13)
- 1972 (15)
- 1971 (8)
- 1970 (6)
- 1969 (5)
- 1968 (1)
Document Type
- Journal article (7873)
- Doctoral Thesis (2817)
- Book article / Book chapter (133)
- Conference Proceeding (107)
- Preprint (107)
- Working Paper (67)
- Review (43)
- Report (27)
- Master Thesis (26)
- Book (19)
Language
- English (11246) (remove)
Keywords
- Toxikologie (119)
- Medizin (99)
- inflammation (95)
- Psychologie (86)
- Biochemie (85)
- cancer (81)
- Organische Chemie (68)
- gene expression (68)
- Anorganische Chemie (66)
- Maus (64)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (1948)
- Graduate School of Life Sciences (809)
- Physikalisches Institut (605)
- Institut für Psychologie (502)
- Neurologische Klinik und Poliklinik (400)
- Medizinische Klinik und Poliklinik II (388)
- Institut für Organische Chemie (374)
- Medizinische Klinik und Poliklinik I (374)
- Institut für Molekulare Infektionsbiologie (361)
- Institut für Anorganische Chemie (357)
- Institut für Informatik (342)
- Institut für Pharmakologie und Toxikologie (302)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (291)
- Rudolf-Virchow-Zentrum (287)
- Institut für Virologie und Immunbiologie (280)
- Institut für Geographie und Geologie (266)
- Julius-von-Sachs-Institut für Biowissenschaften (257)
- Institut für Theoretische Physik und Astrophysik (244)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (237)
- Pathologisches Institut (226)
- Institut für Pharmazie und Lebensmittelchemie (213)
- Institut für Mathematik (206)
- Klinik und Poliklinik für Nuklearmedizin (203)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (197)
- Lehrstuhl für Orthopädie (169)
- Institut für Physikalische und Theoretische Chemie (165)
- Kinderklinik und Poliklinik (162)
- Institut für Anatomie und Zellbiologie (161)
- Institut für Klinische Epidemiologie und Biometrie (157)
- Neurochirurgische Klinik und Poliklinik (152)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (150)
- Institut für Hygiene und Mikrobiologie (149)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (143)
- Institut für Humangenetik (140)
- Institut für Klinische Neurobiologie (138)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (138)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (134)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (132)
- Comprehensive Cancer Center Mainfranken (110)
- Klinik und Poliklinik für Strahlentherapie (90)
- Klinik und Poliklinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie (Chirurgische Klinik II) (90)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (85)
- Lehrstuhl für Biochemie (84)
- Institut für Experimentelle Biomedizin (82)
- Institut für Psychologie (bis Sept. 2007) (80)
- Frauenklinik und Poliklinik (78)
- Medizinische Fakultät (78)
- Neuphilologisches Institut - Moderne Fremdsprachen (78)
- Fakultät für Physik und Astronomie (76)
- Institut Mensch - Computer - Medien (72)
- Klinik und Poliklinik für Hals-, Nasen- und Ohrenkrankheiten, plastische und ästhetische Operationen (72)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (67)
- Physiologisches Institut (64)
- Institut für Sportwissenschaft (62)
- Institut für Funktionsmaterialien und Biofabrikation (56)
- Betriebswirtschaftliches Institut (52)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (50)
- Volkswirtschaftliches Institut (50)
- Center for Computational and Theoretical Biology (49)
- Institut für deutsche Philologie (48)
- Urologische Klinik und Poliklinik (48)
- Institut für Medizinische Strahlenkunde und Zellforschung (47)
- Augenklinik und Poliklinik (45)
- Klinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie (42)
- Institut für Klinische Biochemie und Pathobiochemie (40)
- Lehrstuhl für Molekulare Psychiatrie (39)
- Graduate School of Science and Technology (37)
- Fakultät für Biologie (35)
- Fakultät für Chemie und Pharmazie (32)
- Institut für Kulturwissenschaften Ost- und Südasiens (27)
- Klinik und Poliklinik für Thorax-, Herz- u. Thorakale Gefäßchirurgie (27)
- Institut für Politikwissenschaft und Soziologie (25)
- Poliklinik für Zahnärztliche Prothetik (22)
