Henning Ulrich

University of São Paulo, San Paulo, São Paulo, Brazil

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Publications (123)325.66 Total impact

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    ABSTRACT: The kallikrein-kinin system (KKS) is an endogenous pathway involved in many biological processes. Although primarily related to blood pressure control and inflammation, its activation goes beyond these effects. Neurogenesis and neuroprotection might be stimulated by modulating bradykinin functions being of great interest for different clinical applications following brain injury. This peptide is also an important player in spinal cord injury pathophysiology and recovery, where bradykinin receptor blockers represents substantial therapeutic potential. Here, we highlight the participation of kinin receptors and especially bradykinin in mediating the ischemia pathophysiology in the central and peripheral nervous systems. Moreover, we explore the recent advances on mechanistic and therapeutic targets for biological, pathological and neural repair processes involving kinins.
    Cell Transplantation 03/2015; 24(4). DOI:10.3727/096368915X687778 · 3.57 Impact Factor
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    ABSTRACT: Acetylcholinesterase (AChE) inhibition has been described as the main mechanism of organophosphate (OP)-evoked toxicity. OPs represent a human health threat, because chronic exposure to low doses can damage the developing brain, and acute exposure can produce long-lasting damage to adult brains, despite post-exposure medical countermeasures. Although the main mechanism of OP toxicity is AChE inhibition, several lines of evidence suggest that OPs also act by other mechanisms. We hypothesized that rat neural progenitor cells extracted on embryonic day 14.5 would be affected by constant inhibition of AChE from chronic exposure to OP or pyridostigmine (a reversible AChE blocker) during differentiation. In this work, the OP paraoxon decreased cell viability in concentrations >50 μM, as measured with the MTT assay; however, this effect was not dose-dependent. Reduced viability could not be attributed to blockade of AChE activity, since treatment with 200 µM pyridostigmine did not affect cell viability, even after 6 days. Although changes in protein expression patterns were noted in both treatments, the distribution of differentiated phenotypes, such as the percentages of neurons and glial cells, was not altered, as determined by flow cytometry. Since paraoxon and pyridostigmine each decreased neurite outgrowth (but did not prevent differentiation), we infer that developmental patterns may have been affected.
    Neurochemical Research 03/2015; DOI:10.1007/s11064-015-1548-7 · 2.55 Impact Factor
  • Henning Ulrich, Peter Illes
    Neural Regeneration Research 12/2014; 9(23):2040-1. DOI:10.4103/1673-5374.147925 · 0.23 Impact Factor
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    ABSTRACT: CONTENTS 1. Introduction 1 1.1. Brain tumor glioblastoma multiforme (GBM) 1 1.2. Cancer stem cell (CSC) paradigm 2 1.3. GBM stem-like cells (GSCs) 4 2. Isolation methodologies of GSCs 4 2.1. SP and ABC transporters 5 2.2. Isolation based on biomarkers 5 2.2.1. CD133 5 2.2.2. ALDH 5 2.2.3. Aptamers 5 3. Enrichment of GSC cultures 6 3.1. Effects of medium and substrates 6 3.2. Effects of hypoxia 7 3.3. Effects of endothelial cells 8 3.4. Effects of pericyte cells 9 3.5. Effects of immunosuppressed animals 9 4. Validation of the GSC phenotype 10 4.1. Sphere-formation assay 10 4.2. Tumor formation in vivo 10 4.3. Expression of biomarkers 11 4.4. Chemoresistance assay 11 4.5. Differentiation assay 12 5. Conclusions 12 Acknowledgments 13 References 13 Abstract: Glioblastoma (GBM) stem-like cells (GSCs) represent the most undifferentiated state of malignant cells with distinct biological characteristics. The fraction of these cells within a glial brain tumor, ranging from 2–30%, is correlating with the increasing WHO stage and poor prognosis of patients' survival. GSCs represent the least vulnerable, thus most preferential target cell population to be exposed to various therapeutic modalities, although the underlying mechanisms of this resistance are not yet fully understood. For the development of GSC-targeting therapies, further in depth studies are needed using enriched and stable GSC cell populations. Here, we discuss the current approaches of GSC isolation and validation based on expression of stemness and oncogenic markers as well as on functional assays. The enrichment of GSC phenotypes in established cell lines and/or primary tumor cultures, achieved by different strategies, is reviewed, providing a comprehensive comparison of selected studies and contemplating the characterization of the plethora of variants of reported GBM population exhibiting the GSC phenotype. ABBREVIATIONS: Aldehyde dehydrogenase (ALDH) Brain tumor initiating cells (BTIC) Cancer stem cell (CSC) Epidermal growth factor (EGF) Epithelial to mesenchymal transition (EMT) Fibroblast growth factor (FGF) Glioblastoma multiforme (GBM) Glioblastoma stem-like cell (GSC) Iso-dehydrogenase 1 (IDH1) Neural progenitor cell (NPC) Neural stem cell (NSC) O-6-methylguanine-DNA-methyltransferase (MGMT) Temozolomide (TMZ)
