Showing papers by "Neil R. Smalheiser published in 2003"

EST analyses predict the existence of a population of chimeric microRNA precursor-mRNA transcripts expressed in normal human and mouse tissues

Abstract: A significant population of expressed sequence tags (ESTs) encodes chimeric transcripts containing microRNA (miRNA) precursor sequences as well as pieces of adjacent mRNAs in sense orientation. These chimeric transcripts may potentially be involved in miRNA biosynthesis, and/or affect expression of adjacent mammalian mRNAs.

A reelin–integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes

Abstract: Reelin is synthesized and secreted into extracellular matrix by cortical γ-aminobutyric acid (GABA)ergic interneurons and binds with high affinity to the extracellular domain of integrin receptors expressed in dendritic shaft and spine postsynaptic densities (DSPSD) of pyramidal neurons. In heterozygous reeler mice, reelin bound to DSPSD, and the expression of Arc (activity-regulated cytoskeletal protein) is lower than in wild-type mice. We studied the effect of reelin on Arc and total protein synthesis in synaptoneurosomes (SNSs) prepared from mouse neocortex. Recombinant full-length mouse reelin displaces the high affinity (KD = 60 fM) binding of [125I]echistatin (a competitive integrin receptor antagonist) to integrin receptors with a Ki of 22 pM and with a Hill slope close to 1. Echistatin (50–100 nM) competitively antagonizes and abates reelin binding. The addition of reelin (2–40 pM) to SNSs enhances the incorporation of [35S]methionine into Arc and other rapidly translated proteins in a concentration-dependent manner. This incorporation is virtually abolished by 50–100 nM echistatin or by 5–10 nM rapamycin, a blocker of the mammalian target of rapamycin kinase. We conclude that reelin binds with high affinity to integrin receptors expressed in SNSs and thereby activates Arc protein synthesis.

Towards effective and rewarding data sharing.

Abstract: Recently issued NIH policy statement and implementation guidelines (National Institutes of Health, 2003) promote the sharing of research data. While urging that “all data should be considered for data sharing” and “data should be made as widely and freely available as possible” the current policy requires only high-direct-cost (>US$500,000/yr) grantees to share research data, starting 1 October 2003. Data sharing is central to science, and we agree that data should be made available.

Methodological factors influencing measurement and processing of plasma reelin in humans

Abstract: Reelin, intensively studied as an extracellular protein that regulates brain development, is also expressed in a variety of tissues and a circulating pool of reelin exists in adult mammals. Here we describe the methodological and biological foundation for carrying out and interpreting clinical studies of plasma reelin. Reelin in human plasma was sensitive to proteolysis, freeze-thawing and heating during long-term storage, sample preparation and electrophoresis. Reelin in plasma was a dimer under denaturing conditions. Boiling of samples resulted in laddering, suggesting that each of the 8 repeats expressed in reelin contains a heat-labile covalent bond susceptible to breakage. Urinary-type and tissue-type plasminogen activator converted reelin to a discrete 310 kDa fragment co-migrating with the major immunoreactive reelin fragment seen in plasma and also detected in brain. (In contrast, plasmin produced a spectrum of smaller unstable reelin fragments.) We examined archival plasma of 10 pairs of age-matched male individuals differing in repeat length of a CGG repeat polymorphism of the 5'-untranslated region of the reelin gene (both alleles 11 repeats). Reelin 310 kDa band content was lower in subjects having the long repeats in all 10 pairs, by 25% on average (p < 0.001). In contrast, no difference was noted for amyloid precursor protein. Our studies indicate the need for caution in measuring reelin in archival blood samples, and suggest that assays of plasma reelin should take into account three dimensions that might vary independently: a) the total amount of reelin protein; b) the relative amounts of reelin vs. its proteolytic processing products; and c) the aggregation state of the native protein. Reelin-plasminogen activator interactions may affect their roles in synaptic plasticity. Our results also suggest that the human CGG repeat polymorphism affects reelin gene expression, and may affect susceptibility to human disease.

A probabilistic similarity metric for Medline records: a model for author name disambiguation

Abstract: We present a model for automatically generating training sets and estimating the probability that a pair of Medline records sharing a last and first name initial are authored by the same individual, based on shared title words, journal name, co-authors, medical subject headings, language, and affiliation, as well as distinctive features of the name itself (i.e., presence of middle initial, suffix, and prevalence in Medline).

Linking investigators. A centralized linking facility for data sharing and coordination of samples in tissue banks.

Abstract: Many multifactorial diseases, such as various forms of cancer, diabetes, coronary heart disease and schizophrenia, still pose a considerable challenge for those researchers intent on understanding their causes. Some progress has been made in identifying the genes that contribute to such diseases and the availability of the sequence of the human genome holds further potential. However, scientists are still far from pinpointing the exact genetic causes of most major diseases that now plague humans in the developed world. Clinicians and epidemiologists have amassed a wealth of non‐genetic information, notably lifestyle and environmental factors, and with the rise of genomics, proteomics and imaging methods, banks holding tissue samples from patients have become an increasingly important and precious resource in medical research. However, the full value of all these efforts can only be realized by data sharing. A major problem is the fact that the data generated by researchers around the world are not easily available to those working in a related area. Although it has become considerably easier to identify relevant scientific publications, and to access gene or protein sequence data and analytical software, this unfortunately does not extend to primary data from studies and tissue banks. Indeed, scientists could gain valuable information if they had access to these primary data or to samples from their colleagues‘ studies. Current approaches, namely the pooling of diverse data in central databases and the formation of consortia between investigators, are fraught with the practical problems of data management, ownership of data and confidentiality. An alternative, as proposed in this Viewpoint, would be a centralized linking facility to issue anonymous ’linking numbers'. These would allow independent and autonomous research groups studying samples from the same subjects to be aware of each other, and to form voluntary and temporary collaborations for research on a specific problem. …

Knowledge Discovery in Medline and Other Databases.

Abstract: All neuroscientists are in the business of discovering knowledge about how the brain works. However, only a portion of time is spent in making new discoveries in the laboratory or clinic. An increasingly large task is to learn what has already been reported in the literature: either to assess an hypothesis and to plan out the best way to test it, or to keep abreast of new research trends, or simply to avoid rediscovering something already known. The days are gone when a person could keep up in neuroscience simply by scanning the pages of a few leading journals, or even by using alerting services such as Current

Informatics tools for scientific discovery and collaboration.

Abstract: Smalheiser NR, Swanson DR, Torvik VI, Palmer C, Cragin M, Hogan T, West R, Bischoff-Grethe A, Yu C. (presenters) Informatics tools for scientific discovery and collaboration. Arrowsmith Project short course, UIC Psychiatric Institute, September 3-5, 2003.