- Institut für Allgemeinmedizin (21)
- Institut für Geologie (18)
- Institut für Mineralogie und Kristallstrukturlehre (18)
- Institut für Psychotherapie und Medizinische Psychologie (17)
- Institut für Altertumswissenschaften (16)
- Institut für Geographie (16)
- Abteilung für Parodontologie (in der Poliklinik für Zahnerhaltung und Parodontologie) (15)
- Institut für Systemimmunologie (15)
- Institut für Rechtsmedizin (14)
- Institut für Klinische Transfusionsmedizin und Hämotherapie (13)
- Poliklinik für Zahnerhaltung und Parodontologie (13)
- Graduate School of the Humanities (12)
- Missionsärztliche Klinik (12)
- Institut für Biblische Theologie (11)
- Institut für Philosophie (10)
- Institut für Pädagogik (10)
- Universität Würzburg (10)
- Institut für Medizinische Lehre und Ausbildungsforschung (9)
- Philosophische Fakultät (Histor., philolog., Kultur- und geograph. Wissensch.) (9)
- Wirtschaftswissenschaftliche Fakultät (9)
- Medizinische Klinik (bis 2004) (8)
- Poliklinik für Kieferorthopädie (8)
- Graduate School of Law, Economics, and Society (6)
- Institut für Sonderpädagogik (6)
- Katholisch-Theologische Fakultät (6)
- Fakultät für Humanwissenschaften (Philos., Psycho., Erziehungs- u. Gesell.-Wissensch.) (5)
- Fakultät für Mathematik und Informatik (5)
- Institut für Altertumswissenschaften (bis Sept. 2007) (5)
- Institut für Evangelische Theologie und Religionspädagogik (5)
- Institut für Paläontologie (5)
- Institut für Praktische Theologie (5)
- Klinik für Anaesthesiologie (bis 2003) (5)
- Klinik und Polikliniken für Zahn-, Mund- und Kieferkrankheiten (5)
- Lehrstuhl für Silicatchemie (5)
- Neuphilologisches Institut - Moderne Fremdsprachen (bis 2007) (5)
- Sportzentrum (5)
- Institut für Internationales Recht, Europarecht und Europäisches Privatrecht (4)
- Abteilung für Forensische Psychiatrie (3)
- Institut für Anglistik und Amerikanistik (3)
- Institut für Geschichte der Medizin (3)
- Juristische Fakultät (3)
- Fachgruppe Didaktik der Biologie (2)
- Institut für Geschichte (2)
- Institut für Gesellschafts-, Steuer- und Arbeitsrecht (2)
- Institut für Musikforschung (2)
- Institut für Orientalische Philologie (2)
- Institut für Systematische Theologie (2)
- Institut für medizinische Datenwissenschaften (2)
- Medizinische Poliklinik (bis 2004) (2)
- Botanischer Garten (1)
- Graduate Schools (1)
- Institut für Bürgerliches Recht und Zivilprozessrecht (1)
- Institut für Historische Theologie (1)
- Institut für Kulturwissenschaften Ost- und Südasiens (bis Sept. 2007) (1)
- Institut für Politische Wissenschaft (1)
- Klinik und Poliklinik für Haut- und Geschlechtskrankheiten (bis 2003) (1)
- Krankenhaus für Psychiatrie, Psychotherapie und Neurologie des Bezirks Unterfranken (1)
- Rechenzentrum (1)
- Zentrale Einrichtungen (1)
- Zentrum für Sprachen (1)
Schriftenreihe
- Cultural Animal Studies, Band 3 (24)
- Berichte aus der Informatik (1)
- Deuterocanonical and Cognate Literature Studies (1)
- Deuterocanonical and Cognate Literature Yearbook (1)
- International Archives of the History of Ideas / Archives internationales d’histoire des idées 242 (1)
- Methods in Molecular Biology 2533 (1)
- Methods in Molecular Biology; 2643 (1)
Sonstige beteiligte Institutionen
- VolkswagenStiftung (24)
- Johns Hopkins School of Medicine (17)
- Helmholtz Institute for RNA-based Infection Research (HIRI) (8)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (7)
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (5)
- Fraunhofer-Institut für Silicatforschung ISC (5)
- Johns Hopkins University School of Medicine (5)
- Wilhelm-Conrad-Röntgen-Forschungszentrum für komplexe Materialsysteme (5)
- Bernhard-Heine-Centrum für Bewegungsforschung (4)
- Johns Hopkins School of Medicine, Baltimore, MD, U.S. (4)
ResearcherID
- B-1911-2015 (1)
- B-4606-2017 (1)
- C-2593-2016 (1)
- D-1221-2009 (1)
- D-1250-2010 (1)
- I-5818-2014 (1)
- J-8841-2015 (1)
- M-1240-2017 (1)
- N-2030-2015 (1)
- N-3741-2015 (1)
