CiteULike: Author Elmore

Adobe Flex 2: Training from the Source

Jeff Tapper — 2008-07-07T09:38:45-00:00

(23 October 2006)

Part of the Adobe Training from the Source series, the official curriculum from Adobe, developed by experienced trainers. Using project-based tutorials, this book/CD volume is designed to teach the techniques needed to create sophisticated, professional-level projects. Each book includes a CD that contains all the files used in the lessons, plus completed projects for comparison. This title covers the new development framework for Rich Internet Applications, Adobe Flex 2. In the course of the book, the reader will build several Web applications using Flex Builder and incorporating MXML and ActionScript 3.0.

Molecular dynamics simulation of a phosphatidylglycerol membrane.

Donald E Elmore — 2005-12-25T22:16:47-00:00

FEBS Lett (6 December 2005)

Although molecular dynamics simulations are an important tool for studying membrane systems, relatively few simulations have used anionic lipids. This paper reports the first simulation of a pure phosphatidylglycerol (PG) bilayer. The properties of this equilibrated palmitoyloleoylphosphatidylglycerol membrane agree with experimental observations of PG membranes and with previous simulations of monolayers and mixed bilayers containing PG lipids. These simulations also provide interesting insights into hydrogen bonding interactions in PG membranes. This equilibrated membrane will be a useful starting point for simulations of membrane proteins interacting with PG lipids.

The crystal structure of cytochrome P460 of Nitrosomonas europaea reveals a novel cytochrome fold and heme-protein cross-link.

AR Pearson — 2007-10-07T21:44:29-00:00

Biochemistry, Vol. 46, No. 28. (17 July 2007), pp. 8340-8349.

We have determined the 1.8 A X-ray crystal structure of a monoheme c-type cytochrome, cytochrome P460, from Nitrosomonas europea. The chromophore possesses unusual spectral properties analogous to those of the catalytic heme P460 of hydroxylamine oxidoreductase (HAO), the only known heme in biology to withdraw electrons from an iron-coordinated substrate. The analysis reveals a homodimeric structure and elucidates a new c-type cytochrome fold that is predominantly beta-sheet. In addition to the two cysteine thioether links to the porphyrin typical of c-type hemes, there is a third proteinaceous link involving a conserved lysine. The covalent bond is between the lysine side-chain nitrogen and the 13'-meso carbon of the heme, which, following cross-link formation, is sp3-hybridized, demonstrating the loss of conjugation at this position within the porphyrin. The structure has implications for the analogous tyrosine-heme meso carbon cross-link observed in HAO.

Addendum to: Elmore FA and Lackey D. Effectiveness of endovenous laser treatment in eliminating superficial venous reflux

Elmore — 2008-03-31T17:37:00-00:00

Phlebology, Vol. 23, No. 2. (April 2008), pp. 99-99.

Joint modeling of sensitivity and specificity.

Gavino Puggioni — 2008-03-16T00:51:08-00:00

Stat Med (2 January 2008)

Sensitivity and specificity are two customary performance measures associated with medical diagnostic tests. Typically, they are modeled independently as a function of risk factors using logistic regression, which provides estimated functions for these probabilities. Change in these probabilities across levels of risk factors is of primary interest and the indirect relationship is often displayed using a receiver operating characteristic curve. We refer to this as analysis of 'first-order' behavior. Here, we consider what we refer to as 'second-order' behavior where we examine the stochastic dependence between the (random) estimates of sensitivity and specificity. To do so, we argue that a model for the four cell probabilities that determine the joint distribution of screening test result and outcome result is needed. Such a modeling induces sensitivity and specificity as functions of these cell probabilities. In turn, this raises the issue of a coherent specification for these cell probabilities, given risk factors, i.e. a specification that ensures that all probabilities calculated under it fall between 0 and 1. This leads to the question of how to provide models that are coherent and mechanistically appropriate as well as computationally feasible to fit, particularly with large data sets. The goal of this article is to illuminate these issues both algebraically and through analysis of a real data set. Copyright (c) 2008 John Wiley & Sons, Ltd.

