bluuebunny/crossref_metadata_2025_split huggingface dataset:
New insight into the molecular pathways of metallothionein‐mediated neuroprotection and regeneration
Authors: Chung R. S. , Hidalgo J. , West A. K. 
Published: October 2007

AbstractThere is a large body of evidence demonstrating that metallothioneins (MTs) expressed in astrocytes following CNS injury, exhibit both neuroprotective and neuroregenerative properties and are critical for recovery outcomes. As these proteins lack signal peptides, and have well characterized free radical scavenging and heavy metal binding properties, the neuroprotective functions of MTs have been attributed to these intracellular roles. However, there is an increasing realization that the neuroprotective functions of MTs may also involve an extracellular component. In this issue of Journal of Neurochemistry, Ambjørn et al. reveal considerable insight into this novel function of MTs. In this review, we examine the seminal work of Ambjørn et al. in the context of our current understanding of the role of MT in astrocyte‐neuron interactions in the injured brain, and also discuss the significant therapeutic potential of their work.
Tyr‐701 is a new regulatory site for neurotrophin receptor TrkA trafficking and function
Authors: De Pablo Yolanda , Pérez‐García M. José , Georgieva Maya V. , Sanchis Daniel , Lindqvist Niclas , Soler Rosa M. , Comella Joan X. , Llovera Marta 
Published: October 2007

AbstractTropomyosin‐related kinase A (TrkA) receptor mediates the effects exerted by nerve growth factor on several subpopulations of neuronal cells. Ligand binding to TrkA induces receptor autophosphorylation on several tyrosine residues and the activation of signaling cascades. In this study, we describe a new site relevant for TrkA regulation, the tyrosine 701 (Y701), which is important for receptor trafficking and activation. Y701 replacement by aspartate or phenylalanine reduces receptor internalization rate and decreases the colocalization and association of TrkA with clathrin heavy chain, demonstrating that Y701 constitutes a YxxΦ (YRKF701–704) trafficking motif relevant for the regulation of receptor endocytosis. In accordance with this hypothesis, the colocalization of Y701 mutant receptors with a lysosomal marker is also reduced giving support to the involvement of the YRKF701–704 motif in the lysosomal targeting of TrkA receptors. Contrary to what was expected, substitution of Y701 for an Asp in order to mimic phosphorylation, impairs TrkA ability to mediate nerve growth factor‐induced differentiation, although the mutant receptor retains its in vitro kinase activity. This is the first evidence that a Tyr residue can simultaneously regulate TrkA receptor trafficking and activity.
Crustacean dopamine receptors: localization and G protein coupling in the stomatogastric ganglion
Authors: Clark Merry C. , Khan Reesha , Baro Deborah J. 
Published: October 2007

AbstractNeuromodulators, such as dopamine (DA), control motor activity in many systems. To begin to understand how DA modulates motor behaviors, we study a well‐defined model: the crustacean stomatogastric nervous system (STNS). The spiny lobster STNS receives both neuromodulatory and neurohormonal dopaminergic input, and extensive background information exists on the cellular and network effects of DA. However, there is a void of information concerning the mechanisms of DA signal transduction in this system. In this study, we show that Gs, Gi, and Gq are activated in response to DA in STNS membrane preparations from five crustacean species representing distant clades in the order Decapoda. Three evolutionarily conserved DA receptors mediate this response in spiny lobsters: D1αPan, D1βPan and D2αPan. G protein coupling for these receptors can vary with the cell type. In the native membrane, the D1αPan receptor couples with Gs and Gq, the D1βPan receptor couples with Gs, and the D2αPan receptor couples with Gi. All three receptors are localized exclusively to the synaptic neuropil and most likely generate global biochemical signals that alter ion channels in distant compartments, as well as local signals.
Cellular uptake and lysosomal delivery of galactocerebrosidase tagged with the HIV Tat protein transduction domain
Authors: Zhang Xian‐Yang , Dinh Annie , Cronin James , Li Su‐Chen , Reiser Jakob 
Published: October 2007

