83 research outputs found
Interleukin-1 beta and neurotrophin-3 synergistically promote neurite growth in vitro
Pro-inflammatory cytokines such as interleukin-1 beta (IL-1ÎČ) are considered to exert detrimental effects during brain trauma and in neurodegenerative disorders. Consistently, it has been demonstrated that IL-1ÎČ suppresses neurotrophin-mediated neuronal cell survival rendering neurons vulnerable to degeneration. Since neurotrophins are also well known to strongly influence axonal plasticity, we investigated here whether IL-1ÎČ has a similar negative impact on neurite growth. We analyzed neurite density and length of organotypic brain and spinal cord slice cultures under the influence of the neurotrophins NGF, BDNF, NT-3 and NT-4. In brain slices, only NT-3 significantly promoted neurite density and length. Surprisingly, a similar increase of neurite growth was induced by IL-1ÎČ. Additionally, both factors increased the number of brain slices displaying maximal neurite growth. Furthermore, the co-administration of IL-1ÎČ and NT-3 significantly increased the number of brain slices displaying maximal neurite growth compared to single treatments. These data indicate that these two factors synergistically stimulate two distinct aspects of neurite outgrowth, namely neurite density and neurite length from acute organotypic brain slices
Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4
AbstractMast cells (MCs) are found abundantly in the central nervous system and play a complex role in neuroinflammatory diseases such as multiple sclerosis and stroke. In the present study, we show that MC-deficient KitW-sh/W-sh mice display significantly increased astrogliosis and T cell infiltration as well as significantly reduced functional recovery after spinal cord injury compared to wildtype mice. In addition, MC-deficient mice show significantly increased levels of MCP-1, TNF-α, IL-10 and IL-13 protein levels in the spinal cord. Mice deficient in mouse mast cell protease 4 (mMCP4), an MC-specific chymase, also showed increased MCP-1, IL-6 and IL-13 protein levels in spinal cord samples and a decreased functional outcome after spinal cord injury. A degradation assay using supernatant from MCs derived from either mMCP4â/â mice or controls revealed that mMCP4 cleaves MCP-1, IL-6, and IL-13 suggesting a protective role for MC proteases in neuroinflammation. These data show for the first time that MCs may be protective after spinal cord injury and that they may reduce CNS damage by degrading inflammation-associated cytokines via the MC-specific chymase mMCP4
FOâSPR biosensor calibrated with recombinant extracellular vesicles enables specific and sensitive detection directly in complex matrices
Extracellular vesicles (EVs) have drawn huge attention for diagnosing myriad of diseases, including cancer. However, the EV detection and analyses procedures often lack much desired sample standardization. To address this, we used well-characterized recombinant EVs (rEVs) for the first time as a biological reference material in developing a fiber optic surface plasmon resonance (FO-SPR) bioassay. In this context, EV binding on the FO-SPR probes was achieved only with EV-specific antibodies (e.g. anti-CD9 and anti-CD63) but not with non-specific anti-IgG. To increase detection sensitivity, we tested six different combinations of EV-specific antibodies in a sandwich bioassay. Calibration curves were generated with two most effective combinations (anti-CD9/(B)anti-CD81 and anti-CD63/(B)anti-CD9), resulting in 10(3) and 10(4) times higher sensitivity than the EV concentration in human blood plasma from healthy or cancer patients, respectively. Additionally, by using anti-CD63/(B)anti-CD9, we detected rEVs spiked in cell culture medium and HEK293 endogenous EVs in the same matrix without any prior EV purification or enrichment. Lastly, we selectively captured breast cancer cell EVs spiked in blood plasma using anti-EpCA M antibody on the FO-SPR surface. The obtained results combined with FO-SPR real-time monitoring, fast response time and ease of operation, demonstrate its outstanding potential for EV quantification and analysis
Predicting bee community responses to land-use changes: Effects of geographic and taxonomic biases
Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land-use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises
Calibration of the CMS hadron calorimeters using proton-proton collision data at root s=13 TeV
Methods are presented for calibrating the hadron calorimeter system of theCMSetector at the LHC. The hadron calorimeters of the CMS experiment are sampling calorimeters of brass and scintillator, and are in the form of one central detector and two endcaps. These calorimeters cover pseudorapidities vertical bar eta vertical bar ee data. The energy scale of the outer calorimeters has been determined with test beam data and is confirmed through data with high transverse momentum jets. In this paper, we present the details of the calibration methods and accuracy.Peer reviewe
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers âŒ99% of the euchromatic genome and is accurate to an error rate of âŒ1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Neuroimmune Communication in Skin: Far from Peripheral
The precise nature of the link between stress and exacerbation of skin inflammation has puzzled researchers and clinicians alike. The traditional explanation is that immune balance is altered by activation of two stress axes:activation of the hypothalamicâpituitaryâadrenal (HPA) axis raises cortisol levels, and activation of the sympathetic nervous systems raises adrenaline levels (Figure 1). In this issue, Pavlovic et al. (2008) provide evidence for a third stress axis and report that stress travels to the skin through peripheral neuropeptidergic nerve fibers and exacerbates the neurogenic inflammatory aspect of cutaneous dermatitis. Clarification of the role of this alternative stress axis may enable the design of novel therapeutic strategie
Neuroimmunology of axonal regeneration
Titelblatt und Inhaltsverzeichnis
Einleitung
Zusammenfassung der eigenen Arbeiten
Diskussion
LiteraturverzeichnisIn der vorliegenden Habilitationsschrift konnte gezeigt werden, dass die Haut
hochkontrolliert sich wiederholende Zyklen von Wachstum, Regression und Ruhe
durchlÀuft (92, 93). Dieser physiologische Umbau geht einher mit dramatischen
strukturellen VerÀnderungen, die alle Zelltypen und Kompartimente der Haut
betreffen einschlieĂlich Vaskularisierung (95), Innervation und Neurotrophin-
Millieu (90, 91, 102, 112) sowie wichtige Aspekte des Immunsystems (87, 96,
103, 107, 108, 110, 111, 115). Sowohl die physiologische als auch die
EntzĂŒndungs-assoziierte neuronale PlastizitĂ€t der Haut werden wiederum stark
durch psycho-emotionalen Stress beeinflusst (112). Wir konnten darĂŒber hinaus
zeigen, dass die pro-inflammatorischen Zytokine IL-1b, TNFa und IFNg sowie ein
Cocktail dieser drei Zytokine die NGF-, NT-3-, NT-4 und p75NTR-Expression in
epithelialen und mesenchymalen Zellpopulationen der Haut hochreguliert (85).
