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PubMed2004

A versatile statistical analysis algorithm to detect genome copy number variation.

We have developed a versatile statistical analysis algorithm for the detection of genomic aberrations in human cancer cell lines. The algorithm analyzes genomic data obtained from a variety of array technologies, such as oligonucleotide array, bacterial artificial chromosome array, or array-based comparative genomic hybridization, that operate by hybridizing with genomic material obtained from cancer and normal cells and allow detection of regions of the genome with altered copy number. The number of probes (i.e., resolution), the amount of uncharacterized noise per probe, and the severity of chromosomal aberrations per chromosomal region may vary with the underlying technology, biological sample, and sample preparation. Constrained by these uncertainties, our algorithm aims at robustness by using a priorless maximum a posteriori estimator and at efficiency by a dynamic programming implementation. We illustrate these characteristics of our algorithm by applying it to data obtained from representational oligonucleotide microarray analysis and array-based comparative genomic hybridization technology as well as to synthetic data obtained from an artificial model whose properties can be varied computationally. The algorithm can combine data from multiple sources and thus facilitate the discovery of genes and markers important in cancer, as well as the discovery of loci important in inherited genetic disease.

Algorithms↗
PubMed2024

Tailored UPRE2 variants for dynamic gene regulation in yeast.

Genetic elements are foundational in synthetic biology serving as vital building blocks. They enable programming host cells for efficient production of valuable chemicals and recombinant proteins. The unfolded protein response (UPR) is a stress pathway in which the transcription factor Hac1 interacts with the upstream unfolded protein response element (UPRE) of the promoter to restore endoplasmic reticulum (ER) homeostasis. Here, we created a UPRE2 mutant (UPRE2m) library. Several rounds of screening identified many elements with enhanced responsiveness and a wider dynamic range. The most active element m84 displayed a response activity 3.72 times higher than the native UPRE2. These potent elements are versatile and compatible with various promoters. Overexpression of HAC1 enhanced stress signal transduction, expanding the signal output range of UPRE2m. Through molecular modeling and site-directed mutagenesis, we pinpointed the DNA-binding residue Lys60 in Hac1(Hac1-K60). We also confirmed that UPRE2m exhibited a higher binding affinity to Hac1. This shed light on the mechanism underlying the Hac1-UPRE2m interaction. Importantly, applying UPRE2m for target gene regulation effectively increased both recombinant protein production and natural product synthesis. These genetic elements provide valuable tools for dynamically regulating gene expression in yeast cell factories.

Saccharomyces cerevisiae↗
PubMed1998

Identification of Australian arboviruses in inoculated cell cultures using monoclonal antibodies in ELISA.

An ELISA using a panel of specific monoclonal antibodies was developed to identify all alpha and flaviviruses isolated from mosquitoes caught throughout Australia. This technique is sensitive and rapid and is more specific than the traditional methods used to identify flaviviruses. The ability to identify unknown virus isolates from field-caught mosquitoes quickly and accurately improves the efficiency of arbovirus surveillance programs and allows health authorities to give an early warning of an increased health risk from a mosquito-borne virus in a particular region.

Aedes↗
PubMed2006

Embryonic transcription factors in human breast cancer.

Growing evidence suggests that breast cancer cells often reactivate latent developmental programs in order to efficiently execute the multi-step process of tumorigenesis. This review focuses on key transcriptional regulators of embryonic development that are deregulated in breast cancer and discusses the molecular mechanisms by which these proteins control carcinogenesis. Reminiscent of their function during development, embryonic transcription factors regulate changes in gene expression that promote tumor cell growth, cell survival and motility, as well as a morphogenetic process called epithelial-mesenchymal transition (EMT), which is implicated in both breast metastasis and tumor recurrence. Because of their pivotal roles in breast tumor progression, these factors represent valuable new biomarkers for breast cancer detection as well as promising new targets for anti-invasive drugs.

