Rockefeller University Research Articles

A life in light - in honor of David Mauzerall on his 95th birthday.

David Mauzerall was born on July 22, 1929 to a working-class family in the small, inland textile town of Sanford, Maine. Those humble origins instilled a lifelong frugality and an innovative spirit. After earning his PhD degree in 1954 in physical organic chemistry with Frank Westheimer at the University of Chicago, he joined The Rockefeller Institute for Medical Research (now University) as a postdoctoral fellow that summer, rose to the rank of professor, and remained there for the rest of his career. His work over more than 60 years encompassed porphyrin biosynthesis, photoinduced electron-transfer reactions in diverse architectures (solutions, bilayer lipid membranes, reaction centers, chromatophores, and intact leaves), the light-saturation curve of photosynthesis, statistical treatments of photoreactions, and "all-things porphyrins." His research culminated in studies he poetically referred to as "listening to leaves" through the use of pulsed photoacoustic spectroscopy to probe the course and thermodynamics of photosynthesis in its native state. His research group was always small; indeed, of 185 total publications, 39 were singly authored. In brief, David Mauzerall has blended a deep knowledge of distinct disciplines of physical organic chemistry, photochemistry, spectroscopy and biophysics with ingenious experimental methods, incisive mathematical analysis, pristine personal integrity, and unyielding love of science to deepen our understanding of photosynthesis in its broadest context. He thought creatively - and always independently. His work helped systematize the fields of photosynthesis and the origin of life and made them more quantitative. The present article highlights a number of salient scientific discoveries and includes comments from members of his family, friends, and collaborators (Gary Brudvig, Greg Edens, Paul Falkowski, Alzatta Fogg, G. Govindjee, Nancy Greenbaum, Marilyn Gunner, Harvey Hou, Denise and Michele Mauzerall, Thomas Moore, and William Parson) as part of a celebration of his 95th birthday.

Proteomic Analysis of Arachis hypogaea Seeds from Different Maturity Classes.

Physiological maturity impacts seed quality through various mechanisms including vigor, desiccation tolerance, dormancy induction, synthesis of raw materials (including seed storage proteins), and the reorganization of metabolisms. Peanut seed development can be classified into seven classes with four incremental stages per class. Based on the mesocarp color, the final three stages are commonly referred to as "orange", "brown", and "black". In 2017, freshly harvested pods from one genotype of runner market-type peanuts grown under conventional practices were obtained from the University of Georgia research facility. The pods were removed from the plant material and 'pod blasted' to reveal the mesocarp. After separation, the remainder of the pod outer layer was removed, and the seeds were segregated for proteomic analysis. The raw peanuts were analyzed by bottom-up LC-MS/MS proteomics, which was conducted by the Proteomics Resource Center at the Rockefeller University, to identify the significant protein composition differences in each maturity class. The proteomic data revealed differentially expressed proteins as a function of maturity class with multiple functions including plant defense, metabolism, cell signaling, nutrient accumulation, and packaging. Understanding the processes needed for seed maturation will enable peanut scientists to evaluate the traits needed for robust germination, hardiness of the seed in response to disease, and nutrient quality.

276 Full Spectrum Town Hall Meetings - Advancing Clinician-Patient-Researcher Engagement for Hidradenitis Suppurativa (HS)

OBJECTIVES/GOALS: Full Spectrum Town Halls (FSTH) were organized to bring together patients, scientists, clinicians, advocates and others interested in Hidradenitis Suppurative (HS) – stakeholders across the spectrum of translational research – to infuse patient experiences and voices into designing HS research METHODS/STUDY POPULATION: The Rockefeller University (RU), Clinical Directors Network (CDN), and the HS Foundation organized three hybrid in-person/online HS FSTHs (2018-2023). The 2018 event focused on patients, describing the current state of HS knowledge and new research into HS biology (T2, T3). Patients shared lived experiences in testimonials and a panel discussion. Advocates described community and mental health resources (T4). The 2021 event returned research results (T2, T3) to the community and updates about treatments in the pipeline (T4). The 2023 FSTH targeted clinicians (T4) addressing a critical translational gap in HS care and presenting best practices in diagnosis, surgical, and medical treatments. RESULTS/ANTICIPATED RESULTS: Impact on science: FSTH attendees joined a Community Engagement Studio providing feedback used to refine study variables/procedures. Attendees joined research studies that advanced understanding HS mechanisms of disease, clinical course and treatment.Impact on patient experience: Participants appreciated having a forum to hear/share experiences of shame, mistrust, misdiagnosis and hope. Feedback improved practices for privacy, consenting, and returning study results. Impact on clinical practice and care: FSTH raised awareness of stigma, need for respect and empathy, and advanced learning about in disease mechanisms, effective biologics, importance of epithelial tunnels and surgical care. DISCUSSION/SIGNIFICANCE: HS is a stigmatizing, poorly understood disease. FSTHs fostered bidirectional learning among scientists, clinicians, patients and other stakeholders. Patients engaged with researchers to improve research design and participate in mechanistic and therapeutic clinical research, advancing the field.