Confirming the Revised C-terminal Domain of the MscL Crystal Structure

Joshua Maurer — 2008-03-10T17:42:06-00:00

Biophys. J. (7 March 2008), biophysj.107.127365.

The structure of the C-terminal domain of the mechanosensitive channel of large conductance (MscL) has generated significant controversy. As a result, several structures have been proposed for this region: the original crystal structure (1MSL) of the M. tuberculosis homologue (Tb), a model of the E. coli homologue (Ec), and most recently a revised crystal structure of Tb-MscL (2OAR). In order to understand which of these structures represents a physiological conformation, we measured the impact of mutations to the C-terminal domain on the thermal stability of Tb-MscL using circular dichroism and performed molecular dynamics simulations of the original and the revised crystal structures of Tb-MscL. Our results imply that this region is helical and adopts an alpha-helical bundle conformation similar to that observed in the Ec-MscL model and the revised Tb-MscL crystal structure. 10.1529/biophysj.107.127365

Genome sequencing shows that European isolates of Francisella tularensis subspecies tularensis are almost identical to US laboratory strain Schu S4.

RR Chaudhuri — 2008-03-07T16:30:09-00:00

PLoS ONE, Vol. 2, No. 4. (2007)

BACKGROUND: Francisella tularensis causes tularaemia, a life-threatening zoonosis, and has potential as a biowarfare agent. F. tularensis subsp. tularensis, which causes the most severe form of tularaemia, is usually confined to North America. However, a handful of isolates from this subspecies was obtained in the 1980s from ticks and mites from Slovakia and Austria. Our aim was to uncover the origins of these enigmatic European isolates. METHODOLOGY/PRINCIPAL FINDINGS: We determined the complete genome sequence of FSC198, a European isolate of F. tularensis subsp. tularensis, by whole-genome shotgun sequencing and compared it to that of the North American laboratory strain Schu S4. Apparent differences between the two genomes were resolved by re-sequencing discrepant loci in both strains. We found that the genome of FSC198 is almost identical to that of Schu S4, with only eight SNPs and three VNTR differences between the two sequences. Sequencing of these loci in two other European isolates of F. tularensis subsp. tularensis confirmed that all three European isolates are also closely related to, but distinct from Schu S4. CONCLUSIONS/SIGNIFICANCE: The data presented here suggest that the Schu S4 laboratory strain is the most likely source of the European isolates of F. tularensis subsp. tularensis and indicate that anthropogenic activities, such as movement of strains or animal vectors, account for the presence of these isolates in Europe. Given the highly pathogenic nature of this subspecies, the possibility that it has become established wild in the heartland of Europe carries significant public health implications.

Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer

Julius Gudmundsson — 2008-02-27T13:30:58-00:00

Nature Genetics, Vol. 40, No. 3. (10 February 2008), pp. 281-283.

Distinct patterns of DeltaFosB induction in brain by drugs of abuse.

L I Perrotti — 2008-02-24T18:36:16-00:00

Synapse, Vol. 62, No. 5. (21 February 2008), pp. 358-369.

The transcription factor DeltaFosB accumulates and persists in brain in response to chronic stimulation. This accumulation after chronic exposure to drugs of abuse has been demonstrated previously by Western blot most dramatically in striatal regions, including dorsal striatum (caudate/putamen) and nucleus accumbens. In the present study, we used immunohistochemistry to define with greater anatomical precision the induction of DeltaFosB throughout the rodent brain after chronic drug treatment. We also extended previous research involving cocaine, morphine, and nicotine to two additional drugs of abuse, ethanol and Delta(9)-tetrahydrocannabinol (Delta(9)-THC, the active ingredient in marijuana). We show here that chronic, but not acute, administration of each of four drugs of abuse, cocaine, morphine, ethanol, and Delta(9)-THC, robustly induces DeltaFosB in nucleus accumbens, although different patterns in the core vs. shell subregions of this nucleus were apparent for the different drugs. The drugs also differed in their degree of DeltaFosB induction in dorsal striatum. In addition, all four drugs induced DeltaFosB in prefrontal cortex, with the greatest effects observed with cocaine and ethanol, and all of the drugs induced DeltaFosB to a small extent in amygdala. Furthermore, all drugs induced DeltaFosB in the hippocampus, and, with the exception of ethanol, most of this induction was seen in the dentate. Lower levels of DeltaFosB induction were seen in other brain areas in response to a particular drug treatment. These findings provide further evidence that induction of DeltaFosB in nucleus accumbens is a common action of virtually all drugs of abuse and that, beyond nucleus accumbens, each drug induces DeltaFosB in a region-specific manner in brain. Synapse 358-369, 2008. (c) 2008 Wiley-Liss, Inc.

