Actin : its cumbersome pilgrimage through cellular compartments In this article , we follow the history of one of the most abundant , most intensely studied proteins of the eukaryotic cells : actin . We report on hallmarks of its discovery , its structural and functional characterization and localization over time , and point to present days ' knowledge on its position as a member of a large family . We focus on the rather puzzling number of diverse functions as proposed for actin as a dual compartment protein . Finally , we venture on some speculations as to its origin . Introduction A common incident , ubiquitous and frequently observed by the experienced teacher : a student wants to purify protein X from an eukaryotic organism Y. Sooner or later the undergraduate stares at SDS polyacrylamide gels and is surprised , disappointed , depressed , furious about those horrible actin contaminations that seem to be everywhere . The student does not care about the advisor 's soothing explanations : `` actin is the most abundant protein '' , `` actin exists as globular monomer -LRB- G-actin -RRB- in the soluble supernatant '' , `` but it is also sedimentable as filamentous actin -LRB- F-actin -RRB- '' . It will be difficult to calm the young scientist down . Looking at these copious amounts of the protein , the student can not believethat a long time ago it was a scientific breakthrough to show that actin exists at all , that it took years and years to convince truculent groups of actin pioneers that a non-muscle cell contains actin as well , that actin is not a singular and once for all invention in evolution , but is the founder of a large family of isoforms and related proteins , andthat quite a number of these proteins can be found in different subcellular compartments . For example , it has been established as a regular component of both , the cytoplasm and the nucleus ; but this perception is the result of a fight that went on for decades . The dawn : actin as a muscle component The first traceable report that described contractile substances in muscle goes back to 1859 and Wilhelm Friedrich Kühne -LRB- Kuehne 1859 -RRB- . He belonged to the best known physiologists of his time and coined modern designations like `` enzyme '' or `` myosin '' . The latter one he described as a substance that could be isolated from frog muscle and forms a contractile clot under certain conditions . Today we would call this clot a contractile pellet , consisting mainly of actomyosin . Halliburton followed shortly afterwards and was intrigued by this clot formation -LRB- Halliburton 1887 -RRB- . He compared it to blood clotting and the transformation of fibrinogen to fibrin . In tedious experiments he extracted mammalian muscle tissue at different time scales , temperatures , salt concentrations and found that myosin apparently needed an additional component to perform fast aggregation and contraction . Without really knowing it , Halliburton worked with actin and produced with this so-called `` myosin ferment '' an actomyosin precipitate . In our days one reads Halliburton 's publication with some amazement . The report covers 70 pages and looks with its descriptions and tables like a lab-book , e.g. : `` Extract # 1 -- 10 a.m. -- Diluted with an equal amount of water -- 10 a.m. next day -- No change '' . Surely , at that time editors were not as busy as they are today . Muscle actin comes of age Then , it took almost 60 years until Brúnó F. Straub in Albert Szent-György 's laboratory at the Hungarian University of Szeged was able to purify actin in good qualities and quantities . At that time ATP was known and available , i.e. Straub could study the influence of ATP on the viscosity of myosin preparations in the presence and absence of other extractable muscle components . The decrease in viscosity upon addition of ATP was considered `` activation '' of myosin , the protein responsible for this activation was named `` actin '' , and the complex of these two proteins was `` actomyosin '' . Straub and Szent-Györgyi discovered these interrelationships 1941/1942 in the middle of World War II and , therefore , published the data only in local periodicals -LRB- `` Studies from the Institute of Medical Chemistry '' , University of Szeged -RRB- . The research on actin and myosin , the political situation and the excitement in Szent-Györgi 's group in the early 1940s are nicely summarized by W. · F. Mommaerts who was a witness of the original experiments -LRB- Mommaerts 1992 -RRB- , and by A.G. Szent-Györgyi himself -LRB- Szent-Gyorgyi 2004 -RRB- . It is far beyond the scope of this review to cover the avalanche of actin and myosin research that started after those first molecular characterizations . Of course , muscle was and still is the major source to purify actin from , and , consequently , the research during the following decades used exclusively muscle actin . Actin conquers the cytoplasm But as it is in science , one opens one door and discovers ten closed ones . Keeping that in mind a scientist should always be suspicious regarding dogmas of all sorts . For some time it was almost a law that actin exists only in skeletal muscle and that the well-known conventional myosin is the only motor protein which turns the world go round . Today it is a common place that both assumptions were wrong , although it was quite a task to convince the scientific community . Many minor publications pointed at the presence of actin in non-muscle cells . For example , one found actomyosin-like components and Mg2 + ATP-dependent viscosity changes in extracts from sea urchin eggs -LRB- Ohnishi 1962 -RRB- , and an actin-like protein from calf thymus nuclei -LRB- Ohnishi et al. 1963 -RRB- , and it was assumed that the filaments seen in fibroblasts are analogous to filaments in muscle , responsible for cell motility -LRB- Buckley and Porter 1967 -RRB- . Most of these publications never had a really strong impact , especially since they argued against a rock-solid preconception . But to be fair : these tiny reports were the pebbles that paved the road for better equipped groups and more detailed molecular studies . Notably , it was a slime mould , Physarum polycephalum that was used as a model organism to prove the existence of actin and myosin in non-muscle cells . The key experiments have been performed in Japan , in Sadashi Hatano 's group -LRB- Hatano and Oosawa 1966a , b ; Hatano and Tazawa 1968 -RRB- and the data were confirmed shortly afterwards by other laboratories . Especially the decoration of actin filaments in non-muscle cells with myosin was a breakthrough technique that unequivocally proved the existence of the actomyosin system in many non-muscle cells -LRB- for reviews see : Huxley 1973 ; Pollard and Weihing 1974 ; Pollard 1981 ; Tilney 1975 -RRB- . Actin as the prototype of a large family Today conventional actin is thoroughly studied , with respect to its polymerization and depolymerization equilibrium , its function in the cytoskeleton as a morphological stabilizer , its role during motile activities of a cell , its three-dimensional structure , its binding partners , etc. . But the traitorous word in this sentence is `` conventional '' . What hides behind `` conventional '' actin ? And what is an actin-related protein ? A `` conventional '' actin consists of 375 highly conserved amino acids , give or take a few . The polypeptide sequence is folded into a roughly U-shaped molecule , exposing well-characterized binding sites for many different ligands . There are several isoforms as products of different genes , coined alpha , beta and gamma actin , all of which are polymorphic proteins capable to form polymers . `` Conventional actins '' display a particular fold which enables them to interact with a variety of partners , to form specific suprastructures involved in intracellular motility , adhesion and locomotion -LRB- see below -RRB- . Figure 1 shows the dynamics of the actin cortex in a Dictyostelium discoideum amoeba during random migration , pinocytosis , and phagocytosis of a yeast cell . An actin-related protein harbours an actin domain , but it differs from `` conventional '' actin in size and overall amino acid sequence , usually can not form polymers and may differ from the conventional form in subcellular distribution and its physiological activity . The increasing number of completely sequenced genomes is an enormous help towards our