NIH funding longevity by gender.

Women have achieved parity with men among biomedical science degree holders but remain underrepresented in academic positions. The National Institutes of Health (NIH)-the world's largest public funder of biomedical research-receives less than one-third of its new grant applications from women. Correspondingly, women compose less than one-third of NIH research grantees, even though they are as successful as men in obtaining first-time grants. Our study examined women's and men's NIH funding trajectories over time (n = 34,770), exploring whether women remain funded at the same rate as men after receiving their first major research grants. A survival analysis demonstrated a slightly lower funding longevity for women. We next examined gender differences in application, review, and funding outcomes. Women individually held fewer grants, submitted fewer applications, and were less successful in renewing grants-factors that could lead to gender differences in funding longevity. Finally, two adjusted survival models that account for initial investigator characteristics or subsequent application behavior showed no gender differences, suggesting that the small observed longevity differences are affected by both sets of factors. Overall, given men's and women's generally comparable funding longevities, the data contradict the common assumption that women experience accelerated attrition compared with men across all career stages. Women's likelihood of sustaining NIH funding may be better than commonly perceived. This suggests a need to explore women's underrepresentation among initial NIH grantees, as well as their lower rates of new and renewal application submissions.

An Analysis of Recent FDA Oncology Scientific Publications.

In addition to its primary regulatory role, the Office of Hematology and Oncology Products at the U.S. Food and Drug Administration (FDA) is engaged in many forms of scientific authorship. During the period of 2010 to 2018, FDA oncology staff contributed to 356 publications in the scientific literature. Here, we collaborated with analysts in the Office of Program Planning, Analysis, and Evaluation at the National Institute of General Medical Sciences, National Institutes of Health (NIH), to present a series of analyses aimed at quantifying the characteristics and potential impact of these contributions, as well as characterizing the areas of work addressed. We found that FDA oncology papers are enriched for high-impact publications and have about two times the number of citations as an average NIH-funded paper. Further impact of the publications was measured based on the presence of 65 publications that were cited by guidelines and 12 publications cited by publicly listed clinical trials. The results seen here are promising in determining the impact of FDA oncology publication work but prompt further investigation into longer-term impacts, such as the influence of this work on other regulatory activities at FDA. IMPLICATIONS FOR PRACTICE: This article describes the first comprehensive study of scientific publications produced by U.S. Food and Drug Administration (FDA) oncology staff. The analysis illustrates that staff are highly engaged in publishing in the scientific literature in addition to completing regulatory review work. Publications are generally in clinical medicine, consistent with the large number of medical oncologists working at the Office of Hematology and Oncology Products (OHOP). OHOP publications generally focus either on communicating important regulatory work (approval summaries) or highlighting regulatory science issues to encourage dialogue with the scientific community (commentaries, reviews, and expert working papers). The analysis also suggests that several FDA oncology publications may influence clinical guidelines, but further work is needed to evaluate impact.

Increasing Clinician-Scientist Workforce Diversity through the National Institute of General Medical Sciences' Medical Scientist Training Program.

The National Institute of General Medical Sciences Medical Scientist Training Program (MSTP) has been successful in producing clinician-scientists, with a majority of graduates pursuing research-related careers. However, there are a number of areas of continuing concern for the program. In particular, women and individuals from certain racial and ethnic backgrounds remain persistently underrepresented in MSTPs relative to the average college-aged U.S. population and to students receiving life sciences bachelor's degrees. The authors, who include leaders of NIGMS, identify a number of challenges and opportunities for enhancing diversity, equity and inclusion in the MSTPs and suggest strategies for addressing them.

Protein crowding tunes protein stability.

Thirty percent of a cell's volume is filled with macromolecules, and protein chemistry in a crowded environment is predicted to differ from that in dilute solution. We quantified the effect of crowding by globular proteins on the equilibrium thermodynamic stability of a small globular protein. Theory has long predicted that crowding should stabilize proteins, and experiments using synthetic polymers as crowders show such stabilizing effects. We find that protein crowders can be mildly destabilizing. The destabilization arises from a competition between stabilizing excluded-volume effects and destabilizing nonspecific interactions, including electrostatic interactions. This competition results in tunable stability, which could impact our understanding of the spatial and temporal roles of proteins in living systems.

Volume exclusion and soft interaction effects on protein stability under crowded conditions.

Most proteins function in nature under crowded conditions, and crowding can change protein properties. Quantification of crowding effects, however, is difficult because solutions containing hundreds of grams of macromolecules per liter often interfere with the observation of the protein being studied. Models for macromolecular crowding tend to focus on the steric effects of crowders, neglecting potential chemical interactions between the crowder and the test protein. Here, we report the first systematic, quantitative, residue-level study of crowding effects on the equilibrium stability of a globular protein. We used a system comprising poly(vinylpyrrolidone)s (PVPs) of varying molecular weights as crowding agents and chymotrypsin inhibitor 2 (CI2) as a small globular test protein. Stability was quantified with NMR-detected amide (1)H exchange. We analyzed the data in terms of hard particle exclusion, confinement, and soft interactions. For all crowded conditions, nearly every observed residue experiences a stabilizing effect. The exceptions are residues for which stabilities are unchanged. At a PVP concentration of 100 g/L, the data are consistent with theories of hard particle exclusion. At higher concentrations, the data are more consistent with confinement. The data show that the crowder also stabilizes the test protein by weakly binding its native state. We conclude that the role of native-state binding and other soft interactions needs to be seriously considered when applying both theory and experiment to studies of macromolecular crowding.

