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The MAM (meprin/A5-protein/PTPmu) domain is present in numerous proteins with diverse functions. PTPμ belongs to the MAM-containing subclass of protein-tyrosine phosphatases (PTP) able to promote cell-to-cell adhesion. Here we provide experimental evidence that the MAM domain is a homophilic binding site of PTPμ. We demonstrate that the MAM domain forms oligomers in solution and binds to the PTPμ ectodomain at the cell surface. The presence of two disulfide bridges in the MAM molecule was evidenced and their integrity was found to be essential for MAM homophilic interaction. Our data also indicate that PTPμ ectodomain forms oligomers and mediates the cellular adhesion, even in the absence of MAM domain homophilic binding. Reciprocally, MAM is able to interact homophilically in the absence of ectodomain trans binding. The MAM domain therefore contains independent cis and trans interaction sites and we predict that its main role is to promote lateral dimerization of PTPμ at the cell surface. This finding contributes to the understanding of the signal transduction mechanism in MAM-containing PTPs.
The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207. Moreover, G207 infection caused the destruction of endothelial cell tubes in vitro. In the in vivo Matrigel plug assay in mice, G207 suppressed the formation of perfused vessels. Intratumoral treatment of established human rhabdomyosarcoma xenografts with G207 led to the destruction of tumor vessels and tumor regression. Ultrastructural investigations revealed the presence of viral particles in both tumor and endothelial cells of G207-treated xenografts, but not in adjacent normal tissues. These findings show that G207 may suppress tumor growth, in part, due to inhibition of angiogenesis.
We consider three sets of phenomena that feature prominently - and separately - in the financial economics literature: conditional mean dependence (or lack thereof) in asset returns, dependence (and hence forecastability) in asset return signs, and dependence (and hence forecastability) in asset return volatilities. We show that they are very much interrelated, and we explore the relationships in detail. Among other things, we show that: (a) Volatility dependence produces sign dependence, so long as expected returns are nonzero, so that one should expect sign dependence, given the overwhelming evidence of volatility dependence; (b) The standard finding of little or no conditional mean dependence is entirely consistent with a significant degree of sign dependence and volatility dependence; (c) Sign dependence is not likely to be found via analysis of sign autocorrelations, runs tests, or traditional market timing tests, because of the special nonlinear nature of sign dependence; (d) Sign dependence is not likely to be found in very high-frequency (e.g., daily) or very low-frequency (e.g., annual) returns; instead, it is more likely to be found at intermediate return horizons; (e) Sign dependence is very much present in actual U.S. equity returns, and its properties match closely our theoretical predictions; (f) The link between volatility forecastability and sign forecastability remains intact in conditionally non-Gaussian environments, as for example with time-varying conditional skewness and/or kurtosis.
Vowel dispersion in Truku
(2004)
This study investigates the dispersion of vowel space in Truku, an endangered Austronesian language in Taiwan. Adaptive Dispersion (Liljencrants and Lindblom, 1972; Lindblom, 1986, 1990) proposes that the distinctive sounds of a language tend to be positioned in phonetic space in a way that maximizes perceptual contrast. For example, languages with large vowel inventories tend to expand the overall acoustic vowel space. Adaptive Dispersion predicts that the distance between the point vowels will increase with the size of a language's vowel inventory. Thus, the available acoustic vowel space is utilized in a way that maintains maximal auditory contrast.
The current study focuses on the prosodic realization of negators in Saisiyat, an endangered aboriginal language of Taiwan, and compares its prosodic realization of negation with that of English. The results of this study indicate that sentential subjects are the most acoustically prominent items in the Saisiyat negative sentences measured. This contrasts sharply with the English experimental sentences, in which the negator itself was the most acoustically prominent item. These findings suggest that Saisiyat is a pitch-accent language; thus, the presence of negators does not significantly change the prosodic parameters of surrounding words. English, in contrast, is an intonation language, so the presence of negation results in substantial prosodic modification. This suggests that the phenomenon of negation is universally prominent; however, languages with different prosodic systems will adopt different strategies for realizing prominence.
The transporter associated with antigen processing (TAP) is a key component of the cellular immune system. As a member of the ATP-binding cassette (ABC) superfamily, TAP hydrolyzes ATP to energize the transport of peptides from the cytosol into the lumen of the endoplasmic reticulum. TAP is composed of TAP1 and TAP2, each containing a transmembrane domain and a nucleotide-binding domain (NBD). Here we investigated the role of the ABC signature motif (C-loop) on the functional non-equivalence of the NBDs, which contain a canonical C-loop (LSGGQ) for TAP1 and a degenerate C-loop (LAAGQ) for TAP2. Mutation of the leucine or glycine (LSGGQ) in TAP1 fully abolished peptide transport. However, TAP complexes with equivalent mutations in TAP2 still showed residual peptide transport activity. To elucidate the origin of the asymmetry of the NBDs of TAP, we further examined TAP complexes with exchanged C-loops. Strikingly, the chimera with two canonical C-loops showed the highest transport rate whereas the chimera with two degenerate C-loops had the lowest transport rate, demonstrating that the ABC signature motifs control peptide transport efficiency. All single site mutants and chimeras showed similar activities in peptide or ATP binding, implying that these mutations affect the ATPase activity of TAP. In addition, these results prove that the serine of the C-loop is not essential for TAP function but rather coordinates, together with other residues of the C-loop, the ATP hydrolysis in both nucleotide-binding sites.