    11/2014; DOI:10.14343/JCSCR.2014.2e1007
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    ABSTRACT: Uric acid and purines (such as adenosine) regulate mood, sleep, activity, appetite, cognition, memory, convulsive threshold, social interaction, drive, and impulsivity. A link between purinergic dysfunction and mood disorders was first proposed a century ago. Interestingly, a recent nationwide population-based study showed elevated risk of gout in subjects with bipolar disorder (BD), and a recent meta-analysis and systematic review of placebo-controlled trials of adjuvant purinergic modulators confirmed their benefits in bipolar mania. Uric acid may modulate energy and activity levels, with higher levels associated with higher energy and BD spectrum. Several recent genetic studies suggest that the purinergic system - particularly the modulation of P1 and P2 receptor subtypes - plays a role in mood disorders, lending credence to this model. Nucleotide concentrations can be measured using brain spectroscopy, and ligands for in vivo positron emission tomography (PET) imaging of adenosine (P1) receptors have been developed, thus allowing potential target engagement studies. This review discusses the key role of the purinergic system in the pathophysiology of mood disorders. Focusing on this promising therapeutic target may lead to the development of therapies with antidepressant, mood stabilization, and cognitive effects.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 11/2014; PMID: 25445063. DOI:10.1016/j.pnpbp.2014.10.016 · 4.03 Impact Factor
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    ABSTRACT: Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens.
    Journal of Cellular and Molecular Medicine 10/2014; 19(1). DOI:10.1111/jcmm.12416 · 3.70 Impact Factor
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    ABSTRACT: Immunomodulators regulate stem cell activity at all stages of development as well as during adulthood. Embryonic stem cell (ESC) proliferation as well as neurogenic processes during embryonic development are controlled by factors of the immune system. We review here immunophenotypic expression patterns of different stem cell types, including ESC, neural (NSC) and tissue-specific mesenchymal stem cells (MSC), and focus on immunodulatory properties of these cells. Immune and inflammatory responses, involving actions of cytokines as well as toll-like receptor (TLR) signaling are known to affect the differentiation capacity of NSC and MSC. Secretion of pro- and anti-inflammatory messengers by MSC have been observed as the consequence of TLR and cytokine activation and promotion of differentiation into specified phenotypes. As result of augmented differentiation capacity, stem cells secrete angiogenic factors including vascular endothelial growth factor, resulting in multifactorial actions in tissue repair. Immunoregulatory properties of tissue specific adult stem cells are put into the context of possible clinical applications.
    Stem Cell Reviews and Reports 09/2014; DOI:10.1007/s12015-014-9556-6 · 3.21 Impact Factor
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    ABSTRACT: Novel developmental functions have been attributed to the P2X7 receptor (P2X7R) including proliferation stimulation and neural differentiation. Mouse embryonic stem cells (ESC), induced with retinoic acid to neural differentiation, closely assemble processes occurring during neuroectodermal development of the early embryo. P2X7R expression together with the pluripotency marker Oct-4 was highest in undifferentiated ESC. In undifferentiated cells, the P2X7R agonist Bz-ATP accelerated cell cycle entry, which was blocked by the specific P2X7R inhibitor KN-62. ESC induced to neural differentiation with retinoic acid, reduced Oct-4 and P2X7R expression. P2X7R receptor-promoted intracellular calcium fluxes were obtained at lower Bz-ATP ligand concentrations in undifferentiated and in neural-differentiated cells compared to other studies. The presence of KN-62 led to increased number of cells expressing SSEA-1, Dcx and β3-tubulin, as well as the number of SSEA-1 and β3-tubulin-double-positive cells confirming that onset of neuroectodermal differentiation and neuronal fate determination depends on suppression of P2X7R activity. Moreover, an increase in the number of Ki-67 positive cells in conditions of P2X7R inhibition indicates rescue of progenitors into the cell cycle, augmenting the number of neuroblasts and consequently neurogenesis. In embryonic cells, P2X7R expression and activity is upregulated, maintaining proliferation, while upon induction to neural differentiation P2X7 receptor expression and activity needs to be suppressed.