Auf diesen Daten aufbauend untersuchten wir die Hypothese, ob die im Rahmen
der Axotomie hochregulierten Zytokine IL-1b, IL-4, IL-6, TNFa und IFNg primÀr
Neurotrophin-abhÀngiges Axonwachstum modulieren (86). Es zeigte sich, dass
durch rekombinante Neurotrophine induziertes axonales Auswachsen durch alle
untersuchten Zytokine auĂer durch IL-1b moduliert wurde. IL-6 und IFNg
steigerten die Neurotrophin-abhÀngige Neuriten-Extension, wÀhrend TNFa einen
inhibierenden Einfluss hatte. IL-4 hatte einen dosisabhÀngigen Effekt: in
niedriger Konzentration inhibierte und in hoher Konzentration förderte es
NT-4-abhÀngiges Axonwachstum (86). Dies ist der erste Hinweis, dass das T
-Zell-Zytokin IL-4 einen förderlichen Einfluss auf axonales Auswachsen hat.
SchlieĂlich konnten wir zeigen, dass T-Helfer-Zellen via IL-4 eine
entscheidende Rolle bei der axonalen Regeneration nach mechanischer ZNS-
SchĂ€digung spielen (64). Aktivierte Th2-Zellen fördern ĂŒber IL-4 signifikant
das Neurotrophin-abhÀngige axonale Auswachsen nach entorhinaler Kortex-LÀsion
in vitro und in vivo sowie nach einer Kontusionsverletzung des RĂŒckenmarks in
MĂ€usen. Dies ist der erste formale Beleg, dass Th2-Zellen durch ihr Marker-
Zytokin IL-4 Neurotrophin-abhÀngiges axonales Auswachsen nach ZNS-LÀsion
fördern (64).
Die hier zusammengefassten Arbeiten sind ein klarer Hinweis darauf, dass die
Zytokin/Neurotrophin-Achse in der neurowissenschaftlichen Forschung ein
attraktives und neues pharmakologisches Ziel darstellt, um die Wundheilung und
die axonale Regeneration nach traumatischer SchÀdigung des PNS und ZNS zu
fördern.In the studies presented here, we were able to demonstrate that skin undergoes
highly controlled cycles of growth, regression and rest. This physiological
remodeling is associated with dramatic structural changes involving all cell
types and compartments of skin including vascularization, innervation and
neurotrophin milieu, as well as important aspects of the immune system.
Additionally, physiological and inflammation-associated neuronal plasticity
are substantially influenced by psycho-emotional stress. Furthermore, we
demonstrated that proinflammatory cytokines such as IL-1-beta, TNF-alpha and
IFN-gamma as well as a cocktail of these cytokines upregulate the expression
of the neurotrophins NGF, NT-3, NT-4 and their receptor p75NTR in epithelial
and mesenchymal cell populations of the skin. Based on these data, we tested
the hypothesis that axotomy-induced upregulation of IL-1-beta, IL-4, IL-6,
TNF-alpha and IFN-gamma modulate neurotrophin-dependent axon growth. We showed
that axon outgrowth induced by recombinant neurotrophins is modulated by all
factors investigated except IL-1-beta. IL-6 and IFN-gamma increase
neurotrophin-dependent neurite extension, while TNF-alpha shows an inhibitory
effect. IL-4 displays a dose-dependent effect: low concentrations inhibit and
high concentrations stimulate NT-4-dependent axon growth. Finally, we
demonstrated that T helper cells play a major role in axonal regeneration via
IL-4 after traumatic CNS injury, such as entorhinal cortex lesion in vitro and
in vivo, and contusion injury of the spinal cord in mice in vivo. This is the
first formal proof that T helper cells stimulate neurotrophin-dependent axonal
outgrowth after CNS injury via their marker cytokine IL-4. The studies
summarized here indicate that the cytokine/neurotrophin axis is a promising,
new pharmacological target in neuroscience research on wound healing and
axonal outgrowth after traumatic injury of the PNS and CNS
Both Whistleblowers and the Scientists They Accuse Are Vulnerable and Deserve Protection
Whistleblowers play an important role diagnosing research misconduct, but often experience severe negative consequences. That is also true for incorrectly accused scientists. Both categories are vulnerable and deserve protection. Whistleblowers must proceed carefully and cautiously. Anonymous whistleblowing should be discouraged but cannot be ignored when the allegations are specific, serious, and plausible. When accused of a breach of research integrity it is important to be as transparent as possible. Sometimes accusations are false in the sense that the accuser knows or should know that the allegations are untrue. A mala fide whistleblower typically does not act carefully and we postulate a typology that may help in detecting them. Striking the right balance between whistleblower protection and timely unmasking false and identifying incorrect accusations is a tough dilemma leaders of research institutions have to face
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