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3 Advances in Technologies with Relevance to Biology: The Future Landscape
Pages 139-212

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From page 139...
... illustrates the general principles by which technological growth alters the nature of future biological threats; and, (3) highlights how and why some technologies are complementary or synergistic in bolstering defense against future threats while also enhancing or altering the nature of future threats.
From page 140...
... A CLASSIFICATION SCHEME FOR BIOLOGICAL TECHNOLOGIES Despite the seemingly disparate and scattered goals of recent advances in life sciences technologies, the committee concluded that there are classes or categories of advances that share important features. These shared characteristics are based on common purposes, common conceptual underpinnings, and common technical enabling platforms.
From page 141...
... Examples include the use of transgenic plants as production platforms, aerosol technology, microencapsulation, microfluidics/microfabrication; nanotechnology; and, gene therapy technology. [Some of these technologies are related to the manipulation of biological systems -- e.g., nanotechnology -- and may also be applied to the generation (category 1)
From page 142...
... The coverage of these issues for each of the technologies is not intended to be exhaustive. The technologies covered in this chapter include not only those that open up new possibilities for the creation of novel or enhanced biological agents but also those that expose new vulnerabilities (i.e., targets for biological attack)
From page 143...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 143 Techniques have been developed to expand both the diversity of nucleotide or amino acid sequences of nucleic acids or proteins, respectively (which in both cases ultimately hold the information specifying the folding and thus the conformation of biologically active molecules) , or for creating a diversity of small molecules with different shapes, sizes, and charge characteristics.
From page 144...
... 144 GLOBALIZATION, BIOSECURITY, AND THE FUTURE OF THE LIFE SCIENCES cued following its transfection into permissive cells.5 The following year scientists announced the successful assembly of a bacterial virus genome.6 Parallel efforts in industry and academia led to the synthesis and assembly of large segments of the hepatitis C virus genome, from which replication competent RNA molecules were rescued. These studies raised concerns in the media that larger, more complex organisms, such as the smallpox virus (which is approximately 186,000 base pairs long)
From page 145...
... The proposal focuses on instrument and reagent licensing (e.g., restricting the sale and maintenance of oligonucleotide synthesis machines to licensed entities) ; regulation for the screening of select agents; establishing a method for testing these newly implemented licensing and, screening systems; criteria for exemption from the whole process; and, strategies for keeping the cost down.16 The proposal is mentioned here not to endorse it, but rather to highlight the need for a careful analysis and thoughtful discussion of the issues.
From page 146...
... 146 GLOBALIZATION, BIOSECURITY, AND THE FUTURE OF THE LIFE SCIENCES DNA Shuffling Description Classical genetic breeding has proven itself over and over again throughout human history as a powerful means to improve plant and animal stocks to meet changing societal needs. The late 20th century discovery of restriction endonucleases, enzymes that cut DNA molecules at sites comprising specific short nucleotide sequences, and the subsequent emergence of recombinant DNA technology provided scientists with high-precision tools to insert (or remove)
From page 147...
... Future Applications Ultimately, this rapid molecular method of directed evolution will allow biologists to generate novel proteins, viruses, bacteria, and other organisms with desired properties in a fraction of the time required with classical breeding and in a more cost-effective manner. For example, virologists are using DNA shuffling to optimize viruses for gene therapy and vaccine applications.23 Synthetic biologists are using the technology to speed up their discovery process (see "Synthetic Biology" later in this chapter)
From page 148...
... Even as high-throughput technologies like combinatorial chemistry, described above, have practically revolutionized drug discovery, modern therapeutics is still largely dependent on compounds derived from natural products. Excluding biologics (products made from living organisms)
From page 149...
... This kind of approach can synergize with the DNA shuffling technology described above. Recent, early forays into "community genomics," or large-scale random sequencing of the DNA from complex environmental microbial communities, reflect the immense future potential of this approach for the discovery and harnessing of previously unimagined biological activities.33 For example, Diversa Corporation (San Diego, CA)
From page 150...
