Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of Guam: Descriptive epidemiology, secular trends, and birth cohort effects on incidence, 1950--1989

This study describes the patterns of occurrence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) of Guam during 1950-1989. Both ALS and PDC occur with high frequency among the indigenous Chamorro population, first recognized in the early 1950's. Reports in the early 1980's indicated that both ALS and PDC were disappearing, due to a purported reduction in exposure to harmful environmental factors as a result of the dramatic changes in lifestyle that took place after World War II. However, this study provides compelling evidence that ALS and PDC have not disappeared on Guam and that rates for both are higher during 1980-1989 than previously reported.^ The patterns of occurrence for both ALS and PDC overlap in most respects: (1) incidence and mortality are decreasing; (2) median age at onset is increasing; (3) males are at increased risk for developing disease; (4) risk is higher for those residing in the south compared to the non-south; and (5) age-specific incidence is decreasing over time except in the oldest age groups.^ Age-specific incidence of ALS and PDC, separately and together, is generally higher for cohorts born before 1920 than for those born after 1920. A significant birth cohort effect on the incidence of PDC for the 1906-1915 birth cohort was found, but not for ALS and for ALS and PDC together. Whether or not a cohort effect, period effect, or both are associated with incidence of ALS and PDC cannot be determined from the data currently available and will require additional follow-up of individuals born after 1920.^ The epidemiological data amassed over this 40-year period provide evidence that supports an environmental exposure model for disease occurrence as opposed to a simple genetic or infectious disease model. Whether neurodegenerative disease in this population occurs as a consequence of a single exposure or is explained by a multifactorial model such as a genetic predisposition with some environmental interaction is yet to be determined. However, descriptive studies such as this can provide clues concerning timing and location of potential adverse exposures but cannot determine etiology, underscoring the urgent need for analytic studies of ALS and PDC to further investigate existing etiologic hypotheses and to test new hypotheses. ^

A tritrophic signal that attracts parasitoids to host-damaged plants withstands disruption by non-host herbivores

Background: Volatiles emitted by herbivore-infested plants are highly attractive to parasitoids and therefore have been proposed to be part of an indirect plant defense strategy. However, this proposed function of the plant-provided signals remains controversial, and it is unclear how specific and reliable the signals are under natural conditions with simultaneous feeding by multiple herbivores. Phloem feeders in particular are assumed to interfere with plant defense responses. Therefore, we investigated how attack by the piercing-sucking cicadellid Euscelidius variegatus influences signaling by maize plants in response to the chewing herbivore Spodoptera littoralis.Results: The parasitoid Cotesia marginiventris strongly preferred volatiles of plants infested with its host S. littoralis. Overall, the volatile emissions induced by S. littoralis and E. variegatus were similar, but higher levels of certain wound-released compounds may have allowed the wasps to specifically recognize plants infested by hosts. Expression levels of defense marker genes and further behavioral bioassays with the parasitoid showed that neither the physiological defense responses nor the attractiveness of S. littoralis infested plants were altered by simultaneous E. variegatus attack.Conclusions: Our findings imply that plant defense responses to herbivory can be more robust than generally assumed and that ensuing volatiles convey specific information about the type of herbivore that is attacking a plant, even in complex situations with multiple herbivores. Hence, the results of this study support the notion that herbivore-induced plant volatiles may be part of a plant's indirect defense stratagem. © 2010 Erb et al; licensee BioMed Central Ltd.

Simple hormones but complex signalling

It has not been easy to make sense of the pleiotropic effects of plant hormones, especially of auxins; but now, it has become possible to study these effects within the framework of what we know about signal transduction in general. Changes in local auxin concentrations, perhaps even actively maintained auxin gradients, signal to networks of transcription factors, which in turn signal to downstream effectors. Transcription factors can also signal back to hormone biosynthetic pathways.

