The Validation of Peer Review through Research Impact Measures and the Implications for Funding Strategies

There is a paucity of data in the literature concerning the validation of the grant application peer review process, which is used to help direct billions of dollars in research funds. Ultimately, this validation will hinge upon empirical data relating the output of funded projects to the predictions implicit in the overall scientific merit scores from the peer review of submitted applications. In an effort to address this need, the American Institute of Biological Sciences (AIBS) conducted a retrospective analysis of peer review data of 2,063 applications submitted to a particular research program and the bibliometric output of the resultant 227 funded projects over an 8-year period. Peer review scores associated with applications were found to be moderately correlated with the total time-adjusted citation output of funded projects, although a high degree of variability existed in the data. Analysis over time revealed that as average annual scores of all applications (both funded and unfunded) submitted to this program improved with time, the average annual citation output per application increased. Citation impact did not correlate with the amount of funds awarded per application or with the total annual programmatic budget. However, the number of funded applications per year was found to correlate well with total annual citation impact, suggesting that improving funding success rates by reducing the size of awards may be an efficient strategy to optimize the scientific impact of research program portfolios. This strategy must be weighed against the need for a balanced research portfolio and the inherent high costs of some areas of research. The relationship observed between peer review scores and bibliometric output lays the groundwork for establishing a model system for future prospective testing of the validity of peer review formats and procedures.     

The Microbial Diversity of Traditional Spontaneously Fermented Lambic Beer

Lambic sour beers are the products of a spontaneous fermentation that lasts for one to three years before bottling. The present study determined the microbiota involved in the fermentation of lambic beers by sampling two fermentation batches during two years in the most traditional lambic brewery of Belgium, using culture-dependent and culture-independent methods. From 14 samples per fermentation, over 2000 bacterial and yeast isolates were obtained and identified. Although minor variations in the microbiota between casks and batches and a considerable species diversity were found, a characteristic microbial succession was identified. This succession started with a dominance of Enterobacteriaceae in the first month, which were replaced at 2 months by Pediococcus damnosus and Saccharomyces spp., the latter being replaced by Dekkera bruxellensis at 6 months fermentation duration.     

Phytoplankton Succession in Recurrently Fluctuating Environments

Coastal marine systems are affected by seasonal variations in biogeochemical and physical processes, sometimes leading to alternating periods of reproductive growth limitation within an annual cycle. Transitions between these periods can be sudden or gradual. Human activities, such as reservoir construction and interbasin water transfers, influence these processes and can affect the type of transition between resource loading conditions. How such human activities might influence phytoplankton succession is largely unknown. Here, we employ a multispecies, multi-nutrient model to explore how nutrient loading switching mode might affect phytoplankton succession. The model is based on the Monod-relationship, predicting an instantaneous reproductive growth rate from ambient inorganic nutrient concentrations whereas the limiting nutrient at any given time was determined by Liebig’s Law of the Minimum. When these relationships are combined with population loss factors, such as hydraulic displacement of cells associated with inflows, a characterization of a species’ niche can be achieved through application of the R* conceptual model, thus enabling an ecological interpretation of modeling results. We found that the mode of reversal in resource supply concentrations had a profound effect. When resource supply reversals were sudden, as expected in systems influenced by pulsed inflows or wind-driven mixing events, phytoplankton were characterized by alternating succession dynamics, a phenomenon documented in inland water bodies of temperate latitudes. When resource supply reversals were gradual, as expected in systems influenced by seasonally developing wet and dry seasons, or annually occurring periods of upwelling, phytoplankton dynamics were characterized by mirror-image succession patterns. This phenomenon has not been reported previously in plankton systems but has been observed in some terrestrial plant systems. These findings suggest that a transition from alternating to “mirror-image” succession patterns might arise with continued coastal zone development, with crucial implications for ecosystems dependent on time-sensitive processes, e.g., spawning events and migration patterns.     

Remnant epitopes, autoimmunity and glycosylation

The role of extracellular proteolysis in innate and adaptive immunity and the interplay between cytokines, chemokines and proteinases are gradually becoming recognized as critical factors in autoimmune processes. Many of the involved proteinases, including those of the plasminogen activator and matrix metalloproteinase cascades, and also several cytokines and chemokines, are glycoproteins. The stability, interactions with inhibitors or receptors, and activities of these molecules are fine-controlled by glycosylation. We studied gelatinase B or matrix metalloproteinase-9 (MMP-9) as a glycosylated enzyme involved in autoimmunity. In the joints of rheumatoid arthritis patients, CXC chemokines, such as interleukin-8/CXCL8, recruit and activate neutrophils to secrete prestored neutrophil collagenase/MMP-8 and gelatinase B/MMP-9. Gelatinase B potentiates interleukin-8 at least tenfold and thus enhances neutrophil and lymphocyte influxes to the joints. When cartilage collagen type II is cleaved at a unique site by one of several collagenases (MMP-1, MMP-8 or MMP-13), it becomes a substrate of gelatinase B. Human gelatinase B cleaves the resulting two large collagen fragments into at least 33 peptides of which two have been shown to be immunodominant, i.e., to elicit activation and proliferation of autoimmune T cells. One of these two remnant epitopes contains a glycan which is important for its immunoreactivity. In addition to the role of gelatinase B as a regulator in adaptive immune processes, we have also demonstrated that it destroys interferon-beta, a typical innate immunity effector molecule and therapeutic cytokine in multiple sclerosis. Furthermore, glycosylated interferon-beta, expressed in Chinese hamster ovary cells, was more resistant to this proteolysis than recombinant interferon-beta from bacteria. These data not only prove that glycosylation of proteins is mechanistically important in the pathogenesis of autoimmune diseases, but also show that targeting of glycosylated proteinases or the use of glycosylated cytokines seems also critical for the treatment of autoimmune diseases.     