... . Whereas DNA synthesis enables the acquisition of genetic sequence diversity, these techniques allow for the generation of libraries of chemical compounds having a diversity of shapes, sizes, and charge characteristics -- all of which may be of interest for their varied abilities to interact with and bind to biologically active proteins or macromolecular complexes, thereby altering the biological properties of these proteins and complexes.
From page 151...
... A recent trend noted in the pharmaceutical industry is the move from the development of large, unfocused, general screening libraries to smaller, less diverse libraries for screening against a particular target or family of related targets. The origins of this new branch of chemistry can be traced back to the early 1960s, when methods were developed for the solid-phase synthesis of peptides.40 This involved attaching an amino acid to a solid support (i.e., beads of plastic resin)
From page 152...
... Numerous additional tagging techniques and agents have since been developed.47 Current State of the Art Solution-phase parallel synthesis is becoming the combinatorial chemistry technique of choice in the pharmaceutical industry, driven primarily by advances in laboratory automation, instrumentation, and informatics. Compounds can be synthesized either as single discrete compounds per reaction vessel or as mixtures of compounds in a single reaction vessel, so many of the same principles described above for solid-phase (resinbound)
From page 153...
... Although most companies have little use for the tens of thousands of these compounds identified each year as toxic, some might have potential as biochemical weapons (Chapter 1) .50 Although most of the information derived from combinatorial and high-throughput technology is held in proprietary databases, a new public database recently proposed as part of the National Institutes of Health (NIH)
From page 154...
... Over the past several years, the industry has witnessed an evolution in screening capabilities, resulting in the ability of a user to screen more than 100,000 compounds per day for potential biological activity. Evaluating upward of 1 million compounds for biological (or various other)
From page 155...
... assays; · development of improved primary screening hardware; · miniaturization as a means to increase throughput and decrease cost; · improvements in the capabilities and efficiency of robotic systems in the life sciences; · application of HTS to lead compound optimization; and, · novel approaches for identification of biologically-relevant targets.
From page 156...
... Coupled with methods to generate enhanced sequence and structural diversity beyond that seen in nature, these assays and technologies will permit the identification and selection of novel molecules with important biological functions, with ramifications for all of the life sciences.
From page 157...
... 157 the status time 2004 A 2003 the bank: 2002 from 2001 data 2000 uctures Str 1999 uctures (black) Str protein 1998 1997 Deposited otalT PDB the the in 1996 of 1995 1994 1993 holdings complexes 1992 1991 total 1990 and 1989 1988 1987 earY (gray)
From page 158...
... Current State of the Art Although rational drug design has received a great deal of attention from the pharmaceutical industry and is recognized as having great potential for the future, most efforts today by the drug discovery industry reflect a combination of structure-aided rational design of compounds and the HTS screening of libraries of diverse compounds. Thus, the use of structure, when known for a given molecular target, may come into play once a lead compound has been identified through an HTS process and efforts are made to optimize this lead and improve the biological activity or pharmacological properties of the compound.
From page 159...
... While there are dual-use implications for such technologies, as there are for almost any advancing life sciences technology, the infrastructure required to pursue such structure-based design of novel biologically active compounds is likely to limit its use to the legitimate pharmaceutical industry for a number of years. It should be noted, however, that like the nucleotide sequence databases that are open to the public, rapidly growing numbers of protein structures are being placed in the public domain.
From page 160...
... Future Applications Synthetic biology technology has many potential applications, including designing bacteria that can detect chemical or biological agent signatures, engineering bacteria that can clean up environmental pollutants, and engineering organisms or compounds that can diagnose disease or fix faulty genes. Although initial efforts are focused on microbial cells, some synthetic biologists imagine a day when they will be able to pro
From page 161...
... is one of many scientists promoting the idea that synthetic biologists and ethicists hold an Asilomar-like conference on synthetic biology -- much like that held at the dawn of genetic engineering research in the mid-1970s -- to define bioengineers' "responsibilities to society" should these engineered organisms survive outside the laboratory to cause harm to human health or the environment.62 Several efforts have now been planned to examine the implications of this kind of work, including one foundation-funded study involving three institutions, two of which play a major role in synthetic genomics research.63 In addition, the National Science Advisory Board for Biosecurity has identified synthetic genomics as a major area of interest. Many of the same issues are raised by the genetic engineering of viruses.