understanding of actin and actin-related proteins . One can take any sequenced genome to analyze actin as a founder of a large protein family . We chose the recently unravelled D. discoideum genome since it represents the genome of a model organism that can locomote as a single cell and in cell assemblies , and can differentiate into simple tissues in a developmental cycle . Hence , it is a social amoeba at the evolutionary border between unicellular and multicellular organisms -LRB- Eichinger et al. 2005 -RRB- . Notably , the number of actin genes does not tell us very much about the complexity of an organism . Whereas the genome of budding yeast contains only one single and , not surprisingly , essential gene that codes for a conventional actin , mouse harbours 35 , and the plant Arabidopsis thaliana 10 actin genes . The D. discoideum genome contains 33 genes that code for a bona fide conventional actin . Most puzzling , 17 of these actins share identical amino acid sequences , but are encoded by 17 distinct genes , and many of these are developmentally regulated . Why would evolution allow this seemingly luxurious feature ? Elimination of redundant genes can only be avoided if they represent a selective advantage . If the identical actins are translated in a developmental pattern , then posttranslational modifications might play a much larger role than we are aware of today . Indeed , actin 's posttranslational modifications are numerous . Actins are acetylated , acylated , arginylated , Ser/Thr/Tyr-phosphorylated , ubiquitinylated etc. . This suggests that a developmentally regulated expression of actin genes requires a similarly regulated expression of enzymes that catalyze posttranslational modifications . Such a hypothesis opens a completely new search for our understanding of actin and its isoforms.Fig . 1Dynamics of the actin cortex during amoeboid movement , pino - and phagocytosis . D. discoideum was transformed with a truncated LimE construct , tagged to green fluorescent protein -LRB- GFP -RRB- . LimE binds specifically to filamentous actin -LRB- Bretschneider et al. 2004 -RRB- . The transformed cells are depicted in phase contrast -LRB- left panels -RRB- and fluorescence -LRB- right -RRB- , which reveals the concentration of actin filaments by GFP-LimE . Upper panels : optical section through the actin cortex during random amoeboid movement . Bottom panels : during uptake of a rhodamine-labelled yeast cell the actin cortex forms a phagocytic cup around the particle . The engulfment of liquids by macropinocytosis requires the actin system as well -LRB- arrow -RRB- . Size bar 5 μm The picture became even more complicated after the discovery of the actin-related proteins -LRB- Arps -RRB- . Calculation of the putative structures shows very nicely that actin and Arps share a common three-dimensional fold -LRB- Fig. 2 , taken from Muller et al. 2005 -RRB- . Most characteristic is the nucleotide-binding cleft which divides the protein in roughly two halves . The depicted structures all show the same orientation . For actin itself , this means that , when incorporated into a `` conventional '' actin filament , the bottom part of the folded monomer points towards the fast growing -LRB- `` barbed '' -RRB- end , the upper part towards the slow growing -LRB- `` pointed '' -RRB- end -LRB- see also Fig. 3 -RRB- . Figure 2 shows strikingly -LRB- 1 -RRB- that all Arps can be moulded into a structure quite similar to the overall structure of conventional actin and -LRB- 2 -RRB- that they display a clearly distinct pattern of patches with conserved amino acids . As seen in the comparative scale -LRB- Fig. 2 , right -RRB- Arps 1 , 2 and 3 are most closely related to actin , whereas all the other Arps show a much lower percentage of identity . Arps 2 and 3 have been shown to form a tight complex that , after activation through several actin binding proteins and ATP , binds to actin filaments and induces their branching -LRB- Kiselar et al. 2007 -RRB- . However , it should be noted that the role of the Arp2/3 complex for branching of actin filaments in vivo is still heavily challenged -LRB- Koestler et al. 2008 -RRB- . It is quite amusing to read Vic Small 's statement in the Research Roundup of J Cell Biol : -LRB- Feb 25 , 2008 -RRB- : `` We have n't disproven branching yet . We 'll need 3D imaging to put the nail in that coffin . But what we 've seen makes the branching model unlikely '' . Undoubtedly , we are still on thin ice with our knowledge on Arp2/3 function in vivo.Fig . 2Structural conservation in the ARP subfamily -LRB- adapted from Muller et al. 2005 , with permission -RRB- . The conservation scale weights identity from 0 -LRB- blue -RRB- to 100 % -LRB- red -RRB- . All Arps can adopt a global actin conformation -LRB- upper left -RRB- but only Arps 1 , 2 and 3 show a pronounced sequence homologyFig . 3Generation of different actin polymers as a result of different subunit interactions -LRB- adapted from Jockusch et al. 2006 , with permission -RRB- . The subdomains of the actin monomer , as deduced from the crystal structure , are numbered 1 -- 4 . In the process that leads to the `` conventional '' actin filament -LRB- F-actin -RRB- , three such monomers -LRB- a -- c -RRB- form intermolecular contact sites involving the subdomains as indicated left of the trimeric seed . Under physiological conditions , these trimers convert subsequently into the polar F-actin filaments that are depicted in the electron micrograph -LRB- top right -RRB- . In a more rapid process , the actin monomers may form an antiparallel dimer which , at least in vitro , can form bipolar filaments -LRB- LD filaments -RRB- that show a strikingly different appearance in the electron microscope -LRB- bottom right -RRB- Let us risk some sort of a heretical view . Trivial as it may be , one has to repeat it again and again : not the three-dimensional fold , but the surface of a protein determines its function . There are curious examples for this . Hisactophilin , a histidine-rich actin-binding protein from D. discoideum , has a structure nearly identical to that of interleukin-1β and fibroblast growth factor , despite its unrelated amino acid sequence . Luckily for the authors , these data were published in a high ranking journal -LRB- Habazettl et al. 1992 -RRB- , although there was no functional similarity between these three proteins whatsoever . Today , their structural similarity is not considered important at all and , like many others , they are just members of the large trefoil protein superfamily -LRB- Liu et al. 2002 -RRB- . Sippl and coworkers systematically analyzed novel proteins based on known structures -LRB- Koppensteiner et al. 2000 -RRB- . They came to the conclusion that almost 30 % of the studied proteins have similar structures but different functions . Coming back to actins and Arps . Is it possible that the name `` actin '' for all of these proteins is utterly misleading ? Are we wasting time in our search for cytoskeleton-related activities just because the fold triggered a wrong name ? Is the so-called actin fold another example for a successful superfamily which contains only a few proteins that play a role in the cytoskeleton , while many other members are e.g. subunits of larger protein complexes in chromatin or hexokinases or proteins with yet unknown functions ? Actin-like proteins in the nucleus : the early period The first reports on actin as a nuclear protein appeared already 5 years after its acceptance as a ubiquitous cytoplasmic component . Nuclear filament bundles resembling microfilaments were observed in oocytes when transcription was inhibited by actinomycin D -LRB- Lane 1969 -RRB- , and biochemical analyses identified a prominent protein present in isolated nuclei of the multinucleated plasmodia of Physarum polycephalum -LRB- Jockusch et al. 1971 ; Jockusch et al. 1974 ; Lestourgeon et al. 1975 -RRB- . The concentration of actin in the nucleus fluctuated with the cell cycle phase of the plasmodia , leading to suggestions that nuclear actin might either have a role in the constriction of the nuclear membrane in Physarum plasmodia that exhibit an intranuclear mitosis -LRB- Jockusch et al. 1971 -RRB- , or with changes in transcriptional activity during the cell cycle -LRB- Lestourgeon et al. 1975 -RRB- , or during transition from active growth to the formation of sklerotia -LRB- spherules -RRB- from plasmodia after starvation -LRB- McAlister et al. 1977 -RRB- . All this remained speculation at that time , and the majority of the cell biological community dismissed these findings as an artifact , caused by a contamination of nuclei with cytoplasmic actin . However , between 1979 and 1984 three reports appeared which supported the concept of actin being involved in transcription : -LRB- 1 -RRB- actin was identified in a complex of RNA polymerase II from Physarum -LRB- Smith et al. 1979 -RRB- , -LRB- 2 -RRB- it stimulated markedly the transcriptional activity of RNA polymerase II purified from HeLa cell extracts at the preinitiation phase -LRB- Egly et al. 1984 -RRB- , and -LRB- 3 -RRB- antibodies specific for actin , when injected into the large amphibian oocyte nuclei , caused a dramatic collapse of lampbrush chromosome loops , concommitant with a complete stop of mRNA transcription -LRB- Scheer et al. 1984 -RRB- . However , these observations still did not overcome the scepticism at that time -- it took another two decades to recognize actin as a dual compartment protein that can execute different functions by selectively associating with ligands specific either for the cytoplasm or the nucleus . Actin and Arps in the nucleus In the last 20 years , studies on nuclear actin became fashionable , and now a new area began which firmly established actin , its relatives and binding partners as nuclear components . Several important steps served as signposts in this process : Cell biologists began to understand that proteins are not necessarily confined to a single intracellular compartment . Numerous examples proved that proteins may shuttle between intracellular regions and even adopt different , compartment-specific activities . Shuttling of actin and actin-related proteins between the nucleus and the cytoplasm can not be considered any longer as an exceptional , exotic behaviour.Genetic studies , for example performed with yeast or Drosophila , showed that activities specific for the nucleus , like chromatin remodelling or transcription required the presence of the beta actin isoform , in a configuration that could bind to nuclear protein complexes , but were inhibited with actin mutants that failed in this respect.The development of cell biological and immunological methods over the past 20 years , like cellular expression of flurorochrome-tagged proteins in conjunction with video microscopy , and the generation of epitope-characterized monoclonal antibodies allowed to follow actin trafficking throughout the cell and its location in the nucleus.And finally , some old observations made in structural biology came back into people 's mind : actin is a highly polymorphic protein , which can give rise to several different and distinct polymers -LRB- Aebi et al. 1981 ; Millonig et al. 1988 -RRB- . Thus , while there are functionally quite unrelated proteins that may share the same structure -LRB- see above -RRB- , it is also conceivable that a particular protein may adopt slightly different `` unconventional forms '' , possibly induced by specific binding partners . Such `` distortions '' may then trigger the formation of specific oligomers or polymers and complex formation with still other partners . Thus , intranuclear actins need not necessarily adopt the same structures found so abundantly in the cytoplasm , like G - or F-actin . This topic is discussed in detail in -LRB- Pederson and Aebi 2002 -RRB- , and this concept is supported by monoclonal anti-actins that specifically decorate nuclear actin -LRB- Gonsior et al. 1999 ; Schoenenberger et al. 2005 -RRB- . In Fig. 3 -LRB- taken from Jockusch et al. 2006 -RRB- , we show actin in two different forms that both can form polymers . The conventional actin filament requires the interaction of three actin monomers in a specific orientation . Such a trimeric seed will then grow into the polarized F-actin filaments -LRB- Fig. 3 , top -RRB- . However , there is also evidence for another pathway : two actin monomers can bind to each other in another orientation , and this `` lower dimer '' may then lead to nonpolar , quite different filaments -LRB- Fig. 3 , bottom -RRB- . It is of course tempting to speculate that such `` unconventional '' actin polymers may play a role in vivo , for example in the nucleus , but so far , there is no solid evidence for this assumption . Not surprisingly , the wealth of data on nuclear actin and its relatives stimulated numerous hypotheses on their function . The relevant findings and the conclusions on putative functions are the topic of a number of interesting reviews , and in this article , we can only refer the reader to them and to the list of original references covered there -LRB- Bettinger et al. 2004 ; Blessing et al. 2004 ; Franke 2004 ; Jockusch et al. 2006 ; Pederson and Aebi 2002 ; Rando et al. 2000 -RRB- . The brave reader who works himself through all this information will arrive at two conclusions : the actin-like proteins have definitely conquered a firm position among the group of respectable , important nuclear proteins , and they seem to be involved in a plethora of different activities . While the tasks for actin in the cytoplasm all are connected with the conventional G - and F-actin structures and the dynamic equilibrium between these two states , nuclear functions of these proteins seem associated with several different forms or configurations which are ill or even not at all defined . In the following paragraphs , we will briefly mention the most important tasks proposed for nuclear actins . Actin filaments and a caryoskeleton It is generally accepted that nuclear activities require a precise topographical arrangement of chromatin , to spatially separate hetero - from euchromatin and allow for the complex mechanism of chromatin remodelling during gene activation and transcription . Hence , when electron microscopy provided elegant images of networks of intranuclear filaments , preferably in large objects like the amphibian oocyte nuclei -LRB- germinal vesicles -RRB- , it seemed quite plausible to conclude that a `` nuclear matrix '' or scaffold is composed of F-actin filaments -LRB- Clark and Merriam 1977 ; Clark and Rosenbaum 1979 ; Gard 1999 -RRB- that could provide mechanical stability to the nucleus and serve as a platform to anchor , at least temporarily , chromatin constituents . Indeed , there is evidence from both earlier and more recent investigations that actin associates with filamentous structures : actin antibodies and myosin subfragment 1 decorate such filaments in amphibian oocyte nuclei -LRB- Clark and Rosenbaum 1979 ; Gard 1999 ; Scheer et al. 1984 -RRB- , and fluorescently labelled actin is found in a polymeric form in Xenopus and HeLa cell nuclei -LRB- Kiseleva et al. 2004 ; McDonald et al. 2006 -RRB- . Yet , in general , these filaments do not stain with fluorescent phalloidin , a small drug binding with high affinity to actin filaments of the conventional `` F-actin '' type . It is only after subjecting cells to stress or fixation protocols that nuclear filaments bind phalloidin , thus , the suspicion arises that such treatments rearrange actin into conventional filaments -LRB- Gall 2006 ; Jockusch et al. 2006 -RRB- . This , of course , does not preclude the concept that actin participates in a nuclear matrix , especially in the very large , actin-rich nuclei of amphibian oocytes . There is good evidence that it engages in providing mechanical support to this cellular compartment -LRB- Bohnsack et al. 2006 ; Stuven et al. 2003 -RRB- . The nuclear Arps from yeast , Arp 7 and Arp 9 , have been shown to build heterodimers and have the potential to form filaments from tetramers -LRB- Szerlong et al. 2003 -RRB- . However , it is not clear whether they do in vivo , and whether they might coassemble with nuclear actin in polymers -LRB- Blessing et al. 2004 -RRB- . Actin/Arps and their connection with the nuclear envelope Several structural proteins that are essential for the assembly and maintenance of an intact , functional nuclear envelope and its underlying lamina , display well defined binding motifs for actin . These include spectrin , protein 4.1 , the nesprins , lamin A and emerin , -LRB- Krauss et al. 2003 ; Shumaker et al. 2003 , more references in Blessing et al. 2004 ; Rando et al. 2000 -RRB- . Hence , it has been speculated , but not proven , that at least part of the nuclear actin is involved in the structural organization of