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1.
The main component of senile plaques found in AD brain is amyloid β-peptide (Aβ), and the neurotoxicity and aggregation of
Aβ are associated with the formation of β-sheet structure. Experimentally, beta sheet breaker (BSB) peptide fragment Leu-Pro-Phe-Phe-Asp
(LPFFD) can combine with Aβ, which can inhibit the aggregation of Aβ. In order to explore why LPFFD can inhibit the formation
of β-sheet conformation of Aβ at atomic level, first, molecular docking is performed to obtain the binding sites of LPFFD
on the Aβ(1–42) (LPFFD/Aβ(1–42)), which is taken as the initial conformation for MD simulations. Then, MD simulations on LPFFD/Aβ(1–42)
in water are carried out. The results demonstrate that LPFFD can inhibit the conformational transition from α-helix to β-sheet
structure for the C-terminus of Aβ(1–42), which may be attributed to the hydrophobicity decreasing of C-terminus residues
of Aβ(1–42) and formation probability decreasing of the salt bridge Asp23-Lys28 in the presence of LPFFD. 相似文献
2.
Gehman JD O'Brien CC Shabanpoor F Wade JD Separovic F 《European biophysics journal : EBJ》2008,37(3):333-344
Aβ(1–42) peptide, found as aggregated species in Alzheimer’s disease brain, is linked to the onset of dementia. We detail
results of 31P and 2H solid-state NMR studies of model membranes with Aβ peptides and the effect of metal ions (Cu2+ and Zn2+), which are found concentrated in amyloid plaques. The effects on the lipid bilayer and the peptide structure are different
for membrane incorporated or associated peptides. Copper ions alone destabilise the lipid bilayer and induce formation of
smaller vesicles, but not when Aβ(1–42) is associated with the bilayer membrane. Aβ(25–35), a fragment from the C-terminal
end of Aβ(1–42), which lacks the metal coordinating sites found in the full length peptide, is neurotoxic to cortical cortex
cell cultures. Addition of metal ions has little effect on membrane bilayers with Aβ(25–35) peptides. 31P magic angle spinning NMR data show that Aβ(1–42) and Aβ(1–42)-Cu2+ complexes interact at the surface of anionic phospholipid membranes. Incorporated peptides, however, appear to disrupt the
membrane more severely than associated peptides. Solid-state 13C NMR was used to compare structural changes of Aβ(1–42) to those of Aβ(25–35) in model membrane systems of anionic phospholipids
and cholesterol. The Aβ peptides appeared to have an increase in β-strand structure at the C-terminus when added to phospholipid
liposomes. The inclusion of Cu2+ also influenced the observed chemical shift of residues from the C-terminal half, providing structural clues for the lipid-associated
Aβ/metal complex. The results point to the complex pathway(s) for toxicity of the full-length peptide.
Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience. 相似文献
3.
Louise A. Scrocchi Yan Chen Feng Wang Kyung Han Katherine Ha Ling Wu Paul E. Fraser 《International journal of peptide research and therapeutics》2003,10(5-6):545-551
Human islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in the pancreas of over 90% of all
cases of type-2 diabetes. Although it may be a secondary event in the etiology of diabetes, the accumulation of insoluble
IAPP fibrils is considered to be a primary cause of β-cell failure in affected individuals. A possible means of inhibiting this process is through the use of small peptides that
bind to IAPP and prevent fibril polymerization. This approach has been examined using a series of overlapping hexamers that
target the known amyloidogenic regions of IAPP. Peptides were examined usingin vitroassays and active inhibitors were identified by their ability to prevent amyloid-related conformational transitions and IAPP
aggregation. Fragments such as those corresponding to the IAPP-derived sequences, SNNFGA (residues 20–25) and GAILSS (residues
24–29), were potent inhibitors ofβ-sheet folding and amyloid fibril formation. Negative stain electron microscopy revealed that co-incubation of these peptides
with IAPP significantly decreased the density of fibrils and any remaining structures displayed altered morphology. In some,
but not all cases, inhibition of amyloid fibrils also correlated with an ability to reduce IAPP-mediated cytotoxicity as determined
in cell culture studies. The results from these studies suggest that these two peptide inhibitors differ in their mechanisms
of action possibly due to unique interactions with the full-length IAPP molecule. These inhibitors form the basis of a therapeutic
strategy to prevent amyloid accumulation leading to improved islet survival and a potentially novel treatment for type-2 diabetes. 相似文献
4.
