A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Self-administration of psychoactive substances by the monkey

A method has been developed which permits monkeys to self-administer drug solutions, at will, through indwelling intravenous catheters. Psychological dependence on the effects of a drug occurs when a naive monkey voluntarily initiates and maintains self-administration of the drug. If, in addition to psychological dependence, the drug also produces psychotoxicity, either directly or upon abrupt withdrawal, it has a potential abuse liability.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46354/1/213_2004_Article_BF00405254.pd

Determinants of Bacteriophage 933W Repressor DNA Binding Specificity

We reported previously that 933W repressor apparently does not cooperatively bind to adjacent sites on DNA and that the relative affinities of 933W repressor for its operators differ significantly from that of any other lambdoid bacteriophage. These findings indicate that the operational details of the lysis-lysogeny switch of bacteriophage 933W are unique among lambdoid bacteriophages. Since the functioning of the lysis-lysogeny switch in 933W bacteriophage uniquely and solely depends on the order of preference of 933W repressor for its operators, we examined the details of how 933W repressor recognizes its DNA sites. To identify the specificity determinants, we first created a molecular model of the 933W repressor-DNA complex and tested the predicted protein-DNA interactions. These results of these studies provide a picture of how 933W repressor recognizes its DNA sites. We also show that, opposite of what is normally observed for lambdoid phages, 933W operator sequences have evolved in such a way that the presence of the most commonly found base sequences at particular operator positions serves to decrease, rather than increase, the affinity of the protein for the site. This finding cautions against assuming that a consensus sequence derived from sequence analysis defines the optimal, highest affinity DNA binding site for a protein

Cooperative versus Conflictive Problem Solving in Three Telecommunication Modes

48 two-person teams communicated through channels simulating various modes of telecommunication, teletypewriter, telephone, and closed-circuit television, and, as a control, face-to-face conversation. Each team was required to solve one of four problems. Two cooperative problems, a class scheduling and a geographic orientation problem, required the mutual exchange of factual information to reach the unique problem solution. Two conflictive problems, an issue ranking and a budget negotiation problem, were formulated to engender contention between the two team members. Performance was assessed on three classes of dependent measures: time to solution, behavioral measures of activity, and measures of verbal productivity. Additionally, the protocols and outcomes of the conflictive problem-solving sessions were examined to arrive at a measure of the degree of persuasion exhibited by the two communicators. For both kinds of problem solving, there was a sharp dichotomy in performance, on all three classes of dependent variable, between the teletypewriter mode and the other three modes all of which had a voice channel. Solutions to all problems in the voice modes were much faster but at the same time far more verbose than those in the teletypewriter mode. The addition of a visual channel to a voice mode does not appreciably decrease solution times, nor does it matter whether the visual channel is “live,” that is, face-to-face, or mediated by a closed-circuit television system. For the most part, mode effects were robust and held for all problems. The characteristics of the several modes of communication were largely independent of the kind of task assigned to the teams of subjects. </jats:p

Potential morphogens involved in pattern formation during <i>Dictyostelium</i> differentiation

Upon starvation, Dictyostelium amoebae aggregate together and then differentiate into either the stalk or spore cells that, respectively, form the stalk and sorus of the fruiting body. During differentiation, the prestalk and prespore cells become spatially segregated in a clearly defined developmental pattern. Several low molecular weight molecules that influence cell type determination during in vitro differentiation have been identified. The possible role of these molecules as morphogens, responsible for the formation of the developmental pattern, is discussed.Key words: development, pattern formation, morphogen, Dictyostelium differentiation. </jats:p

Studies on the unmasking of membrane-bound alkaline phosphatase during the differentiation of <i>Dictyostelium discoideum</i>

Evidence has been presented recently to suggest that the 5′-nucleotidase and alkaline phosphatase activities of culmination phase cells of Dictyostelium discoideum are due to a single protein. However, we find that the membrane bound 5′-nucleotidase activity is only marginally activated by either 50 °C treatment or by dialysis, conditions that markedly activate alkaline phosphatase activity. In contrast, the 5′-nucleotidase activity of Triton X-100 extracts is activated by dialysis to the same extent as alkaline phosphatase activity. The available evidence suggests that, although a single protein is responsible for both alkaline phosphatase and 5′-nucleotidase activities, the characteristics of binding of the two substrates p-nitrophenyl phosphate and AMP to this enzyme are somewhat different. The alkaline phosphatase activity of dialyzed vegetative cell membranes is inhibited by the addition of concentrated dialyzate and this inhibition is reversed by further dialysis. The culmination phase enzyme is also inhibited by concentrated dialyzate from vegetative cells, suggesting that the removal of inhibitor from the enzyme can completely account for the developmental regulation. Dialyzates from culmination phase membranes do not inhibit enzyme activity, indicating the absence of inhibitor in these preparations. Alkaline phosphatase and 5′-nucleotidase activities of a partially purified enzyme preparation are equally inhibited by the addition of the concentrated dialyzate. </jats:p