Universally conserved translation initiation factors

The process by which translation is initiated has long been considered similar in Bacteria and Eukarya but accomplished by a different unrelated set of factors in the two cases. This not only implies separate evolutionary histories for the two but also implies that at the universal ancestor stage, a translation initiation mechanism either did not exist or was of a different nature than the extant processes. We demonstrate herein that (i) the “analogous” translation initiation factors IF-1 and eIF-1A are actually related in sequence, (ii) the “eukaryotic” translation factor SUI1 is universal in distribution, and (iii) the eukaryotic/archaeal translation factor eIF-5A is homologous to the bacterial translation factor EF-P. Thus, the rudiments of translation initiation would seem to have been present in the universal ancestor stage. However, significant development and refinement subsequently occurred independently on both the bacterial lineage and on the archaeal/eukaryotic line.     

Star scientists and institutional transformation: Patterns of invention and innovation in the formation of the biotechnology industry

The most productive (“star”) bioscientists had intellectual human capital of extraordinary scientific and pecuniary value for some 10–15 years after Cohen and Boyer’s 1973 founding discovery for biotechnology [Cohen, S., Chang, A., Boyer, H. & Helling, R. (1973) Proc. Natl. Acad. Sci. USA 70, 3240–3244]. This extraordinary value was due to the union of still scarce knowledge of the new research techniques and genius and vision to apply them in novel, valuable ways. As in other sciences, star bioscientists were very protective of their techniques, ideas, and discoveries in the early years of the revolution, tending to collaborate more within their own institution, which slowed diffusion to other scientists. Close, bench-level working ties between stars and firm scientists were needed to accomplish commercialization of the breakthroughs. Where and when star scientists were actively producing publications is a key predictor of where and when commercial firms began to use biotechnology. The extent of collaboration by a firm’s scientists with stars is a powerful predictor of its success: for an average firm, 5 articles coauthored by an academic star and the firm’s scientists result in about 5 more products in development, 3.5 more products on the market, and 860 more employees. Articles by stars collaborating with or employed by firms have significantly higher rates of citation than other articles by the same or other stars. The U.S. scientific and economic infrastructure has been particularly effective in fostering and commercializing the bioscientific revolution. These results let us see the process by which scientific breakthroughs become economic growth and consider implications for policy.     

Measuring cosmological parameters

In this review, the status of measurements of the matter density (Ω_m), the vacuum energy density or cosmological constant (Ω_Λ), the Hubble constant (H₀), and the ages of the oldest measured objects (t₀) are summarized. Three independent types of methods for measuring the Hubble constant are considered: the measurement of time delays in multiply imaged quasars, the Sunyaev–Zel’dovich effect in clusters, and Cepheid-based extragalactic distances. Many recent independent dynamical measurements are yielding a low value for the matter density (Ω_m ≈ 0.2–0.3). A wide range of Hubble constant measurements appear to be converging in the range of 60–80 km/sec per megaparsec. Areas where future improvements are likely to be made soon are highlighted—in particular, measurements of anisotropies in the cosmic microwave background. Particular attention is paid to sources of systematic error and the assumptions that underlie many of the measurement methods.     

Plasmodium falciparum antigenic diversity: Evidence of clonal population structure

Plasmodium falciparum, the agent of malignant malaria, is one of mankind’s most severe scourges. Efforts to develop preventive vaccines or remedial drugs are handicapped by the parasite’s rapid evolution of drug resistance and protective antigens. We examine 25 DNA sequences of the gene coding for the highly polymorphic antigenic circumsporozoite protein. We observe total absence of silent nucleotide variation in the two nonrepeated regions of the gene. We propose that this absence reflects a recent origin (within several thousand years) of the world populations of P. falciparum from a single individual; the amino acid polymorphisms observed in these nonrepeat regions would result from strong natural selection. Analysis of these polymorphisms indicates that: (i) the incidence of recombination events does not increase with nucleotide distance; (ii) the strength of linkage disequilibrium between nucleotides is also independent of distance; and (iii) haplotypes in the two nonrepeat regions are correlated with one another, but not with the central repeat region they span. We propose two hypotheses: (i) variation in the highly polymorphic central repeat region arises by mitotic intragenic recombination, and (ii) the population structure of P. falciparum is clonal—a state of affairs that persists in spite of the necessary stage of physiological sexuality that the parasite must sustain in the mosquito vector to complete its life cycle.     