From page 162...
... The transcribed RNA can then be transfected back into a permissive cell and, if the introduced mutations are compatible with continued viability of the virus, will give rise to novel infectious viruses. The process by which virologists use this method, involving the conversion of the genetic sequence of the virus from RNA to DNA and back to RNA, generally in order to assess the impact of mutations on the viral life cycle or pathogenic properties, is known as "reverse genetic engineering." This approach is widely used by positive-strand molecular virologists.
From page 163...
... , a previously undescribed coronavirus.72 Similarly, the reverse genetic engineering of negative-strand RNA viruses73 has proven much more difficult, given the fact that the RNA genomes of these viruses do not function directly as messenger RNAs and thus do not give rise to infectious virus progeny following their introduction into permissive cells. These RNAs require the expression of certain viral proteins, in order to make positive-strand copies of the negativestranded RNA genome and to initiate the replicative cycle.
From page 164...
... HA is a major surface protein that stimulates the production of neutralizing antibodies in the host, and changes in the genome segment that encodes it may render the virus resistant to preexisting neutralizing antibodies, thus increasing the potential for epidemics or pandemics of disease. Moreover, the reverse engineered viruses expressing 1918 viral HA elicited hallmark symptoms of the illness produced during the original pandemic.89 With the complete genetic sequencing of the H1N1 influenza A virus, referred to in Chapter 1, some have questioned whether these studies should have been published90 in the open literature given concerns that terrorists could, in theory, use the information to reconstruct the 1918 flu virus.91 It should be noted that in addition to the "normal" scientific peer review, the editors of Science required the authors to demonstrate that they had obtained approval to publish their research from the director of the Centers for Disease Control and Prevention, and the director of the National Institute of Allergy and Infectious Diseases.92 Furthermore, the National Science Advisory Board for Biosecurity (NSABB)
From page 165...
... Critical components can then serve as targets for therapeutic and preventive intervention or manipulation; they can also serve as targets for malevolent manipulation and as the basis for novel kinds of biological attack. Concurrently, technologies that facilitate a better understanding of intracellular, organ, and whole-animal control "circuitry" will enhance the ability of scientists to manipulate these complex systems.
From page 166...
... The interaction of endogenous miRNAs with cellular mRNAs encoding specific proteins leads to suppression of protein expression, either by impairing the stability of the mRNA or by suppressing its translation into protein. The fact that small, largely double-stranded RNAs of this type, about 21 nucleotides in length, could play such an apparently broad and fundamental role in development and in the control of cellular homeostasis was not at all appreciated just a few years ago and highlights the sudden, unpredictable paradigm shifts and sharp turns in the way scientists think that are possible in the advance of the life sciences (Figure 3-3)
From page 167...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 167 FIGURE 3-3 The process of RNA interference. SOURCE: Steven Block, presentation to the committee, April 2004.
From page 168...
... 168 GLOBALIZATION, BIOSECURITY, AND THE FUTURE OF THE LIFE SCIENCES delivery of in vivo gene silencing with RNAi.99 Also in 2003, researchers announced the successful use of high-pressured, high-volume intravenous injection of synthetic siRNA.100 Other studies have demonstrated the potential to deliver RNAi to specific organs, such as the eyes,101 lungs,102 and central nervous system.103 Although human trials of RNAi have begun for the treatment of age-related macular degeneration,104 a systemic mode of delivery would arguably have greater clinical utility. Substantial progress is being made toward this aim, however, using liposome and lipid nanoparticle formulations of chemically modified, and hence stabilized, siRNAs.
From page 169...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 169 maintenance of tumorigenesis and whether it might be a good target for late-stage cancer treatments. It is reasonable to expect significant additional advances in the formulation of siRNAs for use as pharmacological agents, particularly with contributions from the field of nanotechnology.
From page 170...
... Future Applications Their sensitivity, dynamic range, and, in the case of tadpoles, precise quantification make these high-affinity binding molecules potentially very useful tools for disease diagnosis and environmental detection, including pathogen and other biological agent detection in the event of a naturally occurring or deliberate biological attack. Despite their promise as therapeutic agents, aptamers are very expensive to synthesize and are still a largely unknown entity (with respect to administration, formulation, adverse effects, etc.)
