NIH Director Research Articles

AUTHOR REPLY

We thank the reviewer for their comments and agree that focusing on recruitment of women and underrepresented minorities as speakers will bring diversity of opinion to the podium which will greatly enrich the AUA meeting. The responsibility of having diversity of the podium cannot fall on women and minorities alone, it needs to come from a top down approach. Recently, the NIH director Francis Collins declared that he would no longer participate in all male panels or “manels.” He felt this declaration was necessary despite the fact that the NIH has had a longstanding policy focused on the inclusion of women on panels.

NIH director apologizes for racism in biomedical research

NIH director apologizes for racism in biomedical research

NIH director apologizes for structural racism in biomedical research, vows change

NIH director apologizes for structural racism in biomedical research, vows change

NIH director apologizes for ‘structural racism,’ pledges actions

NIH director apologizes for ‘structural racism,’ pledges actions

Editors' note: Understanding and addressing gender equity for women in neurology

In “Understanding and addressing gender equity for women in neurology,” Dr. Julie Silver proclaims the need for medical schools, academic medical centers, funding agencies, journals, and medical societies to recognize and correct gender disparities for women in medicine and in neurology, in particular. Dr. Jennifer Graves responds that systematic biases must be overcome via advocacy from all neurologists, akin to the actions of NIH Director Francis Collins who refused to sit on an all-male scientific panel. Dr. Jill Farmer praises both Dr. Silver and the women who paved the way to allow today's women physicians to be “liberate[d], empower[ed] and embolden[ed].” Dr. Elizabeth Loder also lauds Dr. Silver for drawing attention to the multitude of challenges women clinicians face including sexual harassment, pay disparities, blatant discrimination, and sexism. Dr. Silver responds to the comments of these 3 women physicians in a befitting manner by highlighting and praising the accomplishments of each in addition to addressing the substance of their replies. In “Understanding and addressing gender equity for women in neurology,” Dr. Julie Silver proclaims the need for medical schools, academic medical centers, funding agencies, journals, and medical societies to recognize and correct gender disparities for women in medicine and in neurology, in particular. Dr. Jennifer Graves responds that systematic biases must be overcome via advocacy from all neurologists, akin to the actions of NIH Director Francis Collins who refused to sit on an all-male scientific panel. Dr. Jill Farmer praises both Dr. Silver and the women who paved the way to allow today's women physicians to be “liberate[d], empower[ed] and embolden[ed].” Dr. Elizabeth Loder also lauds Dr. Silver for drawing attention to the multitude of challenges women clinicians face including sexual harassment, pay disparities, blatant discrimination, and sexism. Dr. Silver responds to the comments of these 3 women physicians in a befitting manner by highlighting and praising the accomplishments of each in addition to addressing the substance of their replies.

Reader response: Understanding and addressing gender equity for women in neurology.

For over 20 years, we have had the pipeline in place—training near equal numbers of women and men in neurology, yet gender disparity remains. The time has come for all genders to come to the table for action. Dr. Silver,1 in her article “Understanding and Addressing Gender Equity for Women in Neurology,” astutely recommends we “plan an intentional path forward” with systematic methods for institutional change and metrics to judge institutional performance. As Dr. Silver also highlights, the pay gap (women neurologists are paid 85 cents on the dollar2) is only one area of inequity. There are critical gaps in leadership, awards, publishing, recruitment offers and endowed chair positions, and promotion.1 The data suggest that inequity is not a pipeline issue nor is it related to pregnancy or part-time positions2; it is related to biases of systems. These are fixable. Progress will be more rapid with active advocacy from diverse neurologists and with a strong intolerance of gross inequities and harassment. We have to shoulder the burden as a community and work to advance each other in the process. NIH Director Francis Collin's recent decision to not sit on any scientific panel without female members is an excellent example of how to set the tone from a leadership position.3

The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society

As the Brain Research through Advancing Neurotechnologyies, better known as the BRAIN Initiative moves forward at a rapid pace increasing attention has focused on neuroethics. The National Institutes of Health recently mandated a review of the progress of the BRAIN Initiative progress with the goal of fine-tuning its future directions. The BRAIN Working Group 2 focused its discussion on science while the BRAIN Neuroethics Subgroup focused on neuroethics. The Brain Neuroethics Subgroup deliberated for over a year collecting information and recommendations through in person and video meetings, a public one-day neuroethics symposium and soliciting input from neuroscientists and neuroethicist’s. The resulting report entitled “The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society” was accepted by Director of NIH in October of 2019. The recommendations span many BRAIN research neuroethics concerns including privacy considerations, the use of nonhuman primate model systems, neural modulation and enhancement, subject participation in BRAIN research and equity in neuroscience research. Further the group recommended a transformative project whose goal of detailing the scientific mechanisms and ethical underpinnings of consciousness is one of the most daunting issues that impact our perceptions of ourselves. It is anticipated that the report?s recommendations will provide a foundation or “roadmap” for ensuring that neuroethics and BRAIN research move forward as an integrated effort thereby insuring that BRAIN research is of the highest quality.