A Time-based Passive Source Localization System for Narrow-band Signal

Time-based indoor localization has been investigated for several years but the accuracy of existing solutions is limited by several factors, e.g., imperfect synchronization, signal bandwidth and indoor environment. In this paper, we compare two time-based localization algorithms for narrow-band signals, i.e., multilateration and fingerprinting. First, we develop a new Linear Least Square (LLS) algorithm for Differential Time Difference Of Arrival (DTDOA). Second, fingerprinting is among the most successful approaches used for indoor localization and typically relies on the collection of measurements on signal strength over the area of interest. We propose an alternative by constructing fingerprints of fine-grained time information of the radio signal. We offer comprehensive analytical discussions on the feasibility of the approaches, which are backed up by evaluations in a software defined radio based IEEE 802.15.4 testbed. Our work contributes to research on localization with narrow-band signals. The results show that our proposed DTDOA-based LLS algorithm obviously improves the localization accuracy compared to traditional TDOA-based LLS algorithm but the accuracy is still limited because of the complex indoor environment. Furthermore, we show that time-based fingerprinting is a promising alternative to power-based fingerprinting.

A Passive Source Localization System for IEEE 802.15.4 Signal

In this work, we provide a passive location monitoring system for IEEE 802.15.4 signal emitters. The system adopts software defined radio techniques to passively overhear IEEE 802.15.4 packets and to extract power information from baseband signals. In our system, we provide a new model based on the nonlinear regression for ranging. After obtaining distance information, a Weighted Centroid (WC) algorithm is adopted to locate users. In WC, each weight is inversely proportional to the nth power of propagation distance, and the degree n is obtained from some initial measurements. We evaluate our system in a 16m-18m area with complex indoor propagation conditions. We are able to achieve a median error of 2:1m with only 4 anchor nodes.

Two enzymes responsible for the formation of herbivore-induced volatiles of maize, the methyltransferase AAMT1 and the terpene synthase TPS23, are regulated by a similar signal transduction pathway

Herbivore-induced volatiles play an important role in the indirect defense of plants. After herbivore damage, volatiles are released from the plant and can attract herbivore enemies that protect the plant from additional damage. The herbivore-induced volatile blend is complex and usually consists of mono- and sesquiterpenes, aromatic compounds, and indole. Although these classes of compounds are generally produced at different times after herbivore damage, the release of the terpene (E)-β-caryophyllene and the aromatic ester methyl anthranilate appear to be tightly coordinated. We have studied the herbivore induction patterns of two terpene synthases from Zea mays L. (Poaceae), TPS23 and TPS10, as well as S-adenosyl-L-methionine:anthranilic acid carboxyl methyltransferases (AAMT1), which are critical for the production of terpenes and anthranilate compounds, respectively. The transcript levels of tps23 and aamt1 displayed the same kinetics after damage by the larvae of Spodoptera littoralis (Boisduval) (Lepidoptera: Noctuidae), and showed the same organ-specific and haplotype-specific expression patterns. Despite its close functional relation to TPS23, the terpene synthase TPS10 is not expressed in roots and does not display the haplotype-specific expression pattern. The results indicate that the same JA-mediated signaling cascade maycontrol the production of both the terpene (E)-β-caryophyllene and aromatic ester methyl anthranilate.

Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti-MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL-2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.

Molecular interactions and signal transfer between sensory rhodopsin-I and its cognate transducer