the nuclear envelope . Actin/Arps and the nucleo-cytoplasmic traffic Actin-containing , intranuclear filaments were seen to connect to nuclear pore complexes in the amphibian oocyte nucleus -LRB- Hofmann et al. 2001 ; Kiseleva et al. 2004 -RRB- . In the Xenopus oocyte , but also in dipteres and mammalian cells , actin is engaged in the transport and nucleocytoplasmic export of mRNA -LRB- Hofmann et al. 2001 -RRB- and RNA-protein complexes , in particular in those containing a subset of hnRNPs -LRB- Percipalle et al. 2001 , 2002 , reviewed in Bettinger et al. 2004 ; Pederson and Aebi 2005 -RRB- . Actin/Arps and chromatin remodelling Actin and nuclear Arps were both reported as being critically involved in chromatin remodelling -LRB- reviewed in -LRB- Bettinger et al. 2004 ; Blessing et al. 2004 ; Olave et al. 2002 ; Percipalle and Visa 2006 ; Rando et al. 2000 -RRB- . Chromatin remodelling complexes operate as large , multiunit machines in mammals , insects , yeast and plants to reorganize the genetic material by unravelling nucleosomes and converting the genetic material into a form suitable for transcription . Many of these steps require energy , and thus many of these protein complexes contain ATPases , comprised of several subunits , that can be grouped into subfamilies . Actin was identified in complex with specific subunits of most ATPases , together with four nuclear Arps -LRB- 4 , 5 , 6 and 8 -RRB- in all organisms , with the exception of yeast . Here , the two yeast-specific nuclear Arps -LRB- 7 and 9 -RRB- are found in the corresponding ATPases . One of the histone acetyl transferases that also contribute to chromatin remodelling and subsequent transcription -LRB- NuA4 , Doyon et al. 2004 -RRB- is highly conserved from yeast to man and is also found in a complex with actin and Arp 4 -LRB- Harata et al. 2002 -RRB- . Structural organization and function of the actin and Arp molecules in these ATPase and acetyl transferase complexes are largely unknown , and speculations for their respective roles range from stabilizing the enzymatic and a chaperoning activity to connecting these gigantic protein complexes to nuclear filamentous scaffolds . Actin/Arps and transcription Actin has been identified as a regular component of all the three nuclear RNA polymerases -LRB- Pol I , II and III -RRB- , apparently interacting with two subunits that are shared among all three enzyme complexes . In vitro transcription by all three enzymes is actin-dependent -LRB- reviewed in Grummt 2006 ; Percipalle and Visa 2006 -RRB- . In the nucleus , pre-mRNA is complexed with ribonucleoproteins to form hnRNPs , and , presumably , there is co-translational recruitment of beta actin to these particles during their formation , as deduced from findings that several hnRNP components bind directly actin . Actin 's association with the RNA polymerases may precede , be simultaneous with or follow the initiation of actin-dependent chromatin remodelling by ATP-dependent complexes and/or histone acetylation , as described above -LRB- Grummt 2006 ; Percipalle and Visa 2006 -RRB- . Most of the data available today are derived from studies with Pol II , in insects and vertebrates , supporting and confirming the conclusions drawn more than two decades earlier from work on Xenopus oocyte and HeLa cell nuclei -LRB- Egly et al. 1984 ; Scheer et al. 1984 -RRB- . There is solid evidence that actin 's role in Pol II-dependent transcription is executed by the beta actin isoform -LRB- Hofmann et al. 2004 ; McDonald et al. 2006 -RRB- , and no other isoform seems involved . While actin 's contribution to the formation of pre-initiation complexes and subsequent transport of pre-mRNPs through the nucleus towards their export through nuclear pores is well accepted today -LRB- Bettinger et al. 2004 ; Franke 2004 -RRB- , it is completely unknown whether actin might mediate such intranuclear movements in filamentous or even contractile structures -LRB- Pederson and Aebi 2005 -RRB- . Actin ligands in the nucleus The nuclear constituents harbouring actin , like those of the nuclear matrix , the nuclear envelope , the nuclear pores , chromatin remodelling complexes , RNA polymerases and pre-mRNPs are all highly insoluble , gigantic structures . However , there are also actin ligands that are found in the cytoplasmic as well in the nuclear compartment , possibly in rather dynamic and temporary complexes with actin . Since the discovery of actin as a prominent component in the cytoplasm of practically all eukaryotic cells , a plethora of such actin-binding proteins has been described and characterized . They arrange actin into the various suprastructures required for cytoplasmic functions , such as intracellular motility and locomotion , by either regulating the balance between monomeric and filamentous actin , or generating networks and bundles of filaments -LRB- Winder and Ayscough 2005 -RRB- . Remarkably , many of these actin ligands are evolutionary well conserved , like actin itself -LRB- Korn 1982 ; Schleicher et al. 1988 -RRB- . Members of the various subfamilies , with affinity to either monomeric or filamentous actin , are dual compartment proteins that can shuttle between the nucleus and the cytoplasm , their main location frequently being dependent on the differentiation state of cells . Comprehensive lists of these proteins that have previously been described as cytoplasmic actin ligands but were also identified in the nucleus are given in -LRB- Rando et al. 2000 ; Bettinger et al. 2004 ; Pederson and Aebi 2005 -RRB- . Among them are several which form complexes with actin and interfere with the formation of conventional actin filaments , like profilin , binding to monomeric actin , and cofilin , a ligand for both , monomeric and polymeric actin . Nuclear profilin is apparently involved in the regulation of the level of nuclear actin , as profilin -- actin complexes are recognized and exported from mammalian nuclei by a specific exportin -LRB- Stuven et al. 2003 -RRB- , while actin free of profilin can apparently be exported by a different exportin , due to its nuclear export sequences -LRB- Wada et al. 1998 -RRB- . Profilin and cofilin both can sligthly change the fold of actin . Profilin induces a form which faciliates the exchange of bound ATP in G-actin -LRB- reviewed in Jockusch et al. 2007 -RRB- . Cofilin , a phosphoprotein , contains a nuclear location sequence , and in its dephosphorylated state can transport actin `` piggy-back '' into the nucleus -LRB- Pendleton et al. 2003 -RRB- . When bound to actin polymers , it distorts their conformation such that these filaments do not bind phalloidin anymore . Thus , these proteins might be critical in creating forms specific for nuclear actin , as detected by specific antibodies -LRB- Gonsior et al. 1999 ; Jockusch et al. 2006 ; Schoenenberger et al. 2005 -RRB- . Among the actin ligands solely found in the nuclear compartment are a nuclear actin binding protein identified in Acanthamoeba -LRB- Rimm and Pollard 1989 -RRB- , an actin binding protein composed of two different subunits in mammalian cells -LRB- Ankenbauer et al. 1989 -RRB- , and a nucleus-specific form of myosin I -LRB- Pestic-Dragovich et al. 2000 -RRB- . The latter is a small , monomeric myosin that does not form filaments as would be needed for contraction of putative actin filaments in the nucleus . It is apparently involved in transcription of ribosomal genes by Pol I , where it binds to a transcription initiation factor but also to components of a chromatin remodelling complex . It has been speculated that in this location it may recruit actin associated with Pol I to the site of rRNA transcription , but so far , there is no evidence that these two proteins interact directly in vivo -LRB- reviewed in -LRB- Grummt 2006 ; Percipalle and Farrants 2006 -RRB- . Conclusions So , have we now lost the student being confronted with actin for the first time in his scientific education , or have we been able to attract his curiosity for this abundant , highly conserved , mysterious protein ? Actin has come a long way from the times of its discovery in muscle and we have learned to know it as a member of a large family of structurally related proteins , some of which are dual compartment proteins . Concomitant with this , there is an overwhelming expansion of their putative functions , and both , the fine structural conformation as well as the different functions are probably determined by the numerous actin binding proteins . As a cartoon , Fig. 4 summarizes the most important players in the cytoplasmic and the nuclear compartment . It is obvious that the putative activities in the nucleus outnumber those in the cytoplasm . Taken together , these findings allow for the view that actin and its relatives were originally engaged in nuclear activities , and that their appearance in the cytoplasm is related to a specialization in functions connected solely with intracellular motility and locomotion -LRB- F-actin filament formation , actin dynamics -RRB- . Further functional narrowing would then result in the special case of skeletal muscle , where a specific isoform , alpha actin , is overexpressed and knows nothing else than to allow myosin-driven contraction.Fig . 