Carrotta R Barthès J Longo A Martorana V Manno M Portale G San Biagio PL 《European biophysics journal : EBJ》2007,36(7):701-709
Self-assembly of amyloid β-protein (Aβ) and its deposition into senile plaques are distinctive features of Alzheimer’s disease.
Aβ forms typical linear aggregates known as amyloid fibrils, with a diameter of a few tens of nanometers and a length spanning
from hundreds of nanometers to micrometers. Fibrils eventually assemble into large size clusters and precipitate in vivo in
the brain deposits. Here, we study the late stage of aggregation of Aβ(1–40) in vitro at pH 3.1. We characterize the structure
of fibrillar aggregates by a combined use of different experimental techniques. Small angle light scattering, heterodyne near
field scattering, large angle light scattering, ultra small angle X-ray scattering and small angle X-ray scattering measurements
have been performed to highlight the structural features of amyloid bundles over several lengthscales, from nanometers to
tens of micrometers. Phase contrast optical microscopy has been used to complement scattering measurements and directly visualize
some morphological details. We show that elongated fibrils of Aβ with a diameter of a few nanometers are packed into large
size compact bundles having a typical size of tens of micrometers. The linear morphology of fibrils is reflected in the elongated
shape of bundles.
Proceedings of the XVIII Congress of the Italian Society of Pure and Applied Biophysics (SIBPA), Palermo, Sicily, September
2006. 相似文献
5.
Cryptotanshinione Inhibits β-Amyloid Aggregation and Protects Damage from β-Amyloid in SH-SY5Y Cells
The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels
is a hallmark of Alzheimer’s disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death
and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone
(CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several
pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work
shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study,
we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron
microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells.
MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced
Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS
may be useful in the inhibition or prevention of AD development and progression. 相似文献
6.
It has been shown by fluorescence analysis in vitro that the water-soluble sodium salt of the polycarboxylic derivative of
fullerene C60, fullerenol, and complexes of fullerene C60 with polyvinylpyrrolidone (mol. wt. 25000 and 10000) destroy amyloid fibrils of the brain peptide Aβ(1–42) and prevent their
formation. The results of fluorescence analysis confirmed the data obtained earlier by high-resolution electron microscopy.
Fluorescence analysis and electron microscopy are complementary methods for the selection of effective antiamyloid drugs. 相似文献
7.
Sundaram RK Kasinathan C Stein S Sundaram P 《International journal of peptide research and therapeutics》2012,18(2):99-106
Alzheimer’s disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39–43 amino
acid peptide (amyloid β or Aβ) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that
interfere with Aβ–Aβ interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids
16–20) region in the Aβ molecule have been investigated as possible drug candidates. Retro-inverso (RI) peptide of this pentapeptide,
ffvlk, has been shown to bind artificial fibrils made from Aβ with moderate affinity. We hypothesized that a ‘detox gel’, which
is synthesized by covalently linking a tetrameric version of RI peptide ffvlk to poly(ethylene glycol) polymer chains will act like a ‘sink’ to capture Aβ peptides from the surrounding environment. We
previously demonstrated that this hypothesis works in an in vitro system. The present study extended this hypothesis to an
in vivo mouse model of AD and determined the therapeutic effect of our detox gel. We injected detox gel subcutaneously to
AD model mice and analyzed brain levels of Aβ-42 and improvement in memory parameters. The results showed a reduction of brain
amyloid burden in detox gel treated mice. Memory parameters in the treated mice improved. No undesirable immune response was
observed. The data strongly suggest that our detox gel can be used as an effective therapy to deplete brain Aβ levels. Considering
recent abandonment of failed antibody based therapies, our detox gel appears to have the advantage of being a non-immune based
therapy. 相似文献
8.
