Transthyretin: a review from a structural perspective

Transthyretin (formerly called prealbumin) plays important physiological roles as a transporter of thyroxine and retinol-binding protein. X-ray structural studies have provided information on the active conformation of the protein and the site of binding of both ligands. Transthyretin is also one of the precursor proteins commonly found in amyloid deposits. Both wild-type and single-amino-acid-substituted variants have been identified in amyloid deposits, the variants being more amyloidogenic. Sequencing of the gene and the resulting production of a transgenic mouse model have resulted in progress toward solving the mechanism of amyloid formation and detecting the variant gene in individuals at risk. Received 23 January 2001; received after revision 4 April 2001; accepted 30 April 2001     

Invited review combining forecasts—twenty years later

The combination of forecasts is a simple, pragmatic and sensible way to possibly produce better forecasts. Simple extensions of the original idea involve the use of various available ‘forecasts’ even if some are rather inefficient. Some unsolved questions relate to combining forecasts with horizons longer than one period. More complicated extensions are associated with ‘encompassing’ and the combination of confidence intervals or quantiles. The relevance of information sets is emphasized in both the underlying theory and the interpretation of combinations.     

The ATP-binding cassette family: a structural perspective

The ATP-binding cassette family is one of the largest groupings of membrane proteins, moving allocrites across lipid membranes, using energy from ATP. In bacteria, they reside in the inner membrane and are involved in both uptake and export. In eukaryotes, these transporters reside in the cell’s internal membranes as well as in the plasma membrane and are unidirectional—out of the cytoplasm. The range of substances that these proteins can transport is huge, which makes them interesting for structure–function studies. Moreover, their abundance in nature has made them targets for structural proteomics consortia. There are eight independent structures for ATP-binding cassette transporters, making this one of the best characterised membrane protein families. Our understanding of the mechanism of transport across membranes and membrane protein structure in general has been enhanced by recent developments for this family.     

The muscle ultrastructure: a structural perspective of the sarcomere

Muscle ultrastructure is characterised by a complex arrangement of many protein-protein interactions. The sarcomere is the basic repeating unit of muscle, formed by two transverse filament systems: the thick and thin filaments. While actin and myosin are the main contractile elements of the sarcomere, other proteins act as scaffolds, control ultrastructure composition, regulate muscle contraction, and transmit tension between sarcomeres and hence to the whole myofibril. Elucidation of the structures of muscle proteins by X-ray crystallography and nuclear magnetic resonance spectroscopy has been essential in understanding muscle contraction, enabling us to relate biological to structural information. These structures reveal how components of the muscle interact, how different factors influence conformational changes within these proteins, and how mutant muscle proteins may interfere with the regulatory fine-tuning of the contractile machinery, hence leading to disease in some cases. Here, structures solved within the sarcomere have been reviewed in order to put the numerous components into context.Received 28 June 2004; received after revision 25 July 2004; accepted 28 July 2004     

Economic factors and the stock market: a new perspective

It has been widely accepted that many financial and economic variables are non‐linear, and neural networks can model flexible linear or non‐linear relationships among variables. The present paper deals with an important issue: Can the many studies in the finance literature evidencing predictability of stock returns by means of linear regression be improved by a neural network? We show that the predictive accuracy can be improved by a neural network, and the results largely hold out‐of‐sample. Both the neural network and linear forecasts show significant market timing ability. While the switching portfolio based on the linear forecasts outperforms the buy‐and‐hold market portfolio under all three transaction cost scenarios, the switching portfolio based on the neural network forecasts beats the market only if there is no transaction cost. Copyright © 1999 John Wiley & Sons, Ltd.     

Mental processes and disorders: a neurobehavioral perspective in human biometeorology

Research concerning the complex relation between weather and psychological processes has emphasized three important issues: methodological problems, the determination of the major behavioral factors, and the isolation of neurobiological mechanisms. This paper reviews the current status of each issue. Weather changes are most frequently associated with behaviors that are the endpoints of inferred psychological processes that include mood, subclinical pain, anxiety, and the correlates of schedule shifts. Learning and conditioning appear to mediate a powerful influence over weather-related responses. This may explain the large individual variability in these behaviors. The most well-known group effects associated with weather changes involve psychiatric populations. Clinical subpopulations may respond in different ways to different aspects of the same weather system as well as to different types of air masses. Likely neurobiological mechanisms through which meteorogenic stimuli may mediate whole organismic effects include the locus coeruleal and limbic systems. Expected psychobiological consequences are examined in detail. The magnitude and temporal-spatial characteristics of weather effects indicate they are the subject matter of behavioral epidemiology.     

