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Preparation of oligonucleotide arrays for hybridization studies: Final report, 2/15/92-5/4/96: We have developed several novel ways to prepare DNA. In each, the deprotection step in each synthesis cycle is accomplished with light. The group we developed for this process is dimethoxybenzoin (DMB) which, when attached to acidic functionalities, is readily removed with long wavelength (350nm) UV irradiation that will not damage the DNA bases.
Immunological memory is associative: The purpose of this paper is to show that immunological memory is an associative and robust memory that belongs to the class of sparse distributed memories. This class of memories derives its associative and robust nature by sparsely sampling the input space and distributing the data among many independent agents. Other members of this class include a model of the cerebellar cortex and Sparse Distributed Memory (SDM). First we present a simplified account of the immune response and immunological memory. Next we present SDM, and then we show the correlations between immunological memory and SDM. Finally, we show how associative recall in the immune response can be both beneficial and detrimental to the fitness of an individual.
Identifying features in biological sequences: Sixth workshop report: This report covers the sixth of an annual series of workshops held at the Aspen Center for Physics concentrating particularly on the identification of features in DNA sequence, and more broadly on related topics in computational molecular biology. The workshop series originally focused primarily on discussion of current needs and future strategies for identifying and predicting the presence of complex functional units on sequenced, but otherwise uncharacterized, genomic DNA. We addressed the need for computationally-based, automatic tools for synthesizing available data about individual consensus sequences and local compositional patterns into the composite objects (e.g., genes) that are -- as composite entities -- the true object of interest when scanning DNA sequences. The workshop was structured to promote sustained informal contact and exchange of expertise between molecular biologists, computer scientists, and mathematicians.
Bifunctional chelates of Rh-105 and Au-199 as potential radiotherapeutic agents: Since last year we have (1) Investigated the production of Rh-105 by the Szilard-Chalmers process using Ru(acac){sub 3} targets, (2) Synthesized several new ligands and their rhodium complexes, (3) Done preliminary studies of the radiochemical properties of some of these complexes of Rh-105 at 10{sup -4} -10{sup -3} M concentration, and (4) Done preliminary animal studies on one of the complexes.
Sequential cloning of chromosomes: A method for sequential cloning of chromosomal DNA and chromosomal DNA cloned by this method are disclosed. The method includes the selection of a target organism having a segment of chromosomal DNA to be sequentially cloned. A first DNA segment, having a first restriction enzyme site on either side. homologous to the chromosomal DNA to be sequentially cloned is isolated. A first vector product is formed by ligating the homologous segment into a suitably designed vector. The first vector product is circularly integrated into the target organism`s chromosomal DNA. The resulting integrated chromosomal DNA segment includes the homologous DNA segment at either end of the integrated vector segment. The integrated chromosomal DNA is cleaved with a second restriction enzyme and ligated to form a vector-containing plasmid, which is replicated in a host organism. The replicated plasmid is then cleaved with the first restriction enzyme. Next, a DNA segment containing the vector and a segment of DNA homologous to a distal portion of the previously isolated DNA segment is isolated. This segment is then ligated to form a plasmid which is replicated within a suitable host. This plasmid is then circularly integrated into the target chromosomal DNA. The chromosomal DNA containing the circularly integrated vector is treated with a third, retrorestriction enzyme. The cleaved DNA is ligated to give a plasmid that is used to transform a host permissive for replication of its vector. The sequential cloning process continues by repeated cycles of circular integration and excision. The excision is carried out alternately with the second and third enzymes.
ANNUAL REPORT, JULY 1, 1960: Research facilities, general construction progress, research activities, and administration are discussed and a financial statement is given. Fairly detailed accounts are given of research programs in the fields of physics, accelerator development, instrumentation, applied mathematics, chemistry, nuclear engineering, biology, and medicine. (M.C.G.)
Plant biochemistry course, 1993: This paper provides a brief description of a summer lecture course on metabolic pathways and regulation of flow through these pathways in plants. Descriptions of the 1992 course held at La Jolla,Ca; 1993 course held in Madison, Wis, and plans for the 1994 course projected for East Lansing, MI.