Living beings evolved in an environment with cyclic changing conditions where a variety of factors such as light, temperature, or food availability oscillate in a daily 24-h rhythm. Endogenous circadian clocks in addition to controlling daily rhythms, are also thought to serve as an internal reference for measuring day length. This allows animals to adapt to seasonal changes through photoperiodic responses. While these responses are well-documented in insects, the underlying timing mechanisms for day-length discrimination remain incompletely understood. This thesis aimed at the characterization of the circadian clock of a strongly photoperiodic insect, the pea aphid Acyrthosiphon pisum, that allowed us to find putative neuronal connection between the circadian clock and the photoperiodic system of this insect. In the first chapter, we characterized the neuronal organization of aphid clock clusters using antibodies against the clock proteins Period and Cryptochrome. These clusters were found in the dorsal and lateral protocerebrum, and in the lamina and exhibited daily oscillations. Notably, the clusters expressing Cryptochrome showed light-dependent oscillations, indicating their potential role as clock photoreceptors. These Cryptochrome-positive clusters projected towards the pars intercerebralis, a region crucial for photoperiodism in aphids. In the second chapter, we focused on the Pigment-dispersing factor (PDF), the most important clock neuropeptide in insects. We discovered significant changes in the, otherwise highly conserved, insect C-terminal amino acid sequence of the newly identified pdf gene. PDF was identified in the lateral clock neurons, and their terminals in the dorsal protocerebrum close to the insulin-producing cells located in the pars intercerebralis. These terminals showed daily and seasonal variations, suggesting PDF’s involvement in regulating neurohormone release. To further explore the neuroanatomy of the aphid circadian clock and identify clock-related neuropeptides, we conducted transcriptomic analysis, mass spectrometry, and fluorescent immunohistochemistry. We found that the lateral clock neurons expressed various neuropeptides (in particular Allatotropin, FMRFamide, Orcokinin-A and PDF), similar to those in cockroaches involved in light input pathways. The dorsal clock neurons also exhibit neuropeptide immunoreactivity (precisely of Allatostatin A, Diuretic Hormone31, FMRFamide and Myoinhibitory Peptide), supporting their involvement in modulating circadian and seasonal neurohormonal rhythms. Finally, in the fourth chapter, we provide an overview of the putative mechanisms of photoperiodic control in aphids, from the photoreceptors involved in this process to the circadian clock and the neuroendocrine system.
Patients diagnosed with the rare autoimmune disease of Stiff Person Syndrome (SPS) suffer from varying motor symptoms mainly characterized by painful spasms and muscle stiffness. Among patients suffering from Stiff Person spectrum, clinical presentation, course of disease and treatment responses also differ. Regardless of disease severity, which ranges from mild and intermittent motor impairments to the most severe form progressive encephalomyelitis with rigidity and myoclonus (PERM), autoantibodies are the underlying cause. One of the autoantibody targets associated with SPS is the glycine receptor (GlyR). Functional impairment of this protein interferes with inhibitory signal transmission in the central nervous system and subsequently causes motor symptoms. Similar to functional alterations of the GlyR upon autoantibody binding, GlyR function can be altered in patients with mutations in genes encoding GlyR subunits. Such mutations underlie hereditary hyperekplexia. Understanding the GlyR physiology and how different molecular mechanisms contribute to disease pathology is crucial for development of more targeted and effective disease options.
Therefore, novel GlyR β subunit mutations identified in hyperekplexia patients were investigated towards their expression, trafficking and receptor function. The findings suggest that impaired recruitment into functional receptors at the synapses might underlie the functional alterations revealed by electrophysiological recordings for most cases.
