In This Issue
ECONOMIC SCIENCES
Federal research investment would transform aging workforce
The first baby boomers will soon turn 65 years old. Driven by this cohort, the average age of the U.S. population is increasing, while younger people are entering the workforce later in life. As a result, to maintain the growth rate of the labor force and to remain competitive in the global economy, U.S. citizens will need to remain productive beyond the age of 65. To remain competitive, the federal government should greatly increase its funding for research in biotechnology, medicine, and nanotechnology, according to Kenneth Manton et al. This research would extend current advances that increase both life expectancy and the length of time workers remain active. The authors fed economic and demographic data from prior national surveys and studies into a mathematical model to predict the state of the future U.S. economy. Based on an interest rate of 6.3% and a moderate amount of research redundancy, they found that the optimal level of research investment is 12.8% of GDP, equal to $1.6 trillion yearly. Current funding for organizations such as the National Institutes of Health is approximately one-third of the optimum. The changes should not disrupt federal budgets if half of the new funding is drawn from taxes on economic growth stimulated by the research. — K.M.
“Labor force participation and human capital increases in an aging population and implications for U.S. research investment” by Kenneth G. Manton, Gene R. Lowrimore, Arthur D. Ullian, XiLiang Gu, and H. Dennis Tolley (see pages 10802–10807)
BIOPHYSICS
Nanoscale order in a designed fiber
In cells, monomers of actin and microtubules self-assemble into cytoskeletal protein filaments. Bioengineers who seek to designfibers for use in industry and regenerative medicine strive to understand and exploit the principles that drive self-assembly. David Papapostolou et al., who previously custom-designed peptides that self-assembled into fibers, now report that rational alteration in design of the peptides introduces significant nanoscale order. The original fibers consisted of monomers of two types bound together by leucine zipper motifs. The resulting coiled-coil fibrils extend for tens of micrometers in length. In the new work, the authors replaced two residues on one monomer with arginine, which bound electrostatically to aspartate on the second monomer and induced further lateral fibril assembly. Compared with the first generation of fibers, the new fibers were thicker and self-assembled at higher temperatures and lower critical concentration, which are desirable industrial properties. The authors characterized the structure using x-ray diffraction and transmission electron microscopy (TEM) to find fibrils packed laterally into a hexagonal lattice of spacing 1.8 nm. Staining necessary for TEM revealed striations on the fibers that were separated by exactly the length of one monomer. Functional groups could be added to the monomers to optimize fiber properties, according to the authors. — K.M.
Nanometer-scale striations in a designed protein fiber.
“Engineering nanoscale order into a designed protein fiber” by David Papapostolou, Andrew M. Smith, Edward D. T. Atkins, Seb J. Oliver, Maxim G. Ryadnov, Louise C. Serpell, and Derek N. Woolfson (see pages 10853–10858)
MEDICAL SCIENCES
Isozymes' multiple roles in cancer
Drugs that interfere with the DNA topoisomerase II enzyme (Top2) are among the best treatments for cancer, yet they can sometimes cause secondary malignancies. Anna Azarova et al. report that the β form of Top2 is largely responsible for these secondary cancers, whereas the α form is most susceptible to chemotherapy. The authors studied the effects of the drug VP-16etoposide on skin cancer rates in mice. They found that mice with the Top2β gene had a higher incidence of skin cancer than those with no Top2 gene. They also found that DNA rearrangements and double-strand breaks caused by VP-16 depend on the presence of Top2β. VP-16's carcinogenic actions could be inhibited by adding a proteasome inhibitor, which suggests that processing of Top2β-DNA complexes by proteasome is an important step in VP-16-induced DNA rearrangement and carcinogenesis. In cells with both forms of Top2, the authors found that the α form is primarily responsible for causing cell death in VP-16-treated cells. Drugs that act specifically on Top2α should be more effective anticancer agents, with less chance of causing secondary cancers, according to the authors. — P.D.
VP-16-induced carcinogenesis model.
“Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies” by Anna M. Azarova, Yi Lisa Lyu, Chao-Po Lin, Yuan-Chin Tsai, Johnson Yiu-Nam Lau, James C. Wang, and Leroy F. Liu (see pages 11014–11019)
MICROBIOLOGY
Manipulating noroviruses
Noroviruses are the most common cause of nonbacterial gastroenteritis worldwide, often causing outbreaks in crowded communities like cruise ships and schools. These pathogens have been difficult to culture and to manipulate in the laboratory, and little is known about their biology. Vernon Ward et al. report a system for growing and for manipulating the genome of murine norovirus (MNV). Baculovirusesand plasmids were used to introduce the complete MNV cDNA sequence into human cells. Complete, functional viral particles were recovered and used to infect mouse macrophage cells and to continue the replication cycle. Recovery of infectious virus from plasmid DNA provides a simple way to apply genetic approaches to answer fundamental questions in norovirus biology and infection. Ward et al. used their system to mutate the cleavage site between viral genes (pro and pol) to identify a sequence that is essential for MNV replication. The authors say that their reverse infectious genetics system will be an essential tool for understanding the replication and molecular biology of this and human noroviruses. — P.D.
Murine RAW264.7 cells infected with recombinant murine norovirus 1.
“Recovery of infectious murine norovirus using pol II-driven expression of full-length cDNA” by Vernon K. Ward, Christopher J. McCormick, Ian N. Clarke, Omar Salim, Christiane E. Wobus, Larissa B. Thackray, Herbert W. Virgin IV, and Paul R. Lambden (see pages 11050–11055)
NEUROSCIENCE
Prion protein's role in Alzheimer's disease
Transmissible spongiform encephalopathies (TSEs) such as “mad cow disease” share many pathological, genetic, and mechanistic features with Alzheimer's disease. Due to the similarities, researchers have sought a link between the diseases. Edward Parkin et al. demonstrate an important role for prion proteins, the causative agents in TSEs, in the formation of β-amyloid peptide, the proposed pathogenic agent of Alzheimer's disease. The authors found that overexpression of the normal form of prion protein (PrPc) in cultured cells reduced β-amyloid formation by inhibiting β-secretase, the first enzyme that cleaves amyloid precursor protein into β-amyloid fragments. Conversely, depletion of PrPc, both in cultured cells and by genetic knockout in mice, increased β-amyloid formation. Additionally, mutations in PrPc linked to familial forms of prion disease did not inhibit β-amyloid formation. The findings identify a previously unknown role for the prion protein, whose normal function had so far remained unclear, in regulating the production of β-amyloid. The authors predict that mutations in PrPc could facilitate β-amyloid formation and possibly contribute to Alzheimer's disease, and suggest that therapies that mimic PrPc's inhibitory effect may offer a therapeutic approach for Alzheimer's disease. — M.M.
“Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein” by Edward T. Parkin, Nicole T. Watt, Ishrut Hussain, Elizabeth A. Eckman, Christopher B. Eckman, Jean C. Manson, Herbert N. Baybutt, Anthony J. Turner, and Nigel M. Hooper (see pages 11062–11067)