Feda E. Ali Frances Separovic Colin J. Barrow Shenggen Yao Kevin J. Barnham 《International journal of peptide research and therapeutics》2006,12(2):153-164
The accumulation of senile plaques composed primarily of aggregated amyloid β-peptide (Aβ), is the major characteristic of Alzheimer’s disease. Many studies correlate plaque accumulation and the presence of metal ions, particularly copper and zinc. The metal binding sites of the amyloid Aβ peptide of Alzheimer’s disease are located in the N-terminal region of the full-length peptide. In this work, the interactions with metals of a model peptide comprising the first 16 amino acid residues of the amyloid Aβ peptide, Aβ(1–16), were studied. The effect of Cu2+ and Zn2+ binding to Aβ(1–16) on peptide structure and oligomerisation are reported. The results of ESI-MS, gel filtration chromatography and NMR spectroscopy demonstrated formation of oligomeric complexes of the peptide in the presence of the metal ions and revealed the stoichiometry of Cu2+ and Zn2+ binding to Aβ(1–16), with Cu2+ showing a higher affinity for binding the peptide than Zn2+. 相似文献
9.
A. G. Bobylev L. G. Marsagishvili M. D. Shpagina V. S. Romanova R. A. Kotelnikova Z. A. Podlubnaya 《Biophysics》2010,55(3):353-357
The antiamyloidogenic capacity of water-soluble nitroderivatives of fullerene C60: methyl ester of L-N-[(2-nitroglyceryl) fullerenyl] proline, methyl ester of L-N-[(2,3-dinitroglyceryl) fullerenyl] proline,
and 2-nitroxyethyl ester of L-N-([2-(nitroxy) ethyl] fullerenyl) proline has been studied in vitro by high-resolution electron
microscopy. It was shown that these fullerene C60 nitroderivatives are able to prevent the formation of amyloid fibrils by the brain Aβ(1–42)-peptide and muscle X-protein
and to destroy mature fibrils. Electron microscopy is a promising method for selecting effective antiamyloidogenic drugs.
The antiamyloidogenic activity of nanodimensional fullerene C60 nitroderivatives offers strong possibilities for creating a new nanotechnology for the therapy of amyloidoses. 相似文献
10.
Aggregation of the amyloid β-peptide (Aβ) into insoluble fibrils is a key pathological event in Alzheimer’s disease. Cu(II)
and Zn(II) ions were reported to be able to induce Aβ aggregation at nearly physiological concentrations in vitro. In this
study, the binding modes of Cu(II) and Zn(II) in this process were explored by molecular modeling. In the pre-associated Aβ,
Nτ atom of imidazole ring of His14, O atom of carbonyl of main-chain and two O atoms of water occupied the four ligand positions
of the complex. While in the aggregated form of Aβ, the His13(N)–Metals–His14(N) bridges were formed through metal cross-linking
action. These results would be helpful to put insight on revealing the formation mechanism of pathogenic Aβ aggregates in
brain. 相似文献
11.
The physiological relationship between brain cholesterol content and the action of amyloid β (Aβ) peptide in Alzheimer’s disease (AD) is a highly controversially discussed topic. Evidences for modulations of the Aβ/membrane interaction induced by plasma membrane cholesterol have already been observed. We have recently reported that Aβ(25–35) is capable of inserting in lipid membranes and perturbing their structure. Applying neutron diffraction and selective deuteration, we now demonstrate that cholesterol alters, at the molecular level, the capability of Aβ(25–35) to penetrate into the lipid bilayers; in particular, a molar weight content of 20% of cholesterol hinders the intercalation of monomeric Aβ(25–35) completely. At very low cholesterol content (about 1% molar weight) the location of the C-terminal part of Aβ(25–35) has been unequivocally established in the hydrocarbon region of the membrane, in agreement with our previous results on pure phospholipids membrane. These results link a structural property to a physiological and functional behavior and point to a therapeutical approach to prevent the AD by modulation of membrane properties. 相似文献
12.
Luitgard Nagel-Steger Borries Demeler Wolfgang Meyer-Zaika Katrin Hochdörffer Thomas Schrader Dieter Willbold 《European biophysics journal : EBJ》2010,39(3):415-422
A peptide with 42 amino acid residues (Aβ42) plays a key role in the pathogenesis of the Alzheimer’s disease. It is highly
prone to self aggregation leading to the formation of fibrils which are deposited in amyloid plaques in the brain of diseased
individuals. In our study we established a method to analyze the aggregation behavior of the Aβ peptide with a combination
of sedimentation velocity centrifugation and enhanced data evaluation software as implemented in the software package UltraScan.