To unravel the autoantibody-related pathology causing the highly diverse clinical appearance of the Stiff Person spectrum, antibody binding abilities were studied. Neutralization assays confirmed that presence of the entire target protein, a sub-domain or a short peptide eliminates the autoantibodies from patient samples. Epitope characterization using residue exchanges within the GlyR in cell-based assays uncovered that GlyR autoantibody epitopes are polyclonal and their combination is patient-specific. Tissue-based binding assays emphasized the high variability in autoantibody distribution within spinal cord and brain sections regardless of the patients’ primary diagnosis. The irregular binding patterns among the patient groups of SPS, PERM, epilepsy and ‘others’ reflected the variation in the symptomatic arrangement. Passive transfer of GlyR autoantibodies from patients with different courses and severity of disease similarly revealed variable effects on murine motor and anxiety-related behavior. The detected small effects on motor function and post-mortem analyses indicate glycinergic disorganization and a possible onset of compensatory mechanisms.
Altogether, this study demonstrates that GlyR impairment is patient-specific and of greater variability than expected.
Within this PhD thesis, starting from simple alkene precursors a series of novel boron-doped PAHs were successfully in a sequential one-pot synthetic approach, comprising a hydroboration/borylation cascade as the key step. By applying different postsynthetic reactions, the properties of these boron-doped PAHs were further adjusted, aiming for appealing packing motifs, strong electron-acceptors, and NIR-emitters. The thesis thereby focussed on the synthesis of tailor-made molecules, the investigation of their optical and electronic properties and the discussion on the influence of various factors, e.g. doping pattern, size, shape, and substituents, on these properties.
Fear and anxiety are fundamental emotional states that are critical for survival. These states are characterized by a variety of coordinated responses, including behavioral and autonomic changes, that need to be properly integrated. For the past decades, most studies have separated the behavioral and autonomic elements, generating a gap in understanding their integrative nature. In this thesis, a framework analysis is presented that allows for the integration of cardiac, behavioral, and neuronal readouts in freely moving mice during different emotional states. Furthermore, a growing body of evidence demonstrates that a vital component of these states is the physiological report of bodily states, or interoception, which allows for quick adaptation to changing situations. A set of distinctive interoceptive pathways has been described from the periphery to the brainstem; however, the circuits that process and integrate cardiac interoceptive signals in higher orders are poorly understood. The midbrain periaqueductal gray (PAG) is a region crucially involved in defensive states through its modulation of both, cardiac and behavioral components. Preliminary studies demonstrate an anatomical connection between the major cardiac interoception brainstem area, the nucleus of the solitary tract, and the PAG; however, the functional characterization and the specific neuronal substrates responsible for interoception in this area have not been described. An interesting particularity of the PAG is that the ventro-lateral subcolumn is the highest order of the neuraxis where inhibitory neurons that express the glycine can be found. In the lower brainstem and spinal cord, glycinergic inhibitory neurons have demonstrated a role in processing sensory and autonomic signals from the periphery, raising the question of whether the PAG glycinergic neurons could be involved in integrating cardiac interoceptive signals as part of a defensive state. In this thesis, using virally mediated trans-synaptic retrograde tracing, I showed that glycinergic PAG neurons receive inputs from cardiac regulatory areas in the brainstem and project massively to forebrain and midbrain regions. By employing advanced techniques such as deep brain calcium imaging with a miniaturized microscope and optogenetics, this study provides compelling evidence for the involvement of glycinergic PAG neurons in controlling heart rate and maintaining cardiac macrostate dynamics within physiological levels. The results of the optogenetic manipulation further revealed that a change in the heart rate macrostate caused by the glycinergic PAG neurons leads to anxiety-like behaviors, providing further evidence for the role of these neurons in regulating defensive states. Overall, by unraveling the neural circuitry underlying interoception in the PAG, our study paves the way to better understand fear and anxiety disorders.
This thesis focusses on the synthesis of functional chiral molecules using carbo- or hetero[7]helicenes as a chiral element, combined with multiple helicenes, phthalocyanines, and 1,4-azaborine units. The objective is to achieve properties that surpass those of the parent compounds.