4The manifold functions of nuclear actin . The G - / F-actin equilibrium is only a highly specialized function of actin in the cytoplasm -LRB- top -RRB- ; in the nucleus -LRB- bottom -RRB- the actin system plays a quite different regulatory and structural role . Actin can execute its tasks as monomer or as nucleus-specific polymer . It interacts with heterogenous ribonucleoproteins -LRB- hnRNPs -RRB- and is thought to function as a track for RNA transport through NPCs . It remains to be shown how nuclear actin cooperates with nuclear myosin-1 to enhance movement of RNA polymerases or to re-organize chromatin -LRB- Nunez et al. 2008 -RRB- . Positioning of the nucleus in the cell is achieved by nuclear membrane -LRB- NM -RRB- proteins that , like the large nesprins , hook the nucleus to the actin cytoskeleton . Anchorage of nesprins is guaranteed by SUN proteins in the inner nuclear membrane -LRB- Worman and Gundersen 2006 -RRB- . The stabilization of the nucleoskeleton involves the interaction of inner nuclear membrane proteins like emerin or nesprins with lamins as well as polymeric actin -LRB- Libotte et al. 2005 -RRB- . It should , however , be borne in mind that the level of nuclear actin is apparently tightly regulated in mammalian cells by exportin 6 which selectively transports profilin -- actin complexes from the nucleus into the cytoplasm -LRB- Bohnsack et al. 2006 -RRB- . The nuclear functions of many dual compartment actin binding proteins are not well understood , but one has to assume that their interaction can discriminate between nuclear and cytoplasmic actin -LRB- Pederson and Aebi 2005 -RRB- . For example , the recently described cyclase associated protein CAP2 is nuclear in myoblasts but sarcomeric in myotubes -LRB- Peche et al. 2007 -RRB- . Actin-related proteins are only summarized in one symbol and are either nucleus specific subunits in chromatin remodelling complexes -LRB- Arp4 , Arp8 etc. -RRB- , cytoplasmic or belong also to the group of dual compartment proteins If one was to speculate further , one might imagine that prokaryotic precursors of present days ' actin , related to the proteins that spatially and temporally control macromolecular trafficking , chromosome segregation and cell polarity in recent bacteria -LRB- Carballido-Lopez 2006 -RRB- , appeared first as `` nuclear actin '' in an ancestor eukaryotic cell as part of the endosymbiontic engulfment . But , it will require several decades and lots of industrious students to decide whether this is science fiction or facts about actin .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

actin history
cytoplasmic motility
nucleocytoplasmic traffick


Alterations in aortic elasticity in noncompaction cardiomyopathy Background Noncompaction cardiomyopathy -LRB- NCCM -RRB- is a recently recognized disorder frequently associated with systolic and diastolic heart failures . This study was designed to examine aortic stiffness in NCCM patients and to compare these results to age - and gender-matched controls . Introduction Noncompaction cardiomyopathy -LRB- NCCM -RRB- is a recently recognized rare disorder -LSB- 1 , 2 -RSB- . It is characterized by prominent myocardial trabecularizations , and deep intertrabecular recesses leading to the spongy appearance of the myocardium -LSB- 3 -RSB- . The disease is frequently associated with systolic and diastolic heart failure -LRB- HF -RRB- , ventricular arrhythmias , and systemic embolization -LSB- 4 -RSB- . Alterations in arterial function have been demonstrated in patients with HF -LSB- 5 , 6 -RSB- . With two-dimensional transthoracic echocardiography -LRB- TTE -RRB- , ascending aortic diameter changes during a heart cycle can be measured . When blood pressure data are also available , aortic elasticity can be characterized -LSB- 7 , 8 -RSB- . This study was designed to examine aortic stiffness in NCCM patients and to compare these results to age - and gender-matched controls . Methods Study population A total of 20 patients with typical echocardiographic features of NCCM were investigated -LSB- 3 , 9 -RSB- . Their clinical and demographic data are presented in Table 1 . Clinical assessment included medical and family history , physical examination , electrocardiography , two-dimensional echocardiography , and , in most cases , contrast echocardiography . Their results were compared to 20 age - and gender-matched controls without apparent cardiovascular disease . Informed consent was obtained from each patient , and the study was approved by the institutional review board and complied with the Declaration of Helsinki . Table 1 . Clinical and demographic data of NCCM patientsNCCM patientsAge -LRB- years -RRB- 38 ± 16Male -LRB- % -RRB- 8 -LRB- 40 -RRB- Diabetes -LRB- % -RRB- 1 -LRB- 5 -RRB- Index eventArrhythmia -LRB- % -RRB- 6 -LRB- 30 -RRB- Heart failure -LRB- % -RRB- 8 -LRB- 40 -RRB- Screening -LRB- % -RRB- 6 -LRB- 30 -RRB- ElectrocardiogramAtrial fibrillation -LRB- % -RRB- 2 -LRB- 10 -RRB- LV hypertrophy -LRB- % -RRB- 3 -LRB- 15 -RRB- Left bundle branch block -LRB- % -RRB- 6 -LRB- 30 -RRB- NCCM noncompaction cardiomyopathy Diagnostic criteria for NCCM Previously proposed echocardiographic diagnostic criteria for NCCM by Jenni et al. -LSB- 3 -RSB- were used : -LRB- 1 -RRB- absence of coexisting cardiac anomalies , -LRB- 2 -RRB- segmental , excessive thickening of the left ventricular -LRB- LV -RRB- wall with a two-layered structure : a thin , compacted epicardial layer and a much thicker , noncompacted layer with the characteristic appearance of numerous , prominent trabeculations -LRB- meshwork -RRB- and deep intertrabecular recesses , -LRB- 3 -RRB- color Doppler evidence of deeply perfused intertrabecular recesses , and -LRB- 4 -RRB- predominant localization of thickening in the LV apical , midlateral , and midinferior walls . Hypertensive heart disease was excluded by clinical and echocardiographic examinations -LRB- septal thickness < 13 mm -RRB- . Blood pressure measurement Systolic and diastolic blood pressures -LRB- SBP and DBP , respectively -RRB- were measured in the supine position with an automatic mercury cuff sphygmomanometer from the left arm after 10 min of rest . The first and the fifth Koratkoff sounds were taken for the SBP and DBP . Blood pressure values were averaged from three consecutive measurements . None of the patients or controls used coffee or tea within 1 h before blood pressure measurements . Transthoracic echocardiography All patients underwent a complete two-dimensional TTE and Doppler study using a Philips Sonos 7500 echocardiography equipment -LRB- Philips , Best , The Netherlands -RRB- in the left lateral decubitus position from multiple windows . The LV wall segments were analyzed according to the 9-segment model as described by Jenni et al. -LSB- 3 -RSB- . Systolic and diastolic ascending aortic diameters -LRB- SD and DD , respectively -RRB- were recorded in M-mode at a level of 3 cm above the aortic valve from a parasternal long-axis view -LRB- Fig. 1 -RRB- . Gain , depth , and sector angles were individualized for the best measurement . The SD and DD were measured at the time of maximum anterior motion of the aorta and at the peak of the QRS complex , respectively . Fig. 1Measurements of systolic -LRB- SD -RRB- and diastolic -LRB- DD -RRB- diameters of the ascending aorta are shown on the M-mode tracing obtained at a level 3 cm above the aortic valve Evaluation of aortic stiffness Aortic stiffness index -LRB- β -RRB- was defined as ln -LRB- SBP/DBP -RRB- / -LSB- -LRB- SD - DD -RRB- / DD -RSB- , where ln is the natural logarithm . Statistical analysis Data are reported