Tracing Long-Term Outcomes of Basic Research Using Citation Networks.

In recent years, the science of science policy has been facilitated by the greater availability of and access to digital data associated with the science, technology, and innovation enterprise. Historically, most of the studies from which such data are derived have been econometric or "scientometric" in nature, focusing on the development of quantitative data, models, and metrics of the scientific process as well as outputs and outcomes. Broader definitions of research impact, however, necessitate the use of qualitative case-study methods. For many years, U.S. federal science agencies such as the National Institutes of Health have demonstrated the impact of the research they support through tracing studies that document critical events in the development of successful technologies. A significant disadvantage and barrier of such studies is the labor-intensive nature of a case study approach. Currently, however, the same data infrastructures that have been developed to support scientometrics may also facilitate historical tracing studies. In this paper, we describe one approach we used to discover long-term, downstream outcomes of research supported in the late 1970's and early 1980's by the National Institute of General Medical Sciences, a component of the National Institutes of Health.

Protein nuclear magnetic resonance under physiological conditions.

Almost everything we know about protein biophysics comes from studies on purified proteins in dilute solution. Most proteins, however, operate inside cells where the concentration of macromolecules can be >300 mg/mL. Although reductionism-based approaches have served protein science well for more than a century, biochemists now have the tools to study proteins under these more physiologically relevant conditions. We review a part of this burgeoning postreductionist landscape by focusing on high-resolution protein nuclear magnetic resonance (NMR) spectroscopy, the only method that provides atomic-level information over an entire protein under the crowded conditions found in cells.

Using database linkages to measure innovation, commercialization, and survival of small businesses.

Here, we report the results of an outcomes evaluation of the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Programs at the National Institute of General Medical Sciences (NIGMS). Since the programs' inception, assessments of the SBIR/STTR programs at several federal agencies have utilized surveys of former grantees as the primary source of data. Response rates have typically been low, making non-response bias a potential threat to the validity of some of these studies' results. Meanwhile, the availability of large publicly-available datasets continues to grow and methods of text mining and linking databases continue to improve. By linking NIGMS grant funding records, U.S. Patent and Trademark Office data, and business intelligence databases, we explored innovation, commercialization and survival for recipients of NIGMS SBIR/STTR funding. In doing so, we were able to more completely assess several key outcomes of the NIGMS SBIR/STTR program. Our evaluation demonstrated that the NIGMS program performed above baseline expectations along all dimensions, and comparably to other federal agency SBIR/STTR grant programs. In addition, we show that the use of extant data increasingly is a viable, less expensive, and more reliable approach to gathering data for evaluation studies.

Competitive interactions of ligands and macromolecular crowders with maltose binding protein.

Cellular signaling involves a cascade of recognition events occurring in a complex environment with high concentrations of proteins, polysaccharides, and other macromolecules. The influence of macromolecular crowders on protein binding affinity through hard-core repulsion is well studied, and possible contributions of protein-crowder soft attraction have been implicated recently. Here we present direct evidence for weak association of maltose binding protein (MBP) with a polysaccharide crowder Ficoll, and that this association effectively competes with the binding of the natural ligand, maltose. Titration data over wide ranges of maltose and Ficoll concentrations fit well with a three-state competitive binding model. Broadening of MBP (1)H-(15)N TROSY spectra by the addition of Ficoll indicates weak protein-crowder association, and subsequent recovery of sharp NMR peaks upon addition of maltose indicates that the interactions of the crowder and the ligand with MBP are competitive. We hypothesize that, in the Escherichia coli periplasm, the competitive interactions of polysaccharides and maltose with MBP could allow MBP to shuttle between the peptidoglycan attached to the outer membrane and the ATP-binding cassette transporter in the inner membrane.

An upper limit for macromolecular crowding effects.

BACKGROUND: Solutions containing high macromolecule concentrations are predicted to affect a number of protein properties compared to those properties in dilute solution. In cells, these macromolecular crowders have a large range of sizes and can occupy 30% or more of the available volume. We chose to study the stability and ps-ns internal dynamics of a globular protein whose radius is ~2 nm when crowded by a synthetic microgel composed of poly(N-isopropylacrylamide-co-acrylic acid) with particle radii of ~300 nm. RESULTS: Our studies revealed no change in protein rotational or ps-ns backbone dynamics and only mild (~0.5 kcal/mol at 37°C, pH 5.4) stabilization at a volume occupancy of 70%, which approaches the occupancy of closely packing spheres. The lack of change in rotational dynamics indicates the absence of strong crowder-protein interactions. CONCLUSIONS: Our observations are explained by the large size discrepancy between the protein and crowders and by the internal structure of the microgels, which provide interstitial spaces and internal pores where the protein can exist in a dilute solution-like environment. In summary, microgels that interact weakly with proteins do not strongly influence protein dynamics or stability because these large microgels constitute an upper size limit on crowding effects.

Using NMR-detected backbone amide 1H exchange to assess macromolecular crowding effects on globular-protein stability.

The biophysical properties of proteins in the crowded intracellular environment are expected to differ from those for proteins in dilute solution. Crowding can be studied in vitro through addition of polymers at high concentrations. NMR-detected amide (1)H exchange is the only technique that provides equilibrium stability data for proteins on a per-residue basis under crowded conditions. We describe the theory behind amide (1)H exchange and provide a detailed description of the experiments used to quantify globular protein stability at the residue level under crowded conditions. We also discuss the detection of weak interactions between the test protein and the crowding molecules.