Screening for breast cancer.

JG Elmore — 2007-09-11T02:45:52-00:00

JAMA, Vol. 293, No. 10. (9 March 2005), pp. 1245-1256.

CONTEXT: Breast cancer screening in community practices may be different from that in randomized controlled trials. New screening modalities are becoming available. OBJECTIVES: To review breast cancer screening, especially in the community and to examine evidence about new screening modalities. DATA SOURCES AND STUDY SELECTION: English-language articles of randomized controlled trials assessing effectiveness of breast cancer screening were reviewed, as well as meta-analyses, systematic reviews, studies of breast cancer screening in the community, and guidelines. Also, studies of newer screening modalities were assessed. DATA SYNTHESIS: All major US medical organizations recommend screening mammography for women aged 40 years and older. Screening mammography reduces breast cancer mortality by about 20% to 35% in women aged 50 to 69 years and slightly less in women aged 40 to 49 years at 14 years of follow-up. Approximately 95% of women with abnormalities on screening mammograms do not have breast cancer with variability based on such factors as age of the woman and assessment category assigned by the radiologist. Studies comparing full-field digital mammography to screen film have not shown statistically significant differences in cancer detection while the impact on recall rates (percentage of screening mammograms considered to have positive results) was unclear. One study suggested that computer-aided detection increases cancer detection rates and recall rates while a second larger study did not find any significant differences. Screening clinical breast examination detects some cancers missed by mammography, but the sensitivity reported in the community is lower (28% to 36%) than in randomized trials (about 54%). Breast self-examination has not been shown to be effective in reducing breast cancer mortality, but it does increase the number of breast biopsies performed because of false-positives. Magnetic resonance imaging and ultrasound are being studied for screening women at high risk for breast cancer but are not recommended for screening the general population. Sensitivity of magnetic resonance imaging in high-risk women has been found to be much higher than that of mammography but specificity is generally lower. Effect of the magnetic resonance imaging on breast cancer mortality is not known. A balanced discussion of possible benefits and harms of screening should be undertaken with each woman. CONCLUSIONS: In the community, mammography remains the main screening tool while the effectiveness of clinical breast examination and self-examination are less. New screening modalities are unlikely to replace mammography in the near future for screening the general population.

Discovery of a novel small molecule binding site of human survivin.

MD Wendt — 2008-01-10T12:03:40-00:00

Bioorg Med Chem Lett, Vol. 17, No. 11. (1 June 2007), pp. 3122-3129.

Survivin is one of the most tumor-specific genes in the human genome and is an attractive target for cancer therapy. However, small-molecule ligands for survivin have not yet been described. Thus, an interrogation of survivin which could potentially both validate a small-molecule therapy approach, and determine the biochemical nature of any of survivin's functions has not been possible. Here we describe the discovery and characterization of a small molecule binding site on the survivin surface distinct from the Smac peptide-binding site. The new site is located at the dimer interface and exhibits many of the features of highly druggable, biologically relevant protein binding sites. A variety of small hydrophobic compounds were found that bind with moderate affinity to this binding site, from which one lead was developed into a group of compounds with nanomolar affinity. Additionally, a subset of these compounds are adequately water-soluble and cell-permeable. Thus, the structural studies and small molecules described here provide tools that can be used to probe the biochemical role(s) of survivin, and may ultimately serve as a basis for the development of small molecule therapeutics acting via direct or allosteric disruption of binding events related to this poorly understood target.

Non-peptidic small molecule inhibitors of XIAP.

CM Park — 2008-01-04T12:32:35-00:00

Bioorg Med Chem Lett, Vol. 15, No. 3. (1 February 2005), pp. 771-775.

Non-peptidic small molecule SMAC mimetics were designed and synthesized that bind to the BIR3 domain of XIAP using structure-based design. Substituted five-membered heterocycles such as thiazoles and imidazoles were identified that serve as replacements for peptide fragments of the lead.

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.

TK Oost — 2005-01-10T13:05:38-00:00

J Med Chem, Vol. 47, No. 18. (26 August 2004), pp. 4417-4426.

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.

Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

M Bruncko — 2007-11-26T16:46:29-00:00

J. Med. Chem., Vol. 50, No. 4. (22 February 2007), pp. 641-662.

Abstract: Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Tilman Oltersdorf — 2005-05-16T16:53:57-00:00

Nature (15 May 2005)

Coordinating care across diseases, settings, and clinicians: a key role for the generalist in practice.

CJ Stille — 2007-09-11T03:04:15-00:00

Ann Intern Med, Vol. 142, No. 8. (19 April 2005), pp. 700-708.

Coordinated care is a defining principle of primary care, but it is becoming increasingly difficult to provide as the health care delivery system in the United States becomes more complex. To guide recommendations for research and practice, the evidence about implementation of coordinated care and its benefits must be considered. On the basis of review of the published literature this article makes recommendations concerning needs for a better-developed evidence base to substantiate the value of care coordination, generalist practices to be the hub of care coordination for most patients, improved communication among clinicians, a team approach to achieve coordination, integration of patients and families as partners, and incorporation of medical informatics. Although coordination of care is central to generalist practice, it requires far more effort than physicians alone can deliver. To make policy recommendations, further work is needed to identify essential elements of care coordination and prove its effectiveness at improving health outcomes.

Investigating Lipid Composition Effects on the Mechanosensitive Channel of Large Conductance (MscL) Using Molecular Dynamics Simulations

Donald Elmore — 2007-07-30T15:45:35-00:00

Biophys. J., Vol. 85, No. 3. (1 September 2003), pp. 1512-1524.

Previous experimental work has shown that the functional properties of the mechanosensitive channel of large conductance (MscL) are affected by variations in lipid composition. Here, we utilize molecular dynamics simulations of Mycobacterium tuberculosis MscL to investigate such lipid composition effects on a molecular level. In particular, two sets of simulations were performed. In the first, trajectories using lipids with different headgroups (phosphatidylcholine and phosphatidylethanolamine) were compared. Protein-lipid interactions were clearly altered by the headgroup changes, leading to conformational differences in the C-terminal region of M. tuberculosis MscL. In the second set of simulations, lipid tails were gradually shortened, thinning the membrane over a molecular dynamics trajectory. These simulations showed evidence of hydrophobic matching between MscL and the lipid membrane, as previously proposed. For all simulations, protein-lipid interaction energies in the second transmembrane region were correlated to mutagenic data, emphasizing the importance of lipid interactions for proper MscL function.

Apoptosis: a review of programmed cell death.

S Elmore — 2007-07-13T07:57:07-00:00

Toxicol Pathol, Vol. 35, No. 4. (2007), pp. 495-516.

The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

Specificity of clinical breast examination in community practice.

JJ Fenton — 2007-06-29T21:31:59-00:00

Journal of General Internal Medicine, Vol. 22, No. 3. (March 2007), pp. 332-337.