Breast Neoplasms↗
PubMed2006

6 Weeks with the von Rosen splint is sufficient for treatment of neonatal hip instability.

BACKGROUND: There is no concensus on the optimal treatment time for unstable hips in the newborn. We analyzed the efficiency of a treatment program that has been used for 10 years at our hospital, in which all unstable hips (subluxatable, Barlow-positive and Ortolani-positive) are treated with the von Rosen splint for 6 weeks. PATIENTS AND METHODS: Between 1988 and 1997, 32,171 children were born alive at the hospital. During this period 247 children had a clinically unstable hip diagnosed. 223 of the 247 children underwent a radiographic follow-up after 5-15 years. RESULTS: 1 patient with bilateral instability and treated with a splint for 6 weeks showed a dislocated left hip at the radiographic examination at 8 months, which is part of the screening program, and needed operative treatment. 1 patient did not follow the treatment program and showed a dislocated hip at the age of 3. Another 4 patients required more treatment than the 6 weeks with the splint. We found no dysplastic hips at the radiographic follow-up. There was no late dysplasia and there were no late dislocations in children born in Lund between 1988 and 1997 who were diagnosed at other Swedish centers that treat developmental dysplasia of the hip (DDH). INTERPRETATION: We conclude that the present screening and 6-week treatment in a von Rosen splint prevent almost all cases of late dysplasia and late dislocation of the hip.

Adolescent↗
PubMed2006

First year of mandatory reporting of healthcare-associated infections, Pennsylvania: an infection control-chart abstractor collaboration.

BACKGROUND: In 2004, the Commonwealth of Pennsylvania mandated hospitals to report healthcare-associated infections (HAIs). The increased workload led our Infection Control staff to collaborate with Atlas, a group of chart abstractors. OBJECTIVE: The objective of this study was to assess our first year of experience with mandatory reporting of HAIs--specifically, to assess Atlas' contribution to surveillance. DESIGN: Cases were selected if they had 1 or more of the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes designated by Pennsylvania as a possible HAI. After training by the Infection Control staff, Atlas applied National Nosocomial Infection Surveillance (NNIS) system case definitions for catheter-associated urinary tract infections (UTIs) and surgical site infections (SSIs), and they applied NNIS chest imaging criteria to eliminate cases that were not ventilator-associated pneumonia (VAP). To assess Atlas' performance, Infection Control staff conducted a parallel review. RESULTS: For discharges from the hospital during the fourth quarter of 2004, a total of 410 UTIs, 59 SSIs, and 56 VAPs were identified on the basis of state-designated ICD-9-CM codes; review by Atlas/Infection Control determined that 15%, 15%, and 16% of cases met case definitions, respectively. Of cases reviewed by both Infection Control and Atlas, 87% of the assessments made by Atlas were correct for UTI, and 96% were correct for SSI. For VAP, Infection Control concluded that 39% of cases could be ruled out on the basis of chest imaging criteria; Atlas correctly dismissed these 12 cases but incorrectly dismissed an additional 6 (error, 19%). Surveillance was not timely: 1-2 months elapsed between the time of HAI onset and the earliest case review. CONCLUSIONS: With ongoing training by Infection Control, Atlas successfully demonstrated a role in retrospective HAI surveillance. However, despite a major effort to comply with mandates, time lags and other design limitations rendered the data of low utility for Infection Control. States that are planning HAI-reporting programs should standardize an efficient surveillance methodology that yields data capable of guiding interventions to prevent HAI.

Catheterization↗
PubMed2005

Estimating the proportion of disease due to classes of sufficient causes.

Disease can be caused by different mechanisms. A possible causal model proposed by Rothman is a complete causal mechanism or a so-called "sufficient cause" consisting of a set of component causes that can be illustrated in a pie chart. However, this model does not allow finding out what sufficient causes produce the majority of cases. The authors' objective was to extend Rothman's work by quantifying the proportion of disease that can be attributed to a class of sufficient causes. The underlying idea was to consider all combinations of a given set of known risk factors and to assign each combination to a class of sufficient causes. This assignment makes it possible to evaluate a class of sufficient causes by the population attributable fraction of the corresponding combination of risk factors. The approach presented was applied to sufficient causes of myocardial infarction by use of data on participants recruited between 1994 and 1998 into the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. As a result, 51.8% of cases were attributed to only four different classes of sufficient causes. In conclusion, the statistical method described in the paper may be beneficial for quantifying the importance of different sufficient causes and for improving the efficiency of public health programs.