In the first project, an enantiopure, propeller-shaped multi-helicene polycyclic aromatic hydrocarbon containing three (P)-[7]helicene units and three (M)-[5]helicene units was stereospecifically synthesized and can be obtained in gram quantities. Leveraging the configurational stability of [7]helicene and the configurational instability of [5]helicene, we exclusively obtained the most thermodynamically stable enantiomer out of 10 possible enantiomeric pairs. The effects of the multi-helicene structure on optical rotation, UVVis absorption, fluorescence, and electronic circular dichroism (CD) spectroscopy were investigated.1
Building on the success of the first project, the second project used the configurationally stable [7]helicene again. Zinc-[7]helicenocyanine (Zn-7HPc) was stereospecifically synthesized by directly conjugating [7]helicenes with a phthalocyanine (Pc) core. Zn-7HPc demonstrates a CD signal in the near-infrared region, indicating efficient chirality transfer from the helicenes to the Pc core. Zn-7HPc forms stable, discrete homochiral dimers over a wide range of concentrations in tetrahydrofuran and dimethyl sulfoxide, as well as in the solid state. These homochiral dimers are formed even within the racemic mixture due to the interlocking of two homochiral monomers. The large comproportionation constant and the observed intervalence charge transfer band that appeared in spectroelectrochemistry experiments indicate strong communication between the two Pc monomers in the dimer.2
In the third project, aza[7]helicenes were incorporated with a 1,4-azaborine unit, which exhibits a multiple-resonance effect, to achieve narrow-band emission, high fluorescence quantum yield (FL), and a small Stokes shift. These properties are essential for ultrahigh-definition organic light-emitting diodes that emit circularly polarized light (CP-OLEDs). The synthesized series of molecules demonstrate small Stokes shifts (0.06–0.07 eV), exceptionally narrow fluorescence and circularly polarized luminescence bands with small full width at half maximum (FWHM, 17–28 nm, 0.07–0.13 eV), and high FL (72–85%).3
In conclusion, the synthesis of functional chiral molecules based on carbo- or hetero[7]helicenes was successfully achieved. The efficient synthetic strategies and improved properties of these molecules provide valuable insights for further investigations into helicenes with advanced structures and enhanced properties.
Axon growth, a fundamental process of neuron development, is regulated by both intrinsic and external guidance signals. Impairment of axon growth and maintenance is implicated in the pathogenesis of neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease (AD). Axon growth is driven by several post-transcriptional RNA processing mechanisms, including alternative splicing, polyadenylation, subcellular localization, and translation. These mechanisms are controlled by RNA-binding proteins (RBPs) through interacting with their target RNAs in a sequence-dependent manner. In this study, we investigate the cytosolic functions of two neuronal RBPs, Ptbp2 and hnRNP R, which are essential for axon growth in motoneurons.
Polypyrimidine tract binding protein 2 (Ptbp2) contributes to neuronal differentiation and axonogenesis by modulating different splicing programs to adjust the level of proteins involved in these processes. While the nuclear functions of Ptbp2 in alternative splicing have been studied in more detail, the cytosolic roles of Ptbp2 associated with axon growth have remained elusive. In the first part of the study, we show that Ptbp2 is present in cytosolic fractions of motoneurons including axons and axon terminals. Depletion of Ptbp2 impairs axon growth and growth cone maturation in cultured embryonic mouse motoneurons. Moreover, Ptbp2 knockdown affects the level of piccolo protein in the growth cone of cultured motoneurons. We detect Ptbp2 as a top interactor of the 3' UTR of the Hnrnpr transcript encoding the RBP hnRNP R. This interaction results in axonal localization of and thereby local translation of Hnrnpr mRNA in motoneurons. Consequently, axonal synthesis of hnRNP R was diminished upon depletion of Ptbp2 in motoneurons. We present evidence that Ptbp2 through cooperation with translation factor eIF5A2 controls hnRNP R synthesis. Additionally, we observe that re-expression of hnRNP R in Ptbp2-deficient motoneurons rescued axon growth defect while Ptbp2 overexpression failed to normalize the axon elongation defect observed in hnRNP R-deficient motoneurons. Our findings pinpoint axonal synthesized hnRNP R as a mediator of Ptbp2 functions in axon growth.
In the second part of this study, we identify hnRNP R binds to the 3' UTR of microtubule-associated tau (Mapt) transcript encoding tau protein and regulates the axonal translocation and translation of Mapt mRNA. Tau protein has a central role in neuronal microtubule assembly and stability. However, in AD, the accumulation of abnormally hyperphosphorylated tau protein leads to axon outgrowth defects. Loss of hnRNP R reduces axonal tau protein but not the total level of tau. We observe that the brains of 5xFAD mice, as a mouse model of AD, deficient for hnRNP R contain lower phospho-tau and amyloid-β plaques. Likewise, Neurons treated with blocking antisense oligonucleotides (ASO) to prevent binding of hnRNP R to Mapt mRNA show reduced axonal Mapt mRNA and consequently newly synthesized tau protein levels. We show that blocking Mapt mRNA transport to axons impairs axon elongation. Our data thus suggest that reducing tau levels selectively in axons, a major subcellular site of tangle formation, might represent a novel therapeutic approach for the treatment of AD.