as means ± standard deviation . For variables , Student 's t test and analysis of variance -LRB- ANOVA -RRB- test were used where needed . A value of p < 0.05 was considered statistically significant . SPSS 12.0 software was used for statistical calculations . Reproducibility of echocardiographic measurements The reproducibility of the aortic diameter measurements was tested in all NCCM patients at both systole and diastole by two independent , blinded observers . Agreement between the two observers was verified using the Bland -- Altman method -LSB- 10 -RSB- . Results Patient population The presenting symptoms were HF in eight -LRB- 40 % -RRB- and arrhythmias in six -LRB- 30 % -RRB- patients . The remaining six -LRB- 30 % -RRB- asymptomatic patients were NCCM relatives and were diagnosed after family screening -LRB- Table 1 -RRB- . Three HF patients were in NYHA-class III HF and the other five were in NYHA-class II . Cardiac medication used in NCCM patients were : angiotensin-converting enzyme inhibitors in 13 -LRB- 65 % -RRB- , beta-blockers in 11 -LRB- 55 % -RRB- , oral anticoagulant therapy in 10 -LRB- 50 % -RRB- , diuretics in 8 -LRB- 40 % -RRB- , digitalis in 2 -LRB- 10 % -RRB- , and nitrate in 1 -LRB- 5 % -RRB- . None of the controls received any cardiac medication . Transthoracic echocardiography The number of noncompacted segments in the NCCM patients was 4.6 ± 2.0 in the NCCM group and -LRB- as seen in Table 2 -RRB- these patients had significantly increased LV dimensions and reduced LV ejection fraction . Aortic stiffness index -LRB- β -RRB- was significantly increased in NCCM patients compared to controls . For controls , NCCM patients with moderate HF , and NCCM patients with severe HF , β values were 3.5 ± 1.1 , 7.9 ± 5.5 , and 10.4 ± 1.8 , respectively -LRB- p < 0.001 -RRB- . Aortic stiffness indices of all individual patients and controls are presented in Fig. 2 . Table 2 . Transthoracic echocardiographic and blood pressure data in NCCM patients and normal subjectsGroup 1 -LRB- normal subjects -RRB- Group 2 -LRB- NCCM patients -RRB- LV end-diastolic diameter -LRB- mm -RRB- 47.4 ± 3.661.0 ± 10.9 * LV end-systolic diameter -LRB- mm -RRB- 29.9 ± 2.948.2 ± 12.3 * LV ejection fraction -LRB- % -RRB- 67.5 ± 5.936.0 ± 17.6 * Systolic aortic diameter -LRB- mm -RRB- 26.7 ± 4.126.6 ± 4.4 Diastolic aortic diameter -LRB- mm -RRB- 23.3 ± 3.824.6 ± 4.3 Pulsatile change in aortic diameter -LRB- mm -RRB- 3.4 ± 1.12.0 ± 1.2 * Systolic blood pressure -LRB- mmHg -RRB- 125.2 ± 12.9120.4 ± 17.4 Diastolic blood pressure -LRB- mmHg -RRB- 77.8 ± 8.574.1 ± 9.6 Aortic pulse pressure -LRB- mmHg -RRB- 47.4 ± 8.746.3 ± 11.7 Aortic stiffness index -LRB- β -RRB- 3.5 ± 1.18.3 ± 5.2 * Continuous variables are given as mean ± standard deviationLV left ventricular , NCCM noncompaction cardiomyopathy * p < 0.001 Fig. 2Individual β indices of NCCM patients and control subjects . NCCM noncompaction cardiomyopathy Reproducibility The mean ± standard deviation difference in values obtained by two observers for the measurements of aortic diameter at systole was − 0.7 ± 2.2 mm , with a correlation coefficient between these independent measurements of 0.88 -LRB- p < 0.01 -RRB- -LRB- Figs. 3a and 4a -RRB- . At diastole , the difference between these observations was 0.05 ± 1.95 mm , with a correlation coefficient between observations of 0.9 -LRB- p < 0.01 -RRB- . The difference in values that were detected by observers was within twofold of the standard deviation of the mean -LRB- Figs. 3b and 4b -RRB- . Fig. 3a Interobserver correlation -LRB- r = 0.88 , p < 0.01 -RRB- between aortic systolic diameters in NCCM patients . b Interobserver correlation -LRB- r = 0.9 , p < 0.01 -RRB- between aortic diastolic diameters in NCCM patients . NCCM noncompaction cardiomyopathyFig . 4a Reproducibility of systolic aortic measurements in NCCM patients . b Reproducibility of diastolic aortic measurements in NCCM patients . NCCM noncompaction cardiomyopathy Discussion NCCM is a recently recognized disorder characterized by a loosened , spongy myocardium associated with a high incidence of progressive systolic and diastolic HF . In recent studies , alterations have been demonstrated in arterial function in patients with chronic HF -LSB- 11 -- 14 -RSB- . To the best of authors 's knowledge , this is the first time that the aortic distensibility in a series of NCCM patients was examined . In this study , increased aortic stiffness index -LRB- β -RRB- was found in NCCM patients compared to age - and gender-matched controls . In prior studies , it has been shown that pulsatile changes in ascending aortic vessel diameter can be indirectly measured during routine TTE . Stefanadis et al. -LSB- 7 -RSB- found that noninvasive measurements of aortic distensibility were as accurate as invasive methods . Aortic stiffness index -LRB- β -RRB- relies on aortic and blood pressure data and is one of the most frequently used parameters to characterize arterial stiffness -LSB- 7 , 8 -RSB- . Increased aortic stiffness is an independent risk factor , predictor of cardiovascular mortality , and a contributor to LV afterload -LSB- 15 , 16 -RSB- . Increased aortic stiffness occurs early during the development of pacing-induced congestive HF in animals -LSB- 17 , 18 -RSB- and has also been described in clinical patients with HF -LSB- 5 , 6 -RSB- , with comparable changes in arterial distensibility in ischemic and idiopathic dilated cardiomyopathy -LSB- 19 -RSB- . Rerkpattanapipat et al. -LSB- 11 -RSB- demonstrated that the distensibility of the proximal aorta is markedly reduced in older patients with HF due to LV systolic dysfunction beyond the changes from the aging process . They also described a correlation between exercise intolerance and reduced aortic distensibility . Giannattasio et al. -LSB- 12 -RSB- described that arterial compliance is impaired in congestive HF , and although more marked in severe congestive HF , the impairment is manifested in mild congestive HF as well -LSB- 12 -RSB- . Nakamura et al. -LSB- 13 -RSB- described vascular hypertrophic remodeling and endothelial dysfunction-associated alterations in vascular wall elastic properties in limb muscle conduit arteries in patients with congestive HF . Poelzl et al. -LSB- 14 -RSB- described an intriguing relationship between phenotype changes and functional impairment in peripheral conduit arteries of HF patients . This process is very similar to what is known for ventricular remodeling in HF . There are several potential factors affecting aortic function in patients with HF -LSB- 11 -RSB- . Neurohormonal changes associated with HF include an increase in sympathetic drive and an activated renin -- angiotensin system resulting in increased plasma norepinephrine levels causing vasoconstriction and sodium retention -LSB- 20 -- 23 -RSB- . Angiotensin II has a hypertrophic effect on smooth muscle cells of the vascular wall -LSB- 24 -RSB- . Early atheromatous changes and endothelial dysfunction can also be associated with HF -LSB- 25 -RSB- , and can affect vascular elasticity . However , there is also an interaction between aortic stiffening and HF . Aortic stiffening can increase LV load causing LV stiffening with increased wall tension , early impairment in diastolic LV relaxation , and contractility inducing LV hypertrophy and fibrosis -LSB- 26 , 27 -RSB- . These results suggest that aortic stiffness may contribute to the progression of systolic and diastolic LV dysfunctions . Study limitations During this study , brachial cuff pressure measurement instead of a direct assessment of aortic pulse pressure by catheter was used . However , previous studies demonstrated an excellent correlation in aortic distensibility measured by invasive and noninvasive methods -LSB- 7 -RSB- . Coronary artery disease is correlated with increased aortic stiffness and was not excluded in most but not in all our patients by coronary angiography . The aortic elastic properties of control patients were somewhat larger than those described in the literature . The reason for this can be the larger body mass index -LRB- 29.0 ± 5.1 kg/m2 -RRB- in our controls . However , a relatively higher β in the normal subjects in our study only strengthens the abnormal findings in the NCCM patients . Conclusions Increased aortic stiffness can be observed in patients with NCCM with moderate to severe HF . These alterations may be due to HF-induced neurohormonal changes .