Measurement of personal exposure to environmental tobacco smoke in the United States: A study of personal exposure of non-smokers to environmental tobacco smoke (ETS) has been conducted in 16 cities in the United States. Individual participants wear one of two personal sampling pumps, one each at work and away-from-work. Samples of breathing zone air analyzed for both particle- and vapor-phase markers of ETS. In addition, prior- and post-exposure saliva samples are collected, in order that smoking status can be assessed through cotinine levels. The distribution of subjects among smoking and non-smoking workplaces and homes is such that ca. 54% of the participants worked and lived in non-smoking situations. A comparison of the demographic distribution of the sample population with that of the US non-smoking population indicates that the sample population is more female and of higher socioeconomic status. Subjects living and working with smokers are more highly exposed to ETS than those subjects who live and work in predominantly ETS-free environments. However, even the smoke exposures of subjects living and working in smoking venues are low relative to area concentrations of ETS reported in previous studies. It is clear that in general (not considering cell designation), ETS exposure is inversely correlated with household income. Additional data analysis has indicated that although participants perceive their greatest exposures to ETS to occur in the workplace, in fact, exposure to ETS when living with a smoker is demonstrably greater than that received in a smoking workplace, on an individual basis, correlation between salivary cotinine levels and ETS nicotine exposure was non-existent. However, there appears to be significant correlation between the two parameters when participants with measurable exposures are segregated into groups of 25.
Microbial acquisition of iron from ferric iron bearing minerals: This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). Iron is a universal requirement for all life forms. Although the fourth most abundant element in the geosphere, iron is virtually insoluble at physiological pH in oxidizing environments, existing mainly as very insoluble oxides and hydroxides. Currently it is not understood how iron is solubilized and made available for biological use. This research project addressed this topic by conducting a series of experiments that utilized techniques from both soil microbiology and mineral surface geochemistry. Microbiological analysis consisted of the examination of metabolic and physiological responses to mineral iron supplements. At the same time mineral surfaces were examined for structural changes brought about by microbially mediated dissolution. The results of these experiments demonstrated that (1) bacterial siderophores were able to promote the dissolution of iron oxides, (2) that strict aerobic microorganisms may use anaerobic processes to promote iron oxide dissolution, and (3) that it is possible to image the surface of iron oxides undergoing microbial dissolution.
Human Genome Diversity Project. Summary of planning workshop 3(B): Ethical and human-rights implications: The third planning workshop of the Human Genome Diversity Project was held on the campus of the US National Institutes of Health in Bethesda, Maryland, from February 16 through February 18, 1993. The second day of the workshop was devoted to an exploration of the ethical and human-rights implications of the Project. This open meeting centered on three roundtables, involving 12 invited participants, and the resulting discussions among all those present. Attendees and their affiliations are listed in the attached Appendix A. The discussion was guided by a schedule and list of possible issues, distributed to all present and attached as Appendix B. This is a relatively complete, and thus lengthy, summary of the comments at the meeting. The beginning of the summary sets out as conclusions some issues on which there appeared to be widespread agreement, but those conclusions are not intended to serve as a set of detailed recommendations. The meeting organizer is distributing his recommendations in a separate memorandum; recommendations from others who attended the meeting are welcome and will be distributed by the meeting organizer to the participants and to the Project committee.
Small genomes: New initiatives in mapping and sequencing. Workshop summary report: The workshop was held 5--7 July 1993 at the Center for Advanced Research in Biotechnology (CARB) and hosted by the University of Maryland Biotechnology Institute (UMBI) and the National Institute of Standards and Technology (NIST). The objective of this workshop was to bring together individuals interested in DNA technologies and to determine the impact of these current and potential improvements of the speed and cost-effectiveness of mapping and sequencing on the planning of future small genome projects. A major goal of the workshop was to spur the collaboration of more diverse groups of scientists working on this topic, and to minimize competitiveness as an inhibitory factor to progress.
Regulation of terpene metabolism. Final technical report, March 15, 1988--March 14, 1996: This research focuses on the following topics: the biosynthesis and catabolism of monoterpenes; the organization of monoterpene metabolism; the developmental regulation of monoterpene metabolism; the flux control of precursor supply; and the integration of monoterpene and higher terpenoid metabolism.
Automatic feature extraction and classification from digital x-ray images. Final report, period ending 1 May 1995: This investigation focused on automatic recognition of features in medical x-ray images by using a Sobel based algorithm.
The reference individual of radiation protection: The 70-kg {open_quotes}standard man{close_quotes} representing a typical Western adult male has been used in physiological models since at least the 1920s. In 1949 at the Chalk River conference, health physicists from the U.S., UK, and Canada agreed on the concept of a standard man to facilitate comparison of internal dose estimates. The 70-kg standard man included specifications of the masses of 25 organs and tissues, total body content of 15 elements, total water intake and output, water content of the body, and some anatomical and physiological data for the respiratory and gastrointestinal tracts. In 1959, in its Publication 2{sup 2} on permissible doses for internal radiation the International Commission on Radiological Protection (ICRP) modified standard man. In 1963 the ICRP established a task group to revise and extend the standard man concept. The name was changed later to Reference Man and the task group`s work was published in 1975 as ICRP Publication 23{sup 3}. Publication 23 similar to Publication 2, updates and documents the sources of the data. Data on women, children, and fetuses were also collected, where available, but these data were limited primarily to anatomical data and only a few reference values were established for these groups. Information assembled during the course of the effort on the Reference Man report was used at Oak Ridge National Laboratory (ORNL) to construct a mathematical representation of the body (a phantom) that was suitable for use with Monte Carlo methods in the calculation of organ doses. That effort was undertaken to improve estimates of dose from photon-emitting radionuclides residing within organs, so-called internal emitters. The phantom, although updated throughout the years, remains today as the basis for organ dose estimates in nuclear medicine and radiation protection and underlies the radiation risk data derived from the epidemiologic studies of the atomic bomb …
Considerations for patient positioning in static beams for BNCT: The objective of this short communication is to provide a guideline for patient positioning, verification, and immobilization for boron neutron capture therapy.
