Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

The minimal rank correlation,subject to order restrictions,with application to the weighted linear choice model

The weighted linear choice model is one of the most popular models in the social sciences. In this model the utility of a choice object is represented as a weighted sum of attribute-level desirabilities, where the weights are attribute importances. In many empirical contexts the choice objects are such that individuals are highly correlated in terms of their desirability ordering of levels within attribute (e.g., price levels, durability levels, etc.) but may differ appreciably in terms of their evaluations of each attribute's importance.In this paper we address the problem of how dissimilar two individuals may be, in a rank correlation sense, given that they agree completely on the desirability ordering of levels within attributes, but may disagree considerably regarding the importance they attach to the attributes themselves. The problem has interesting implications regarding the potential value of clustering individuals' utility functions for market segmentation or other such purposes.The authors would like to thank the editor and three anonymous reviewers for their excellent comments on an earlier draft of the paper.     

Furocaulerpin,a new acetylenic sesquiterpenoid from the green algaCaulerpa prolifera

Summary Furocaulerpin, an acetylenic sesquiterpenoid possessing a furan ring, has been isolated from the marine algaCaulerpa prolifera, and its stereostructure elucidated mainly on the basis of physico-chemical data.This work was carried out in the frame work of the Progetto Finalizzato per l'Oceanografia e i Fondi Marini, CNR, Rome. Thanks are due to the Centro di Metodologie Chimico-Fisiche of the University of Naples (Mr I. Giudicianni) for the determination of PMR-spectra.     

The microscopic nature of localization in the quantum Hall effect

The quantum Hall effect arises from the interplay between localized and extended states that form when electrons, confined to two dimensions, are subject to a perpendicular magnetic field. The effect involves exact quantization of all the electronic transport properties owing to particle localization. In the conventional theory of the quantum Hall effect, strong-field localization is associated with a single-particle drift motion of electrons along contours of constant disorder potential. Transport experiments that probe the extended states in the transition regions between quantum Hall phases have been used to test both the theory and its implications for quantum Hall phase transitions. Although several experiments on highly disordered samples have affirmed the validity of the single-particle picture, other experiments and some recent theories have found deviations from the predicted universal behaviour. Here we use a scanning single-electron transistor to probe the individual localized states, which we find to be strikingly different from the predictions of single-particle theory. The states are mainly determined by Coulomb interactions, and appear only when quantization of kinetic energy limits the screening ability of electrons. We conclude that the quantum Hall effect has a greater diversity of regimes and phase transitions than predicted by the single-particle framework. Our experiments suggest a unified picture of localization in which the single-particle model is valid only in the limit of strong disorder.     

Structural alteration of hair cells in the contralateral ear resulting from extracochlear electrical stimulation

Chronic electrical stimulation of the auditory nerve in patients with profound sensori-neural deafness is becoming increasingly routine. Therefore, it is important to understand more about the long-term consequences of this procedure. Hitherto, structural studies in animals after electrocochlear stimulation have concentrated on the stimulated cochlea. Here we have examined the effects of unilateral extracochlear electrical stimulation on the spiral organ of both the ipsilateral and contralateral ears of the mature guinea pig, and have found alterations in the structure of the outer hair cells and their efferent nerve terminals in the contralateral as well as the ipsilateral cochlea. This is the first evidence for a structural influence of efferent activity on the cochlea. Although the importance of the efferent system, consisting of the crossed and uncrossed olivo-cochlear bundles, is well established in providing central control of the sensory pathways, its exact role in hearing is incompletely understood. However, it is known that the outer hair cells and their efferent innervation are important in their contribution to inner hair cell responses and in modulating the micromechanics of the whole cochlea. These efferent functions now appear to be related to an important part of cochlear morphology, and are also relevant to our understanding of cochlear neurobiology, normal development and the management of hearing disability in both adult and child.     

The mouse Dreher gene Lmx1a controls formation of the roof plate in the vertebrate CNS

In the vertebrate central nervous system (CNS), a cascade of signals that originates in the ectoderm adjacent to the neural tube is propagated by the roof plate to dorsalize the neural tube. Here we report that the phenotype of the spontaneous neurological mutant mouse dreher (dr) results from a failure of the roof plate to develop. Dorsalization of the neural tube is consequently affected: dorsal interneurons in the spinal cord and granule neurons in the cerebellar cortex are lost, and the dorsal vertebral neural arches fail to form. Positional cloning of dreher indicates that the LIM homeodomain protein, Lmx1a, is affected in three different alleles of dreher. Lmx1a is expressed in the roof plate along the neuraxis during development of the CNS. Thus, Lmx1a is required for development of the roof plate and, in turn, for specification of dorsal cell fates in the CNS and developing vertebrae.     

Chemical communication: butterfly anti-aphrodisiac lures parasitic wasps

To locate their hosts, parasitic wasps can 'eavesdrop' on the intraspecific chemical communications of their insect hosts. Here we describe an example in which the information exploited by the parasitic wasp Trichogramma brassicae is a butterfly anti-aphrodisiac that is passed from male to female Pieris brassicae butterflies during mating, to render them less attractive to conspecific males. When the tiny wasp detects the odour of a mated female butterfly, it rides on her (Fig. 1) to her egg-laying sites and then parasitizes the freshly laid eggs. If this fascinating strategy is widespread in nature, it could severely constrain the evolution of sexual communication between hosts.     

喷动流化床射流穿透度智能拟合

在三维冷态试验台架上对喷动流化床射流穿透度进行了实验研究,得出了射流穿透度随喷口尺寸、载气密度、喷动气速的增大而增大,随静止床高、颗粒尺寸、颗粒密度、流化气率、载气黏度的增大而减小的结论.在实验研究的基础上利用最小二乘支持向量机对射流穿透度与喷动流化床主要设计参数之间的数值关系进行了智能拟合,并利用自适应遗传算法优化了最小二乘支持向量机的初始参数.通过15个预测样本的检验,最小二乘支持向量机模型的预测平均相对误差减小至4.0%,其性能大大优于常用的经验公式以及神经网络.     

Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.     

RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.