From page 171...
... Cyberinfrastructure -- high-end generalpurpose computing centers that provide supercomputing capabilities to the community at large; well-curated data repositories that store and make available to all researchers large volumes and many types of biological data; digital libraries that contain the intellectual legacy of biological researchers and provide mechanisms for sharing, annotating, reviewing, and disseminating knowledge in a collaborative context; and high-speed networks that connect geographically distributed computing resources-will become an enabling mechanism for large-scale, data-intensive biological research that is distributed over multiple laboratories and investigators around the world. New data acquisition technologies such as genomic sequencers will enable researchers to obtain larger amounts of data of different types and at different scales, and advances in informa
From page 172...
... Thus, advances in computational biology will be driven by the need to understand how complex biological systems operate and are controlled and will contribute fundamentally to the development of a systems view in biology. Future Applications The NRC report emphasizes that the life sciences of the future will be an information science and will "use computing and information technology as a language and a medium in which to manage the discrete, nonsymmetric, largely nonreducible, unique nature of biological systems and observations.
From page 173...
... A systems biologist seeks to quantify all of the molecular elements that make up a biological system and then integrate that information into graphical network models that can serve as predictive hypotheses. A growing number of researchers in the life sciences community are recognizing the usefulness of systems biology tools for analyzing complex regulatory networks (both inside the cell, and the regulatory networks that integrate and control the functions of distinctly different cell types in multicellular organisms like humans)
From page 174...
... Future Applications The rise of systems biology is expected to have profound implications for research, clinical practice, education, intellectual property, and industrial competitiveness. As computational technologies advance, simulation of complex biological systems will have more predictive accuracy, aspects of laboratory experimentation will replaced by more cost-effective computational approaches, and physicians will have new decision support tools to help them identify the best preventative and therapeutic approaches for individual genotypes and phenotypes.
From page 175...
... , researchers have begun to understand the implications of human genetic variation for the treatment of disease.124 Patient-tailored therapies hold forth great promise as a new way of treating, or preventing, disease and are an active area of research and investment. Current State of the Art Recent accomplishments in the field include the use of an epidermal growth factor receptor (EGFR)
From page 176...
... 176 GLOBALIZATION, BIOSECURITY, AND THE FUTURE OF THE LIFE SCIENCES "proof of principle" is now emerging for the clinical activity of smallmolecule inhibitors of oncogenic tyrosine kinases such as Glivec (imatinib) against chronic myeloid leukemia129 and preclinical activity in tumor models driven by the tyrosine kinase activity of the platelet-derived growth factor and c-kit receptors.130 Future Applications Understanding and harnessing genomic variation are expected to contribute significantly to improving the health of people worldwide, including the developing world.131 In recognition of this, Mexico is in the process of delivering one of the first genomic medicine platforms in Latin America, one that is expected to serve as a regional model for other countries in their efforts to ease health and financial burdens.
From page 177...
... For almost two decades, researchers have been using adenoviruses to target tumor cells in individuals and steadily refining their techniques for directing viral entry into cells. For example, it is now possible to modify through genetic approaches the fibers used by the virus for cellular attachment so that the virus attaches to particular cell types.135, 136Studies have also shown that preferential attachment and infection of target cells can be markedly elevated.137, 138 Interestingly, while the availability of the complete human genome sequence has revealed numerous SNPs and other polymorphic elements-and has consequently raised greater concern about the possibility of using biological weapons to target specific racial or ethnic populations -- the ability to identify139 and exploit genetic differences among such populations does not require this new information.
From page 178...
... Burgeoning knowledge about the composition and regulation of homeostatic molecular circuits in the body's cells, tissues, and organs, and their dysregulation in disease, epitomizes the dual-use dilemma created by rapid advances in systems biology. The life sciences are undergoing a profound transformation from their historical reliance on descriptive and phenomenological observations to now focus on the detailed underlying mechanisms of disease and identification of the "rule sets" that govern the assembly and function of biological systems in both health and disease.
From page 179...
