| 1. |
- Kövesdi, Erzsébet, et al.
(author)
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A novel PARP inhibitor L-2286 in a rat model of impact acceleration head injury : an immunohistochemical and behavioral study
- 2010
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 11:4, s. 1253-1268
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Journal article (peer-reviewed)abstract
- We examined the neuro/axono-protective potential of a novel poly (ADP-ribose) polymerase (PARP) inhibitor L-2286 in a rat impact acceleration brain injury model. Male Wistar rats (n = 70) weighing 300-350 grams were used to determine the most effective intracerebroventricular (i.c.v.) dose of L-2286 administered 30 min after injury, and to test the neuroprotective effect at two time points (immediately, and 30 min after injury). The neuroprotective effect of L-2286 was tested using immunohistochemical (amyloid precursor protein and mid-sized mouse anti-neurofilament clone RMO-14.9 antibody) and behavioral tests (beam-balance, open-field and elevated plus maze). At both time-points, a 100 microg/rat dose of i.c.v. L-2286 significantly (p < 0.05) reduced the density of damaged axons in the corticospinal tract and medial longitudinal fascicle compared to controls. In the behavioral tests, treatment 30 min post-injury improved motor function, while the level of anxiety was reduced in both treatment protocols.
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| 2. |
- Büki, Andras, 1966-, et al.
(author)
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Clinical and model research of neurotrauma
- 2009
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In: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1064-3745 .- 1940-6029. ; 566, s. 41-55
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Journal article (peer-reviewed)abstract
- Modeling traumatic brain injury represents a major challenge for neuroscientists - to represent extremely complex pathobiological processes kept under close surveillance in the most complex organ of a laboratory animal. To ensure that such models also reflect those alterations evoked by and/or associated with traumatic brain injury (TBI) in man, well-defined, graded, simple injury paradigms should be used with clear endpoints that also enable us to assess the relevance of our findings to human observations. It is of particular importance that our endpoints should harbor clinical significance, and to this end, biological markers ultimately associated with the pathological processes operant in TBI are considered the best candidate. This chapter provides protocols for relevant experimental models of TBI and clinical materials for neuroproteomic analysis.
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| 3. |
- Bukovics, Peter, et al.
(author)
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Changes of PACAP level in cerebrospinal fluid and plasma of patients with severe traumatic brain injury
- 2014
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In: Peptides. - : Elsevier. - 0196-9781 .- 1873-5169. ; 60, s. 18-22
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Journal article (peer-reviewed)abstract
- PACAP has well-known neuroprotective potential including traumatic brain injury (TBI). Its level is up-regulated following various insults of the CNS in animal models. A few studies have documented alterations of PACAP levels in human serum. The time course of post-ictal PACAP levels, for example, show correlation with migraine severity. Very little is known about the course of PACAP levels following CNS injury in humans and the presence of PACAP has not yet been detected in cerebrospinal fluid (CSF) of subjects with severe TBI (sTBI). The aim of the present study was to determine whether PACAP occurs in the CSF and plasma (Pl) of patients that suffered sTBI and to establish a time course of PACAP levels in the CSF and Pl. Thirty eight subjects with sTBI were enrolled with a Glasgow Coma Scale ≤8 on admission. Samples were taken daily, until the time of death or for maximum 10 days. Our results demonstrated that PACAP was detectable in the CSF, with higher concentrations in patients with TBI. PACAP concentrations markedly increased in both Pl and CSF in the majority of patients 24-48h after the injury stayed high thereafter. In cases of surviving patients, Pl and CSF levels displayed parallel patterns, which may imply the damage of the blood-brain barrier. However, in patients, who died within the first week, Pl levels were markedly higher than CSF levels, possibly indicating the prognostic value of high Pl PACAP levels.
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| 4. |
- Czeiter, Endre, et al.