AbstractA number of studies have shown that a short peptide, the protein transduction domain (PTD) derived from the HIV‐1 Tat protein (Tat‐PTD) improved cellular uptake in vitro and distribution in vivo of recombinant proteins bearing such PTDs when administered systemically. To investigate the effects of Tat‐PTD addition on the subcellular localization of the lysosomal enzyme galactocerebrosidase (GALC, EC 3.2.2.46) and with a view towards designing improved therapeutic strategies for Krabbe disease (globoid cell leukodystrophy), mouse GALC was tagged C‐terminally with the Tat‐PTD. Compared with unmodified GALC, GALC bearing a Tat‐PTD, a myc epitope and 6 consecutive His residues [GALC‐TMH (Tat‐PTD, a myc epitope and 6 consecutive His residues)] was found to be secreted more efficiently. Also, GALC‐TMH was found to be taken up by cells both via mannose‐6‐phosphate receptor (M6PR)‐mediated endocytosis as well as by M6PR‐independent mechanisms. GALC‐TMH displayed increased M6PR‐independent uptake in fibroblasts derived from twitcher mice (a murine model of globoid cell leukodystrophy) and in neurons derived from the mouse brain cortex compared with GALC lacking a Tat‐PTD. Immunocytochemical analyses revealed that Tat‐modified GALC protein co‐localized in part with the lysosome‐associated membrane protein‐1. Complete correction of galactosylceramide accumulation was achieved in twitcher mouse fibroblasts lacking GALC activity following addition of GALC‐TMH. Therefore, GALC‐TMH not only maintained the features of the native GALC protein including enzymatic function, intracellular transport and location, but also displayed more efficient cellular uptake.
The C‐terminus of the metabotropic glutamate receptor 1b regulates dimerization of the receptor
Authors: Remelli Rosaria , Robbins Melanie J. , McIlhinney R. A. Jeffrey 
Published: October 2007

AbstractThe Group C G protein‐coupled receptors include the metabotropic glutamate receptors (mGluRs), the GABAB receptor, the calcium sensor and several taste receptors, most of which are obligate dimers, indeed recent work has shown that dimerization is necessary for the activation of these receptors. Consequently factors that regulate their ability to homo‐ or heterodimerize are important. The Group 1 mGluRs include mGluR1 and mGluR5 both of which have splice variants with altered C‐termini. In this study, we show that mGluR1b is a dimer and that it does not efficiently heterodimerize with mGluR1a, unlike the two splice variants of mGluR5 that can heterodimerize. Mutation of a positively charged motif (RRKK) at the C‐terminus of the mGluR1b tail permits mGluR1b to heterodimerize with mGluR1a. Co‐expression of mGluR1a and mGluR1b in COS‐7 cells results in the accumulation of mGluR1b in intracellular inclusions that do not contain mGluR1a. This behaviour is mimicked by a chimera of the lymphocyte antigen CD2 with the C‐terminus of mGluR1b (pCD1b) and depends on the presence of the RRKK motif. These accumulations are immunoreactive for endoplasmic reticulum (ER) markers, but not Golgi and ERGIC markers. This segregation of mGluR1b from other ER proteins may contribute to its failure to dimerize with mGluR1a.
Ca2+/calmodulin‐dependent protein kinase IIα clusters are associated with stable lipid rafts and their formation traps PSD‐95
Authors: Suzuki Tatsuo , Du Feng , Tian Qing‐Bao , Zhang Jingping , Endo Shogo 
Published: October 2007

AbstractRelatively large number of post‐synaptic density (PSD) proteins, including Ca2+/calmodulin‐dependent protein kinase II (CaMKII), have the potential to associate with lipid rafts. We in this study demonstrate that the CaMKIIα clusters induced by ionomycin in human embryonic kidney 293 cells, as well as unclustered CaMKIIα (Du F., Saitoh F., Tian Q. B., Miyazawa S., Endo S. and Suzuki T, 2006, Biochem. Biophys. Res. Commun 347, 814–820), were associated with lipid rafts. The CaMKIIα clusters associated with lipid raft fraction became resistant to treatment with methyl‐β‐cyclodextrin and subsequent cold Triton X‐100, which suggests the stabilization of CaMKIIα cluster‐associated lipid rafts. Next, we found that PSD‐95, which is also a component of lipid raft fraction and does not interact directly with CaMKII, was trapped by stable CaMKIIα cluster‐containing structure. Association of PSD‐95 with CaMKIIα clusters was also observed in cultured neuronal cells. These results suggest the CaMKIIα clusters associated with the lipid rafts in the cytoplasmic region play a role in the assembly and stabilization of certain PSD proteins that have the potential to associate with lipid rafts.
Delta‐like 1 participates in the specification of ventral midbrain progenitor derived dopaminergic neurons
Authors: Bauer Matthias , Szulc Jolanta , Meyer Morten , Jensen Charlotte Harken , Terki Toufik Abbas , Meixner Andrea , Kinkl Norbert , Gasser Thomas , Aebischer Patrick , Ueffing Marius 
Published: October 2007