... The emerging field of toxicogenomics involves profiling the changes in gene and protein expression induced by chemicals found in the industrial workplace to assess potential risk from exposure to occupational and environmental hazards. The pharmaceutical industry and drug regulatory agencies such as the FDA (and their international counterparts)
From page 180...
... However, the availability of information and reagents that enable one to disrupt critical human physiological systems has profound implications for the nature of the future biological and chemical threat spectrum. The difference between the NIH and industrial efforts resides in the fate of the information produced from these largescale screening programs.
From page 181...
... Some of these technologies, which clearly have immense potential future impact on biology, have not been traditionally viewed as biotechnologies or as having relevance to future biological threats. A prime example is the potential now offered by developments in nanoparticle science for the creation of novel and highly efficient delivery systems for previously difficult-to-deliver biologically-active compounds.
From page 182...
... . However, despite the existence of functional prototypes and evidence that the technology works, there are some technical, delivery, and regulatory challenges that are slowing progress in the field.147 Future Applications Plant manufacturing platforms may provide a cost-effective means to produce vaccines, offering the ability to address some of the problems associated with global vaccine manufacture and delivery.148 They are also being used to experiment with plant-derived microbicides, with the goal of finding a cost-effective way to block HIV transmission, and they are being explored as a possible cost-effective way to produce antibodies for use against potential biowarfare agents.149 However, transgenic plants could also be engineered to produce large quantities of bioregulatory or otherwise toxic proteins, which could either be purified from plant cells or used directly as biological agents.
From page 183...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 183 (transgenic plants would be largely indistinguishable from nontransgenic crops) , but it could potentially provide a covert means for producing large amounts of product.150 Microfluidics and Microfabrication Description Microfluidics and microfabrication are rapidly growing technologies in which a wide variety of processes and manipulations are carried out at miniaturized scales (e.g., nanoliter volumes)
From page 184...
... 184 GLOBALIZATION, BIOSECURITY, AND THE FUTURE OF THE LIFE SCIENCES Future Applications As stated in a recent Science review on miniaturized diagnostic systems: "Farther down the road may be personalized health care with diagnosis and disease-monitoring occurring in the home with easy-to-use miniature devices." Although this possibility may be farther into the future than the scope of this report covers, for regulatory as much as technical reasons, steps are being taken in this direction. For example, there have been several recent advances in convenient sampling methods, including breath and saliva sampling, that would be necessary before personalized diagnostic devices become a widely accepted component of personal health care.
From page 185...
... Future Applications The future trajectory of the field, particularly the convergence of nanotechnology and molecular biology, is unclear, although it will almost certainly have multiple medical applications, including therapeutic delivery by nanoparticles.158 In October 2004, scientists from the Institute of Bioengineering and Nanotechnology (Singapore) reported having invented a contact lens capable of releasing precise amounts of medication to treat glaucoma and other eye diseases.159 Nanobiotechnology also promises multiple new approaches to molecular detection and diagnostics.160
From page 186...
... Although its current widespread use is for local treatment of asthma and chronic obstructive pulmonary disease, direct administration of drugs to the respiratory tract has been effectively used or is being tested to treat bacterial lung infections, cystic fibrosis, and lung carcinoma. The effectiveness of aerosol delivery for systemic action is also being explored, as a novel, injection-free way to control pain and deliver various therapeutics for the treatment of diabetes, human growth hormone deficiency (in children)
From page 187...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 187 Current State of the Art In the drug delivery industry the three most common types of aerosol delivery devices currently in medical use are propellant metered-dose inhalers (pMDIs) , dry powder inhalers (DPIs)
From page 188...
... Aerosol delivery is also being explored as a means of gene therapy. Advances in drug delivery technology, including aerosol delivery, have raised concerns about the use of bioregulators for nefarious purposes.
From page 189...
... Between the late 1940s and early 1960s, the concept of chemical microencapsulation generated interest in the pharmaceutical industry as an alternative mode of drug delivery that could offer sustained controlled release. Researchers and entrepreneurs continue to utilize and investigate advances in microencapsulation technology in efforts to make dosages more palatable, make active ingredients more stable and/or soluble, and otherwise improve drug delivery.179 In the decades since the technology first emerged, many other life sciences industrial sectors have benefited tremendously from non-pharmaceutical applications of microencapsulation.