The transporter associated with antigen processing (TAP) plays a pivotal role in the adaptive immune response against virus-infected or malignantly transformed cells. As member of the ABC transporter family, TAP hydrolyzes ATP to energize the transport of antigenic peptides from the cytosol into the lumen of the endoplasmic reticulum. TAP forms a heterodimeric complex composed of TAP1 and TAP2 (ABCB2/3). Both subunits contain a hydrophobic transmembrane domain and a hydrophilic nucleotide-binding domain. The aim of this work was to study the ATP hydrolysis event of the TAP complex and gain further insights into the mechanism of peptide transport process. To analyze ATP hydrolysis of each subunit I developed a method of trapping 8- azido-nucleotides to TAP in the presence of phosphate transition state analogs followed by photocross-linking, immunoprecipitation, and high-resolution SDS-PAGE. Strikingly, trapping of both TAP subunits by beryllium fluoride is peptide-specific. The peptide concentration required for half-maximal trapping is identical for TAP1 and TAP2 and directly correlates with the peptide-binding affinity. Only background levels of trapping were observed for low affinity peptides or in the presence of the herpes simplex viral protein ICP47, which specifically blocks peptide binding to TAP. Importantly, the peptideinduced trapped state is reached after ATP hydrolysis and not in a backward reaction of ADP binding and trapping. In the trapped state, TAP can neither bind nor exchange nucleotides, whereas peptide binding is not affected. In summary, these data support the model that peptide binding induces a conformation that triggers ATP hydrolysis in both subunits of the TAP complex within the catalytic cycle. The role of the ABC signature motif (C-loop) on the functional non-equivalence of the NBDs was investigated. The C-loops of TAP transporter contain a canonical C-loop (LSGGQ) for TAP1 and a degenerated ABC signature motif (LAAGQ) for TAP2. Mutation of the leucine or glycine (LSGGQ) in TAP1 fully abolished peptide transport. TAP complexes with equivalent mutations in TAP2 showed however still residual peptide transport activity. To elucidate the origin of the asymmetry of the NBDs of TAP, we further examined TAP complexes with exchanged C-loops. Strikingly, the chimera with two canonical C-loops showed the highest transport rate whereas the chimera with two degenerated C-loops had the lowest transport rate, demonstrating that the ABC signature motifs control the peptide transport efficiency. All single-site mutants and chimeras showed similar activities in peptide or ATP binding, implying that these mutations affect the ATPase activity of TAP. In addition, these results prove that the serine of the C-loop is not essential for TAP function, but rather coordinates, together with other residues of the C-loop, the ATP hydrolysis in both nucleotide-binding sites. To study the coupling between the ATP binding/hydrolysis and the peptide binding, the putative catalytic bases of the TAP complex were mutated to generate the so-called EQ mutants. The mutations did not influence the peptide-binding ability. Dimerization of the NBDs of EQ mutants upon ATP binding does not alter the peptide binding property. At 27°C, both ATP and ADP could induce the loss of peptide-binding ability (Bmax) only in the variants bearing a mutated TAP2. Further studies are required to deduce at which stage in the catalytic cycle the peptide-binding site is affected. In addition, mutation of the putative catalytic base of both subunits showed a magnesium-dependent peptide transport activity, demonstrating these mutants did not abolish the ATP hydrolysis. Thus, the function of this acidic residue as the catalytic base is not likely to be universe for all ABC transporters.
This study focuses upon a detailed description and analysis of the phonetic structures of Paiwan, an aboriginal language spoken in Taiwan, with around 53,000 speakers, Paiwan, a member of the Austronesian language family, is not typologically related to the other languages such as Mandarin and Taiwanese spoken in its geographically contiguous districts, Earlier work on phonological features of Paiwan (Chang, 1999; Tseng, 2003) sought an account in terms of segments and isolated facts about reduplication and stress, without accounting for the possible roles of phrase-level and sentence-Ievel prosodic structures, Government Teaching Material (1993) listed 25 consonants and 4 vowels, without any description of phonetic features and phonological rules, Chang's (2000) reference grammar included 22 consonants and 4 vowels, with a very brief description of 5 phonological rules on single words, Regional diversity and 25 consonants have been mentioned in Pulaluyan's (2002) teaching material; however, no description of phonological rules was found in his material.
This paper analyzes banks' choice between lending to firms individually and sharing lending with other banks, when firms and banks are subject to moral hazard and monitoring is essential. Multiple-bank lending is optimal whenever the benefit of greater diversification in terms of higher monitoring dominates the costs of free-riding and duplication of efforts. The model predicts a greater use of multiple-bank lending when banks are small relative to investment projects, firms are less profitable, and poor financial integration, regulation and inefficient judicial systems increase monitoring costs. These results are consistent with empirical observations concerning small business lending and loan syndication. JEL Klassifikation: D82; G21; G32.
We take a simple time-series approach to modeling and forecasting daily average temperature in U.S. cities, and we inquire systematically as to whether it may prove useful from the vantage point of participants in the weather derivatives market. The answer is, perhaps surprisingly, yes. Time-series modeling reveals conditional mean dynamics, and crucially, strong conditional variance dynamics, in daily average temperature, and it reveals sharp differences between the distribution of temperature and the distribution of temperature surprises. As we argue, it also holds promise for producing the long-horizon predictive densities crucial for pricing weather derivatives, so that additional inquiry into time-series weather forecasting methods will likely prove useful in weather derivatives contexts.