Research symposium proceedings. Final report: THE research symposium was organized to present the cutting edge research for PET by individuals from leading institutions throughout the world. The Institute for Clinical PET (ICP) has focused its annual meeting on the clinical applications of PET.
Further Studies on the Relationship Between Exposure Time and Depth of Damage of Moderate and Severe Cutaneous Burns: To extend our earlier studies on the relationship between exposure time and depth of damage of moderate and severe burns, injuries were produced by each of six radiant exposures delivered during varying exposure times. The exposures investigated were: 5, 8, 10, 13, 16, and 20 calories per square centimeter. Within this range, as the radiant exposure increased, the exposure time for the production of maximum damage also increased. Injury from a given radiant exposure was less with exposure times either longer or shorter than some immediate time which led to the most severe injury. The relationship between steam bleb formation and decreased depth of injury from short exposure times is pointed out. When the superficial layers of the skin become so hot that vaporization of tissue fluid occurs, energy which might otherwise damage the deep layers is diverted by the conversion of water to steam. For radiant exposures between 8 cal/cm/sup 2/ and 20 cal/cm/sup 2/ delivered with a square pulse, it is possible to predict with fair accuracy the exposure time which will result in the deepest burn. (auth)
[Genome plasticity and catabolic potential of pseudomonas cepacia]. Progress report: This progress report describes efforts directed at understanding the genomic structure of Pseudomonas cepacia. Variously reported are descriptions of the replicons in the genome, organization of macrorestriction fragments comprising the genome, use of a Tn-5- 751S to insertionally inactivate and map selected genes, construction of IS407 derivatives containing a trimethoprim resistance marker and SwaI site, and analysis of nucleotide sequences of IS401 and IS408.
FASEB summer research conference on signal transduction in plants. Final report, June 16, 1996--June 21, 1996: This is the program from the second FASEB conference on Signal Transduction in Plants. Topic areas included the following: environmental signaling; perception and transduction of light signals; signaling in plant microbe interactions; signaling in plant pathogen interactions; cell, cell communication; cytoskeleton, plasma membrane, and cellwall continuum; signaling molecules in plant growth and development I and II. A list of participants is included.
Rural telemedicine project in northern New Mexico: A virtual electronic medical record system is being deployed over the Internet with security in northern New Mexico using TeleMed, a multimedia medical records management system that uses CORBA-based client-server technology and distributed database architecture. The goal of the NNM Rural Telemedicine Project is to implement TeleMed into fifteen rural clinics and two hospitals within a 25,000 square mile area of northern New Mexico. Evaluation of the project consists of three components: job task analysis, audit of immunized children, and time motion studies. Preliminary results of the evaluation components are presented.
Exploration of new perspectives and limitations in Agrobacterium mediated gene transfer technology. Progress report, [June 1, 1992-- May 31, 1994]: This report describes progress aimed at constructing gene-transfer technology for Nicotiana plumbaginifolia. Most actual effort as described herein has so far been directed at exploring new perspectives and limitations in Agrobacterium mediated gene transfer. Accomplishments are described using a core homologous gene targeting vector.
DNA damage action spectroscopy and DNA repair in intact organisms: Alfalfa seedlings: Understanding the effects of UV, and increased levels of UV, on DNA in living organisms requires knowledge of both the frequency of damages induced by the quantities and quality (wavelength composition) of the damaging radiation, and of the capacity of the organisms to carry out efficient and accurate repair. The major levels of uncertainty in understanding the responses of intact organisms, both plant and animal, to UV indicates that we cannot assess accurately the impact of stratospheric ozone depletion without major increases in knowledge of DNA damage and repair. What repair paths does alfalfa use for dealing with UV damages? The rate of pyrimidine dimers induced at a low exposure of 280 nm radiation to alfalfa seedlings, was observed to be about 8 dimers/million bases. After UV exposure, the seedlings were kept in the dark or exposed to blue light filtered by a yellow. filter which excluded wavelengths shorter than about 405 nm. Seedlings so exposed carry out photorepair, but do not seem to remove dimers by excision.