In this work, two techniques, based on the established method of pump--probe spectroscopy were used to investigate the properties of molecular systems in the liquid phase within the visible spectral wavelength range.
The first technique is standard transient absorption (TA) spectroscopy which was applied to a diazo-precursor to identify the formation of a biradical in an inert solvent after UV excitation. With the combination of EPR spectroscopy and quantum chemical calculations, the formation of a biradical in an unpolar and non-protic solvent was proven. Besides, in the presence of air or a polar and protic solvent, the biradical reacts ultrafast to various side products.
The second technique is time-resolved circular dichroism (TRCD) spectroscopy, which was performed in two different ways. The first approach based on a pulse-enantiomer (PE) setup, where an initially circularly polarized pulse was split into two pulses, of which one was mirrored under normal incidence, to flip its polarization. The result was two pulses with mirrored polarization states that propagate collinearly to the sample as left and right circularly polarized probe pulses. The alignment procedure as well as the drawbacks of this setup are described in detail.
However, a new TRCD setup was built that used a polarization grating to get left and right circularly polarized pulses. With the experiences of working with the PE setup, the new TRCD setup could be optimized so that TRCD spectra of a chiral squaraine polymer could be measured. With the help of quantum chemical calculations, the signals were assigned to exciton dynamics that describe spatial and energetic rearrangements of the excitation energy. The alignment and the measurement procedures to perform TRCD spectroscopy with the new setup are described in detail for future experiments.
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7–11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5–40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).
Background
Alveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-failure. The molecular mechanisms of parasite organ tropism towards the liver and influences of liver cytokines and hormones on parasite development are little studied to date.
Methodology/Principal findings
We show that the E. multilocularis larval stage expresses three members of the fibroblast growth factor (FGF) receptor family with homology to human FGF receptors. Using the Xenopus expression system we demonstrate that all three Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which are present in the liver. In all three cases, activation could be prevented by addition of the tyrosine kinase (TK) inhibitor BIBF 1120, which is used to treat human cancer. At physiological concentrations, acidic and basic FGF significantly stimulated the formation of metacestode vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the parasite’s mitogen activated protein kinase signalling system was stimulated upon addition of human FGF. The survival of metacestode vesicles and parasite stem cells were drastically affected in vitro in the presence of BIBF 1120.
Conclusions/Significance
Our data indicate that mammalian FGF, which is present in the liver and upregulated during fibrosis, supports the establishment of the Echinococcus metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling system. These data are valuable for understanding molecular mechanisms of organ tropism and host-parasite interaction in AE. Furthermore, our data indicate that the parasite’s FGF signalling systems are promising targets for the development of novel drugs against AE.
Peptidergic signaling from clock neurons regulates reproductive dormancy in Drosophila melanogaster
(2019)
With the approach of winter, many insects switch to an alternative protective developmental program called diapause. Drosophila melanogaster females overwinter as adults by inducing a reproductive arrest that is characterized by inhibition of ovarian development at previtellogenic stages. The insulin producing cells (IPCs) are key regulators of this process, since they produce and release insulin-like peptides that act as diapause-antagonizing hormones. Here we show that in D. melanogaster two neuropeptides, Pigment Dispersing Factor (PDF) and short Neuropeptide F (sNPF) inhibit reproductive arrest, likely through modulation of the IPCs. In particular, genetic manipulations of the PDF-expressing neurons, which include the sNPF-producing small ventral Lateral Neurons (s-LNvs), modulated the levels of reproductive dormancy, suggesting the involvement of both neuropeptides. We expressed a genetically encoded cAMP sensor in the IPCs and challenged brain explants with synthetic PDF and sNPF. Bath applications of both neuropeptides increased cAMP levels in the IPCs, even more so when they were applied together, suggesting a synergistic effect. Bath application of sNPF additionally increased Ca2+ levels in the IPCs. Our results indicate that PDF and sNPF inhibit reproductive dormancy by maintaining the IPCs in an active state.