SRI is unique among known photoreceptors in that it produces opposite signals depending on the color of light stimuli. Absorption of orange light (587 nm) triggers an attractant response by the cell, whereas absorption of orange light followed by near-UV light (373 run) triggers a repellent response. Using behavioral mutants that exhibit aberrant color-sensing ability, we tested a two-conformation equilibrium model, using FRET and EPR spectroscopy. The essence of the model applied to SRI-HtrI is that the complex exists in a metastable two-conformer equilibrium which is shifted in one direction by orange light absorption (producing an attractant signal) and in the opposite direction by a second UV-violet photon (producing a repellent signal). First, by FRET we found that the E-F cytoplasmic loop of SRI moves toward the RAMP domain of the HtrI transducer during the formation of the orange-light activated signaling state of the complex. This is the first localization of a change in the physical relationship between the receptor and transducer subunits of the complex and provides a structural property of the two proposed conformers that we can monitor. Second, EPR spectra of a spin label probe at this cytoplasmic position showed shifts in the dark in the mutants toward shorter or longer EF loop-RAMP distances, explaining their behavior in terms of their mutations causing pre-stimulus shifts into one or the other conformer. ^ Next, we applied a novel electrophysiological method for monitoring the directionality of proton movement during photoactivation of SRI, to investigate the process of proton transfer in the photoactive site from the chromophore to proton acceptors on both the wildtype and aberrant color-response mutants. We observed an unexpected and critical difference in the two signaling conformations of the SRI-HtrI complex. The finding is that the vectoriality (i.e. movement away or toward the cytoplasm) of the light-induced proton transfer from the chromophore to the protein is opposite in formation of the two conformations. Retinylidene proton transfer is a common critical process in rhodopsins and these results are the first to show differences in vectoriality in a rhodopsin receptor, and to demonstrate functional importance of the direction of proton transfer. ^

Identification and functional characterization of novel phosphotyrosine and phosphoserine residues in the interleukin-2 receptor complex

Interleukin-2 (IL-2) is a major T cell growth factor and plays an essential role in the development of normal immune responses. The Janus kinases (Jaks) and Signal transducers and activators of transcription (Stats) are critical for transducing signals from the IL-2 receptors (IL2Rs) to the nucleus to control cell growth and differentiation. In recent years there has been increasing evidence to indicate that the IL-2 activated Jak3/Stat5 pathway provides a new molecular target for immune suppression. Thus, understanding the regulation of this effector cascade has important therapeutic potential.^ One objective of this work was to identify and define the role and molecular mechanism of novel phosphorylation sites in Jak3. Using functional proteomics, three novel Jak3 phosphorylation sites, Y904, Y939 and S574 were identified. Phosphospecific antibodies confirmed that phosphorylation of Y904 and Y939 were mediated by IL-2 and other IL-2 family cytokines in distinct cell types. Biochemical analysis demonstrated that phosphorylation of both Y904 and Y939 positively regulated Jak3 enzymatic activity, while phosphorylation of S574 did not affect Jak3 in vitro kinase activity. However, a gain-of-function mutation of S574 in Jak3 abrogated IL-2 mediated Stat5 activation, suggesting that phosphorylation of this residue might serve a negative role to attenuate IL-2 signaling. Furthermore, mechanistic analysis suggested that phosphorylation of Y904 in Jak3 affects the KmATP of Jak3, while phosphorylation of Y939 in Jak3 was required to bind one of its substrates, Stat5.^ The second objective was to determine the role of serine/threonine phosphatases in the regulation of the IL2R complex. Activation of Jak3 and Stat5 by IL-2 is a transient event mediated by phosphorylation. Using a specific PP1/PP2A inhibitor, we observed that inhibition of PP1/PP2A negatively regulated the IL-2 activated Jak3/Stat5 signaling pathway in a human NK cell line (YT) and primary human T cells. More importantly, coimmunoprecipitation assays indicated that inhibition of PP1/PP2A blocked the formation of an active IL2R complex. Pretreatment of cells with the inhibitor also reduced the electrophoretic mobility of the IL2Rβ and IL2Rγ subunits in YT cells, suggesting that inhibition of PP1/PP2A directly or indirectly regulates undefined serine/threonine kinases which phosphorylate these proteins. Based on these observations, a model has emerged that serine/threonine phosphorylation of the IL2Rβ and IL2Rγ subunits causes a conformational change of these proteins, which disrupts IL2R dimerization and association of Jak3 and Stat5 to these receptors.^