Directly labeled fluorescent DNA probes for chromosome mapping: A new strategy is briefly described for employing nucleic acid probes that are directly labeled with fluorochromes in fluorescence in situ hybridization techniques. These probes will permit the detection, quantitation, and high-precision spatial analysis of multiple DNA sequences along a single chromosome using video-enhanced fluorescence microscopy and digital image processing and analysis. Potential advantages of direct labeled DNA probes for fluorescence in situ hybridization far surpass currently available, indirect DNA probe labeling techniques in ease of use, versatility, and increased signal- to-noise ratio.
GRAIL and GenQuest Sequence Annotation Tools: Our goal is to develop and implement an integrated intelligent system which can recognize biologically significant features in DNA sequence and provide insight into the organization and function of regions of genomic DNA. GRAIL is a modular expert system which facilitates the recognition of gene features and provides an environment for the construction of sequence annotation. The last several years have seen a rapid evolution of the technology for analyzing genomic DNA sequences. The current GRAIL systems (including the e-mail, XGRAIL, JAVA-GRAIL and genQuest systems) are perhaps the most widely used, comprehensive, and user friendly systems available for computational characterization of genomic DNA sequence.
5. international workshop on the identification of transcribed sequences: This workshop was held November 5--8, 1995 in Les Embiez, France. The purpose of this conference was to provide a multidisciplinary forum for exchange of state-of-the-art information on mapping the human genome. Attention is focused on the following topics: transcriptional maps; functional analysis; techniques; model organisms; and tissue specific libraries and genes. Abstracts are included of the papers that were presented.
Molecular characterization of flow-sorted mammalian centromeres: This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The project involved experiments directed towards developing a molecular characterization of the centromere region of mammalian chromosomes. Attempts to purify this essential chromosomal locus by conventional methods have thus far been unsuccessful. However, preliminary data obtained in collaboration with the National Flow Cytometry Resource (NFCR) showed that it is possible to purify a chromosome fragment that is present in certain cultured mouse cell lines and has all the properties expected of an intact centromere region. To begin sorting this minichromosome for the identification of proteins preferentially associated with centromere regions, standard buffers utilized in chromosome sorting were evaluated for potential effects on maintenance of chromosomal proteins during sorting. The data indicate that the presence of several buffer constituents results in the extraction of all but a few chromosomal proteins. The subsequent use of a magnesium sulfate buffer resulted in the sorting of mouse chromosomes that do not suffer a significant loss of proteins. Several DNA stains were also evaluated for causing protein dissociation, but no significant losses were observed. Although flow-sorted chromosomes have been used extensively for DNA analysis and cloning, this is a pioneering effort by the NFCR, and its collaborators, to exploit chromosome sorting capabilities for the analysis of chromosomal proteins.
Final Report: Complete Sequencing of the 2.3Mbp Genome of the Hyperthermophilic Archaeon Pyrbaculum Aerophilum, January 1, 1998 - December 31, 1998: Pyrobaculum aerophilum is a hyperthermophilic archeon discovered from a boiling marine water hole at Maronti Beach, Italy that is capable of growth at 110 C. This microorganism can grow aerobically, unlike most of it's thermophilic relatives. Due to the tolerance to oxygen, it is possible to grow this microbe in the presence of air, i.e. on plates. Therefore, it is a good candidate a model organism for studying archaeal biology and thermophilism. Sequencing the entire genome of this organism will provide a wealth of information on the evolutionary and phylogenetic relationship between archaea and other organisms as well as the biology of thermophilism. We have constructed a physical map that covers estimated 2,3 Megabase pair genome using a 10X fosmid library. The map currently consists of 96 overlapping fosmid clones. We have completed sequencing the entire genome using in random shotgun approach with the supplement of oligonucleotide primer directed sequencing. Total 16,098 random sequences corresponding to approximately 3.5X genomic coverage were obtained by sequencing from both ends with vector-specific primers the 2-3 kbp genomic DNA fragments cloned into pUC18/19 vector after shearing have been assembled into a number of contigs using Phrap program developed by Dr. Phil Green at University of Washington, Seattle. Gaps and regions of low quality base calls have been a total of 2,300 directed sequencing and reassembly. Our current full length genomic sequence still suffers from low data quality: only approximately 99% of the nucleotide sequences are accurate. This is mainly due to the low redundancy (3.5 fold) in random sequencing. We plan to perform 2-3,000 more directed sequencing to polish the sequence to 99,99% accuracy. Final polishing of the sequence data and annotation is currently being performed by UCLA team and Caltech sequencing core facility.