Important information which becomes accessible by this methodology is the s-value distribution and concomitantly also the shape-distribution of the Aβ peptide aggregates generated by self-association.
With this method we characterized the aggregation modifying effect of a designed β-sheet breaker molecule. This compound is
built from three head-to-tail connected aminopyrazole moieties and represents a derivative of the already described Tripyrazole.
By addition of this compound to a solution of the Aβ42 peptide the maximum of the s-value distribution was clearly shifted to smaller s-values as compared to solutions where only the vehicle DMSO was added. This shift to smaller s-values was stable for at least 7 days. The information about size- and shape-distributions present in aggregated Aβ42 solutions
was confirmed by transmission electron microscopy and by measurement of amyloid formation by thioflavin T fluorescence. 相似文献
13.
Giovanna Cenini Cristina Cecchi Anna Pensalfini Sara Anna Bonini Giulia Ferrari-Toninelli Gianfranco Liguri Maurizio Memo Daniela Uberti 《Amino acids》2010,38(4):1107-1106
A neuropathological characteristic of Alzheimer’s disease is the extracellular accumulation of amyloid beta peptide (Aβ) in
neuritic plaques. Recent evidences suggested that soluble Aβ oligomers are the predominant neurotoxic species for neurons.
Thus, considerable attention has been paid to discriminate the cytotoxic pathways of Aβ pre-fibrillar aggregates and mature
fibrils. We showed that the mechanisms by which Aβ oligomers and fibrils generated reactive oxygen species differ in terms
of site of production and kinetics, suggesting the involvement of different intra/extracellular pathways. 相似文献
14.
Christine Talmard Rodrigue Leuma Yona Peter Faller 《Journal of biological inorganic chemistry》2009,14(3):449-455
The amyloidoses are a group of disorders characterized by aberrant protein folding and assembly, leading to the deposition
of insoluble protein fibrils (amyloid), which provokes cell dysfunction and later cell death. One of the physiologically relevant
environmental factors able to affect the conformation and hence the aggregation properties of amyloidogenic proteins/peptides
is metal ions. Zn(II) promotes aggregation of most amyloidogenic peptides/proteins in vitro, including amyloid β protein (Aβ),
but the underlying mechanism is not known. To better understand this mechanism the present study focused on the partially
α-helical conformer, supposed to be an intermediate in Aβ aggregation. This partially α-helical conformer is stabilized by
10–20% 2,2,2-trifluoroethanol (TFE): therefore, the influence of Zn binding on the aggregation of the amylidogenic model peptide
Aβ(1–28) (Aβ28) was investigated at different TFE concentrations. The results showed a synergistic effect of Zn(II) and 10%
TFE, i.e., that either Zn or 10% TFE accelerated Aβ28 aggregation on its own, but with them together an at least 10 times
promotion of Aβ28 aggregation was observed. Further studies by thioflavin T fluorescence spectroscopy, transmission electron
microscopy, and circular dichroism (CD) spectroscopy suggested that the aggregates of Zn-Aβ28 formed in 10%TFE contain a β-sheet
secondary structure and are more of the amyloid type. CD spectroscopy indicated that Zn binding disrupted partially the α-helical
structure of Aβ28 in TFE. Thus, we propose that the promotion of Aβ28 aggregation by Zn is based on the transformation of
the partially α-helical conformer (intermediate) towards the β-sheet amyloid structure by a destabilization of the α-helix
in the intermediate.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
相似文献
Peter FallerEmail: Email: |
15.
Pomara N Doraiswamy PM Willoughby LM Roth AE Mulsant BH Sidtis JJ Mehta PD Reynolds CF Pollock BG 《Neurochemical research》2006,31(3):341-349
Elevated plasma amyloid beta 1–42 (Aβ42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Aβ levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer’s disease, have not been studied. We compared plasma Aβ in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Aβ42 levels and the Aβ42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Aβ42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Aβ levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Aβ42 and Aβ42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.Presented at the 43rd Annual Meeting, American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 12–16, 2004. 相似文献
16.