Signal transduction of {\it HER-2\/}/{\it neu\/} receptor tyrosine kinase

Overexpression and/or amplification of HER2/neu is frequently detected in many human cancers. Activation of p185 tyrosine kinase can be achieved by point mutation, overexpression, deletion, and heterodimerization with other class I receptors. In this study I investigated the signal transduction pathways mediating the oncogenic signal of the point mutation-activated rat p185. I demonstrated that tyrosine phosphorylation of Shc and formation of Shc/Grb2 complex correlated to the transformation of NIH3T3 cells caused by the point mutation-activated rat HER2/neu. Furthermore, I observed that association with Shc was severely impaired by deletion of most of the major autophosphorylation sites of the point-mutated p185. The truncated p185 product, however, fully retained its ability to transform NIH3T3 cells, induce Shc tyrosine phosphorylation and Shc/Grb2 complex formation. These results suggest that tyrosine phosphorylation of Shc which allows formation of Shc/Grb2 complex may play an important role in cell transformation induced by the point mutation-activated p185, and that stable binding to mutant p185 may not be necessary for Shc to mediate this signaling pathway.^ Recent studies have suggested that formation of the complex containing Sos, Grb2 and Shc is important in coupling receptor tyrosine kinases to the Ras signaling pathway. To clarify the role of this trimer in the oncogenic signaling of the activated p185, I set out to interfere with the protein-protein interactions in Shc/Grb2/Sos complex by introducing Grb2 mutants with deletions in either amino- ($\Delta$N-Grb2) or carboxyl- ($\Delta$C-Grb2) terminal SH3 domains into B104-1-1 cells derived from NIH3T3 cells that express the point mutation-activated HER-2/neu. I found that the transformed phenotypes of the B104-1-1 cells were largely reversed by expression of the $\Delta$N-Grb2. The effect of the $\Delta$C-Grb2 on phenotypic reversion was much weaker. Biochemical analysis showed that the $\Delta$N-Grb2 was able to associate Shc but not the activated p185 nor Sos, while the $\Delta$C-Grb2 bound to Shc, the activated p185, and Sos. The p185-mediated Ras activation was severely inhibited by the $\Delta$N-Grb2 but not the $\Delta$C-Grb2. Taken together, these data demonstrate that interruption of the interaction between Shc and the endogenous Grb2 by the $\Delta$N-Grb2 is able to impair the oncogenic signaling of the mutation-activated p185, indicating that (i) the $\Delta$N-Grb2 functions as a strong dominant-negative mutant, (ii) Shc/Grb2/Sos pathway plays a major role in mediating the oncogenic signal of the mutation-activated p185. Unlike the $\Delta$N-Grb2, the $\Delta$C-Grb2 appears to be a relatively weak dominant-negative mutant, probably due to its ability to largely fulfill the biological functions of the wild-type Grb2. ^

Cross -packing among retroviruses and characterization of the feline immunodeficiency virus (FIV) packaging signal: Implications for the development of FIV-based gene transfer systems

Feline immunodeficiency virus (FIV)-based gene transfer systems are being seriously considered for human gene therapy as an alternative to vectors based on primate lentiviruses, a genetically complex group of retroviruses capable of infecting non-dividing cells. The greater phylogenetic distance between the feline and primate lentiviruses is thought to reduce chances of the generation of recombinant viruses. However, safety of FIV-based vector systems has not been tested experimentally. Since primate lentiviruses such as human and simian immunodeficiency viruses (HIV/SIV) can cross-package each other's genomes, we tested this trait with respect to FIV. Unexpectedly, both feline and primate lentiviruses were reciprocally able to both cross-package and propagate each other's RNA genomes. This was largely due to the recognition of viral packaging signals by the heterologous proteins. However, a simple retrovirus such as Mason-Pfizer monkey virus (MPMV) was unable to package FIV RNA. Interestingly, FIV could package MPMV RNA, but not propagate it for further steps of replication. These findings suggest that upon co-infection of the same host, cross-packaging may allow distinct retroviruses to generate chimeric variants with unknown pathogenic potential. ^ In order to understand the packaging determinants in FIV, we conducted a detailed mutational analysis of the region thought to contain FIV packaging signal. We show that the first 90–120 nt of the 5′ untranslated region (UTR) and the first 90 nt of gag were simultaneously required for efficient FIV RNA packaging. These results suggest that the primary FIV packaging signal is multipartite and discontinuous, composed of two core elements separated by 150 nt of the 5 ′UTR. ^ The above studies are being used towards the development of safer FIV-based self-inactivating (SIN) vectors. These vectors are being designed to eliminate the ability of FIV transfer vector RNAs to be mobilized by primate lentiviral proteins that may be present in the target cells. Preliminary test of the first generation of these vectors has revealed that they are incapable of being propagated by feline proteins. The inability of FIV transfer vectors to express packageable vector RNA after integration should greatly increase the safety of FIV vectors for human gene therapy. ^