National policies for technical change: Where are the increasing returns to economic research?

Improvements over the past 30 years in statistical data, analysis, and related theory have strengthened the basis for science and technology policy by confirming the importance of technical change in national economic performance. But two important features of scientific and technological activities in the Organization for Economic Cooperation and Development countries are still not addressed adequately in mainstream economics: (i) the justification of public funding for basic research and (ii) persistent international differences in investment in research and development and related activities. In addition, one major gap is now emerging in our systems of empirical measurement—the development of software technology, especially in the service sector. There are therefore dangers of diminishing returns to the usefulness of economic research, which continues to rely completely on established theory and established statistical sources. Alternative propositions that deserve serious consideration are: (i) the economic usefulness of basic research is in the provision of (mainly tacit) skills rather than codified and applicable information; (ii) in developing and exploiting technological opportunities, institutional competencies are just as important as the incentive structures that they face; and (iii) software technology developed in traditional service sectors may now be a more important locus of technical change than software technology developed in “high-tech” manufacturing.     

Interactions of the chaperone Hsp104 with yeast Sup35 and mammalian PrP

[PSI+] is a genetic element in yeast for which a heritable change in phenotype appears to be caused by a heritable change in the conformational state of the Sup35 protein. The inheritance of [PSI+] and the physical state of Sup35 in vivo depend on the protein chaperone Hsp104 (heat shock protein 104). Although these observations provide a strong genetic argument in support of the “protein-only” or “prion” hypothesis for [PSI+], there is, as yet, no direct evidence of an interaction between the two proteins. We report that when purified Sup35 and Hsp104 are mixed, the circular dichroism (CD) spectrum differs from that predicted by the addition of the proteins’ individual spectra, and the ATPase activity of Hsp104 is inhibited. Similar results are obtained with two other amyloidogenic substrates, mammalian PrP and β-amyloid 1-42 peptide, but not with several control proteins. With a group of peptides that span the PrP protein sequence, those that produced the largest changes in CD spectra also caused the strongest inhibition of ATPase activity in Hsp104. Our observations suggest that (i) previously described genetic interactions between Hsp104 and [PSI+] are caused by direct interaction between Hsp104 and Sup35; (ii) Sup35 and PrP, the determinants of the yeast and mammalian prions, respectively, share structural features that lead to a specific interaction with Hsp104; and (iii) these interactions couple a change in structure to the ATPase activity of Hsp104.     

Spontaneous mutations recovered as mosaics in the mouse specific-locus test

The specific-locus test (SLT) detects new mutants among mice heterozygous for seven recessive visible markers. Spontaneous mutations can be manifested not only as singleton whole-body mutants in controls (for which we report new data), but as mosaics—either visible (manifesting mottled coat color) in the scored generation (G₂) or masked, among the wild-type parental generation (G₁). Masked G₁ mosaics reveal themselves by producing clusters of whole-body mutants in G₂. We provide evidence that most, if not all, mosaics detected in the SLT (both radiation and control progenies) result from a single-strand spontaneous mutation subsequent to the last premeiotic mitosis and before the first postmeiotic one of a parental genome—the “perigametic interval.” Such events in the genomes of the G₁ and G₀ result, respectively, in visible and masked 50:50 mosaics. Per cell cycle, the spontaneous mutation rate in the perigametic interval is much higher than that in pregamete mitotic divisions. A clearly different locus spectrum further supports the hypothesis of different origin, and casts further doubt on the validity of the doubling-dose risk-estimation method. Because mosaics cannot have arisen in mitotic germ cells, and are not induced by radiation exposure in the perigametic interval, they should not be included in calculations of radiation-induced germ-line mutation rates. For per-generation calculations, inclusion of mosaics yields a spontaneous frequency 1.7 times that calculated from singletons alone for mutations contributed by males; including both sexes, the multiple is 2.2.     