Experimental assessment of absorbed dose to mineralized bone tissue from internal emitters: An electron paramagnetic resonance study: EPR resonances attributable to radiation-induced centers in hydroxyapatite were not detectable in bone samples supplied by the USTUR. These centers are the basis for imaging and dose assessment. Presumable, the short range of the alpha particles emitted precluded the formation of appreciable amounts of hydroxyapatite centers. However, one bone sample did offer a suggestion of hydroxyapatite centers and newly-developed methods to extract this information will be pursued.
Femtosecond spectroscopy on PSII reaction centers: New results: Time evolution of transient absorption changes excited by pumping Photosystem II (PSII) RCs at 683 nm (where P680 absorbs) or 665 nm (where RC antenna pigments absorb) and probing at 544 nm elicited a rapid increase in absorption within the time of the pump pulse, and, subsequently, three distinct kinetic components representing decreases in absorption: A fast component with {tau}s on the order of 1--3 ps, an intermediate one with {tau}s of 10--25 ps, and a slow one with {tau}s ranging from 50--100 ps. The amplitudes of the three bleach components versus pump energy are linear up to 250 nJ at both pump wavelengths. Between 250 nJ and 1 {mu}J the amplitudes continue to increase but at a lesser slope. Zero-crossing times increase with increasing pump energy from a minimum of about 10 ps at 683 nm excitation and 20 ps at 665 nm excitation. ZCTs provide a convenient way of comparing from laboratory to laboratory the actual pump intensity seen by a sample. Whereas the amplitudes of the three kinetic components increase with pump energy, there does not seem to be a consistent change in the relative percentage of the three components over the pump energy range investigated. However, the percentage of intermediate time component appears greater, and the lifetimes of all three components increase somewhat when pumping at 665 nm vs. 683 nm. To examine this point, we obtained transient absorption spectra of PSII RCs at 500 ps and 1 ps after low energy pump pulses at 665 nm and 683 nm. At 500 ps, transient absorption spectra in the 500-nm to 600-nm range are independent of pump wavelength. This indicates that energy transfer from antenna pigments, absorbing at 665 nm, to P680 is close to 100% efficient. On the other hand, at short time there is a …
The first synthesis of [9,Amino-{sup 15}N{sub 2}]adenine and {beta}- 2{prime}-Deoxy-[9,Amino-{sup 15}N{sub 2}]adenosine: {beta}-2{prime}-Deoxy-[9, Amino-{sup 15}N{sub 2}] Adenosine has been constructed in 4 steps from commercially available 5-amino-4,6-dichloropyrimidine and {sup 15}NH{sub 3}. The reactions have been scaled provide grams quantities of labeled nucleoside.
Advanced telemedicine development: This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The objective of this project was to develop a Java-based, electronic, medical-record system that can handle multimedia data and work over a wide-area network based on open standards, and that can utilize an existing database back end. The physician is to be totally unaware that there is a database behind the scenes and is only aware that he/she can access and manage the relevant information to treat the patient.
Summer Undergraduate Research Program: Environmental studies: The purpose of the summer undergraduate internship program for research in environmental studies is to provide an opportunity for well-qualified students to undertake an original research project as an apprentice to an active research scientist in basic environmental research. The students are offered research topics at the Medical University in the scientific areas of pharmacology and toxicology, epidemiology and risk assessment, environmental microbiology, and marine sciences. Students are also afforded the opportunity to work with faculty at the University of Charleston, SC, on projects with an environmental theme. Ten well-qualified students from colleges and universities throughout the eastern United States were accepted into the program.
DNA sequence pattern recognition methods in GRAIL: The goal of the GRAIL project has been to create a comprehensive analysis environment where a host of questions about genes and genome structure can be answered as quickly and accurately as possible. Constructing this system has entailed solving a number of significant technical challenges including: (a) making coding recognition in sequence more sensitive and accurate, (b) compensating for isochore base compositional effects in coding prediction, (c) developing methods to determine which parts of each strand of a long genomic DNA are the coding strand, (d) improving the accuracy of splice site prediction and recognizing non-consensus sites, and (e) recognizing variable regulatory structures such as polymerase II promoters. An additional challenge has been to construct algorithms which compensate for the deleterious effects of insertion or deletion (indel) errors in the coding region recognition process. This paper addresses progress on these technical issues and the current state of sequence feature recognition methods.
Microbial stabilization of sulfur-landen sorbents; Technical report, September 1--November 30, 1993: Clean coal technologies that involve limestone for sulfur capture generate lime/limestone products laden with sulfur at various oxidation states. If sulfur is completely stabilized as sulfate, the spent sorbent is ready for commercial utilization as gypsum. However, the presence of reduced sulfur species requires additional processing. Thermal oxidation of reduced sulfur can result in undesirable release of SO{sub 2}. Microbial oxidation might provide an inexpensive and effective alternative. Sorbents laden with reduced forms of sulfur such as sulfide, sulfite, or various polythionate species serve as growth substrates for sulfur-oxidizing bacteria, which have the potential to convert all sulfur to sulfate. This quarter, efforts focused on determining the combined effects of dibasic acids (DBA) and Ca{sup +2} concentration on several strains of neutrophilic thiobacilli, including Thiobacillus neapolitanus ATCC 23639 and ATCC 23641, and an isolate, TQ1, which was obtained from a commercial sulfur dioxide scrubber that utilizes DBA.