From page 190...
... .184 Japanese researchers recently demonstrated the use of a novel nanoencapsulation drug delivery method for the external treatment of photo-damaged skin.185 Advanced BioNutrition Corporation (Columbia, Maryland) was recently awarded a National Science Foundation grant to further develop its proprietary microencapsulation technology for the incorporation of functional ingredients -- such as enzymes, fatty acids, probiotics, even vaccines -- into its animal and human food products.186 The company will use the money to scale up its microencapsulation technology production process.
From page 191...
... In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal," disease-causing gene. A carrier molecule -- called a vector -- must be used to deliver the "healthy" gene to a recipient's target cells.
From page 192...
... The few human clinical trials that have been conducted have not been as successful as originally hoped.190 Although substantial progress has been made, and some clinical successes seem to be on the horizon, further vector refinement and/or development is required before gene therapy will become standard care for any individual disorder. Future Applications When gene therapy does become a clinical reality, it will be used to correct faulty or defective disease-causing genes.
From page 193...
... to the more challenging objectives of targeted delivery to specific cell types (e.g., cancer cells versus their normal counterparts) or delivery of a drug or other bioactive agents to a specific compartment inside the cell (e.g., nuclear uptake of genes into chromosomal DNA for gene therapy or targeted therapeutic ablation of deleterious genes)
From page 194...
... One of the more concerning assaults, yet attainable even with today's delivery technology, could arise from the use of targeted delivery systems to insert genes into chromosomal DNA. For example, viral delivery vectors developed for human gene therapy exploit the ability of viruses to bind selectively to specific cell types as a way to deliver genes encapsulated inside the viral particle into the target cells.
From page 195...
... Nanotechnology enables biotechnology by developing new imaging techniques, probes, and sensors; it also contributes to the miniatur
From page 196...
... Based on extensive deliberations on a wide range of advancing technologies with relevance to the life sciences, including many technologies and fields of knowledge not traditionally viewed within the rubric of biotechnology, the committee was particularly struck by the extent to which various tools and technologies are interacting and converging191 -both additively and synergistically -- and creating unanticipated opportunities for these technologies to be used for either beneficial or malicious intent (or with beneficial intent but unintended consequences)
From page 197...
... The field of bioinformatics represents another key example of converging technologies -- in this case biology, computer science, and information technologies -- all of which have merged to form what is now a single discipline. Over the past 10 years, major advances in the field of molecular biology, coupled with advances in genomic technologies, have led to an explosive growth in biological information generated by the life sciences community.
From page 198...
... to affect the human body in targeted, covert, and insidious ways. A controversial issue that arose from these discussions is how all research on immune system evasion could be considered potentially dangerous, thus highlighting the very important need to uphold the norms of the Biological and Toxin Weapons Convention.
From page 199...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 199 minute fission time, only about 1045 have existed over the history of the earth, which is tiny compared to the number of possible 108 base pair DNA sequences. 3See discussion of virulence and evolution of pathogens in Chapter 1.
From page 200...
... 1999. Drug discovery from nature.
From page 201...
... Emerging Infectious Diseases 5(1)
From page 202...
... 2002. Biotechnology and biochemical weapons.
From page 203...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 203 57 Registry of Standard Biological Parts. The Endy Lab, Massachusetts Institute of Technology.
From page 204...
... 1999. Rescue of influenza A virus from recombinant DNA.Journal of Virology 73(11)
From page 205...
... ADVANCES IN TECHNOLOGIES WITH RELEVANCE TO BIOLOGY 205 88Bridgen, A
From page 206...
... 2005. Illuminating drug discovery with biological pathways.
From page 207...
... Gene Therapy 7(3)
From page 208...
... microspheres as a novel approach for immunogene therapy. Journal of Controlled Release 57(1)
From page 209...
... 2005. An International Perspective on Advancing Technologies and Strategies for Managing Dual-Use Risks.
From page 210...
... 2002. Delivery of biological agents by aerosols.
From page 211...
... 2005. Airway gene therapy and cystic fibrosis.


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