Apparent mtDNA heteroplasmy in Alzheimer’s disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes

In an unprecedented finding, Davis et al. [Davis, R. E., Miller, S., Herrnstadt, C., Ghosh, S. S., Fahy, E., Shinobu, L. A., Galasko, D., Thal, L. J., Beal, M. F., Howell, N. & Parker, W. D., Jr. (1997) Proc. Natl. Acad. Sci. USA 94, 4526–4531] used an unusual DNA isolation method to show that healthy adults harbor a specific population of mutated mitochondrial cytochrome c oxidase (COX) genes that coexist with normal mtDNAs. They reported that this heteroplasmic population was present at a level of 10–15% in the blood of normal individuals and at a significantly higher level (20–30%) in patients with sporadic Alzheimer’s disease. We provide compelling evidence that the DNA isolation method employed resulted in the coamplification of authentic mtDNA-encoded COX genes together with highly similar COX-like sequences embedded in nuclear DNA (“mtDNA pseudogenes”). We conclude that the observed heteroplasmy is an artifact.     

Experimental Research of Fibrous Materials for Two-Stage Filtration of the Intake Air of Internal Combustion Engines

Pollutant properties in intake air to internal combustion engines were analyzed. Mineral dust particles’ influence on accelerated engine components’ wear was discussed. Dust concentration values in the air under various operating conditions in trucks and special vehicles were presented. The idea and necessity for using two-stage filters, operating in a “multi-cyclone–porous partition” system for vehicles operated in dusty air conditions, are presented. Information from the literature information has been presented, showing that impurities in small grain sizes reduce fiber bed absorbency. It has been shown that such a phenomenon occurs during filter material operation, located directly behind the inertial filter (multi-cyclone), which off-road vehicles are equipped with. It results in a greater pressure drop intensity increase and a shorter proper filter operation period. It has been shown that filter material selection for the motor vehicle air filter requires knowledge of the mass of stopped dust per filtration unit area (dust absorption coefficient k_m) determined for a given permissible resistance value Δp_fdop. It has been shown that there is no information on absorption coefficient values for filter materials operating in a two-stage “multi-cyclone–porous partition” separation system. Original methodology and conditions for determining dust absorption coefficient (k_m) of a separation partition, operating under the conditions of two-stage filtration, were presented. The following characteristics were tested: separation efficiency, filtration performance, and pressure drop characteristics of three different filtration partitions. These were A (cellulose), B (cellulose and polyester), and C (cellulose, polyester, and nanofibers layer), working individually and in a two-stage system—behind the cyclone. Granulometric dust composition dosed into the cyclone and cyclone downstream was determined. During tests, conditions corresponding to air filter’s actual operating conditions, including separation speed and dust concentration in the air, were maintained. For the pressure drop values, the dust absorption coefficient (k_m) values of three different filtration partitions (A, B, and C), working individually and in a two-stage system—behind the cyclone—were determined experimentally.     

Single-strand DNA intermediates in phage λ’s Red recombination pathway

An assay was developed to assess early intermediates arising in λ’s Red recombination pathway. Double-strand breaks were delivered in vivo to nonreplicating λ chromosomes. Analysis by blot hybridization of total DNA extracts revealed the following: (i) long (>1.4 kilobases) single-strand DNA (ssDNA) intermediates; (ii) resection proceeding bidirectionally from the break site; (iii) single-strand overhangs of 3′ polarity; and (iv) in the absence of λ’s ninR functions, a requirement of the redα gene product for the production of ssDNA. Therefore, the physical characteristics exhibited by these ssDNA molecules are consistent with their being an early recombination intermediate in the Red recombination pathway as proposed previously from genetic and in vitro biochemical analyses.     

Lipidic cubic phases: A novel concept for the crystallization of membrane proteins

Understanding the mechanisms of action of membrane proteins requires the elucidation of their structures to high resolution. The critical step in accomplishing this by x-ray crystallography is the routine availability of well-ordered three-dimensional crystals. We have devised a novel, rational approach to meet this goal using quasisolid lipidic cubic phases. This membrane system, consisting of lipid, water, and protein in appropriate proportions, forms a structured, transparent, and complex three-dimensional lipidic array, which is pervaded by an intercommunicating aqueous channel system. Such matrices provide nucleation sites (“seeding”) and support growth by lateral diffusion of protein molecules in the membrane (“feeding”). Bacteriorhodopsin crystals were obtained from bicontinuous cubic phases, but not from micellar systems, implying a critical role of the continuity of the diffusion space (the bilayer) on crystal growth. Hexagonal bacteriorhodopsin crystals diffracted to 3.7 Å resolution, with a space group P6₃, and unit cell dimensions of a = b = 62 Å, c = 108 Å; α = β = 90° and γ = 120°.     