Fibroblast growth factor 21: an overview from a clinical perspective

Fibroblast growth factor 21 (FGF21) has been proposed as a novel putative therapeutic agent in type 2 diabetes. A large amount of data, predominantly obtained from murine models but also from non-human primates, suggest that FGF21 ameliorates obesity-associated hyperglycemia and hyperlipidemia primarily via effects on adipose tissue and the pancreas. In addition, FGF21 has been reported to play a pivotal regulatory role in starvation and ketosis. However, while it is clear that FGF21 has potent effects in vivo in several animal models, the exact mechanisms remain elusive. Moreover, very recent results from different human cohort studies have shown a paradoxical regulation of plasma FGF21 in obesity and type 2 diabetes as well as other important qualitative differences in the effects and regulation of FGF21 between rodents and humans. This review focuses on the most recently published data on FGF21 with emphasis on results obtained in humans.     

[FeFe] hydrogenases and their evolution: a genomic perspective

Most hydrogenases (H2ases), the enzymes that produce or oxidize dihydrogen, possess dimetallic active sites and belong to either one of two phylogenetically distinct classes, the [NiFe] and the [FeFe] H2ases. These families of H2ases share a number of similarities regarding active site structure and reaction mechanism, as a result of convergent evolution. They are otherwise alien to each other, in particular with respect to protein sequence and structure, maturation mechanisms, and distribution among the realms of life. One of the interesting features of [FeFe] H2ases is their occurrence in anaerobic bacteria, anaerobic protists, and mitochondriate eukaryotes. They thus have the potential to report on important evolutionary events, including transitions from the prokaryote to the eukaryote lifestyle. Genome sequences yield a variety of [FeFe] H2ase sequences that have been implemented to shed light on the evolution of these proteins and their host organisms.     

Fifty years of amanitin

Pharmacokinetic studies have provided new insights into humanAmanita poisoning, but it appears to be impossible to treat this intoxication by immunotherapy. New synthetic analogs have revealed structure-activity relationships that were unknown so far. The main toxin, α-amanitin, is in constant use as a tool in molecular biology and in biological research. First experiments have been reported in which amanitin bound to polymers could be internalized into tumor cells via a receptor-mediated endocytosis.     

Modular localization and the holistic structure of causal quantum theory,a historical perspective

Recent insights into the conceptual structure of localization in QFT (modular localization) led to clarifications of old unsolved problems. The oldest one is the Einstein–Jordan conundrum which led Jordan in 1925 to the discovery of quantum field theory. This comparison of fluctuations in subsystems of heat bath systems (Einstein) with those resulting from the restriction of the QFT vacuum state to an open subvolume (Jordan) leads to a perfect analogy; the globally pure vacuum state becomes upon local restriction a strongly impure KMS state. This phenomenon of localization-caused thermal behavior as well as the vacuum-polarization clouds at the causal boundary of the localization region places localization in QFT into a sharp contrast with quantum mechanics and justifies the attribute “holstic”. In fact it positions the E–J Gedankenexperiment into the same conceptual category as the cosmological constant problem and the Unruh Gedankenexperiment. The holistic structure of QFT resulting from “modular localization” also leads to a revision of the conceptual origin of the crucial crossing property which entered particle theory at the time of the bootstrap S-matrix approach but suffered from incorrect use in the S-matrix settings of the dual model and string theory.The new holistic point of view, which strengthens the autonomous aspect of QFT, also comes with new messages for gauge theory by exposing the clash between Hilbert space structure and localization and presenting alternative solutions based on the use of stringlocal fields in Hilbert space. Among other things this leads to a reformulation of the Englert–Higgs symmetry breaking mechanism.     

Evolution of anti-Rh antibodies idiotypy in a blood donor over 9 years]

Anti-idiotypic sera were obtained in Rabbits immunized with Rh antibodies (isolated from the serum sample collected in 1974 from a Blood Donor). The sera agglutinate, at high titers, red cells coated with the immunizing antibodies and, at different titers, cells coated with antibodies from serum samples taken at other periods. Inhibition of hemagglutination of anti-idiotypic sera by different samples from the same Donor was complete with the immunizing serum and partial with other samples. These results show that idiotypes or idiotypic specificities appeared or disappeared during the period studied and represent the first observation on evolution of antibody idiotypy in Man.