AbstractDelta‐like 1 (Dlk1), a member of the Delta/Notch protein family, is expressed in the mouse ventral midbrain (VM) as early as embryonic day 11.5 (E11.5) followed by exclusive expression in tyrosine 3‐monooxygenase (TH) positive neurons from E12.5 onwards. To further elucidate the yet unknown function of Dlk1 in VM neuron development, we investigated the effect of soluble Dlk1 protein as well as the intrinsic Dlk1 function in the course of VM progenitor expansion and dopaminergic (DA) neuron differentiation in vitro. Dlk1 treatment during expansion increased DA progenitor proliferation and the proportion of NR4A2+ neurons expressing TH after differentiation, whereas Dlk1 treatment during the course of DA precursor differentiation did not alter TH+ neuron counts. In contrast, silencing of endogenously expressed Dlk1 prior to DA precursor differentiation partially prevented the expression of DA neuron markers, which was not accompanied with alteration of overall or local proliferation. Due to the latter finding in combination with the absence of Dlk1 negative DA neurons in differentiated cultures, we suggest that Dlk1 expression might have a permissive effect on DA neuron differentiation in vitro. The study presented here is the first publication identifying Dlk1 effects on ventral midbrain‐derived DA precursor differentiation.
Variable phenotype of Alzheimer’s disease with spastic paraparesis
Authors: Karlstrom Helena , Brooks William S , Kwok John B. J , Broe G. Anthony , Kril Jillian J , McCann Heather , Halliday Glenda M , Schofield Peter R. 
Published: October 2007

AbstractPedigrees with familial Alzheimer’s disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin‐1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non‐cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid β peptide (Aβ) ending at position 42 or 43, and the main component of CWP is amino‐terminally truncated forms of amyloid β peptide starting after the alternative β‐secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.
Rapid purification of active γ‐secretase, an intramembrane protease implicated in Alzheimer’s disease
Authors: Cacquevel Matthias , Aeschbach Lorene , Osenkowski Pamela , Li Dongyang , Ye Wenjuan , Wolfe Michael S. , Li Huilin , Selkoe Dennis J. , Fraering Patrick C. 
Published: October 2007

Abstractγ‐Secretase is an unconventional aspartyl protease that processes many type 1 membrane proteins within the lipid bilayer. Because its cleavage of amyloid‐β precursor protein generates the amyloid‐β protein (Aβ) of Alzheimer’s disease, partially inhibiting γ‐secretase is an attractive therapeutic strategy, but the structure of the protease remains poorly understood. We recently used electron microscopy and single particle image analysis on the purified enzyme to generate the first 3D reconstruction of γ‐secretase, but at low resolution (15 Å). The limited amount of purified γ‐secretase that can be produced using currently available cell lines and procedures has prevented the achievement of a high resolution crystal structure by X‐ray crystallography or 2D crystallization. We report here the generation and characterization of a new mammalian cell line (S‐20) that overexpresses strikingly high levels of all four γ‐secretase components (presenilin, nicastrin, Aph‐1 and Pen‐2). We then used these cells to develop a rapid protocol for the high‐grade purification of proteolytically active γ‐secretase. The cells and purification methods detailed here provide a key step towards crystallographic studies of this ubiquitous enzyme.
Minoxidil prevents 3,4‐methylenedioxymethamphetamine‐induced serotonin depletions: role of mitochondrial ATP‐sensitive potassium channels, Akt and ERK
Authors: Goñi‐Allo Beatriz , Puerta Elena , Ramos María , Lasheras Berta , Jordán Joaquín , Aguirre Norberto 
Published: October 2007