Analysis of offsite dose calculation methodology for a nuclear power reactor: This technical study reviews the methodology for calculating offsite dose estimates as described in the offsite dose calculation manual (ODCM) for Pennsylvania Power and Light - Susquehanna Steam Electric Station (SSES). An evaluation of the SSES ODCM dose assessment methodology indicates that it conforms with methodology accepted by the US Nuclear Regulatory Commission (NRC). Using 1993 SSES effluent data, dose estimates are calculated according to SSES ODCM methodology and compared to the dose estimates calculated according to SSES ODCM and the computer model used to produce the reported 1993 dose estimates. The 1993 SSES dose estimates are based on the axioms of Publication 2 of the International Commission of Radiological Protection (ICRP). SSES Dose estimates based on the axioms of ICRP Publication 26 and 30 reveal the total body estimates to be the most affected.
Tandem metal-mediated synthesis: This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). Boronic acids RB(OH){sub 2} are currently of interest for applications involving molecular recognition such as amine and sugar sensors and selective transport of biomolecules. They have also been shown to be powerful enzyme inhibitors and alpha-aminoboronic acids (ABAs) are particularly selective inhibitors of serine proteases. Unfortunately, current multistep synthetic routes to the latter compounds do not allow for the incorporation of a wide variety of organic substituents R that may lead to new, more selective enzyme inhibitors. In this work the author describes several direct routes to ABAs based on metal-catalyzed addition of diboron compounds to imines and nitriles. Several other applications of diboron additions to heteroatom-containing unsaturated organics are also described.
The ROVCO2 surface decontamination system: DOE needs to decontaminated over one million square feet of nuclear contaminated concrete surfaces. The 1000 lb ROVCO2 system, which automates blasting functions and eliminates secondary blasting waste, integrates a remotely operated vehicle and an enhanced commercial CO{sub 2} blasting system with an Oceaneering-developed work arm and control system. The remote operation protects the operation from contamination and supports functional automation of tedious tasks. The blasting system shoots pellets of dry ice propelled by pressurized gas at the surface to be cleaned. Impact of the pellets fractures and scales off a layer of the contaminated surface. At impact, the pellets return to a gaseous state which is vacuumed up with the debris. The CO{sub 2} gas and debris are passed through the vacuum filter, leaving only the removed material for waste disposal. Phase 2 testing achieved nearly all of the success criteria, with the exception of the commercial workhead`s performance.
Parallel continuation-based global optimization for molecular conformation and protein folding: This paper presents the authors` recent work on developing parallel algorithms and software for solving the global minimization problem for molecular conformation, especially protein folding. Global minimization problems are difficult to solve when the objective functions have many local minimizers, such as the energy functions for protein folding. In their approach, to avoid directly minimizing a ``difficult`` function, a special integral transformation is introduced to transform the function into a class of gradually deformed, but ``smoother`` or ``easier`` functions. An optimization procedure is then applied to the new functions successively, to trace their solutions back to the original function. The method can be applied to a large class of nonlinear partially separable functions including energy functions for molecular conformation and protein folding. Mathematical theory for the method, as a special continuation approach to global optimization, is established. Algorithms with different solution tracing strategies are developed. Different levels of parallelism are exploited for the implementation of the algorithms on massively parallel architectures.
Laser mass spectrometry for DNA fingerprinting for forensic applications: The application of DNA fingerprinting has become very broad in forensic analysis, patient identification, diagnostic medicine, and wildlife poaching, since every individual`s DNA structure is identical within all tissues of their body. DNA fingerprinting was initiated by the use of restriction fragment length polymorphisms (RFLP). In 1987, Nakamura et al. found that a variable number of tandem repeats (VNTR) often occurred in the alleles. The probability of different individuals having the same number of tandem repeats in several different alleles is very low. Thus, the identification of VNTR from genomic DNA became a very reliable method for identification of individuals. DNA fingerprinting is a reliable tool for forensic analysis. In DNA fingerprinting, knowledge of the sequence of tandem repeats and restriction endonuclease sites can provide the basis for identification. The major steps for conventional DNA fingerprinting include (1) specimen processing (2) amplification of selected DNA segments by PCR, and (3) gel electrophoresis to do the final DNA analysis. In this work we propose to use laser desorption mass spectrometry for fast DNA fingerprinting. The process and advantages are discussed.