Ionic effects on the elasticity of single DNA molecules

We used a force-measuring laser tweezers apparatus to determine the elastic properties of λ-bacteriophage DNA as a function of ionic strength and in the presence of multivalent cations. The electrostatic contribution to the persistence length P varied as the inverse of the ionic strength in monovalent salt, as predicted by the standard worm-like polyelectrolyte model. However, ionic strength is not always the dominant variable in determining the elastic properties of DNA. Monovalent and multivalent ions have quite different effects even when present at the same ionic strength. Multivalent ions lead to P values as low as 250–300 Å, well below the high-salt “fully neutralized” value of 450–500 Å characteristic of DNA in monovalent salt. The ions Mg²⁺ and Co(NH₃)₆³⁺, in which the charge is centrally concentrated, yield lower P values than the polyamines putrescine²⁺ and spermidine³⁺, in which the charge is linearly distributed. The elastic stretch modulus, S, and P display opposite trends with ionic strength, in contradiction to predictions of macroscopic elasticity theory. DNA is well described as a worm-like chain at concentrations of trivalent cations capable of inducing condensation, if condensation is prevented by keeping the molecule stretched. A retractile force appears in the presence of multivalent cations at molecular extensions that allow intramolecular contacts, suggesting condensation in stretched DNA occurs by a “thermal ratchet” mechanism.     

Changes in multiple brain regions underlie species differences in a complex, congenital behavior

The evolutionary brain modifications that produce any complex, congenital behavioral difference between two species have never been identified. Evolutionary processes may (i) alter a single, “higher” brain area that generates and/or coordinates the diverse motor components of a complex act; (ii) separately change independent, “lower” brain areas that modulate the fine motor control of the individual components; or (iii) modify both types of areas. This study explores the brain localization of a species difference in one such behavior, the crowing of chickens (Gallus gallus domesticus) and Japanese quail (Coturnix coturnix japonica). Two major subcomponents of the behavioral difference can be independently transferred with interspecies transplantation of separate brain regions, despite the fact that these components, sound and patterned head movement, occur together in a highly integrated fashion. To our knowledge, this is the first experimental demonstration that species differences in a complex behavior are built up from separate changes to distinct cell groups in different parts of the brain and that these cell groups have independent effects on individual behavioral components.     

A National Survey on Patient Provider Agreements When Prescribing Opioids for Chronic Pain

BackgroundMany national guidelines recommend the use of patient provider agreements (PPAs) when prescribing opioids for chronic pain. There are no standards for PPA content, readability, or administration processes.ObjectiveConduct a national survey of providers who use PPAs to describe the process of administering them, assess views on their utility, and obtain PPAs to evaluate thematic content and readability.DesignCross-sectional electronic survey and request for PPAs.ParticipantsRegistrants for the Safer/Competent Opioid Prescribing Education (SCOPE of Pain) Program between March 2013 and June 2017.Main MeasuresRespondents’ reports on how PPAs are administered and views on their usefulness. A sample of PPAs assessed for themes and readability.Key ResultsUsing a convenience sample of 62,530 SCOPE of Pain registrants, we obtained a cohort of 430 individuals from 43 states who use PPAs. The majority of respondents worked in primary care (64%) and pain (18%) specialties. Reviewing PPAs with patients was primarily done by prescribers (80%), and the average perceived time to administer PPAs was 13 min. Although 66% of respondents thought PPAs were “often” or “always” worth the effort, only 28% considered them “often” or “always” effective in reducing opioid misuse. The PPA reading burden surpassed recommended patient education standards, with only 2.5% at or below fifth-grade reading level. PPAs focused more on rules and consequences of patients’ non-compliance than on a shared treatment plan.ConclusionsMost respondents perceive patient provider agreements (PPAs) as time-consuming and minimally effective in reducing opioid misuse yet still view them as valuable. PPAs are written far above recommended reading levels and serve primarily to convey consequences of non-compliance. Because PPAs are recommended by national safer opioid prescribing guidelines as a risk mitigation strategy, it would be beneficial to develop a standard PPA and study its effectiveness.KEY WORDS: patient provider agreements, chronic pain, opioids     

