Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test.

Dopaminergic abnormalities are implicated in the pathogenesis of Tourette syndrome (TS) and chronic multiple tics. We used the transmission-disequilibrium test (TDT) method to test for linkage disequilibrium between a specific allele (the seven-repeat allele (DRD4*7R) of the exon 3 VNTR polymorphic site) at the D4 dopamine receptor locus (DRD4) and expression of chronic multiple tics and TS. This particular allele had been shown in functional studies to have different binding properties compared with the other common alleles in this DRD4 polymorphic system. We studied 64 family trios (consisting of an affected person and two parents, at least one heterozygous for DRD4*7R), including 12 nuclear family trios and 52 trios from four large TS kindreds. The DRD4*7R allele was transmitted significantly more frequently than expected (chi 2 TDT ranging from 8.47 [P < .004] to 10.80 [P = .001], depending on breadth of disease definition and inclusion or exclusion of inferred genotypes). Confirmation of this finding will depend on either replication in other samples or the identification of a transmitted functional mutation within this sample.     

Reduced space sequence alignment

Motivation: Sequence alignment is the problem of finding theoptimal character-by-character correspondence between two sequences.It can be readily solved in O(n²) time and O(n²) space on aserial machine, or in O(n) time with O(n) space per O(n) processingelements on a parallel machine. Hirschberg's divide-and-conquerapproach for finding the single best path reduces space useby a factor of n while inducing only a small constant slowdownto the serial version. Results: This paper presents a family of methods for computingsequence alignments with reduced memory that are well suitedto serial or parallel implementation. Unlike the divide-and-conquerapproach, they can be used in the forward-backward (Baum-Welch)training of linear hidden Markov models, and they avoid data-dependentrepartitioning, making them easier to parallelize. The algorithmsfeature, for an arbitrary integer L, a factor proportional toL slowdown in exchange for reducing space requirement from O(n²)to O(n). A single best path member of this algorithm familymatches the quadratic time and linear space of the divide-and-conqueralgorithm. Experimentally, the O(n1.5)-space member of the familyis 15–40% faster than the O(n)-space divide-and-conqueralgorithm. Availability: The methods will soon be incorporated in the SAMhidden Markov modeling package http: //www.cse.ucs-c.edu/research/compbio/sam.html. Contact: wzrph{at}cse.ucsc.edu     

Nest survival,causes of failure and productivity of British Hawfinches Coccothraustes coccothraustes

Capsule: Nest success rate of Hawfinches Coccothraustes coccothraustes within our study areas averaged 36% across five seasons, a level unlikely to be driving population declines and considerably higher than was suggested by recent estimates from the long-term Nest Record Scheme.

Aims: To investigate potential habitat correlates of nest success and identify nest predators from an intensive study on Hawfinches. To compare nest success and habitat of these nests with those found by Nest Record Scheme (NRS) recorders and test whether there is evidence of a decline in nest success over time from the NRS data.

Methods: Females trapped at feed sites were fitted with radio-tags and tracked back to nest sites providing a sample of nests for subsequent monitoring. Habitat measures potentially influencing survival were collected at nest sites and modelled against nest outcome. Nest success was compared with that from the long-term Nest Record Scheme. Nest cameras were deployed to identify predators.

Results: Nest success varied among years, but the mean value was not substantially lower than other Hawfinch studies or from other species with similar nesting strategies. Apparent recent declines in success suggested by Nest Record Scheme data were not evident in our study areas. Only avian species were recorded predating nests and a number of partial predations were recorded. No correlation was found between overall success for study nests and the habitat or temporal measurements collected.

Conclusions: Within our study areas, average Hawfinch nest success and productivity appeared to be sufficient to maintain local population stability though our sample size was modest and further work would be beneficial. General nest recording may have inherent biases that lead to an over-estimation of nest failure compared to those found by more structured study. Drivers of recent UK Hawfinch declines may be operating outside of the nesting season and/or in landscapes outside primary woodland.     

The Interplay between Myc and CTP Synthase in Drosophila

CTP synthase (CTPsyn) is essential for the biosynthesis of pyrimidine nucleotides. It has been shown that CTPsyn is incorporated into a novel cytoplasmic structure which has been termed the cytoophidium. Here, we report that Myc regulates cytoophidium formation during Drosophila oogenesis. We have found that Myc protein levels correlate with cytoophidium abundance in follicle epithelia. Reducing Myc levels results in cytoophidium loss and small nuclear size in follicle cells, while overexpression of Myc increases the length of cytoophidia and the nuclear size of follicle cells. Ectopic expression of Myc induces cytoophidium formation in late stage follicle cells. Furthermore, knock-down of CTPsyn is sufficient to suppress the overgrowth phenotype induced by Myc overexpression, suggesting CTPsyn acts downstream of Myc and is required for Myc-mediated cell size control. Taken together, our data suggest a functional link between Myc, a renowned oncogene, and the essential nucleotide biosynthetic enzyme CTPsyn.     

Ribonuclease H/DNA Polymerase HIV-1 Reverse Transcriptase Dual Inhibitor: Mechanistic Studies on the Allosteric Mode of Action of Isatin-Based Compound RMNC6

The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC₅₀ values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC₅₀ in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT.