Amino acid position 11 of HLA-DRß1 is a major determinant of chromosome 6p association with ulcerative colitis.

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRß1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRß1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.

Genetic analysis of vertebral trabecular bone density and cross-sectional area in older men.

We investigated 383 bone candidate genes for associations between single nucleotide polymorphisms and vertebral trabecular volumetric bone mineral density (vBMD) and cross-sectional area (CSA) in 2,018 Caucasian men aged ≥ 65 years. SNPs in TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE were associated with vBMD and SNPs in CYP11B1, DVL2, DLX5, WNT4, and PAX7 were associated with CSA in independent study samples (p < 0.005). INRODUCTION: Vertebral bone mineral density and cross-sectional area are important determinants of vertebral bone strength. Little is known about the specific genetic variants that influence these phenotypes in humans. METHODS: We investigated the potential genetic variants associated with vertebral trabecular volumetric BMD and CSA measured by quantitative computed tomography. We initially tested for association between these phenotypes and 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes in 862 community-dwelling Caucasian men aged ≥ 65 years in the Osteoporotic Fractures in Men Study. RESULTS: SNP associations were then validated by genotyping an additional 1,156 randomly sampled men from the same cohort. We identified 11 SNPs in 10 genes (TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE) that were consistently associated with trabecular vBMD and five SNPs in five genes (CYP11B1, DVL2, DLX5, WNT4, and PAX7) that were consistently associated with CSA in both samples (p < 0.005). CONCLUSION: None of the SNPs associated with trabecular vBMD were associated with CSA. Our findings raise the possibility that at least some of the loci for vertebral trabecular BMD and bone size may be distinct.

Compliance to adjuvant therapy in breast cancer patients.

During recent years a continuous reduction of mortality from breast cancer has taken place in the Western countries. We wanted to verify whether the actual therapy for our own cases deviates from our recommendations, although the surgeon, radiotherapist and gynaecological oncologist are on the same premises. We sent out questionnaires to all newly diagnosed breast cancer patients in the last seven years regarding their adjuvant therapy. Comparing these answers to our own recommendation showed a very good compliance regarding chemotherapy and radiation therapy. Adjuvant endocrine therapy showed a very poor compliance with an adherence of 77%. Overall we can conclude that endocrine therapy causes many side-effects that seem to burden the patients. In combination with the duration of the therapy this causes a severe reduction in compliance and length of the therapy.

Auditory system of noctuid moths.

Insect-eating bats find their aerial food by sonar, through emitting ultrasonic chirps and locating sources of echoes. Certain moths have ears sensitive to these chirps and can detect bats well beyond the range of the bats' sonar. On hearing a distant bat, many moths turn and fly directly away from the source of ultrasound. Only one sense cell in each ear of a moth provides the primary nervous information for this response. This article describes my initial attempts to find out how a moth's central nervous system processes the train of chirps reaching its two ears. The ear of a restrained moth is exposed to a sequence of artifically generated ultrasonic pulses that approximates the cries made by a bat. This stimulus can be varied with respect to ultrasonic frequency (pitch), pulse intensity, pulse duration, the interval between pulses, and pulse-train duration. The more sensitive acoustic sense cell responds to all frequencies between about 15,000 and 80,000 cycles per second, but the signal that it transmits to the moth's central nervous system contains no measure of frequency within this range. However, this nerve signal reports variations in the other parameters of the stimulus. The acoustic fiber connects, in the central nervous system, with various nerve cells that transform the signal farther. The signal from a pulse-marker neuron contains no measures of pulse intensity or pulse duration, reporting only changes in interpulse interval and pulse-train duration. A train-marker neuron reports only the duration of the pulse train. The stimulus parameters may be likened to keys, each of which is necessary to gain admittance through a given door but becomes superfluous once this door has been passed. This analogy suggests one of the ways in which a signal is transformed in its passage through the nervous system, and how its specificity is assured in eliciting a given response. In addition to undergoing this kind of transformation, neural signals generated in the two directionally sensitive ears must be combined if a flying moth is to steer a course away from a distant bat. Neurons have been discovered in the central ganglia which summate signals from the right and left ears. Other neurons are inhibited in their activity by stimulation of one ear. The moth may combine signals from these neurons with motor-nerve information on the attitude of its own wings, which act as oscillating baffles modifying its directional acoustic sensitivity 20 to 40 times a second as it flaps an erratic path through the darkness.