(author)
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Calpain inhibition reduces axolemmal leakage in traumatic axonal injury
- 2009
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In: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 14:12, s. 5115-5123
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Journal article (peer-reviewed)abstract
- Calcium-induced, calpain-mediated proteolysis (CMSP) has recently been implicated to the pathogenesis of diffuse (traumatic) axonal injury (TAI). Some studies suggested that subaxolemmal CMSP may contribute to axolemmal permeability (AP) alterations observed in TAI. Seeking direct evidence for this premise we investigated whether subaxolemmal CMSP may contribute to axolemmal permeability alterations (APA) and pre-injury calpain-inhibition could reduce AP in a rat model of TAI. Horseradish peroxidase (HRP, a tracer that accumulates in axons with APA) was administered one hour prior to injury into the lateral ventricle; 30 min preinjury a single tail vein bolus injection of 30 mg/kg MDL-28170 (a calpain inhibitor) or its vehicle was applied in Wistar rats exposed to impact acceleration brain injury. Histological detection of traumatically injured axonal segments accumulating HRP and statistical analysis revealed that pre-injury administration of the calpain inhibitor MDL-28170 significantly reduced the average length of HRP-labeled axonal segments. The axono-protective effect of pre-injury calpain inhibition recently demonstrated with classical immunohistochemical markers of TAI was further corroborated in this experiment; significant reduction of the length of labeled axons in the drug-treated rats implicate CMSP in the progression of altered AP in TAI.
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| 5. |
- Czeiter, Endre, et al.
(author)
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Traumatic axonal injury in the spinal cord evoked by traumatic brain injury
- 2008
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 25:3, s. 205-213
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Journal article (peer-reviewed)abstract
- Although it is well known that traumatic brain injury (TBI) evokes traumatic axonal injury (TAI) within the brain, TBI-induced axonal damage in the spinal cord (SC) has been less extensively investigated. Detection of such axonal injury in the spinal cord would further the complexity of TBI while also challenging some functional neurobehavioral endpoints frequently used to assess recovery in various models of TBI. To assess TAI in the spinal cord associated with TBI, we analyzed the craniocervical junction (CCJ), cervico-thoracic (CT), and thoraco-lumber (ThL) spinal cord in a rodent model of impact acceleration of TBI of varying severities. Rats were transcardially fixed with aldehydes at 2, 6, and 24 h post-injury (n = 36); each group included on sham-injured rodent. Semi-serial vibratome sections were reacted with antibodies targeting TAI via alteration in cytoskeletal integrity or impaired axonal transport. Consistent with previous observations in this model, the CCJ contained numerous injured axons. Immunoreactive, damaged axonal profiles were also detected as caudal, as the ThL spinal cord displayed morphological characteristics entirely consistent with those described in the brainstem and the CCJ. Quantitative analyses demonstrated that the occurrence and extent of TAI is positively associated with the impact/energy of injury and negatively with the distance from the brainstem. These observations show that TBI can evoke TAI in regions remote from the injury site, including the spinal cord itself. This finding is relevant to shaken baby syndrome as well as during the analysis of data in functional recovery in various models of TBI.
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| 6. |
- Czobor, Pal, et al.
(author)
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The European Adolescent Assessment Dialogue (EuroADAD) : A Psychometric Evaluation
- 2011
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In: European Addiction Research. - : S. Karger AG. - 1022-6877 .- 1421-9891. ; 17:6, s. 302-315
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Journal article (peer-reviewed)abstract
- Background: The Adolescent Drug Abuse Diagnosis (ADAD) has been a gold standard for assessing drug use and associated problems in adolescents. Criticism of the instrument has been increasing. A new instrument, the European Adolescent Assessment Dialogue (EuroADAD) that builds on ADAD's strengths but seeks to address its limitations is now available, but has not been subjected to comprehensive psychometric evaluation. Objective: To examine the psychometric properties of the EuroADAD across various settings in adolescent populations who developed or were at a high risk of developing substance use and psychosocial adaptation problems. Participants and Settings: Three of the samples were collected in Hungary, including: institutionalized youths from juvenile residential facility (n = 295); adolescents from outpatient psychiatry facility (n = 278), and controls (n = 59). An additional sample was collected in the Netherlands, and consisted of adolescent boys from an independent residential institution for youth with severe behavioral problems (n = 51). Procedure: The EuroADAD was administered by trained interviewers. Data were collected through face-to-face interviews and self-report questionnaires. Results: Reliability: the intraclass correlation was high for all domains of the EuroADAD; reliability analyses indicated good test-retest reliability, and internal consistency. Validity: difference among study samples was significant (p < 0.05) for the majority of the domains, with juvenile institution and psychiatric outpatient subjects exhibiting higher severity in most areas compared to controls. The Hungarian and Dutch samples were comparable, expect for the legal domain, due to the higher severity of behavioral problems in the Dutch sample. Several domains of the instrument, including 'alcohol', 'drugs' and 'legal' showed an association with trait aggression as measured by the Buss-Perry Aggression Questionnaire and with Novelty Seeking on the Cloninger Temperament and Character Inventory. Conclusion: Based on the pattern and significance of group differences, and correlations with other measures, the scale has good criterion, and convergent and discriminant construct validity. The EuroADAD is a reliable and valid tool for the assessment of alcohol and drug use, and related psychosocial problems in adolescents.
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| 7. |
- Farkas, Orsolya, et al.
(author)
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Effects of pituitary adenylate cyclase activating polypeptide in a rat model of traumatic brain injury
- 2004
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In: Regulatory Peptides. - : Elsevier. - 0167-0115 .- 1873-1686. ; 123:1-3, s. 69-75
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Journal article (peer-reviewed)abstract
- Pituitary adenylate cyclase activating polypeptide (PACAP) is a widely distributed neuropeptide that has numerous different actions. Recent studies have shown that PACAP exerts neuroprotective effects not only in vitro but also in vivo, in animal models of global and focal cerebral ischemia, Parkinson's disease and axonal injuries. Traumatic brain injury has an increasing mortality and morbidity and it evokes diffuse axonal injury which further contributes to its damaging effects. The aim of the present study was to examine the possible neuroprotective effect of PACAP in a rat model of diffuse axonal injury induced by impact acceleration. Axonal damage was assessed by immunohistochemistry using an antiserum against beta-amyloid precursor protein, a marker of altered axoplasmic transport considered as key feature in axonal injury. In these experiments, we have established the dose response curves for PACAP administration in traumatic axonal injury, demonstrating that a single post-injury intracerebroventricular injection of 100 microg PACAP significantly reduced the density of damaged, beta-amyloid precursor protein-immunoreactive axons in the corticospinal tract.
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| 8. |
- Kövesdi, Erzsébet, et al.
(author)
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Posttraumatic administration of pituitary adenylate cyclase activating polypeptide in central fluid percussion injury in rats
- 2008
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In: Neurotoxicity research. - : Springer. - 1029-8428 .- 1476-3524. ; 13:2, s. 71-78
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Journal article (peer-reviewed)abstract
- Several in vitro and in vivo experiments have demonstrated the neuroprotective effects of pituitary adenylate cyclase activating polypeptide (PACAP) in focal cerebral ischemia, Parkinson's disease and traumatic brain injury (TBI). The aim of the present study was to analyze the effect of PACAP administration on diffuse axonal injury (DAI), an important contributor to morbidity and mortality associated with TBI, in a central fluid percussion (CFP) model of TBI. Rats were subjected to moderate (2 Atm) CFP injury. Thirty min after injury, 100 mu g PACAP was administered intracerebroventricularly. DAI was assessed by immunohistochemical detection of beta-amyloid precursor protein, indicating impaired axoplasmic transport, and RMO-14 antibody, representing foci of cytoskeletal alterations (neurofilament compaction), both considered classical markers of axonal damage. Analysis of damaged, immunoreactive axonal profiles revealed significant axonal protection in the PACAP-treated versus vehicle-treated animals in the corticospinal tract, as far as traumatically induced disturbance of axoplasmic transport and cytoskeletal alteration were considered. Similarly to our former observations in an impact acceleration model of diffuse TBI, the present study demonstrated that PACAP also inhibits DAI in the CFP injury model. The finding indicates that PACAP and derivates can be considered potential candidates for further experimental studies, or purportedly for clinical trials in the therapy of TBI.
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| 9. |
- Kövesdi, Erzsébet, et al.