Causality↗
PubMed2001

SCOPE: a probabilistic model for scoring tandem mass spectra against a peptide database.

Proteomics, or the direct analysis of the expressed protein components of a cell, is critical to our understanding of cellular biological processes in normal and diseased tissue. A key requirement for its success is the ability to identify proteins in complex mixtures. Recent technological advances in tandem mass spectrometry has made it the method of choice for high-throughput identification of proteins. Unfortunately, the software for unambiguously identifying peptide sequences has not kept pace with the recent hardware improvements in mass spectrometry instruments. Critical for reliable high-throughput protein identification, scoring functions evaluate the quality of a match between experimental spectra and a database peptide. Current scoring function technology relies heavily on ad-hoc parameterization and manual curation by experienced mass spectrometrists. In this work, we propose a two-stage stochastic model for the observed MS/MS spectrum, given a peptide. Our model explicitly incorporates fragment ion probabilities, noisy spectra, and instrument measurement error. We describe how to compute this probability based score efficiently, using a dynamic programming technique. A prototype implementation demonstrates the effectiveness of the model.

Amino Acid Sequence↗
PubMed1991

Designing a neural network simulator--the MENS modelling environment for network systems: II.

During recent years, neural network research has been extended to a large number of different fields, increasingly attracting the interest of workers from various disciplines. The computer simulations carried out with this research require an appropriate software environment. The computational similarities of many kinds of simulations allow the design of software components that are largely independent of the specific application. These considerations are reflected, for example, by the general layout of the MENS network simulator, as described in the accompanying first paper. This paper presents the design considerations for the simulator's different software components in more detail. In particular, design and implementation are discussed with respect to computational and memory efficiency. The discussion includes, for example, the representation of a network by the simulator's data structure, the file-driven configuration and initialization of a network, the simulator's stimulus and monitor system, and the simulator's control structures. In addition, the separation and interaction of application-specific and application-independent software components are addressed. Particular performance aspects comprise the implementation of synaptic delays, the dynamic deletion of synaptic links in network learning, and the preprocessing of stimulus films. In addition, some general aspects of simulator performance and testing are considered. The material presented in this paper concerns both the development of new simulation software and the efficient use of existing programs. Therefore, both the general user as well as the software designer may hopefully benefit from this presentation.

Animals↗
PubMed2001

A microsatellite-based genetic linkage map for channel catfish, Ictalurus punctatus.

Microsatellite loci were identified in channel catfish gene sequences or random clones from a small insert genomic DNA library. Outbred populations of channel catfish contained an average of eight alleles per locus and an average heterozygosity of 0.70. A genetic linkage map of the channel catfish genome (N = 29) was constructed from two reference families. A total of 293 microsatellite loci were polymorphic in one or both families, with an average of 171 informative meioses per locus. Nineteen type I loci, 243 type II loci, and one EST were placed in 32 multipoint linkage groups covering 1958 cM. Nine more type II loci were contained in three two-point linkage groups covering 24.5 cM. Twenty-two type II loci remained unlinked. Multipoint linkage groups ranged in size from 11.9 to 110.5 cM with an average intermarker distance of 8.7 cM. Seven microsatellite loci were closely linked with the sex-determining locus. The microsatellite loci and genetic linkage map will increase the efficiency of selective breeding programs for channel catfish.

Alleles↗
PubMed2001

Mergers involving academic health centers: a formidable challenge.

Escalating economic pressures on the clinical enterprise threaten the missions of education and research in many of the most prestigious academic health centers. Following the model of industry, mergers of the healthcare delivery systems of teaching hospitals and clinics held promise for economies of scale and an improved operating margin. Failure to follow business principles in constructing the merged entity, differences in organizational governance and culture, and inability of physician leadership to prioritize, downsize, and consolidate clinical programs to optimize operational efficiencies all compromise the success of such mergers in academic medicine. Academic institutions and their respective governing boards need to exercise greater discipline in financial analysis and a willingness to make difficult decisions that show favor to one parent institution over another if mergers are to be effective in this setting. To date, an example of a vibrant and successful merger of academic health centers remains to be found.