A differential anemometer for measuring the turning tendency of insects in stationary flight.

A pair of thermistors forming part of a direct current bridge circuit was mounted in the wake of a moth in stationary flight. Differential changes in the thermistors' resistance provided a sensitive index of changes in the direction of the airstream as the insect made attempts to turn away from a source of ultrasonic pulses.

No excess of homozygosity at loci used for DNA fingerprinting.

Variable number of tandem repeat (VNTR) loci are extremely valuable for the forensic technique known as DNA fingerprinting because of their hypervariability. Nevertheless, the use of these loci in forensics has been controversial. One criticism of DNA fingerprinting is that the VNTR loci used for the "fingerprints" violate the assumption of Hardy-Weinberg equilibrium (H-W), making it difficult to calculate the probability of observing a genotype in the population. If one can assume H-W, the probability of observing the pair of alleles constituting an individual's genotype can be calculated by taking the product of the alleles' frequencies in the population and multiplying by two if the alleles are different. The evidence cited against assuming H-W is homozygote excess, which is presumed to be caused by an undetected mixture of two or more populations with limited interpopulational mating and distinct allele frequencies. For most VNTR loci, measurement error makes it impossible to test these claims by standard methods. The Lifecodes database of three VNTR loci used for forensics was used to show that the claimed excess of homozygotes is not necessarily real because many heterozygotes with similar allele sizes are misclassified as homozygotes. A simple test of H-W that takes such misclassifications into account was developed to test for an overall excess or dearth of heterozygotes in the sample (the complement of homozygote dearth or excess). The application of this test to the Lifecodes database revealed that there was no consistent evidence of violation of H-W for the Caucasian, black, or Hispanic populations.

Auditory sense in certain sphingid moths.

Moths of the genus Celerio, hovering and feeding from blossoms, have been observed to react vigorously to high-pitched sounds. The acoustic receptor appears to involve the labial palps. Its characteristics have been determined from responses made, when the moth is exposed to artificial sound pulses, by an interneuron originating in its head. These responses have been found only in 4 out of 19 sphingid species tested.

Distal lobe of the pilifer: an ultrasonic receptor in choerocampine hawkmoths.

Evidence is presented for a novel mechanism mediating the auditory sense in the Choerocampinae (Lepidoptera: Sphingidae). Vibrations in the scale-free medial wall of the enlarged labial palp segment are transmitted by contact to the distal lobe of the pilifer, a derivative of the labrum, and are there transduced into afferent impulses in the labral nerve.

A statistical model for locating regulatory regions in genomic DNA.

In addition to genes, chromosomal DNA contains sequences that serve as signals for turning on and off gene expression. These signals are thought to be distributed as clusters in the regulatory regions of genes. We develop a Bayesian model that views locating regulatory regions in genomic DNA as a change-point problem, with the beginning of regulatory and non-regulatory regions corresponding to the change points. The model is based on a hidden Markov chain. The data consist of nucleotide positions of protein-binding elements in a genomic DNA sequence. These positions are identified using a reference catalogue containing elements that interact with transcription factors implicated in controlling the expression of protein-encoding genes. Among the protein-binding elements in a genomic DNA sequence, the statistical model automatically selects those that tend to predict regulatory regions. We test the model using viral sequences that include known regulatory regions and provide the results obtained for human genomic DNA corresponding to the beta globin locus on chromosome 11.

Comments on the statistical aspects of the NRC's report on DNA typing.

The goal of the NRC report on DNA typing was to answer a "crescendo of questions concerning DNA typing," many of them in the areas of population genetics and statistics. Unfortunately, few of these questions were answered adequately. In lieu of answering these questions, the panel proposed another conservative method of forensic inference, the "ceiling principle." Aside from its extreme conservativeness, this new method is difficult to justify because it is based on inadequate population genetics and statistical theory. Moreover, in its ultimate implementation, the panel's method will depend on a population genetics study whose rationale is questionable. In this article, we elaborate some of the general comments we made about the NRC report in a recent article [1]. Specifically we cover three topics. First we question the statistical basis for the ceiling principle, showing that the empirical results that motivated the method are likely to be misinterpreted and showing, by power calculations, that the effects of population substructure cannot be substantial. Second, we show that the study design to determine "ceiling" allele frequencies has several undesirable statistical properties. Finally, we discuss the estimation of handling errors from the statistical perspective, a subject treated inadequately by the report.