NIH Director Francis Collins honored for work to bridge science and religion

NIH Director Francis Collins honored for work to bridge science and religion

NIH consortium to tackle COVID-19 research

The US National Institutes of Health has formed a partnership among multiple federal agencies and pharmaceutical companies to speed the response to the COVID-19 pandemic. The goal of the partnership, called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), is to break down traditional barriers between companies and the federal government to get safe, effective treatments and vaccines to the public as quickly as possible. The partnership first met on April 3, and four areas of focus came out of it, according to NIH director Francis Collins: preclinical drugs, repurposing drugs, clinical trial capacity, and vaccine development. ACTIV is being led by the Foundation for the National Institutes of Health, an NIH-associated nonprofit. Work between government agencies and companies can often be complicated by intellectual property issues, but those have been largely put aside in an attempt to accelerate the process, says David Wholley, senior vice president of research partnerships at

Perceptions of the adult US population regarding the novel coronavirus outbreak.

The Coronavirus Disease 2019 (COVID-19) outbreak is spreading globally. Although COVID-19 has now been declared a pandemic and risk for infection in the United States (US) is currently high, at the time of survey administration the risk of infection in the US was low. It is important to understand the public perception of risk and trust in sources of information to better inform public health messaging. In this study, we surveyed the adult US population to understand their risk perceptions about the COVID-19 outbreak. We used an online platform to survey 718 adults in the US in early February 2020 using a questionnaire that we developed. Our sample was fairly similar to the general adult US population in terms of age, gender, race, ethnicity and education. We found that 69% of the respondents wanted the scientific/public health leadership (either the CDC Director or NIH Director) to lead the US response to COVID-19 outbreak as compared to 14% who wanted the political leadership (either the president or Congress) to lead the response. Risk perception was low (median score of 5 out of 10) with the respondents trusting health professionals and health officials for information on COVID-19. The majority of respondents were in favor of strict infection prevention policies to control the outbreak. Given our results, the public health/scientific leadership should be at the forefront of the COVID-19 response to promote trust.

Translation Initiation Rates Govern Protein Self‐Assembly In Vivo

Living proteomes are necessarily far from equilibrium. Otherwise cells could not use the energy released by phase separation to organize protein activities in space and time. It is paradoxical, then, that reducing protein influx into the proteome ‐‐ which should promote equilibration ‐‐ instead prolongs the lives of organisms from yeast to human. We therefore reasoned that kinetic barriers must exist to delay equilibration, and that these decrease with protein influx. We further hypothesized that the probabilistic nucleation of protein self‐assemblies ‐‐ or deposits ‐‐ could underlie those barriers. To investigate the effects of influx on protein deposition, we probed phase boundaries and nucleation barriers for structurally diverse protein assemblies at different rates of translation initiation in living cells. We discovered that at protein concentrations that were globally supersaturated with respect to deposition as amyloids or other ordered phases, rapid translation promoted nucleation and thereby equilibration of that protein. We tentatively attribute this effect to unexpectedly slow diffusion of proteins away from sites of translation. The resulting local accumulation appears to facilitate protein clustering into nucleation competent multimers, even at global concentrations that are subsaturated with respect to liquid‐liquid phase separation. Finally, we show that longevity‐enhancing reductions in global protein initiation, as occur during stress responses or calorie restriction, similarly sharpen phase boundaries and nucleation barriers. Together, these observations suggest that living proteomes are supersaturated with respect to highly ordered, collectively lethal deposits.Support or Funding InformationThis work was funded by NIH Director’s Early Independence Award DP5‐OD009152, NIH grant P30 AG035982, and the Stowers Institute for Medical Research.