A bibliometrics study on the status quo and hot topics of pathogenesis of psoriasis based on Web of Science.

Psoriasis is an immune-mediated chronic inflammatory skin disease. Great progress has been made in the pathogenesis of psoriasis in recent years, but there is no bibliometric study on the pathogenesis of psoriasis. The purpose of this study was to use bibliometrics method to analyze the research overview and hot spots of pathogenesis of psoriasis in recent 10years, so as to further understand the development trend and frontier of this field. The core literatures on the pathogenesis of psoriasis were searched in the Web of Science database, and analyzed by VOSviewer, CiteSpace, and Bibliometrix in terms of the annual publication volume, country, institution, author, journal, keywords, and so on. A total of 3570 literatures were included. China and the United States were the main research countries in this field, and Rockefeller University was the main research institution. Krueger JG, the author, had the highest number of publications and the greatest influence, and Boehncke (2015) was the most cited local literature. J INVEST DERMATOL takes the top spot in terms of the number of Dermatol articles and citation frequency. The main research hotspots in the pathogenesis of psoriasis are as follows: (1) The interaction between innate and adaptive immunity and the related inflammatory loop dominated by Th17 cells and IL-23/IL-17 axis are still the key mechanisms of psoriasis; (2) molecular genetic studies represented by Long Non-Coding RNA (LncRNA); (3) integrated research of multi-omics techniques represented by gut microbiota; and (4) Exploring the comorbidity mechanism of psoriasis represented by Metabolic Syndrome (MetS). This study is a summary of the current research status and hot trend of the pathogenesis of psoriasis, which will provide some reference for the scholars studying the pathogenesis of psoriasis.

Cell Death & Certainty

I’m Diya Mukherjee, a high school senior based in San Jose, CA with an interest in computational biology and public health. The summer of 2023 marked a turning point for me that is familiar to any science student: my first wet lab experience. I was given the incredible opportunity to participate in the Summer Science Research Program (SSRP) at Rockefeller University in New York, NY, working with research mentors from the Fuchs Lab of Mammalian Cell Biology and Development on a project about the role of inflammation in skin cancer. Cell Death & Certainty depicts an incident from my third week of the program, in which many of my cell samples began to mysteriously die overnight. I deliberately wrote the story with a melodramatic tone, because I think that science so often feels that way.

Bibliometric analysis and description of research trends on T cells in psoriasis over the past two decades (2003–2022)

BackgroundIt is now understood that T cells play a key role in the occurrence and development of psoriasis. Herein, a bibliometric analysis was conducted to summarize the content and trends of T cell-related research in psoriasis. MethodsA bibliometric analysis was conducted on publications pertaining to T cells in psoriasis between 2003 and 2022 retrieved from the Web of Science Core Collection (WoSCC) database using tools such as CiteSpace, the Bibliometrix R package, and VOSviewer. ResultsThe study included a total of 3595 articles authored by 14,188 individuals, including all coauthors in article bylines. The Laboratory for Investigative Dermatology at Rockefeller University, led by James G Krueger, has made significant contributions to this field through focusing on the pathogenesis of psoriasis and exploring the potential of using biological agents to treat psoriasis. Furthermore, targeted inhibitors have significantly impacted the treatment of psoriasis, with researchers focusing on small-molecule targeted drugs as a new area of research that could potentially replace biological agents. ConclusionsResearch has established the efficacy and long-term safety of targeted inhibition of T cell-related targets. Deucravacitinib, a psoriasis treatment drug targeting TYK2 as an allosteric inhibitor, has attracted significant attention and raised high expectations.

Transitions in development - an interview with Amy Shyer and Alan Rodrigues.

Amy Shyer and Alan Rodrigues co-lead the Laboratory of Morphogenesis at Rockefeller University. Having first met as graduate students in Cliff Tabin's lab at Harvard University, they then moved to the Bay Area (California), where Amy carried out her postdoctoral work in Richard Harland's lab while Alan pursued independent postdoctoral research based on the work of Pere Alberch. In 2018, they were recruited to Rockefeller, where their lab investigates how morphogenesis regulates patterning across length-scales, with a focus on collective behaviours operating at the supracellular scale. We met Amy and Alan over zoom to discuss their unique approach to understanding morphogenesis, the importance of emotional resilience in becoming a PI, and the benefits and challenges of running a singular research programme through two people.