Stable isotope labeling of oligosaccharide cell surface antigens: The overall goal of this Laboratory Directed Research and Development (LDRD) project was to develop new methods for synthesis of {sup 13}C-labeled oligosaccharides that are required for nuclear magnetic resonance (NMR) studies of their solution conformation. Oligosaccharides are components of the cell`s outer surface and are involved in important processes such as cell-cell recognition and adhesion. Recently, Danishefsky and coworkers at Slone-Kettering Cancer Center developed a method for the solid-phase chemical synthesis of oligosaccharides. The specific goal of this LDRD project was to prepare uniform {sup 13}C-labeled aldohexose precursors required for the solid-phase synthesis of the Lewis blood-group antigenic determinants. We report the synthesis of {sup 13}C-labeled D-glucal, D-galactal and Fucosyl precursors. We have been collaborating with the Danishefsky group on the synthesis of the Lewis oligosaccharides and the NMR analysis of their solution conformation.
Alpha-emitters for medical therapy workshop: A workshop on ``Alpha-Emitters for Medical Therapy`` was held May 30-31, 1996 in Denver Colorado to identify research goals and potential clinical needs for applying alpha-particle emitters and to provide DOE with sufficient information for future planning. The workshop was attended by 36 participants representing radiooncology, nuclear medicine, immunotherapy, radiobiology, molecular biology, biochemistry, radiopharmaceutical chemistry, dosimetry, and physics. This report provides a summary of the key points and recommendations arrived at during the conference.
Disability rights in dialogue with clinical genetics conference, May 31 to June 2, 1996: The issue of prenatal diagnosis and selective abortion has been hotly debated in the medical, genetic counselling, feminist, parents, disability rights and bio-ethics literature, each of the various positions critiquing each other. People from the disability rights community in particular have began to articulate a critical view of the practice of widespread prenatal diagnosis with intent to abort because the pregnancy might result in a child with a disability. Unfortunately, people from the various disciplines and perspectives, such as bioethics, disability rights, feminism and so forth, by and large, have tended only to write for themselves and their colleagues. Few people have crossed disciplines to try to talk to people with other views. The rapid advances of genome research have continued to produce new prenatal tests, raising many complex ethical questions regarding the applications of prenatal testing. But the widely disparate positions of the various factions has made it difficult to move toward formulation of public policy change necessary to encompass these new genetic technologies. Genetic counselling is in the front lines of the controversial social and ethical issues arising from prenatal diagnosis, in its interface between medical science and the consumer of services. The primary intent of the conference was to invite and facilitate productive dialogue between individuals and groups of people who have traditionally not interacted as a result of their disparate views on these issues and to learn from this process, emphasizing the involvement of people with disabilities and people who work in clinical genetics.
DNA sequencing technology, walking with modular primers. Final report: The success of the Human Genome Project depends on the development of adequate technology for rapid and inexpensive DNA sequencing, which will also benefit biomedical research in general. The authors are working on DNA technologies that eliminate primer synthesis, the main bottleneck in sequencing by primer walking. They have developed modular primers that are assembled from three 5-mer, 6-mer or 7-mer modules selected from a presynthesized library of as few as 1,000 oligonucleotides ({double_bond}4, {double_bond}5, {double_bond}7). The three modules anneal contiguously at the selected template site and prime there uniquely, even though each is not unique for the most part when used alone. This technique is expected to speed up primer walking 30 to 50 fold, and reduce the sequencing cost by a factor of 5 to 15. Time and expensive will be saved on primer synthesis itself and even more so due to closed-loop automation of primer walking, made possible by the instant availability of primers. Apart from saving time and cost, closed-loop automation would also minimize the errors and complications associated with human intervention between the walks. The author has also developed two additional approaches to primer-library based sequencing. One involves a branched structure of modular primers which has a distinctly different mechanism of achieving priming specificity. The other introduces the concept of ``Differential Extension with Nucleotide Subsets`` as an approach increasing priming specificity, priming strength and allowing cycle sequencing. These approaches are expected to be more robust than the original version of the modular primer technique.
Polysaccharides and bacterial plugging. [Quarterly report], January 1--March 31, 1993: Micromodel experiments were conducted to determine the effect of polysaccharide production on cell capture, retention, and release in porous media. The micromodels are glass plates which are etched with patterns representing flow channels within porous media. These micromodels are placed under a microscope and monitored via video camera and recorder which allows direct observation of physical processes occuring within the network of flow channels. Based on the results of these experiments, four regimes are identified that describe the transport of the polysaccharide-producing cells.