    PLoS ONE 05/2014; 9(5):e96281. DOI:10.1371/journal.pone.0096281 · 3.53 Impact Factor
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    ABSTRACT: The N-methyl D-aspartate (NMDA) class of ionotropic glutamate receptors plays important roles in learning and memory as well as in a number of neurological disorders including Huntington's disease and cerebral ischemia. Here, we describe the isolation and characterization of a 2́ F-modified RNA aptamers directed against GluN2A-containing NMDA receptors. By adding a negative selection step towards the closely related AMPA and kainate receptors, the RNA aptamers specifically recognize NMDA receptors with dissociation constants in the nanomolar range. Electrophysiological characterization of these aptamers using rapid perfusion in outside-out patches reveals that they selectively inhibit the GluN2A containing subtype of NMDA receptors with little effect on the AMPA and kainate receptor subtypes. We also demonstrate that this RNA aptamer significantly reduces neurotoxicity in an in vitro model of cerebral ischemia. Given that the RNA based antagonist can be readily modified it can be used as a tool in targeted drug delivery or for imaging purposes in addition to having the potential use as a therapeutic intervention in disorders involving glutamate receptors.
    ACS Chemical Neuroscience 04/2014; 5(7). DOI:10.1021/cn500041k · 4.21 Impact Factor
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    Henning Ulrich, Attila Tárnok
    Cytometry Part A 03/2014; 85(3):201-2. DOI:10.1002/cyto.a.22441 · 3.07 Impact Factor
  • H Ulrich, J Bocsi, T Glaser, A Tárnok
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    ABSTRACT: During brain development, a population of uniform embryonic cells migrates and differentiates into a large number of neural phenotypes - origin of the enormous complexity of the adult nervous system. Processes of cell proliferation, differentiation and programmed death of no longer required cells, do not occur only during embryogenesis, but are also maintained during adulthood and are affected in neurodegenerative and neuropsychiatric disease states. As neurogenesis is an endogenous response to brain injury, visible as proliferation (of to this moment silent stem or progenitor cells), its further stimulation can present a treatment strategy in addition to stem cell transfer for cell regeneration therapy. Concise techniques for studying such events in vitro and in vivo permit understanding of underlying mechanisms. Detection of subtle physiological alterations in brain cell proliferation and neurogenesis can be explored, that occur during environmental stimulation, exercise and ageing. Here, we have collected achievements in the field of basic research on applications of cytometry, including automated imaging for quantification of morphological or fluorescence-based parameters in cell cultures, towards imaging of three-dimensional brain architecture together with DNA content and proliferation data. Multi-parameter and more recently in vivo flow cytometry procedures, have been developed for quantification of phenotypic diversity and cell processes that occur during brain development as well as in adulthood, with importance for therapeutic approaches.
    Cell Proliferation 02/2014; 47(1):12-9. DOI:10.1111/cpr.12087 · 3.28 Impact Factor
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    ABSTRACT: Oligonucleotide aptamers are selected from libraries typically comprising up to 10(15) different sequences by an iterative process of binding, separation, amplification and purification, called SELEX. During this process, the diversity of the oligonucleotide pool decreases until, presumably, only sequences with highest binding affinities towards chosen targets remain. This selection technique is time-consuming, labor-intensive and expensive. Though well posed in principles, the SELEX procedure is noise sensitive, due to amplification of unspecific-binding sequences, and it is not surprising that aptamer selection is often not successful in practice. In view of that, a follow-up of the progress of selection during its course with simple yet reliable methods is necessary. In this paper, we describe five independent assays to estimate the sequence complexity of SELEX pools including qualitative restriction fragment length polymorphism analysis, melting curve analysis, quantitative fluorescence intensity measurements of bound ssDNA, real time PCR quantification and pool dissociation constant analysis during the progress of aptamer selection against streptavidin. Properties and features of each method are discussed and compared. Pool dissociation constant analysis and sequencing serve as reference methods.