Shai Shaham.

Interview with Shai Shaham, who studies glia-neuron interactions in C. elegans at The Rockefeller University.

Research Hotspots in Psoriasis: A Bibliometric Study of the Top 100 Most Cited Articles.

(1) Introduction: Psoriasis is a chronic, immune-mediated disease that negatively impacts patients' quality of life and predisposes them to cardiovascular or metabolic diseases. This paper aims to summarize the knowledge structure and future directions in psoriasis research by means of bibliometrics. (2) Material and methods: The Thomson Reuters Web of Science database was interrogated using preestablished keywords. A list of the top 100 most cited articles focusing solely on psoriasis was compiled and analyzed. VOSviewer software was used to assess and visualize collaboration networks, citation, co-citation and co-wording analysis, and bibliographic coupling. (3) Results: The articles were written by 902 authors from 20 countries and were published in 31 journals. The United States was at the forefront of this field. Griffiths, CEM had the most citations, while the most prolific institution was Rockefeller University, New York City. Pathogenesis, especially key-pathogenic factors, immune pathways, and epidemiology were the most discussed topics. Work published in the last decade focused on the use of biologics. Keywords such as "quality of life", "efficacy", and "necrosis-factor alpha" have been widely used. (4) Conclusion: Research interest regarding psoriasis is high, leading to the rapid development of this field. Treatment modalities, especially novel-targeted therapies, immune pathways, and an integrative approach to such cases are receiving great interest and represent research hotspots in the future.

114-LB: Early Time-Restricted Feeding Reduces Time in Elevated Glucose Range in Adults With Prediabetes

Objective: Early time-restricted feeding (eTRF) is an intermittent fasting strategy restricting caloric intake to the first 6-8 hours of the day. While previous studies have shown that eTRF improves glycemia, it is unclear if the effect is due to associated weight loss or metabolic benefits of the feeding strategy itself. In this study, we evaluated the weight-independent effects of eTRF on glycemia using multiple CGM-based time in range (TIR) metrics. Methods: We conducted a randomized 7-day isocaloric crossover supervised feeding study comparing eTRF (80% of calories consumed between 8am-1pm) to a usual feeding pattern (UFP, 50% of calories consumed after 4pm) among participants with prediabetes and BMI > 28 kg/m2 in a metabolic ward. Participants were randomized 1:1 to eTRF or UFP for days 1-7, then crossed over to the other arm on days 8-14. Food intake was tailored to meet weight stable caloric needs. Participants also wore blinded Abbott Freestyle Libre CGMs throughout the study period. We evaluated time spent below 70 mg/dL (TBR<70), in 70-140 mg/dL (TIR70-140), and in 140-180 mg/dL (TIR140-180) glucose range per arm. Further, we compared TIR140-180 between arms stratified by time of day: Daytime and Overnight (6am-12am and 12am-6am CGM readings, respectively) using linear mixed effect regression adjusting for type and order of intervention. Results: We analyzed data from 10 participants (age 58 (10) years, 50% female, 80% Black, BMI: 37.3 (5.4) kg/m2, HbA1c: 5.8 (0.1)%). Weight change over the study period was not significant (p=0.08). Compared to UFP, eTRF was associated with a decrease in TIR140-180 overall (3.3%, p=0.01) and during Daytime (4.3%, p=0.02) but not Overnight (0.4%, p=0.73). We observed no significant differences in TBR<70 (p=0.28) and TIR70-140 (p=0.88) between arms. Conclusion: eTRF may improve glucose control in adults with prediabetes and high BMI by reducing daytime excursions into the elevated 140-180 mg/dL range. Disclosure S. Barua: None. J. Bruno: None. S. Nasserifar: None. S. M. Vanegas: None. C. Popp: None. J. M. Walker: None. J. O. Aleman: Advisory Panel; Intellihealth, Consultant; Novo Nordisk, Employee; Veterans Administration, Research Support; NIH - National Institutes of Health, Veterans Administration. Funding Shapiro-Silverberg Foundation; The Rockefeller University; Doris Duke Charitable Foundation; American Heart Association (17-SFRN33490004); National Institutes of Health (K08DK117064); National Heart, Lung, and Blood Institute (5T32HL098129-12)