Electrospray/Ion Trap Mass Spectrometry for the Detection and Identification of Organisms: Current electrospray ion trap methodology for rapid mixture analysis of proteins used for the identification of microorganisms is described. Development of ion/ion reaction techniques (e.g. reactions of multiply-charged protein cations with singly-charged anions) from both a fundamental and practical approach are presented, detailing the necessary steps and considerations involved in complex mixture analysis. Data describing the reduction of the initial charge states of electrospray ions to arbitrarily low values, the utility of ion/ion reactions for mixture separation on the millisecond time scale, and effects of excess singly-charged reactants on detection and storage efficiency are illustrated.
The Human Genome Diversity Project: The Human Genome Diversity Project (HGD Project) is an international anthropology project that seeks to study the genetic richness of the entire human species. This kind of genetic information can add a unique thread to the tapestry knowledge of humanity. Culture, environment, history, and other factors are often more important, but humanity`s genetic heritage, when analyzed with recent technology, brings another type of evidence for understanding species` past and present. The Project will deepen the understanding of this genetic richness and show both humanity`s diversity and its deep and underlying unity. The HGD Project is still largely in its planning stages, seeking the best ways to reach its goals. The continuing discussions of the Project, throughout the world, should improve the plans for the Project and their implementation. The Project is as global as humanity itself; its implementation will require the kinds of partnerships among different nations and cultures that make the involvement of UNESCO and other international organizations particularly appropriate. The author will briefly discuss the Project`s history, describe the Project, set out the core principles of the Project, and demonstrate how the Project will help combat the scourge of racism.
American College of Nuclear Physics 1991 DOE day symposium: Aids and nuclear medicine: Since first described in 1981, the acquired immunodeficiency syndrome (AIDS) has become the medical dilemma of the century. AIDS retrovirus, and the economic consequences of this exposure are staggering. AIDS has been the topic of conferences and symposia worldwide. This symposium, to be held on January 25, 1991, at the 17th Annual Meeting and Scientific Sessions of the American College of Nuclear Physicians, will expose the Nuclear Medicine Physicians/Radiologists to their role in the diagnosis of AIDS, and will educate them on the socio-economic and ethical issues related to this problem. In addition, the Nuclear Medicine Physicians/Radiologists must be aware of their role in the management of their departments in order to adequately protect the health care professionals working in their laboratories. Strategies are currently being developed to control the spread of bloodborne diseases within the health care setting, and it is incumbent upon the Nuclear Medicine community to be aware of such strategies.
[Malignant transformation of human fibroblasts by neutrons and by gamma radiation: Relationship to mutations induced]: A brief overview if provided of selected reports presented at the International Symposium on Molecular Mechanisms of Radiation- and Chemical Carcinogen-Induced Cell Transformation held at Mackinac Island, Michigan on September 19-23, 1993.
Report of the second Human Genome Diversity workshop: The Second Human Genome Diversity Workshop was successfully held at Penn State University from October 29--31, 1992. The Workshop was essentially organized around 7 groups, each comprising approximately 10 participants, representing the sampling issues in different regions of the world. These groups worked independently, using a common format provided by the organizers; this was adjusted as needed by the individual groups. The Workshop began with a presentation of the mandate to the participants, and of the procedures to be followed during the workshop. Dr. Feldman presented a summary of the results from the First Workshop. He and the other organizers also presented brief comments giving their perspective on the objectives of the Second Workshop. Dr. Julia Bodmer discussed the study of European genetic diversity, especially in the context of the HLA experience there, and of plans to extend such studies in the coming years. She also discussed surveys of world HLA laboratories in regard to resources related to Human Genome Diversity. Dr. Mark Weiss discussed the relevance of nonhuman primate studies for understanding how demographic processes, such as mate exchange between local groups, affected the local dispersion of genetic variation. Primate population geneticists have some relevant experience in interpreting variation at this local level, in particular, with various DNA fingerprinting methods. This experience may be relevant to the Human Genome Diversity Project, in terms of practical and statistical issues.
A neural network system for prediction of RNA polymerase II promoters: One of the most difficult problems in the analysis of eucaryotic genes is the detection of RNA polymerase II promoter regions. Although promoter regions vary in the primary DNA sequence, a basic group of core promoter elements has been suggested in the literature. Many human promoter sequences contain a TATAA sequence element at approximately 30 bases upstream of the cap site (transcription start site). Other elements are the GC box which binds SPA and upregulates transcription, the CAAT box, and the ATG initiator codon. To characterize promoters, we constructed frequency matrices for each element using experimentally mapped human promoter regions. Additionally, we constructed histograms for the distances separating the various elements. We then used a neural network to combine these informational elements. The output of the neural network is then processed using a set of expert rules which depend on GRAIL`s ability to find exons in anonymous DNA. This improves the selectivity of promoter detection and reduces the false positive rate.

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