O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O

echocardiography
noncompaction
aortic stiffness


Intramanual and intermanual transfer of the curvature aftereffect The existence and transfer of a haptic curvature aftereffect was investigated to obtain a greater insight into neural representation of shape . The haptic curvature aftereffect is the phenomenon whereby a flat surface is judged concave if the preceding touched stimulus was convex and vice versa . Single fingers were used to touch the subsequently presented stimuli . A substantial aftereffect was found when the adaptation surface and the test surface were touched by the same finger . Furthermore , a partial , but significant transfer of the aftereffect was demonstrated between fingers of the same hand and between fingers of both the hands . These results provide evidence that curvature information is not only represented at a level that is directly connected to the mechanoreceptors of individual fingers but is also represented at a stage in the somatosensory cortex shared by the fingers of both the hands . Introduction The neural representation of haptic information can be investigated using different approaches . The representation of object shape perceived with the fingers has mainly been studied using neurophysiological tools . It has been found that especially slowly adapting type I -LRB- SAI -RRB- mechanoreceptors in the finger but also fast-adapting type I -LRB- FAI -RRB- receptors are sensitive to curvature -LRB- Goodwin et al. 1997 ; Jenmalm et al. 2003 -RRB- . In order to perceive curvature , a combination of responses from a population of receptors is required -LRB- Goodwin and Wheat 2004 -RRB- . This processing occurs along several stages up to at least the somatosensory cortex -LRB- SI -RRB- -LRB- Gardner and Kandel 2000 -RRB- . Taking a neurophysiological approach is useful to uncover the pathways underlying curvature processing , but is less appropriate to establish the levels at which perceived curvature is essentially represented . A psychophysical approach that has been successful in providing greater insight into the neural representation of perceived properties is the study of the aftereffect , and especially , the transfer of the aftereffect . In vision , for example , the finding of partial , interocular transfer of the motion aftereffect has been explained by the involvement of both monocular and binocular cells in the processing of motion information from the stimulus -LRB- Moulden 1980 ; Wade et al. 1993 ; Tao et al. 2003 -RRB- . In a similar way , establishing the transfer characteristics of a haptic curvature aftereffect would provide insight into the representation of shape information . Finding aftereffect transfer between different fingers would indicate that curvature is represented at a level shared by these fingers , whereas no transfer would imply that each finger has a separate representation of curvature . A curvature aftereffect is the phenomenon whereby a flat test surface feels concave following prolonged contact with a convex adaptation surface -LRB- see Fig. 1a -RRB- . Curvature aftereffects have been found for different shapes and exploration modes . Gibson -LRB- 1933 -RRB- reported that a flat cardboard edge felt concave after the prolonged dynamic exploration of a convex cardboard edge . Vogels et al. -LRB- 1996 -RRB- demonstrated the existence of an aftereffect when the whole hand was placed on spherically curved shapes . They performed extensive experiments to examine the characteristics of this static curvature aftereffect . They found a linear relationship between the magnitude of the aftereffect and the curvature of the adaptation stimulus . Furthermore , they showed that the magnitude of the aftereffect increased with the adaptation time up to about 10 s. Finally , they found a decrease of the aftereffect with an increase of the interstimulus interval . In a follow-up study , they showed that the aftereffect also existed for alternative exploration modes , like touching a stimulus with only the five fingertips of the hand or performing small movements of the hand over the stimulus surface -LRB- Vogels et al. 1997 -RRB- . Given the strength and consistency of these findings , we supposed that curvature aftereffects should also occur for alternative ways of touching , such as the situation in which curved surfaces are statically being touched with only a single fingertip . However , this phenomenon has not yet been investigated , and consequently , any curvature aftereffect transfer between the fingers also remains unexplored.Fig . 1a Schematic overview of a haptic curvature aftereffect : when you first touch a convex -LRB- concave -RRB- surface for some time , say 10 s , and subsequently touch a flat surface , this latter surface feels concave -LRB- convex -RRB- . b Schematic drawings of the cross-sections of a convex and a concave stimulus . The stimuli had a cylindrical shape with a spherical top -LRB- see illustration a -RRB- . The distance from the bottom to the centre of the top -LRB- h -RRB- was consistently 30 mm . The diameter of the cylinders -LRB- d -RRB- was also 30 mm . c Examples of two psychometric curves . The circular data points and the fit through these points results from adaptation to the convex adaptation stimulus . The PSE is represented by PV . The square data points and the fit through these points result from adaptation to the concave adaptation stimulus . In this case , the PSE is represented by PC . The magnitude of the aftereffect -LRB- AE -RRB- is defined as the difference between PV and PC The purpose of the present study was to obtain a better understanding of the representation of haptically perceived shape information , by probing the transfer of the curvature aftereffect . In the first experiment , we established the existence of an aftereffect when a curved surface is touched by a single finger and measured whether this aftereffect transferred to other fingers of the same hand . The second experiment was set up to determine whether the aftereffect depended on the finger used . Finally , in the third and fourth experiments , we investigated the transfer of the aftereffect between fingers of both hands . Materials and methods Subjects A total number of 40 subjects participated -LSB- n = 8 for experiments 1 , 2 and 4 , n = 16 for experiment 3 ; 18 were male and 22 were female ; the mean age was 22 years ; 37 were right-handed , 3 were left-handed , according to a standard questionnaire -LRB- Coren 1993 -RRB- -RSB- . Subjects in experiments 1 and 2 received course credit for their participation . Subjects in the third and fourth experiments received monetary compensation . Stimuli The stimuli comprised of a compound of polyurethane foam and artificial resin -LRB- Cibatool BM 5460 -RRB- . A computer-controlled milling machine was used to produce cylinders with a flat bottom and a spherically curved top . The top was either pointing outward -LRB- convex -RRB- or inward -LRB- concave -RRB- . Both convex and concave adaptation stimuli were used , with curvature values of +36 and − 36 m − 1 , respectively ; the curvature of the nine test stimuli ranged from − 16 to +16 m − 1 , in steps of 4 m − 1 . Illustrations of the stimuli and their cross-sections are given in Fig. 1a , b , respectively . Procedure A subject was seated behind a table . The preferred arm rested on a platform , which was 30 mm above the tabletop . In the third and fourth experiments , both arms rested on the platform . Only the fingertips projected over the platform . The experimenter placed the stimulus underneath a fingertip . A curtain prevented the subjects from seeing the stimulus . During a trial , the tip of one finger was placed on an adaptation stimulus for 10 s. Subsequently , the subject placed a finger on a test stimulus and had to judge whether this test stimulus felt convex or concave . Subjects were not allowed to move the finger over the stimulus surface , and the experimenter checked for this . No instructions were given on the force to contact the stimulus , nor was it measured . No feedback was provided on the response . Three conditions were measured in the first experiment . In all conditions , the adaptation stimulus was touched with the index finger . In one condition , the test stimulus was also touched with the index finger . In the other two conditions , the test stimulus was touched with the middle finger or the little finger of the same hand , respectively . Each condition consisted of 10 repetitions of a group of 18 trials -LRB- two adaptation stimuli × nine test stimuli -RRB- with trials randomized within a group . One complete condition was measured in a single session of about one and a half hours . The separate sessions were spread over different days . The order in which the conditions were conducted was counterbalanced for the first six subjects and randomly chosen for the last two subjects . In the second experiment , both the adaptation and the test stimuli were touched by the middle finger . In the third and fourth experiments , the adaptation stimulus was contacted by the index finger of the preferred hand ; the test stimuli were touched with the index finger -LRB- third experiment -RRB- or middle finger -LRB- fourth experiment -RRB- of the non-preferred hand . Analysis The data for each subject and each condition were analyzed separately for the convex and the concave adaptation stimuli . The percentage of `` convex '' responses was plotted against the curvature of the test stimulus . The point of subjective equality -LRB- PSE -RRB- was determined by fitting a psychometric function -LRB- cumulative Gaussian -RRB- to the data . The PSE represents the curvature value that in 50 % of the test cases was judged `` convex '' and in 50 % of the cases was judged `` concave '' . The magnitude of the aftereffect is defined as the difference between the PSE resulting from the adaptation to a convex surface and the PSE resulting from the adaptation to a concave surface . Examples of psychometric curves for a convex and a concave adaptation are given in Fig. 1c . Results The mean results for the aftereffect values are shown in Fig. 2 . The error bars indicate the standard errors of the mean.Fig . 