AbstractPreconditioning has emerged as a valid strategy against different neurotoxic insults. Although the mechanisms underlying preconditioning are not fully understood, the activation of ATP‐sensitive potassium (KATP) channels has been proposed to play a pivotal role in neuronal preconditioning. In the present work we examine whether minoxidil a KATP channel activator protects against the long‐term toxicity caused by the amphetamine derivative 3,4‐methylenedioxymethamphetamine (MDMA) in rats. Our data show that intrastriatal administration of minoxidil prevents MDMA‐induced long‐term indole depletions in the rat striatum. This effect was not related to an effect on core temperature, as pre‐treatment with minoxidil did not significantly alter MDMA‐induced hyperthermia. Taking into account that minoxidil opens both sarcolemmal and mitochondrial KATP channels, we examined the role of each type of channels in the protective effects of minoxidil using specific inhibitors. The administration of HMR‐1098, a blocker of the sarcolemmal KATP channels, along with minoxidil did not affect the protection afforded by the latter. On the contrary the selective mitochondrial KATP channel blocker 5‐hydroxydecanoic acid completely reversed the protection afforded by minoxidil, thereby implicating the involvement of mitochondrial (but not sarcolemmal) KATP channels. Furthermore our data show the participation of Akt and extracellular signal‐regulated kinases in minoxidil‐afforded protection. Intrastriatal administration of wortmannin or PD98059 (inhibitors of phosphatidylinositol‐3‐kinase and mitogen‐activated protein kinase/extracellular regulated protein kinase, respectively), along with minoxidil abolished the protective effect of minoxidil against the serotonergic toxicity caused by MDMA. These results demonstrate that minoxidil by opening mitochondrial KATP channels completely prevents MDMA toxicity and that Akt and MAP kinases are involved in minoxidil‐afforded neuroprotection.
Atorvastatin attenuates mitochondrial toxin‐induced striatal degeneration, with decreasing iNOS/c‐Jun levels and activating ERK/Akt pathways
Authors: Lee Soon‐Tae , Chu Kon , Park Jung‐Eun , Hong Nan Hyung , Im Woo‐Seok , Kang Lami , Han Zhe , Jung Keun‐Hwa , Kim Min‐Wook , Kim Manho 
Published: October 2007

AbstractMitochondrial dysfunction is a major contributor to neurodegeneration, and causes vulnerability to oxidative stress and the activations of downstream cell death pathways. 3‐Hydroxy‐3‐methyl‐glutaryl‐CoA reductase inhibitors, statins, were originally developed as cholesterol lowering agents, and have cholesterol‐independent anti‐excitotoxic and anti‐oxidative properties. We investigated whether atorvastatin can prevent the neurodegeneration induced by a mitochondrial toxin, 3‐nitropropionic acid (3NP), which inhibits succinate dehydrogenase complex II. Male Lewis rats were administered 3NP (63 mg/kg/day) using osmotic pumps for 5 days to induce striatal degeneration, and were also treated with either atorvastatin (1 or 10 mg/kg/day, orally) or vehicle (control) on five consecutive days. Atorvastatin‐treated rats showed fewer neurologic deficits than control animals as measured at day 3–5. Atorvastatin‐treated animals showed reduced striatal lesion volumes by Nissl staining, and decreased numbers of TUNEL‐positive apoptosis and Fluoro‐Jade C‐positive degenerating neurons at 5 days. Atorvastatin reduced the numbers of c‐Jun‐positive and p‐c‐Jun‐positive cells, as well as 3‐nitrotyrosin‐positive cells. In addition, atorvastatin increased p‐extracellular signal‐regulated kinase and p‐Akt levels, and attenuated the up‐regulation of inducible nitric oxide synthase by 3NP. When N(omega)‐nitro‐l‐arginine methyl ester hydrochloride was administered concomitantly with the 3NP infusion, atorvastatin failed to further reduce the striatal lesion volume and c‐Jun levels compared to the vehicle treatment. In summary, atorvastatin decreased striatal neurodegeneration induced by 3NP, with attenuating inducible nitric oxide synthase and c‐Jun levels as well as activating extracellular signal‐regulated kinase and Akt.
Reverse Epidemiology: A Confusing, Confounding, and Inaccurate Term
Authors: Levin Nathan W. , Handelman Garry J. , Coresh Josef , Port Friedrich K. , Kaysen George A. 
Published: October 2007