(author)
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Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics
- 2010
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In: Acta Neurochirurgica. - : Springer. - 0001-6268 .- 0942-0940. ; 152:1, s. 1-17
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Research review (peer-reviewed)abstract
- Purpose: This review summarizes protein biomarkers in mild and severe traumatic brain injury in adults and children and presents a strategy for conducting rationally designed clinical studies on biomarkers in head trauma.Methods: We performed an electronic search of the National Library of Medicine's MEDLINE and Biomedical Library of University of Pennsylvania database in March 2008 using a search heading of traumatic head injury and protein biomarkers. The search was focused especially on protein degradation products (spectrin breakdown product, c-tau, amyloid-beta(1-42)) in the last 10 years, but recent data on "classical" markers (S-100B, neuron-specific enolase, etc.) were also examined.Results: We identified 85 articles focusing on clinical use of biomarkers; 58 articles were prospective cohort studies with injury and/or outcome assessment.Conclusions: We conclude that only S-100B in severe traumatic brain injury has consistently demonstrated the ability to predict injury and outcome in adults. The number of studies with protein degradation products is insufficient especially in the pediatric care. Cohort studies with well-defined end points and further neuroproteomic search for biomarkers in mild injury should be triggered. After critically reviewing the study designs, we found that large homogenous patient populations, consistent injury, and outcome measures prospectively determined cutoff values, and a combined use of different predictors should be considered in future studies.
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| 10. |
- Lückl, Jááos, et al.
(author)
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Protein biomarkerek szerepe a koponyasérüles kísérletes modelljeiben és a klinikumban : [Protein biomarkers in experimental models and in clinical care of traumatic brain injury]
- 2007
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In: Ideggyogyaszati Szemle. - : Literatura Medica Kiado. - 0019-1442 .- 2498-6208. ; 60:7-8, s. 284-294
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Research review (peer-reviewed)abstract
- Traumatic brain injury is the leading cause of mortality in Hungary in the population under 40 years of age. In Western societies, like the United Sates, traumatic brain injury represents an extreme social-economic burden, expected to become the third leading cause of mortality until 2020. Despite its' epidemiological significance, experimental therapeutic modalities developed in the last few decades did not prove efficient in the clinical care of severe traumatic brain injury. The reason for such a lack of success in terms of translating experimental results to clinical treatment at least partially could be explained by the paucity and the low sensitivity and specificity of clinical parameters endowing us to monitor the efficacy of the therapy. The drive for finding clinical parameters and monitoring tools that enable us to monitor treatment efficacy as well as outcome focused recent attention on biomarkers (and) surrogate markers that are based on rational pathological processes associated with/operant in traumatic brain injury. This review summarizes those biomarkers that could purportedly be used to monitor the treatment of the severely head injured while also providing information on salvageability facilitating the conduction of more rationally designed clinical studies.
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| 11. |
- Matuszka, Balazs, et al.
(author)
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Psychometric Characteristics of the Drug Use Disorders Identification Test (DUDIT) and the Drug Use Disorders Identification Test-Extended (DUDIT-E) Among Young Drug Users in Hungary
- 2014
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In: International Journal of Behavioral Medicine. - : Springer Science and Business Media LLC. - 1070-5503 .- 1532-7558. ; 21:3, s. 547-555
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Journal article (peer-reviewed)abstract
- AbstractThe Drug Use Disorders Identification Test (DUDIT) was developed for problematic substance use screening, and for a more detailed assessment of problematic use, the Drug Use Disorders Identification Test-Extended (DUDIT-E) was additionally developed.Examining the psychometric properties of DUDIT and DUIT-E across diverse settings in populations of young drug users.We examined the psychometric characteristics of these instruments across various settings in populations of young substance users differing in substance use severity and treatment status. Data were collected from three clinically relevant groups (n = 259) as well as a control sample of college students (n = 109).Reliability analyses indicated good internal consistency for both instruments; high intraclass correlations further indicated good test-retest reliability. Differences among study groups were significant on the DUDIT scale and all DUDIT-E subscales (p < 0.01), with the target groups exhibiting higher scores compared to controls. A two-factor solution was identified for the factor structure of DUDIT.The Hungarian version of DUDIT and DUDIT-E can effectively identify substance use problems among young users.
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| 12. |
- Tamas, Andrea, et al.