2Mean results of the aftereffect . The indicated error bars are the standard error in the mean for each condition . Experiment 1 : eight subjects participated . Adaptation was performed by the index finger of the preferred hand . Testing was done using the index finger , middle finger , or little finger of the same hand . Experiment 2 : eight subjects participated . Adaptation and testing was performed by the middle finger of the preferred hand . Experiment 3 : sixteen subjects participated . Adaptation was performed by the index finger of the preferred hand ; testing was done by the opposite index finger . Experiment 4 : eight subjects participated . Adaptation was performed by the index finger of the preferred hand ; testing was done by the middle finger of the non-preferred hand Experiment 1 We tested the occurrence of an aftereffect in each condition by performing separate one-tailed t tests . A significant result was obtained in all conditions -LRB- t7 = 6.3 , P < 0.001 for the index finger ; t7 = 9.8 , P < 0.001 for the middle finger ; t7 = 3.4 , P = 0.006 for the little finger -RRB- . Subsequently , an ANOVA with a repeated measures design was performed to determine any differences between conditions . A significant main effect was found -LRB- F2 ,14 = 22.5 , P < 0.001 -RRB- . Pairwise comparisons showed a significant difference between the index finger and the middle finger -LRB- P = 0.007 -RRB- and between the index finger and the little finger -LRB- P = 0.004 -RRB- , but not between the middle finger and the little finger -LRB- P = 1.0 -RRB- . The P values were adjusted with a Bonferroni correction . Experiment 2 A one-tailed t test showed that there was a significant aftereffect -LRB- t7 = 8.0 , P < 0.001 -RRB- . Inspection of Fig. 2 shows that the aftereffect of the middle finger condition of the second experiment was comparable to the index finger condition of the first experiment and was much higher than the middle finger condition of the first experiment . Independent samples t test confirmed that there was no significant difference in the first case -LRB- t14 = 0.6 , P = 0.6 -RRB- , but that there was a significant difference in the second case -LRB- t7 .4 = 6.1 , P < 0.001 -RRB- . Experiment 3 A one-tailed t test highlighted a significant aftereffect -LRB- t15 = 2.7 , P = 0.009 -RRB- . The magnitude of this aftereffect was much lower than for the index finger condition of the first experiment . This was confirmed by an independent sample t test -LRB- t22 = 5.0 , P < 0.001 -RRB- . Experiment 4 A significant aftereffect was obtained , as was confirmed by a one-tailed t test -LRB- t7 = 7.4 , P < 0.001 -RRB- . Discussion The first novel observation of this paper is that the perception of surface curvature by a single fingertip is influenced by preceding contact of this finger with another curved surface . The magnitude of this curvature aftereffect did not depend on the finger employed , as shown by a comparison between the results of the first and the second experiment . Previously , Vogels et al. -LRB- 1996 , 1997 -RRB- reported the existence of a static curvature aftereffect , when the whole hand was used . We suppose that our finding of a one-finger aftereffect falls in the same class of phenomena . A quantitative comparison between the results of Vogels et al. -LRB- 1996 -RRB- and our finding can be made by calculating the relative magnitude of the aftereffect , i.e. the aftereffect divided by the difference between the adaptation stimuli . This value equals 0.17 ± 0.02 for the results of Vogels et al. , whereas it was 0.15 ± 0.07 for the index finger condition of the first experiment and 0.17 ± 0.06 for the middle finger condition of the second experiment , respectively . These values are in the same order of magnitude , irrespective of the differences in manner of touching and curvature range of the stimuli . The second important finding of our study is that the aftereffect partially transfers between fingers of the same hand . This means that the sensation of shape with a certain finger influences the perception of a shape touched by another finger . This suggests that the sensations obtained by the different fingers share a common representation . However , the transfer is far from complete , indicating that curvature perception by each finger also yields a substantial , individual part in the representation . Interestingly , the aftereffect does not only transfer from the index finger to the neighboring middle finger , but also to the distant little finger . This result is unlike recently performed localization -LRB- Schweizer et al. 2000 -RRB- and learning studies -LRB- Sathian and Zangaladze 1997 ; Harris et al. 2001 -RRB- , in which the reported transfer effects were obtained in the neighboring finger , but not in the distant fingers . This indicates that the processes involved in detecting the finger that is stimulated or increasing the skills to discriminate punctate pressure or roughness are quite different from those concerned in shape perception of an object . The third interesting result of this study is that there was a small , but significant transfer of the aftereffect between fingers of both hands , irrespective of whether opposite fingers -LRB- experiment 3 -RRB- or different fingers -LRB- experiment 4 -RRB- were employed . This result is different from the result reported by Vogels et al. 1997 , who did not find intermanual transfer . However , in their experiments , whole hands were involved , whereas only single fingertips were used in our experiment . Moreover , their conclusion was based on the performance of only 2 subjects , whereas 24 participants provided the data for our study . The results of the third and fourth experiments suggest that the representation of shape information obtained with one hand is not completely distinct from the representation of shape information received by the other hand , but shares a common , bilateral component . How can our findings be interpreted in the context of neurophysiological literature ? Firstly , our finding that the aftereffect only transfers partially between fingers of the same hand shows that a substantial part of the processing occurs at a stage where each finger is individually represented . On this stage , which spreads from the mechanoreceptors in the fingers up to area 3b in SI , no overlap occurs in signals from the slowly adapting receptors and the fast-adapting receptors -LRB- Gardner and Kandel 2000 -RRB- . Slowly adapting receptors respond with a sustained discharge when the finger is in contact with a surface , whereas fast-adapting receptors only respond at the onset and removal phase of the finger -LRB- Johansson and Vallbo 1983 -RRB- . Vogels et al. -LRB- 1996 -RRB- showed that the magnitude of their curvature aftereffect increased with an increase in adaptation time . These findings point to an important role for the slowly adapting receptors in the curvature aftereffect . Therefore , we suggest that the aftereffect at the stage related to an individual finger mainly originates from the processing of the slowly adapting receptors . Secondly , the fact that we found a transfer between the fingers of the same hand implies that a significant part of the processing of curvature information occurs at a level shared by the different fingers . In physiological terms , this indicates that at least area 1 or 2 of SI are involved , as receptive fields in these areas cover several fingers of a single hand -LRB- Gardner and Kandel 2000 -RRB- , but processing may also occur at an even higher stage . Thirdly , our finding of an intermanual transfer shows that the processing of curvature information also takes place on a higher , bilateral level . We can only speculate on the neural correlates of this bilateral processing . Possible candidates include area 2 of SI , areas 5 and 7 of the posterior parietal cortex , and the secondary somatosensory cortex -LRB- Iwamura 2000 ; Gardner and Kandel 2000 -RRB- . It is interesting to mention that the aftereffects in the intramanual transfer conditions -LRB- experiment 1 -RRB- and the intermanual transfer conditions -LRB- experiment 3 and 4 -RRB- are similar in magnitude . This suggests that no important curvature processing occurs at a level that is devoted to a single hand , but that all processing takes place at a higher stage . The similar results for experiments 3 and 4 provide further support that the hands and fingers are not somatotopically represented at this stage . From a previous study , it is known that subjects also performed similarly in intramanual and intermanual curvature discrimination tasks , but that higher performance was obtained when only a single finger was employed -LRB- Van der Horst and Kappers 2007 -RRB- . The analogy between that study and the current study is that curvature information is mainly represented at the level of the individual finger , but partly available at a higher , finger - and hand-independent level . We should be careful in ascribing a specific function to the involvement of the higher level areas in the processing of curvature information . The role of more cognitive aspects should not be excluded , since it is known that processes like tactile attention -LRB- Burton and Sinclair 2000 ; Spence and Gallace 2007 -RRB- , working memory -LRB- Burton and Sinclair 2000 -RRB- , and object recognition -LRB- Reed et al. 2004 -RRB- also engage the somatosensory areas . The aftereffect that we found in the present study is a similar phenomenon as the aftereffect that was previously reported by Vogels et al. -LRB- 1996 , 1997 -RRB- . However , this does not entail that the representation of curvature is identical for touching with a single finger or with the whole hand . Vogels et al. -LRB- 1997 -RRB- already showed that , although similar aftereffects were found when either the whole hand or only the five fingertips were used , only a small transfer between these exploration modes was obtained , which points to a limited overlap in representation . Similarly , we suppose that there is a difference in representation between curvature that is perceived by a single finger and curvature that is perceived by the whole hand . In the single finger case , the representation is mainly at the level of the individual finger , whereas in the whole hand case , the representation is spread over all fingers and the palm of the hand . This study shows that establishing the intramanual and intermanual transfer of the aftereffect is a useful tool in obtaining more insight into the representation of object properties as perceived by the fingers . In general , studying aftereffect transfer is attractive , because it enables a connection between psychophysics and neurophysiology . The convergence of these approaches leads to a better understanding of human perception .

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O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O 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aftereffect curvature somatosensory tactile touch transfer