Nuclear translocation contributes to regulation of DNA excision repair activities

DNA mutations are circumvented by dedicated specialized excision repair systems, such as the base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR) pathways. Although the individual repair pathways have distinct roles in suppressing changes in the nuclear DNA, it is evident that proteins from the different DNA repair pathways interact [Y. Wang, D. Cortez, P. Yazdi, N. Neff, S.J. Elledge, J. Qin, BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures, Genes Dev. 14 (2000) 927–939; M. Christmann, M.T. Tomicic, W.P. Roos, B. Kaina, Mechanisms of human DNA repair: an update, Toxicology 193 (2003) 3–34; N.B. Larsen, M. Rasmussen, L.J. Rasmussen, Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion 5 (2005) 89–108]. Protein interactions are not only important for function, but also for regulation of nuclear import that is necessary for proper localization of the repair proteins. This review summarizes the current knowledge on nuclear import mechanisms of DNA excision repair proteins and provides a model that categorizes the import by different mechanisms, including classical nuclear import, co-import of proteins, and alternative transport pathways. Most excision repair proteins appear to contain classical NLS sequences directing their nuclear import, however, additional import mechanisms add alternative regulatory levels to protein import, indirectly affecting protein function. Protein co-import appears to be a mechanism employed by the composite repair systems NER and MMR to enhance and regulate nuclear accumulation of repair proteins thereby ensuring faithful DNA repair.     

Escherichia coli O157:H7 Infection in Dutch Belted and New Zealand White Rabbits

Enterohemorrhagic Escherichia coli (EHEC) produce one or more types of Shiga toxins and are foodborne causes of bloody diarrhea. The prototype EHEC strain, Escherichia coli O157:H7, is responsible for both sporadic cases and serious outbreaks worldwide. Infection with E. coli that produce Shiga toxins may lead to diarrhea, hemorrhagic colitis, or (less frequently) hemolytic uremic syndrome, which can cause acute kidney failure. The exact mechanism by which EHEC evokes intestinal and renal disease has not yet been determined. The development of a readily reproducible animal oral-infection model with which to evaluate the full pathogenic potential of E. coli O157:H7 and assess the efficacy of therapeutics and vaccines remains a research priority. Dutch belted (DB) rabbits are reported to be susceptible to both natural and experimental EHEC-induced disease, and New Zealand white (NZW) rabbits are a model for the intestinal manifestations of EHEC infection. In the current study, we compared the pathology caused by E. coli O157:H7 infection in DB and NZW rabbits. Both breeds of rabbits developed clinical signs of disease and intestinal lesions after experimental infection. In addition, one of the infected DB rabbits developed renal lesions. Our findings provide evidence that both breeds are susceptible to E. coli O157:H7 infection and that both may be useful models for investigating EHEC infections of humans.Abbreviations: EHEC, enterohemorrhagic E. coli; HUS, hemolytic uremic syndrome; DB, Dutch belted; STEC, Shiga-toxin– producing E. coli; NZW, New Zealand whiteEscherichia coli O157:H7 is the prototype enterohemorrhagic strain of Shiga-toxin–producing E. coli (STEC), which cause food and waterborne outbreaks and sporadic cases of serious intestinal disease that manifest as diarrhea or hemorrhagic colitis (or both).^12,13,31 Enterohemorrhagic E. coli (EHEC) are a subset of STEC that, in addition to elaborating Shiga toxins, encode the locus of enterocyte effacement, whose products allow intimate attachment of the bacteria to the epithelium.^16,19 Children infected with STEC are more susceptible than adults and may subsequently develop hemolytic uremic syndrome (HUS) that is characterized by hemolytic anemia, thrombocytopenia, and kidney dysfunction or failure.²⁹ Shiga toxins are considered to be major determinants involved in the pathogenesis of these E. coli-induced infections. Indeed, the capacity of STEC to cause bloody diarrhea and HUS derives from the activity of the Stx.^8,25,30,40 The 2 types of Shiga toxins, Stx1 and Stx2, are quite similar in sequence and structure, although their polyclonal antisera do not crossreact.^7,38,39,42A vaccine is currently not available to protect humans from infection or disease caused by STEC. There is a need to define the pathogenic mechanisms by which STEC cause disease and to develop strategies for the prevention and treatment of STEC-mediated HUS. Achieving this goal would benefit from a small animal model that displays gastroenteritis or signs of HUS similar to those occurring in humans. Naturally infected DB rabbits mimic the clinical and pathologic signs (including diarrhea, hemorrhagic colitis, and HUS) produced by STEC in humans.¹¹ In addition, infant NZW rabbits become infected with EHEC and subsequently exhibit diarrhea and hemorrhagic colitis.^20,28,34,36 The current study compared DB and NZW rabbits for breed-specific differences in response to E. coli O157:H7 infection.