People mistake the internet’s knowledge for their own

People frequently search the internet for information. Eight experiments (n = 1,917) provide evidence that when people “Google” for online information, they fail to accurately distinguish between knowledge stored internally—in their own memories—and knowledge stored externally—on the internet. Relative to those using only their own knowledge, people who use Google to answer general knowledge questions are not only more confident in their ability to access external information; they are also more confident in their own ability to think and remember. Moreover, those who use Google predict that they will know more in the future without the help of the internet, an erroneous belief that both indicates misattribution of prior knowledge and highlights a practically important consequence of this misattribution: overconfidence when the internet is no longer available. Although humans have long relied on external knowledge, the misattribution of online knowledge to the self may be facilitated by the swift and seamless interface between internal thought and external information that characterizes online search. Online search is often faster than internal memory search, preventing people from fully recognizing the limitations of their own knowledge. The internet delivers information seamlessly, dovetailing with internal cognitive processes and offering minimal physical cues that might draw attention to its contributions. As a result, people may lose sight of where their own knowledge ends and where the internet’s knowledge begins. Thinking with Google may cause people to mistake the internet’s knowledge for their own.

No one can know everything. Throughout history, people have overcome this fundamental limitation of the individual brain by relying on the knowledge of others. Friends, lovers, and colleagues intuitively form “transactive memory systems” that divide the mental labor of attending to, processing, and remembering information between the members of the group (1). These shared cognitive systems allow people to navigate the informational demands of the world in ways that no individual could do alone. No one person needs to know everything—they simply need to know who knows it. More broadly, people frequently build their own understanding on the presumed understanding of others (2, 3). Breakthroughs in cancer treatment and rocket science are possible not because individual experts know everything there is to know on the subject but because people are capable of drawing on and using knowledge that does not reside in their own heads. These forms of knowledge sharing may help explain the remarkable success of the human species (4); they enable people to conquer complex problems, make new scientific discoveries, and manage the minutiae of everyday life. The frequency and facility with which people incorporate others’ knowledge into their own cognitive processes also reveals that individual human cognition is not really individual at all. Thinking, remembering, and knowing are often collaborative, a product of the interplay between internal and external cognitive resources (1–6).Over the past quarter century, human cognition has become increasingly intertwined with a new cognitive collaborator: the internet. The knowledge-sharing systems that long forged connections between individual brains now link to a vast compendium of collective knowledge that can be accessed any time, from anywhere. Like the memory partners that have shaped and supported individual cognition throughout human history, the internet allows for the expansion of the mind by serving as a form of external memory that can be consulted on an as-needed basis (7). However, the internet is also different from traditional memory partners. It knows practically everything and is almost always available. Through search engines like Google, it delivers information in fractions of a second; and it delivers this information seamlessly, dovetailing with internal cognitive processes and providing minimal cues to its contributions. Together, these distinctive features of the internet and online search may blur the boundaries between internal knowledge—stored in personal memory—and external knowledge—found online. They may cause people to mistake the internet’s knowledge for their own. The present research investigates this possibility.In a world in which the answer to virtually any question can be called up at a moment’s notice, people may frequently fail to recognize the limits of their own knowledge. Of course, people are often aware of what they do and do not know; for example, most Americans know that they know the name of the current US president and that they do not know where to find Ulaanbaatar on a map. However, for the wide swath of topics in between—everything that is not immediately known but not immediately known to be unknown—people frequently experience a “feeling of knowing” (8); they believe that they do or could know information, even if they cannot immediately bring it to mind. These feelings of knowing may be falsely confirmed by on-demand access to online information. People often search the internet for information before searching their own memories (9), even when they believe they could probably answer these questions on their own (10). Search engines like Google return answers in fractions of a second (11), often faster than knowledge can be found in—or found to be missing from—long-term memory (12, 13). When the desired information appears on screen before people can finish searching their own memory, they may erroneously believe that they knew it all along. Thinking with Google may cause people to believe that they always knew what they never could have known alone.At times, people may not only believe that knowledge found online could have been found in personal memory; they may believe that they actually did retrieve this knowledge from their own minds. Research on authorship processing (14, 15) and source monitoring (16, 17) reveals that people do not have direct insight into the source of their mental contents; rather, they distinguish between internally and externally generated knowledge based on differences between the typical experiences of recalling information from personal memory versus encountering information in the world. People attribute knowledge to the self when it follows the logical and temporal flow of the stream of consciousness (14, 15)—that is, when it is associated with the cognitive operations involved in thinking alone (16, 17). In contrast, people recognize that information originated outside their heads when it is accompanied by additional sensory and contextual information that does not exist in the environs of the mind (14–17). These implicit rules for differentiating between internal and external knowledge may work well when external knowledge is housed in traditional memory partners. The lengthy, laborious, and embodied process of phoning a friend or consulting a reference volume not only differs from the cognitive operations involved in searching one’s own memory but also provides experiential cues indicating where the information was ultimately found. However, the cognitive operations involved in searching Google are similar to those involved in retrieving facts from one’s own memory: A question is posed and, a short time later, an answer appears (18). Moreover, this information is delivered as unobtrusively as possible. As stated by cofounder Sergey Brin, Google is intentionally designed to be less like an external tool and more like “the third half of your brain” (19)—a knowledge interface so seamless that searching feels like thinking. This interface between internal cognitive processes and online information may further fade from view as users habitually search the internet for information throughout their day-to-day lives (20, 21). As a result, one’s own memory may be the most salient explanation for information that appears on screen—and in mind—and people may misattribute online search results to their own memory. Thinking with Google may cause people to believe they remembered what they actually just found.Eight experiments (n = 1,917) examine the possibility that when people use Google to search for and access information, they fail to accurately distinguish between internal knowledge—retrieved from their own memories—and external knowledge—found on the internet. In a typical experiment, participants answer a series of general knowledge questions either with or without Google. Those who use Google invariably answer more questions correctly. The critical question is not one of performance but of attribution: Do Google users appropriately acknowledge the internet as the source of their knowledge, or do they erroneously misattribute this knowledge to themselves? Experiments 1 through 4 provide evidence that people mistake the internet’s knowledge for their own. After using Google to answer questions, people are more confident in their personal cognitive ability; they are more likely to endorse statements such as “I am smart” and “I have a better memory than most people.” They also erroneously predict that they will perform better on subsequent knowledge tests taken without access to the internet. Beyond providing converging evidence of knowledge misattribution using validated measures (22, 23), these results are also meaningful in their own right. Self-evaluations speak to how interfacing with online information may shape the self-concept, and performance predictions represent a practically important consequence of misattributing online search results to personal memory: overconfidence when the internet’s knowledge is no longer available. Experiments 5 through 8 examine how the speed and seamlessness of internet search may explain these effects.     