BACKGROUND: Millions of women receive clinical breast examination (CBE) each year, as either a breast cancer screening test or a diagnostic test for breast symptoms. While screening CBE had moderately high specificity (approximately 94%) in clinical trials, community clinicians may be comparatively inexperienced and may conduct relatively brief examinations, resulting in even higher specificity but lower sensitivity. OBJECTIVE: To estimate the specificity of screening and diagnostic CBE in clinical practice and identify patient factors associated with specificity. DESIGN: Retrospective cohort study. SUBJECTS: Breast-cancer-free female health plan enrollees in 5 states (WA, OR, CA, MA, and MN) who received CBE (N = 1,484). MEASUREMENTS: Medical charts were abstracted to ascertain breast cancer risk factors, examination purpose (screening vs diagnostic), and results (true-negative vs false-positive). Women were considered "average-risk" if they had neither a family history of breast cancer nor a prior breast biopsy and "increased-risk" otherwise. RESULTS: Among average- and increased-risk women, respectively, the specificity (true-negative proportion) of screening CBE was 99.4% [95% confidence interval (CI): 98.8-99.7%] and 97.1% (95% CI: 95.7-98.0%), and the specificity of diagnostic CBE was 68.7% (95% CI: 59.7-76.5%) and 57.1% (95% CI: 51.1-63.0%). The odds of a true-negative screening CBE (specificity) were significantly lower among women at increased risk of breast cancer (adjusted odds ratio 0.21; 95% CI: 0.10-0.46). CONCLUSIONS: Screening CBE likely has higher specificity among community clinicians compared to examiners in clinical trials of breast cancer screening, even among women at increased breast cancer risk. Highly specific examinations, however, may have relatively low sensitivity for breast cancer. Diagnostic CBE, meanwhile, is relatively nonspecific.

Delivery of IL-12 intranasally leads to reduced IL-12-mediated toxicity

Victor Huber — 2007-05-22T21:33:44-00:00

International Immunopharmacology, Vol. 3, No. 6. (June 2003), pp. 801-809.

Interleukin-12 (IL-12) is a heterodimeric cytokine that enhances immune responses to bacterial, parasitic, and viral pathogens, and leads to tumor regression in animal models. For this reason, the use of IL-12 as a vaccine adjuvant and as a therapeutic agent for the treatment of cancer is being investigated. Unfortunately, the extreme toxicity of this molecule observed during clinical trials has limited its use. This toxicity correlates with increased IFN-[gamma] expression, decreased glucose levels, and altered histological responses in the spleen and duodenum. In this study, we show that intranasal (i.n.) delivery of IL-12 is a less toxic route of inoculation compared to the commonly employed subcutaneous route. When delivered i.n., IL-12 induces less systemic IFN-[gamma] production and fewer pathological tissue changes, yet is efficacious, as indicated by enhanced CD3+ T cell activation and increased production of Th1-associated immunoglobulins (i.e., serum IgG2a). Thus, IL-12 can be delivered safely and effectively by the i.n. route, a finding which may allow IL-12 to fulfill its clinical potential.

Release from prison--a high risk of death for former inmates.

IA Binswanger — 2007-04-11T02:14:30-00:00

N Engl J Med, Vol. 356, No. 2. (11 January 2007), pp. 157-165.

BACKGROUND: The U.S. population of former prison inmates is large and growing. The period immediately after release may be challenging for former inmates and may involve substantial health risks. We studied the risk of death among former inmates soon after their release from Washington State prisons. METHODS: We conducted a retrospective cohort study of all inmates released from the Washington State Department of Corrections from July 1999 through December 2003. Prison records were linked to the National Death Index. Data for comparison with Washington State residents were obtained from the Wide-ranging OnLine Data for Epidemiologic Research system of the Centers for Disease Control and Prevention. Mortality rates among former inmates were compared with those among other state residents with the use of indirect standardization and adjustment for age, sex, and race. RESULTS: Of 30,237 released inmates, 443 died during a mean follow-up period of 1.9 years. The overall mortality rate was 777 deaths per 100,000 person-years. The adjusted risk of death among former inmates was 3.5 times that among other state residents (95% confidence interval [CI], 3.2 to 3.8). During the first 2 weeks after release, the risk of death among former inmates was 12.7 (95% CI, 9.2 to 17.4) times that among other state residents, with a markedly elevated relative risk of death from drug overdose (129; 95% CI, 89 to 186). The leading causes of death among former inmates were drug overdose, cardiovascular disease, homicide, and suicide. CONCLUSIONS: Former prison inmates were at high risk for death after release from prison, particularly during the first 2 weeks. Interventions are necessary to reduce the risk of death after release from prison.