Academic Medical Centers↗
PubMed2005

Reliability of graded exercise testing after traumatic brain injury: submaximal and peak responses.

OBJECTIVE: To assess the reliability of the submaximal and peak responses to a treadmill graded exercise test in individuals recovering from traumatic brain injury. DESIGN: A total of 15 individuals (11 men, 4 women; 28.5 +/- 9.2 yrs) with moderate to severe traumatic brain injury admitted into a postacute residential treatment center 10 +/- 7 mos after injury performed two treadmill graded exercise tests separated by 4-8 days. Heart rate, oxygen consumption (in milliliters per minute per kilogram), minute ventilation (in liters per minute), and respiratory exchange ratio (carbon dioxide output/oxygen consumption) were continuously monitored at 1-min intervals. Submaximal and peak values were analyzed for absolute level of agreement using the intraclass correlation coefficient. RESULTS: The submaximal intraclass correlation coefficient values for all variables between minutes 3 and 7 ranged from 0.80 to 0.93. Submaximal intraclass correlation coefficients before and in the subsequent minutes were less than optimal for heart rate and minute ventilation. Lower intensity workloads elicited slightly better agreement than higher intensity workloads. The peak response intraclass correlation coefficients ranged from 0.77 (heart rate) to 0.92 (oxygen consumption). CONCLUSION: Despite the presence of other co-morbidities, subjects recovering from traumatic brain injury provided consistent individual responses, allowing for reliable assessments of cardiorespiratory conditioning programs. Assessments of ambulatory efficiency, endurance, and aerobic fitness adaptations as a result of treatment for persons with traumatic brain injury should include analyses of submaximal responses to graded exercise.

Adult↗
PubMed2003

Vaccination against rubella: analysis of the temporal evolution of the age-dependent force of infection and the effects of different contact patterns.

In this paper, we analyze the temporal evolution of the age-dependent force of infection and incidence of rubella, after the introduction of a very specific vaccination program in a previously nonvaccinated population where rubella was in endemic steady state. We deduce an integral equation for the age-dependent force of infection, which depends on a number of parameters that can be estimated from the force of infection in a steady state prior to the vaccination program. We present the results of our simulations, which are compared with observed data. We also examine the influence of contact patterns among members of a community on the age-dependent intensity of transmission of rubella and on the results of vaccination strategies. As an example of the theory proposed, we calculate the effects of vaccination strategies for four communities from Caieiras (Brazil), Huixquilucan (Mexico), Finland, and the United Kingdom. The results for each community differ considerably according to the distinct intensity and pattern of transmission in the absence of vaccination. We conclude that this simple vaccination program is not very efficient (very slow) in the goal of eradicating the disease. This gives support to a mixed strategy, proposed by Massad et al., accepted and implemented by the government of the State of São Paulo, Brazil.

Adolescent↗
PubMed2003

Developing wearable bio-feedback systems: a general-purpose platform.

Microprocessors, even those in PocketPCs, have adequate power for many real-time biofeedback applications for disabled people. This power allows design of portable or wearable devices that are smaller and lighter, and that have longer battery life compared to notebook-based systems. In this paper, we discuss a general-purpose hardware/software solution based on industrial or consumer devices and a C++ framework. Its flexibility and modularity make it adaptable to a wide range of situations. Moreover, its design minimizes system requirements and programming effort, thus allowing efficient systems to be built quickly and easily. Our design has been used to build two brain computer interface systems that were easily ported from the Win32 platform.

Biofeedback, Psychology↗
PubMed1992

Computer-assisted realignment of light micrograph images from consecutive section series of cat cerebral cortex.