Lipophosphoglycan from Leishmania suppresses agonist-induced interleukin 1β gene expression in human monocytes via a unique promoter sequence

Leishmania are parasites that survive within macrophages by mechanism(s) not entirely known. Depression of cellular immunity and diminished production of interleukin 1β (IL-1β) and tumor necrosis factor α are potential ways by which the parasite survives within macrophages. We examined the mechanism(s) by which lipophosphoglycan (LPG), a major glycolipid of Leishmania, perturbs cytokine gene expression. LPG treatment of THP-1 monocytes suppressed endotoxin induction of IL-1β steady-state mRNA by greater than 90%, while having no effect on the expression of a control gene. The addition of LPG 2 h before or 2 h after endotoxin challenge significantly suppressed steady-state IL-1β mRNA by 90% and 70%, respectively. LPG also inhibited tumor necrosis factor α and Staphylococcus induction of IL-1β gene expression. The inhibitory effect of LPG is agonist-specific because LPG did not suppress the induction of IL-1β mRNA by phorbol 12-myristate 13-acetate. A unique DNA sequence located within the −310 to −57 nucleotide region of the IL-1β promoter was found to mediate LPG’s inhibitory activity. The requirement for the −310 to −57 promoter gene sequence for LPG’s effect is demonstrated by the abrogation of LPG’s inhibitory activity by truncation or deletion of the −310 to −57 promoter gene sequence. Furthermore, the minimal IL-1β promoter (positions −310 to +15) mediated LPG’s inhibitory activity with dose and kinetic profiles that were similar to LPG’s suppression of steady-state IL-1β mRNA. These findings delineated a promoter gene sequence that responds to LPG to act as a “gene silencer,” a function, to our knowledge, not previously described. LPG’s inhibitory activity for several mediators of inflammation and the persistence of significant inhibitory activity 2 h after endotoxin challenge suggest that LPG has therapeutic potential and may be exploited for therapy of sepsis, acute respiratory distress syndrome, and autoimmune diseases.     