    Journal of pharmaceutical and biomedical analysis 01/2014; 91C:151-159. DOI:10.1016/j.jpba.2013.12.031 · 2.83 Impact Factor
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    ABSTRACT: Stem cells are known for their capacity to self-renew and differentiate into at least one specialized cell type. Mesenchymal stem cells (MSCs) were isolated initially from bone marrow but are now known to exist in all vascularized organ or tissue in adults. MSCs are particularly relevant for therapy due to their simplicity of isolation and cultivation. The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define hMSCs for laboratory investigations and preclinical studies: adherence to plastic in standard culture conditions; in vitro differentiation into osteoblasts, adipocytes, and chondroblasts; specific surface antigen expression in which ≥95% of the cells express the antigens recognized by CD105, CD73, and CD90, with the same cells lacking (≤2% positive) the antigens CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR. In this review we will take an historical overview of how umbilical cord blood, bone marrow, adipose-derived, placental and amniotic fluid, and menstrual blood stem cells, the major sources of human MSC, can be obtained, identified and how they are being used in clinical trials to cure and treat a very broad range of conditions, including heart, hepatic, and neurodegenerative diseases. An overview of protocols for differentiation into hepatocytes, cardiomyocytes, neuronal, adipose, chondrocytes, and osteoblast cells are highlighted. We also discuss a new source of stem cells, induced pluripotent stem cells (iPS cells) and some pathways, which are common to MSCs in maintaining their pluripotent state. © 2013 International Society for Advancement of Cytometry
    Cytometry Part A 01/2014; DOI:10.1002/cyto.a.22402 · 3.07 Impact Factor
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    ABSTRACT: Worldwide the entire human population is at risk of infectious diseases of which a high degree is caused by pathogenic protozoans, worms, bacteria, and virus infections. Moreover the current medications against pathogenic agents are losing their efficacy due to increasing and even further spreading drug resistance. Therefore, there is an urgent need to discover novel diagnostic as well as therapeutic tools against infectious agents. In view of that, the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) represents a powerful technology to target selectively pathogenic factors as well as entire bacteria or viruses. SELEX uses a large combinatorial oligonucleic acid library (DNA or RNA) which is processed a by high-flux in vitro screen of iterative cycles. The selected ligands, termed aptamers, are characterized by high specificity and affinity to their target molecule, which are already exploited in diagnostic and therapeutic applications. In this minireview we will discuss the current status of the SELEX technique applied on bacterial and viral pathogens.
    09/2013; 2013:731516. DOI:10.1155/2013/731516
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    ABSTRACT: Bradykinin-potentiating peptides from Bothrops jararaca (Bj) discovered in the early 1960s, were the first natural inhibitors of the angiotensin-converting enzyme (ACE). These peptides belong to a large family of snake venom proline-rich oligopeptides (PROs). One of these peptides, Bj-PRO-9a, was essential for defining ACE as effective drug target and development of captopril, an active site-directed inhibitor of ACE used worldwide for the treatment of human arterial hypertension. Recent experimental evidences demonstrated that cardiovascular effects exerted by different Bj-PROs are due to distinct mechanisms besides of ACE inhibition. In the present work, we have investigated the cardiovascular actions of four Bj-PROs, namely Bj-PRO-9a, -11e, -12b e -13a. Bj-PRO-9a acts upon ACE and BK activities to promote blood pressure reduction. Although the others Bj-PROs are also able to inhibit the ACE activity and to potentiate the BK effects, our results indicate that antihypertensive effect evoked by them involve new mechanisms. Bj-PRO-11e and Bj-PRO-12b involves induction of [Ca(2+)]i transients by so far unknown receptor proteins. Moreover, we have suggested argininosuccinate synthetase and M3 muscarinic receptor as targets for cardiovascular effects elicited by Bj-PRO-13a. In summary, the herein reported results provide evidence that Bj-PRO-mediated effects are not restricted to ACE inhibition or potentiation of BK-induced effects and suggest different actions for each peptide for promoting arterial pressure reduction. The present study reveals the complexity of the effects exerted by Bj-PROs for cardiovascular control, opening avenues for the better understanding of blood pressure regulation and for the development of novel therapeutic approaches.