Carboxyspermidine Dehydrogenase of Spermidine Biosynthesis from Bacteroides fragilis

The human gut microbiome performs a host of metabolic processes which remain largely unstudied, many of which have implications for human health. For example, human cells uptake the microbial polyamine spermidine ( 1), and increased spermidine levels are associated with the progression of pancreatic and colon cancers ( 2, 3). Thus gut microbe spermidine biosynthesis is a potential therapeutic target. Spermidine is produced by the dominant gut microbes via a unique enzymatic pathway ( 4). The first enzyme in this pathway is carboxyspermidine dehydrogenase (CASDH), an NAD(P)H‐dependent saccharopine dehydrogenase expected to catalyze the reductive condensation of either 1,3‐diaminopropane or putrescine with L‐aspartate semialdehyde to form carboxynorspermidine or carboxyspermidine, respectively ( 5). CASDH enzymes involved in spermidine biosynthesis have not been structurally or kinetically characterized from any species. We propose the characterization of CASDH from a dominant gut microbial species using X‐ray crystallography and steady‐state kinetic analysis. The CASDH gene from Bacteroides fragilis was chosen as this species is known to adhere to colon cancer epithelial cells and has been associated with tumor progression. We have successfully expressed BfCASDH in an E. coli BL21 expression cell line and purified it via affinity chromatography. Crystallization trials and the development of kinetic assays are currently underway. X‐ray crystal structures of BfCASDH will reveal the active site structure and the amino acid residues involved in binding and catalysis. In addition, our kinetic assays will confirm the preferred substrate identities and enzymatic activities of the BfCASDH. These data will contribute basic science knowledge necessary for the future explorations of potential inhibitors.Support or Funding InformationKT was supported by NIH BLaST Undergraduate Research Award RL5GM118990. BLaST is supported by the NIH Common Fund, through the Office of Strategic Coordination, Office of the NIH Director with the linked awards: TL4GM118992, RL5GM118990, & UL1GM118991.

Day and Night Comparison to Maximize Learning in Sprague Dawley Rats (Rattus norvegicus)

Domesticated mice and laboratory rats have been traditionally viewed as nocturnal creatures, the vast majority of their daily activity occurring during the “dark” phase of their circadian cycle. Behavioral studies of rats have been traditionally performed during their “light” period when rats should be sleeping. The purpose of this study is to examine whether learning using a spatial, novel object recognition paradigm is enhanced if rats are trained and tested during the dark phase of their cycle rather than the light phase. 10 Sprague Dawley rats were placed in an open field apparatus and observed for 6 minutes at a time during their “light” phase. Measurements were made of distance traveled within the open field, speed of travel, time spent within different areas of the field, time spent mobile and immobile, time spent on grooming behavior, and time spent “rearing” (standing upright). Learning was assessed by observing differences in time spent with a novel toy and a familiar toy. All tests were repeated 1 week later during the rats’ “dark” phase, and results for the two phases were compared using a t‐test. Results showed no evidence of learning in either the light or dark phases, indicated by an increased time spent interacting with the non‐novel object compared to the novel object. Locomotor activity, total time spent interacting with both objects, and rearing behavior were significantly increased during the dark phase, while total distance traveled was significantly lower, which is likely related to the increased rearing. Though these results do not indicate enhanced learning in the rats during the dark phase, the observed differences in activity and behaviors compared with the light phase warrant further study as they could have implications for other behavior experiments performed on rats during each phase.Support or Funding InformationResearch reported in this publication was supported by the NIH Common Fund, through the Office of Strategic Coordination, Office of the NIH Director with the linked awards: TL4GM118992, RL5GM118990, UL1GM118991. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. UAF is an affirmative action/equal employment opportunity employer and educational institution: www.alaska.edu/nondiscrimination.

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway

The transmembrane domain recognition complex (TRC) targets cytoplasmic C‐terminal tail‐anchored (TA) proteins to their respective membranes in the endoplasmic reticulum (ER), Golgi and mitochondria. It is composed of three proteins, GET4, BAG6 and GET5. We identified an individual with compound heterozygous missense changes (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70–90% in his fibroblasts, suggesting a possible defect in TA protein targeting. He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism and delayed bone age. Indeed, we found the TA protein, syntaxin 5, is poorly targeted to Golgi membranes compared to normal controls. Since GET4 regulates ER to Golgi transport, we hypothesized it would be disrupted in his fibroblasts, and indeed retrograde (but not anterograde) transport is significantly reduced. Despite reduction in these TRC proteins their mRNA levels are unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA‐approved proteasome inhibitor Bortezomib (10nM) restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual with GET4 mutations and suggests a potential therapy.Support or Funding InformationThis work was supported by grant R01DK99551 and The Rocket Fund; the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director; and the NHGRI Intramural Research Program of the National Institutes of Health.