Quality assessment by region in spot images fused by means dual-tree complex wavelet transform

This work is motivated in providing and evaluating a fusion algorithm of remotely sensed images, i.e. the fusion of a high spatial resolution panchromatic image with a multi-spectral image (also known as pansharpening) using the dual-tree complex wavelet transform (DT-CWT), an effective approach for conducting an analytic and oversampled wavelet transform to reduce aliasing, and in turn reduce shift dependence of the wavelet transform. The proposed scheme includes the definition of a model to establish how information will be extracted from the PAN band and how that information will be injected into the MS bands with low spatial resolution. The approach was applied to Spot 5 images where there are bands falling outside PAN’s spectrum. We propose an optional step in the quality evaluation protocol, which is to study the quality of the merger by regions, where each region represents a specific feature of the image. The results show that DT-CWT based approach offers good spatial quality while retaining the spectral information of original images, case SPOT 5. The additional step facilitates the identification of the most affected regions by the fusion process.

Analytic Kramer kernels, Lagrange-type interpolation series and de Branges spaces

The classical Kramer sampling theorem provides a method for obtaining orthogonal sampling formulas. In particular, when the involved kernel is analytic in the sampling parameter it can be stated in an abstract setting of reproducing kernel Hilbert spaces of entire functions which includes as a particular case the classical Shannon sampling theory. This abstract setting allows us to obtain a sort of converse result and to characterize when the sampling formula associated with an analytic Kramer kernel can be expressed as a Lagrange-type interpolation series. On the other hand, the de Branges spaces of entire functions satisfy orthogonal sampling formulas which can be written as Lagrange-type interpolation series. In this work some links between all these ideas are established.

A Recommendation Framework Based on the Analytic Network Process and its Application in the Semantic Technology Domain

When users face a certain problem needing a product, service, or action to solve it, selecting the best alternative among them can be a dicult task due to the uncertainty of their quality. This is especially the case in the domains where users do not have an expertise, like for example in Software Engineering. Multiple criteria decision making (MCDM) methods are methods that help making better decisions when facing the complex problem of selecting the best solution among a group of alternatives that can be compared according to different conflicting criteria. In MCDM problems, alternatives represent concrete products, services or actions that will help in achieving a goal, while criteria represent the characteristics of these alternatives that are important for making a decision.

Simplified small-signal stability analysis for optimized power system architecture

The optimization of power architectures is a complex problem due to the plethora of different ways to connect various system components. This issue has been addressed by developing a methodology to design and optimize power architectures in terms of the most fundamental system features: size, cost and efficiency. The process assumes various simplifications regarding the utilized DC/DC converter models in order to prevent the simulation time to become excessive and, therefore, stability is not considered. The objective of this paper is to present a simplified method to analyze small-signal stability of a system in order to integrate it into the optimization methodology. A black-box modeling approach, applicable to commercial converters with unknown topology and components, is based on frequency response measurements enabling the system small-signal stability assessment. The applicability of passivity-based stability criterion is assessed. The stability margins are stated utilizing a concept of maximum peak criteria derived from the behavior of the impedance-based sensitivity function that provides a single number to state the robustness of the stability of a well-defined minor-loop gain.