Functional domains are specified to single-cell resolution in a Drosophila epithelium

Specification of pattern is fundamental to the development of a multicellular organism. The Malpighian (renal) tubule of Drosophila melanogaster is a simple epithelium that proliferates under the direction of a single tip cell into three morphologically distinct domains. However, systematic analysis of a panel of over 700 P{GAL4} enhancer trap lines reveals unexpected richness for such an apparently simple tissue. Using numerical analysis, it was possible formally to reconcile apparently similar or complementary expression domains and thus to define at least five genetically defined domains and multiple cell types. Remarkably, the positions of domain boundaries and the numbers of both principal and secondary (“stellate”) cell types within each domain are reproducible to near single-cell precision between individual animals. Domains of physiological function were also mapped using transport or expression assays. Invariably, they respect the boundaries defined by enhancer activity. These genetic domains can also be visualized in vivo, both in transgenic and wild-type flies, providing an “identified cell” system for epithelial physiology. Building upon recent advances in Drosophila Malpighian tubule physiology, the present study confirms this tissue as a singular model for integrative physiology.     

Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains

Germ-line mutations of the BRCA1 gene predispose women to early-onset breast and ovarian cancer by compromising the gene’s presumptive function as a tumor suppressor. Although the biochemical properties of BRCA1 polypeptides are not understood, their expression pattern and subcellular localization suggest a role in cell-cycle regulation. When resting cells are induced to proliferate, the steady-state levels of BRCA1 increase in late G₁ and reach a maximum during S phase. Moreover, in S phase cells, BRCA1 polypeptides are hyperphosphorylated and accumulate into discrete subnuclear foci termed “BRCA1 nuclear dots.” BRCA1 associates in vivo with a structurally related protein termed BARD1. Here we show that the steady-state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G₁ phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G₁- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression.     

Neural components of topographical representation

Studies of patients with focal brain damage suggest that topographical representation is subserved by dissociable neural subcomponents. This article offers a condensed review of the literature of “topographical disorientation” and describes several functional MRI studies designed to test hypotheses generated by that review. Three hypotheses are considered: (i) The parahippocampal cortex is critically involved in the acquisition of exocentric spatial information in humans; (ii) separable, posterior, dorsal, and ventral cortical regions subserve the perception and long term representation of position and identity, respectively, of landmarks; and (iii) there is a distinct area of the ventral occipitotemporal cortex that responds maximally to building stimuli and may play a role in the perception of salient landmarks. We conclude with a discussion of the inferential limitations of neuroimaging and lesion studies. It is proposed that combining these two approaches allows for inferences regarding the computational involvement of a neuroanatomical substrate in a given cognitive process although neither method can strictly support this conclusion alone.     

Sematech: Purpose and Performance

In previous research, we have found a steep learning curve in the production of semiconductors. We estimated that most production knowledge remains internal to the firm, but that a significant fraction “spills over” to other firms. The existence of such spillovers may justify government actions to stimulate research on semiconductor manufacturing technology. The fact that not all production knowledge spills over, meanwhile, creates opportunities for firms to form joint ventures and slide down their learning curves more efficiently. With these considerations in mind, in 1987 14 leading U.S. semiconductor producers, with the assistance of the U.S. government in the form of $100 million in annual subsidies, formed a research and development (R&D) consortium called Sematech. In previous research, we estimated that Sematech has induced its member firms to lower their R&D spending. This may reflect more sharing and less duplication of research, i.e., more research being done with each R&D dollar. If this is the case, then Sematech members may wish to replace any funding withdrawn by the U.S. government. This in turn would imply that the U.S. government’s contributions to Sematech do not induce more semiconductor research than would otherwise occur.