A Combination Therapy of Cisplatin and Lovastatin Reduces Ras Activation in an A375 Melanoma Cell Line

In many cancers mutations in the Ras protein lead to cancer growth and metastasis. In a mutated form, Ras allows cells to avoid a normally programed death called apoptosis. Ras is a GTP‐binding protein and attaches to the cell membrane through a prenylated tail. When attached, it will activate and signal for the promotion of cell survival. The prenylated tail and membrane insertion will keep Ras in its activated state. Typical antineoplastic agents are highly toxic therapies, but by using them in combination with alternative therapies such as lovastatin, proliferating cells may be held in check with reduced side effects. The purpose of these experiments was to examine Ras prenylation and activation in a melanoma cell line, following treatment with a combination of lovastatin and cisplatin. Flow cytometry using annexin‐V apoptosis assay was performed to determine drug toxicities for each drug and in combination. Melanoma cells were treated for 48 with 10 uM lovastatin, then 1.5 ug/ml cisplatin was added for an additional 24 hr. Membrane localization of Ras was determined using immunohistochemistry followed by analysis with ImageJ software. The results show that Ras localization to the membrane in cells undergoing the combined treatment was reduced 4‐fold relative to cisplatin alone (p<0.05). These results indicate that statin therapy combined with traditional cancer drugs such as cisplatin may be more effective at slowing cancer growth with lower toxicities, than with cisplatin alone.Support or Funding InformationSupported by the NIH Common Fund, through the Office of Strategic Coordination, Office of the NIH Director with the linked awards: TL4GM118992, RL5GM118990, & UL1GM118991 and a Fort Lewis College Undergraduate Research Grant.

Effects of the Bioflavonoid Quercetin on TLR4 Expression and NFKb activation in A375 Melanoma Cells

Early research indicates that quercetin, a bioflavonoid, seems to limit cancer progression through the down regulation of toll‐like receptor 4 (TLR4). Many cancers, including melanoma, upregulate expression of TLR4 which appears to be associated with cell survival and proliferation. The purpose of this study is to examine TLR4 expression, downstream signaling and changes in target gene expression that may contribute to quercetin’s anti‐proliferative properties. Cells were treated with 100 uM quercetin, vehicle control (DMSO), or no treatment for 24 hours. NFKb activation was quantified by differential centrifugation of cytosolic and nuclear fractions of treated cells by immunoprecipitation and Western blotting. TLR4 was evaluated with immunoblotting. We found that quercetin treated cells had 15% higher NFKb nuclear fraction than the cells with no or vehicle only treatment. TLR4 was, however, effectively downregulated by quercetin treatment. These findings are similar to those seen pancreatic cancer and some other cell models. It appears that this bioflavonoid may have different targets and effects in different types of cancer cells, making it necessary to understand its differential mechanisms of action.Support or Funding InformationSupported by the NIH Common Fund, through the Office of Strategic Coordination, Office of the NIH Director with the linked awards: TL4GM118992, RL5GM118990, UL1GM118991 and by Fort Lewis College MARC‐USTAR.

Pooled Analysis of Global, Regional and Country-Level Prevalence of Childhood Stunting, Wasting and Underweight in 62 Low- and Middle- Income Countries, 2006-2018