    Peptides 08/2013; DOI:10.1016/j.peptides.2013.07.016 · 2.61 Impact Factor
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    ABSTRACT: Throughout the development of the central nervous system, neural crest cells and the primary neural stem cells originate several non-neuronal and neuronal cell types. Undifferentiated stem cells exist in the adult brain, mainly in the dentate gyrus of the hippocampus and in the subventricular zone of the lateral ventricles, and can produce new neurons, participating in brain plasticity and tissue regeneration. Neurogenesis in the embryonic and adult brain occurs under the control of intrinsic and extrinsic factors. However, the mechanisms, by which cell cycle components control neural stem cell proliferation and consequently neurogenesis, still lack further investigation. We discuss here recent knowledge obtained on cell cycle components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain.
    Stem cell reviews 07/2013; 9(6). DOI:10.1007/s12015-013-9460-5 · 3.21 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ) and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs). Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.
    PLoS ONE 07/2013; 8(7):e67194. DOI:10.1371/journal.pone.0067194 · 3.53 Impact Factor
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    ABSTRACT: The kinin-B2 receptor (B2BKR) activated by its endogenous ligand bradykinin participates in various metabolic processes including control of arterial pressure and inflammation. Recently, functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed. Here, we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model. Following slice perfusion for 10 min with diisopropylfluorophosphate (DFP) to initiate the noxious stimulus, responses of pyramidal neurons upon an electric impulse were reduced to less than 30% of control amplitudes. Effects on synaptic-elicited population spikes were reverted when preparations had been exposed to bradykinin 30 min after challenging with DFP. Accordingly, bradykinin-induced population spike recovery was abolished by HOE-140, a B2BKR antagonist. However, the kinin-B1 receptor (B1BKR) agonist Lys-des-Arg(9)-bradykinin, inducing phosphorylation of MEK/MAPK and cell death, abolished bradykinin-mediated neuroprotection, an effect, which was reverted by the ERK inhibitor PD98059. In agreement with pivotal B1BKR functions in this process, antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity. On the other hand pralidoxime, an oxime, reactivating AChE after organophosphate poisoning, induced population spike recovery after DFP exposure in the presence of bradykinin and Lys-des-Arg(9)-bradykinin. Lys-des-Arg(9)-bradykinin did not revert protection exerted by pralidoxime, however when instead bradykinin and Ly-des-Arg(9)-bradykinin were superfused together, recovery of population spikes diminished. These findings again confirm the neuroprotective feature of bradykinin, which is, diminished by its endogenous metabolites, stimulating the B1BKR, providing a novel understanding of physiological roles of these receptors.
    Neuroscience 06/2013; DOI:10.1016/j.neuroscience.2013.05.054 · 3.33 Impact Factor
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  • Tina Smuc, Il-Young Ahn, Henning Ulrich
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    ABSTRACT: Aptamers are small nucleic acid molecules capable of binding to a wide range of target molecules with high affinity and specificity. They have been developed and widely used not only as research tools, but also as biosensors, specific antagonists, and diagnostic markers and as protein purification platform for many pharmaceutical and clinical applications. Here, in this paper we will explore biochemical aspects of aptamer-target interactions and show why aptamers rival antibodies in target recognition and purification procedures. This review will focus on strategies of using aptamers as affinity ligands for molecules of therapeutic and pharmaceutical interest including applications in chromatography and capillary electrophoresis for protein and small molecule purification. Moreover, we will also discuss aptamers whose binding parameters can be controlled on demand for diagnostic approaches and used as sensitive receptors in biosensorics. Aptamers have opened up exciting fields in basic and applied research of pharmaceutical and biotechnological interest.
    Journal of pharmaceutical and biomedical analysis 03/2013; 81-82C:210-217. DOI:10.1016/j.jpba.2013.03.014 · 2.83 Impact Factor

Publication Stats

1k Citations
325.66 Total Impact Points


  • 2002–2014
    • University of São Paulo
      • Department of Biochemistry (IQ)
      San Paulo, São Paulo, Brazil
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
  • 2001
    • University of Leipzig
      • Translational Centre for Regenerative Medicine (TRM)
      Leipzig, Saxony, Germany
  • 1998–2001
    • Cornell University
      • Department of Molecular Biology and Genetics
      Ithaca, New York, United States
    • Zentrum für Molekulare Neurobiologie Hamburg
      Hamburg, Hamburg, Germany
  • 1996
    • University of Hamburg
      • Center for Molecular Neurobiology (ZMNH)
      Hamburg, Hamburg, Germany