Reactions to Uncertainty and the Accuracy of Diagnostic Mammography

Patricia Carney — 2007-01-23T12:08:50-00:00

Journal of General Internal Medicine

Patterns of Sociometric Choices: Transitivity Reconsidered

Scott Feld — 2006-10-16T21:04:21-00:00

Social Psychology Quarterly, Vol. 45, No. 2. (1982), pp. 77-85.

Social psychologists have consistently found that people choose friends of friends as their own friends more often than would be expected in random networks. However, most attempts to explain these findings have been based upon cognitive balance theory, and have paid little attention to other causes of clusters and/or individual variations in numbers of relations. This paper specifically shows how inequality of popularity among individuals implies disproportionate frequencies of particular types of triads, including transitive triad types. Counts of triad types provide evidence that inequality of popularity has predictable consequences for triad frequencies in many situations. Understanding causes of inequality and transitivity requires the study of the organization of clusters and popularity within a social context.

Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis.

AM Petros — 2006-09-05T19:41:33-00:00

J Med Chem, Vol. 49, No. 2. (26 January 2006), pp. 656-663.

The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-x(L) and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x(L) inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K(d)) of approximately 300 microM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x(L) with an inhibition constant (K(i)) of 36 +/- 2 nM.

Dating rupture events on alluvial fault scarps using cosmogenic nuclides and scarp morphology

Fred Phillips — 2006-04-24T22:50:07-00:00

Earth and Planetary Science Letters, Vol. 215, No. 1-2. (15 October 2003), pp. 203-218.

Scarp morphology evolution has commonly been used to estimate the timing of fault-scarp rupture events. However, rates of scarp degradation depend strongly on the geomorphic diffusivity, a parameter that is difficult to constrain independently. This difficulty may lead to large uncertainties in the estimated ages of rupture events. In this study, we have coupled the accumulation of the cosmogenic nuclide 36Cl to a model for scarp morphology in order to constrain the value of the geomorphic diffusivity and thus determine a more accurate rupture chronology than a rupture history based solely on scarp morphology. We measured depth profiles of 36Cl accumulated in situ within alluvial sediments beneath the surface of the Socorro Canyon fault scarp in central New Mexico. The material analyzed consisted of ~150 individual gravel clasts from each depth interval, amalgamated into a single sample. The alluvium was sampled in three vertical profiles ~4 m deep. The first profile was ~1.5 m downslope of the fault plane on the hanging wall, the second ~1.5 m upslope of the fault plane on the footwall, and the third ~27 m upslope of the fault plane on the footwall. The third profile, which served as a control, and which soil geomorphic evidence indicated was beneath a stable surface, showed a simple exponential 36Cl profile from which a depositional age of 122+/-18 ka was calculated. The second profile (on the footwall) showed a 36Cl deficit relative to the control profile, indicating net erosion. The first profile (on the hanging wall) showed a 36Cl excess relative to the control profile, indicating net deposition. Stratigraphic evidence in the hanging wall indicated two rupture events prior to the Late Holocene. We modeled the accumulation of 36Cl in the vicinity of the scarp, simulating erosional redistribution using a diffusion equation for scarp morphology. The model accounted for redistribution of 36Cl along with the sediment and the effects of the changing fault-scarp morphology on the 36Cl production. By matching both the observed hanging-wall and footwall 36Cl profiles to profiles calculated by the model, as well as the observed topographic profile, we obtained ages of 92+16-13 and 28+18-23 ka for the two ruptures. The results of our study indicate that cosmogenic nuclides can be useful in constraining rupture chronologies of fault scarps in alluvium.