Background: In 2016, undernutrition as manifested in childhood stunting, wasting and underweight were estimated to cause 1.0 million deaths, 3.9% of years of life lost, and 3.8% of disability-adjusted life years (DALYs) globally. The high disease burden due to child growth failure demands regular monitoring of its prevalence in all populations. Comparative child growth failure up-to-date information on varying geographical regions around the world is essential both to quantify population health and to prompt decision-makers to proportionately allocate interventional resources. The objective of this study is to calculate the prevalence of undernutrition, including stunting, wasting, and underweight, in low- and middle- income countries (LMICs) using the 2006-2018 demographic and health surveys (DHS), and to explore the sources of regional variations. Method: We pooled prevalence from the DHS data in 62 (LMICs) worldwide that included children aged 0-59 months with information on stunting (n=624,734), wasting (n=625,230) and underweight (n=626,130). Anthropometric measurements (length/height and weight) were assessed by trained field-workers. Pooled prevalence of stunting, wasting and underweight were estimated by random-effects models. Sources of heterogeneity were explored through subgroup meta-analyses and meta-regression. Findings: In these 62 LMICs, overall prevalence was 28.4% (95% CI: 26.3%, 30.7%) for stunting, 5.4% (95% CI: 4.5%, 6.6%) for wasting, and 12.3% (95% CI: 10.4%, 14.6%) for underweight. Substantial heterogeneity was evident ( I 2 =99.9%; P for heterogeneity<0.0001). Subgroup and meta-regression analyses suggested that West Africa, South Asia and Southeast Asia had significantly higher estimated prevalence of all three forms of undernutrition. Estimated prevalence of stunting exceeds 40% among children in Burundi, Democratic Republic of Congo (DR Congo), Madagascar, Mozambique, Niger, Zambia, Yemen, Timor-Leste and Guatemala. Nigeria and Niger (West Africa), India (South Asia) and Timor-Leste (Southeast Asia) displayed the highest prevalence of wasting at approximately 20%. Similarly, the prevalence of underweight of 30% or above was observed in Niger, Bangladesh, India, Yemen, and Timor-Leste. Niger and Timor-Leste consistently displayed very high prevalence of all three forms of undernutrition. In multivariable meta-regression, a combination of malaria prevalence, national gross domestic product (GDP) per capita, and region (a proxy for spatial variation) explained 38%, 32%, and 45% of the variation in stunting, wasting and underweight prevalence respectively. Interpretation: Regional, sub-regional and country disparities in undernutrition still exist. Because of the established health risks of childhood stunting, wasting and underweight, urgent global and local action and leadership are required to assist vulnerable countries to more effectively intervene to achieve the target of the second sustainable development goal — ending all forms of malnutrition by 2030. Funding Statement: Support was provided by NIH Director’s Pioneer Award 1DP1HD086071 (SJS). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: DHS protocols and guidelines were reviewed and approved by the relevant country's Ethical Review Committee and the Institutional Review Board of ICF International, USA. Written informed consent was obtained from the parents or guardians of the children before the survey. The data are entirely de-identified, aggregated and publicly available; therefore, the authors did not seek further ethical clearance.

NIH director pledges to move quickly on recommendations to stop sexual harassment

NIH director pledges to move quickly on recommendations to stop sexual harassment

Cell scientist to watch – Kivanc Birsoy

ABSTRACT Kivanc Birsoy graduated in molecular genetics from Bilkent University, Turkey, and joined the laboratory of Jeffrey Friedman at Rockefeller University, New York City, for his PhD to work on transcriptional regulation and cell programming in adipogenesis. In 2010, Kivanc moved to the Whitehead Institute of Massachusetts Institute of Technology (MIT), Boston, as a postdoctoral fellow with David Sabatini. There, he studied how cancer cells adapt their metabolism in nutrient-deprived environments, and the links between metabolism and mitochondrial dysfunction. Since January 2016, Kivanc has been an Assistant Professor and independent group leader at Rockefeller University. His research focuses on the metabolic pathway changes in cancer and metabolic dysfunction. Kivanc is the recipient of numerous awards such as the Pew-Stewart Scholar Award, Searle Scholar Award, AACR NextGen Award for Transformative Cancer Research, NIH Director's New Innovator Award and the Pershing Square Sohn Prize 2018.

Vaccine Deployment and Ebola Transmission Dynamics Estimation in Eastern DR Congo

Background. Over the last 19 months, the Democratic Republic of the Congo has reported approximately 3000 cases of Ebola virus disease (EVD). Since August 2018, an experimental vaccine has been deployed to curb transmission. Methods. A generalizable data assembly algorithm was developed to automatically curate publicly available cumulative reported case count and vaccine deployment data from the Ministere de la Sante. The Incidence Decay and Exponential Adjustment model was then used to estimate basic and observed reproduction numbers associated with the outbreak for three health zones that have been most affected as well as for the country as a whole. Reproduction number estimates at the national level were paired with a sensitivity analysis to assess immunization rates and to project end-of-year case counts under three different transmission scenarios. Findings. Basic and observed reproduction number estimates at the national level range from 1.13 to 1.99 and from 1.06 to 1.34, respectively. These estimates suggest that approximately 2% to 20% of the affected population across the country has thus far been effectively immunized against EVD and that the outbreak would likely be 4–34 times greater in size today had the vaccine not been deployed. Assuming no changes in transmission dynamics, we estimate that the expected cumulative case count will range between 3479 and 4249 by late December 2019; alternative transmission dynamics scenarios result in lesser and greater case count estimates. Interpretation. Transmission dynamics associated with the outbreak suggest that though the experimental vaccine has likely helped curb the spread of EVD, the outbreak may continue into 2020. Data assembly algorithms like the one presented here will continue to prove useful as this outbreak and others like it persist. Funding. Research reported in this work was supported by the National Institutes of Health through an NIH Director’s New Innovator Award DP2-MD012722.