AbstractThe term “reverse epidemiology” has been proposed to address the apparent different relationship between numerous risk factors and outcomes among dialysis patients: thus, obesity, hypertension, high cholesterol, and elevated creatinine all appear to be associated with decreased risk. Since this is contrary to the general findings in otherwise healthy populations, some kind of “reversal” has been suggested, that would be contrary to classical epidemiology. The authors describe several faults to this conception. The rules of epidemiology have not been reversed in dialysis patients. In fact, the complexity of the population implies a greater need for attention to the distinction between association and causation and the importance of confounding and bias. In particular existing subclinical and clinical disease which is very common among dialysis patients can change associations so drastically that they are dominated by different causal pathways than those seen in the general population. For example, lower cholesterol is a better marker of poor health than of a healthy diet and thus is associated with different outcomes. To the extent the term reverse epidemiology implies either epidemiology or biology is different in dialysis patients it can be misleading and detrimental. The differences between risk factors in end‐stage renal disease (ESRD) and other individuals are surely important, but can themselves be the basis of excellent epidemiology, applied with the classic rules developed for this discipline with the goal of uncovering causal association and hypotheses to be tested in clinical trials.
Volumetric analysis of extraction sockets using cone beam computed tomography: a pilot study on ex vivo jaw bone
Authors: Agbaje Jimoh Olubanwo , Jacobs Reinhilde , Maes Frederik , Michiels Katleen , Van Steenberghe Daniel 
Published: October 2007

AbstractAim: The aim of this study was to determine the accuracy of volumetric analysis of extraction sockets using cone beam computed tomography (CBCT).Material and Methods: The volume of 40 dental alveoli in nine dry skull specimens (four mandibles and five maxillae) was determined by measuring the volume of the tooth socket impression using the water displacement technique. This was considered as the gold standard. Then, the tooth socket was scanned with CBCT and data were uploaded in the semi‐automated Livewire® segmentation software. The software segments the tooth socket in consecutive 1 mm‐thick two‐dimensional slices. After segmentation, the total volume of the delineated socket was computed. The statistical difference between direct volumetric measurements and those obtained with CBCT imaging was assessed using the Student paired t‐test.Result: The mean socket volume of the skull specimens was 227±91 mm3 when obtained by direct measurement and 225±90 mm3 when obtained by CBCT imaging. Student paired t‐test showed no significant differences between both volume measurements (p>0.1).Conclusions: CBCT permits imaging of anatomical structures in three planes and allows for reliable volume estimates. The results should be verified in clinical circumstances and might have potential applicability for evaluation of extraction socket healing under different conditions.
Ligation of CD200R by CD200 is not required for normal murine myelopoiesis
Authors: Rijkers Eva S. K. , De Ruiter Talitha , Buitenhuis Miranda , Veninga Henrike , Hoek Robert M. , Meyaard Linde 
Published: October 2007

AbstractCD200R is an inhibitory receptor involved in the regulation of myeloid cells. It recruits Dok‐1 and Dok‐2, which are potent inhibitors of the Ras signalling pathway used by colony‐stimulating factor (CSF) receptors. Dok‐1/Dok‐2 double knockout (DKO) mice develop leukaemia at 10–12 months of age. We investigated whether disturbed CD200R signalling could be responsible for this phenotype. Therefore, we studied whether CD200−/− mice have altered myelopoiesis and develop leukaemia. We report that CD200R is expressed on haematopoietic progenitor cells. However, CD200−/− mice have normal numbers of myeloid progenitors in the bone marrow and these cells have normal proliferative capacity. These results indicate that the development of leukaemia in Dok‐1/Dok‐2 DKO mice is not solely due to an absence of CD200R signalling. In addition, we show that the previously reported enhanced numbers of myeloid cells do not occur in all CD200−/− mice. We determined whether variations in the numbers of peripheral myeloid cells were due to an enhanced response to granulocyte‐CSF (G‐CSF) or an inflammatory stimulus. Mobilisation of immature neutrophils via G‐CSF and infiltration of mature neutrophils and macrophages upon thioglycolate injection were not altered in CD200−/− mice. We conclude that CD200−/− mice exhibit normal myelopoiesis and that development of leukaemia in Dok‐1/Dok‐2 DKO mice is not caused by a lack of CD200‐mediated CD200R signalling.