Targeted mutation of a Drosophila odor receptor defines receptor requirement in a novel class of sensillum.

T Elmore — 2005-07-28T15:16:43-00:00

J Neurosci, Vol. 23, No. 30. (29 October 2003), pp. 9906-9912.

In vertebrates, individual olfactory neurons are thought to express a single odorant receptor (Or) gene, but it is not clear that all odor-evoked activity in each neuron is exclusively dependent on an individual odorant receptor. In Drosophila, little is known about what receptors impart odor sensitivity to particular olfactory neurons. Here, we demonstrate the use of gene targeting to produce a null mutant of the putative odorant receptor Or43b and find that the mutant is defective for odor-evoked activity in ab8A neurons, a single functional class of olfactory neurons in Drosophila. ab8A neurons lacking Or43b are still present in the mutants and display spontaneous activity but are insensitive to odor stimulation. Therefore, Or43b is required for odor responsiveness in these olfactory neurons in vivo. Or83b, a receptor expressed in a large fraction of olfactory neurons including Or43b neurons, does not confer odor responsiveness in the absence of Or43b. Olfactory behavior elicited by odorants that activate the ab8A neurons is indistinguishable between Or43b mutants and controls, demonstrating a surprising degree of functional redundancy among the limited odor receptor repertoire in this species. These studies demonstrate that a reverse genetic approach can be used to correlate specific olfactory receptors with odor specificity of functional classes of olfactory neurons.

Variability in radiologists' interpretations of mammograms.

JG Elmore — 2005-06-09T18:52:18-00:00

N Engl J Med, Vol. 331, No. 22. (1 December 1994), pp. 1493-1499.

BACKGROUND. Despite the proved value of mammography in screening for breast cancer, its efficacy depends on radiologists' interpretations. The variability in such interpretations is not well understood. METHODS. Using a technique of stratified random sampling, we selected 150 mammograms obtained in 1987: 27 from women with histopathologically confirmed breast cancer and 123 from women with no evidence of breast cancer after three years of follow-up examinations. Ten radiologists, who were unaware of the diagnoses and research hypothesis, each interpreted the 150 mammograms. Disagreement was analyzed within pairs of the 10 radiologists, as well as for the group of 150 women as a whole. RESULTS. The diagnostic consistency between pairs of radiologists was moderate, with a median weighted percentage of agreement of 78 percent (weighted kappa, 0.47). The frequency of the radiologists' recommendations for an immediate workup ranged from 74 to 96 percent for mammograms from the women with cancer and from 11 to 65 percent for films from the women without cancer. A substantial disagreement in management recommendations--in which one radiologist recommended routine follow-up and another recommended a biopsy for the same patient--occurred in 3 percent of the pairwise comparisons but in 25 percent of the comparisons for the group of women as a whole. When two or more radiologists recommended a biopsy for the same patient, a disagreement in the stated location (right or left breast) occurred in 2 percent of the pairwise comparisons among the radiologists but in 9 percent of comparisons for the group of women as a whole. Because some disagreement was likely, given that 10 radiologists read each film, the pairwise comparison is a more conservative estimate of disagreement. CONCLUSIONS. Although mammography is of value in screening women for breast cancer, radiologists can differ, sometimes substantially, in their interpretations of mammograms and in their recommendations for management. Efforts to improve accuracy and reduce variability in interpretation may increase the effectiveness of mammography in detecting early breast cancers.

Idiopathic scrotal elephantiasis

Brad Hornberger — 2005-04-02T05:41:35-00:00

Urology, Vol. 65, No. 2. (February 2005), pp. 389-389.

Scrotal lymphedema (scrotal elephantiasis) is a condition that has historically been described in areas endemic to filariasis. We present a unique case of a 22-year-old man with idiopathic lymphedema isolated to the scrotum. After acquired causes of lymphedema were ruled out, the patient was treated with scrotectomy and scrotal reconstruction.