Lambracht-Washington D Qu BX Fu M Anderson LD Stüve O Eagar TN Rosenberg RN 《Cellular and molecular neurobiology》2011,31(6):867-874
The pathogenesis of Alzheimer’s disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides
in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were
immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory
Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune
response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell
proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42
peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune
response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were
immunized with short-term (1–3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype
profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal
study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response
and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune
system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective
and safe to treat patients with early AD. 相似文献
17.
Céline Rivière Jean-Claude Delaunay Françoise Immel Christophe Cullin Jean-Pierre Monti 《Neurochemical research》2009,34(6):1120-1128
Alzheimer’s disease (AD) is characterized by deposits of amyloid in various tissues. The neuronal cytotoxicity of Aβ peptides
is attributed not only to various mechanisms but also to amyloid fibrils and soluble oligomeric intermediates. Consequently,
finding molecules to prevent or reverse the oligomerization and fibrillization of Aβ could be of therapeutic value in the
treatment of AD. We show that piceid, a polyphenol of the stilbene family, destabilized fibrils and oligomers to give back
monomers that are not neurotoxic molecules. The mechanism of this destabilization could be a dynamic interaction between the
polyphenol and the Aβ that could open the hydrophobic zipper and shift the reversible equilibrium “random coil⇔β-sheet” to
the disordered structure. 相似文献
18.
Ramesh JL Kandimalla Willayat Yousuf Wani Binukumar BK Kiran Dip Gill 《Journal of biomedical science》2012,19(1):2
Background
One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloid β protein (Aβ) within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs γ-secretase cleavage. 相似文献19.
Debasish Haldar Arindam Banerjee 《International journal of peptide research and therapeutics》2007,13(3):439-446
The terminally protected peptide Boc-Leu-Val-Phe-Phe-Ala-OMe bearing sequence similarity with the central hydrophobic cluster
(CHC) of Alzheimer’s Aβ17–21 peptide self-assembles to produce amyloid-like straight unbranched fibrils from organic solvents. The fibrils readily bind
with a physiological dye Congo red (CR) and exhibits green gold birefringence under polarized light, a characteristic feature
of amyloid plaque obtained from many neurodegenerative diseases. FTIR spectroscopy and in silico energy minimization study shed some light on the antiparallel supramolecular β-sheet aggregation of the peptide. 相似文献
20.
This study aims to discuss the effect of preventing pathological changes and cognitive degeneration of Tg2576 mice by inoculating
the subunit fragment of Aβ vaccine. Thirty-two Tg2576 mice were randomly divided into four groups, each having eight mice:
Group I, the control group, inoculated with adjuvants; Group II, the Aβ42 group, inoculated with Aβ42 vaccine; Group III, the Aβ1–15 group, inoculated with Aβ1–15 vaccine; and Group IV, the Aβ36–42 group, inoculated with Aβ36–42 vaccine. The titer of the serum antibody against Aβ42 (Group II) was significantly higher than that of the control group (Group I), and a low level of antibodies could be detected
in the brain homogenate in the three vaccine-inoculated groups. Morris water maze test showed that the Aβ42 group, Aβ1–15 group and Aβ36–42 group were obviously improved compared with the control group. The cultured splenocytes sampled from each group were induced
by Con A or their respective antigens, and the cell proliferation of the three vaccine-inoculated groups was significantly
higher than that of the control group. In the Aβ42 group, IL2 and IFN-γ were relatively low and IL4 and IL10 were relatively high. By contrast, IL4 and IL10 were much higher
in the Aβ1–15 group and IL2 and IFN-γ were much higher in the Aβ36–42 group. The immunohistochemical test showed a large number of senile plaques in the brain cortex and hippocampus of the mice
in the control group, no senile plaque in the brain of the Aβ1–15 group and Aβ42 group mice, and a small number of senile plaques in the brain of the Aβ36–42 group mice. The results suggest that the subunit fragment of Aβ1–15 vaccine could prevent not only cognitive and behavioral degeneration but also Aβ deposition and formation of senile plaques
in Tg2576 mice. 相似文献