Two computer- and image-analysis-based procedures for realignment of images of consecutive light micrographs of nerve tissue (cat motor cortex) have been developed. One procedure (CENT) was interactive, employing the subjective overall 'best fit' of two images to each other and the other (AUTOCENT) was based on an automatic comparison of two images (image thresholding and binary comparison). Images of light micrographs of several hundred consecutive sections were realigned using the interactive and the automatic methods. The interactive procedure was easy to use; realignment of an image took only a few minutes in the hands of an experienced operator and should be easy to implement on commercially available smaller computers like PCs and workstations, but the realignment was possibly disturbed by the operator's subjective expectancy of regular forms. The automatic procedure realigned 1-4 images per hour, might be implemented on smaller computers if the programming is made more efficient, was probably objective and restored the 'true position of images'.

Animals↗
PubMed2005

Brief report: if you build it, they will come: methods for recruiting Latinos into cancer research.

BACKGROUND: Latinos have low representation in cancer prevention trials and intervention studies. Culturally appropriate recruitment strategies are needed to address this issue. OBJECTIVE: To describe and summarize the effectiveness of recruitment strategies used by the Latin American Cancer Research Coalition (LACRC). DESIGN: Descriptive report of recruitment methods. PARTICIPANTS: Uninsured Latino immigrants (N=1,170; 77% female, 23% male) from Central and South America recruited to 7 cancer control studies. APPROACH: The LACRC recruitment model involved inclusion of Latino researchers and providers, and use of culturally acceptable materials released through culturally appropriate outlets such as Latino radio stations. RESULTS: The overall participation rate was high-96% of patients identified as eligible agreed to participate. Women were excellent referrals for recruiting men to research studies. Additionally, a local Latino radio program was used to efficiently recruit eligible study participants. CONCLUSIONS: Latinos are interested and willing to participate in cancer control studies when culturally relevant approaches are used. Research teams that partner with Latino researchers and with Latino service providers are important in educating Latinos about cancer control and encouraging participation in research.

Culture↗
PubMed1978

Congenital hypothyroidism in Sweden. Incidence and age at diagnosis.

A total number of 112 children with congenital hypothyroidism were diagnosed in all Children's Hospitals and Pediatric Wards in Sweden during the 7-year period 1969-1975. Since it may be assumed that all cases of congenital hypothyroidism, which were diagnosed during that period were seen in one of these hospitals, the incidence of congenital hypothyroidism in Sweden can be calculated to be 1:6900 live births. In spite of an efficient National Health Care Program for infants the diagnosis was delayed until after an age of three months in 52% of the cases. This fact supports the view that mass screening of newborns for congenital hypothyroidism has to be introduced in Sweden. However, the beneficial effects of such a program cannot be fully elucidated until it has been considered whether earlier instituted treatment would have improved the outcome of children in whom a diagnosis was made after 3 months of age.

Age Factors↗
PubMed2006

Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1.

Human acute myeloid leukemias with the t(8;21) translocation express the AML1-ETO fusion protein in the hematopoietic stem cell compartment and show impairment in erythroid differentiation. This clinical finding is reproduced in multiple murine and cell culture model systems in which AML1-ETO specifically interferes with erythroid maturation. Using purified normal human early hematopoietic progenitor cells, we find that AML1-ETO impedes the earliest discernable steps of erythroid lineage commitment. Correspondingly, GATA-1, a central transcriptional regulator of erythroid differentiation, undergoes repression by AML1-ETO in a nonconventional histone deacetylase-independent manner. In particular, GATA-1 acetylation by its transcriptional coactivator, p300/CBP, a critical regulatory step in programming erythroid development, is efficiently blocked by AML1-ETO. Fusion of a heterologous E1A coactivator recruitment module to GATA-1 overrides the inhibitory effects of AML1-ETO on GATA-1 acetylation and transactivation. Furthermore, the E1A-GATA-1 fusion, but not wild-type GATA-1, rescues erythroid lineage commitment in primary human progenitors expressing AML1-ETO. These results ascribe a novel repressive mechanism to AML1-ETO, blockade of GATA-1 acetylation, which correlates with its inhibitory effects on primary erythroid lineage commitment.

Acetylation↗