(author)
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Effect of PACAP in central and peripheral nerve injuries
- 2012
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 13:7, s. 8430-8448
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Research review (peer-reviewed)abstract
- Pituitary adenylate cyclase activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. In addition to its more classic role as a neuromodulator, PACAP functions as a neurotrophic factor. Several neurotrophic factors have been shown to play an important role in the endogenous response following both cerebral ischemia and traumatic brain injury and to be effective when given exogenously. A number of studies have shown the neuroprotective effect of PACAP in different models of ischemia, neurodegenerative diseases and retinal degeneration. The aim of this review is to summarize the findings on the neuroprotective potential of PACAP in models of different traumatic nerve injuries. Expression of endogenous PACAP and its specific PAC1 receptor is elevated in different parts of the central and peripheral nervous system after traumatic injuries. Some experiments demonstrate the protective effect of exogenous PACAP treatment in different traumatic brain injury models, in facial nerve and optic nerve trauma. The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in neuronal regeneration indicating that PACAP may also be a promising therapeutic agent in injuries of the nervous system.
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| 13. |
- Tamás, Andrea, et al.
(author)
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Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats
- 2006
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 23:5, s. 686-695
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Journal article (peer-reviewed)abstract
- Pituitary adenylate cyclase activating polypeptide (PACAP) has several different actions in the nervous system. Numerous studies have shown its neuroprotective effects both in vitro and in vivo. Previously, it has been demonstrated that PACAP reduces brain damage in rat models of global and focal cerebral ischemia. Based on the protective effects of PACAP in cerebral ischemia and the presence of common pathogenic mechanisms in cerebral ischemia and traumatic brain injury (TBI), the aim of the present study was to investigate the possible protective effect of PACAP administered 30 min or 1 h postinjury in a rat model of diffuse axonal injury. Adult Wistar male rats were subjected to impact acceleration, and PACAP was administered intracerebroventricularly 30 min (n = 4), and 1 h after the injury (n = 5). Control animals received the same volume of vehicle at both time-points (n = 5). Two hours after the injury, brains were processed for immunohistochemical localization of damaged axonal profiles displaying either beta-amyloid precursor protein (beta-APP) or RMO-14 immunoreactivity, both considered markers of specific features of traumatic axonal injury. Our results show that treatment with PACAP (100 microg) 30 min or 1 h after the induction of TBI resulted in a significant reduction of the density of beta-APP-immunopositive axon profiles in the corticospinal tract (CSpT). There was no significant difference between the density of beta-APP-immunopositive axons in the medial longitudinal fascicle (MLF). PACAP treatment did not result in significantly different number of RMO-14-immunopositive axonal profiles in either brain areas 2 hours post-injury compared to normal animals. While the results of this study highlighted the complexity of the pathogenesis and manifestation of diffuse axonal injury, they also indicate that PACAP should be considered a potential therapeutic agent in TBI.
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| 14. |
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| 15. |
- Wahlgren, Weixiao Yuan, 1970, et al.
(author)
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The catalytic aspartate is protonated in the Michaelis complex formed between trypsin and an in vitro evolved substrate-like inhibitor: a refined mechanism of serine protease action.
- 2011
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In: The Journal of biological chemistry. - 1083-351X. ; 286:5, s. 3587-96
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Journal article (peer-reviewed)abstract
- The mechanism of serine proteases prominently illustrates how charged amino acid residues and proton transfer events facilitate enzyme catalysis. Here we present an ultrahigh resolution (0.93 Å) x-ray structure of a complex formed between trypsin and a canonical inhibitor acting through a substrate-like mechanism. The electron density indicates the protonation state of all catalytic residues where the catalytic histidine is, as expected, in its neutral state prior to the acylation step by the catalytic serine. The carboxyl group of the catalytic aspartate displays an asymmetric electron density so that the O(δ2)-C(γ) bond appears to be a double bond, with O(δ2) involved in a hydrogen bond to His-57 and Ser-214. Only when Asp-102 is protonated on O(δ1) atom could a density functional theory simulation reproduce the observed electron density. The presence of a putative hydrogen atom is also confirmed by a residual mF(obs) - DF(calc) density above 2.5 σ next to O(δ1). As a possible functional role for the neutral aspartate in the active site, we propose that in the substrate-bound form, the neutral aspartate residue helps to keep the pK(a) of the histidine sufficiently low, in the active neutral form. When the histidine receives a proton during the catalytic cycle, the aspartate becomes simultaneously negatively charged, providing additional stabilization for the protonated histidine and indirectly to the tetrahedral intermediate. This novel proposal unifies the seemingly conflicting experimental observations, which were previously seen as either supporting the charge relay mechanism or the neutral pK(a) histidine theory.
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| 16. |
- Zamora, Juan Carlos, et al.
(author)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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