2022 ISPNE Bruce McEwen Lifetime Achievement award: Stress, from molecules to societies

The International Society for Psychoneuroendocrinology meeting in Chicago in 2022 was thrilled to recognize Dr. Robert Sapolsky with the Bruce McEwen Lifetime Achievement award. This is the second year for the award to be named to honor Bruce McEwen and it marks the completion of a special issue edited by Blazej Miziak and Robert Paul Juster in the journal Psychoneuroendocrinology dedicated to Bruce’s legacy and the unfathomable contribution of Allostatic Load to the stress field. Yet, as our award winner writes, Bruce’s legacy is more than scientific as he was well known for mentorship and being an exemplary person, theorist, and scientist. Perhaps understandably for a career favored by humble introverts and shy reclusives, the science shines in the spotlight and personal reflections are cut to accommodate word count limits. For scholars entering the field, stargazing at larger than life luminaries in the field is thrilling yet intimidating as it feels impossible that these experts have the same doubts and distractions as the rest of us primates. Thus, Psychoneuroendocrinology is thrilled to kick off the first perspectives piece in the Cell to Selves series with Dr. Robert Sapolsky sharing that, like his Baboon troops in Kenya, he too sometimes has a bad-hair day.This paper is a written version of a lecture I gave on September 8th, 2022, when receiving the first Bruce McEwen Lifetime Achievement Award from the ISPNE. This was a bittersweet honor; Bruce was my graduate advisor at Rockefeller University and over the next forty years, he was my mentor, teacher and father figure. His death in 2020 left a hole in my life.

Scientists sniff out the structure of a human olfactory receptor

Our noses encounter a vast diversity of chemicals every day, but scientists know little of how odorants stir awake the receptors in our bodies. A recent study is the first to parse the structure of a human olfactory receptor, called OR51E2 ( Nature 2022, DOI: 10.1038/s41586-023-05798-y ). The study’s authors reveal the full molecular picture of how OR51E2 interacts with propionate, the pungent player behind Swiss cheese. “It’s a landmark paper,” says Vanessa Ruta, a Rockefeller University sensory neuroscientist not involved in the study. Our bodies detect environmental stimuli with cellular sentinels called G-protein- coupled receptors (GPCRs). Of the 800 GPCRs encoded by the human genome, roughly half are tied to smell. Smell receptors are notoriously tricky to produce in sufficient quantities for structure studies. According to corresponding author and biochemist Aashish Manglik of the University of California, San Francisco, his team homed in on OR51E2 because it moonlights in

Patient-oriented research and the shiny object syndrome.

Patient-oriented research and the shiny object syndrome.

Susan S. Smyth (1965-2022).

Susan S. Smyth (1965-2022).

Neutrophils and their friends.

Neutrophils and their friends.

Editorial introductions.

Editorial introductions.

Building an infrastructure to support the development, conduct, and reporting of informative clinical studies: The Rockefeller University experience.

Clinical trials are a vital component of translational science, providing crucial information on the efficacy and safety of new interventions and forming the basis for regulatory approval and/or clinical adoption. At the same time, they are complex to design, conduct, monitor, and report successfully. Concerns over the last two decades about the quality of the design and the lack of completion and reporting of clinical trials, characterized as a lack of "informativeness," highlighted by the experience during the COVID-19 pandemic, have led to several initiatives to address the serious shortcomings of the United States clinical research enterprise. Against this background, we detail the policies, procedures, and programs that we have developed in The Rockefeller University Center for Clinical and Translational Science (CCTS), supported by a Clinical and Translational Science Award (CTSA) program grant since 2006, to support the development, conduct, and reporting of informative clinical studies. We have focused on building a data-driven infrastructure to both assist individual investigators and bring translational science to each element of the clinical investigation process, with the goal of both generating new knowledge and accelerating the uptake of that knowledge into practice.

Peter Satir (1936–2022), cell biology pioneer and mentor

Peter Satir (1936–2022), cell biology pioneer and mentor

The path to condensates—19th Wiley Prize in Biomedical Sciences laureates share their discovery stories

AbstractPreface by Prof. Titia de Lange, Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USAThe 19th Annual Wiley Prize in Biomedical Sciences celebrated a breakthrough in cell biology: how membrane‐less cellular compartments are formed. The existence of membrane‐less organelles, often called bodies or puncta, has been known for a long time, but what exactly they represented and how they were formed was not known. This problem was solved by a physicist, Clifford Brangwynne, a cell biologist, Anthony Hyman, and a chemist, Michael Rosen. Each, synergistically, made groundbreaking contributions to the discovery that membrane‐less organelles are liquid–liquid phase‐separated entities. The two independent discoveries leading to the principle that multivalent low‐affinity interactions between selected sets of macromolecules, some containing intrinsically disordered regions, formed a molecular condensate with unique dynamic properties, gave birth to the large, blossoming field of biomolecular condensates. The implications of those findings have influenced almost all further research of intracellular processes, including RAS signaling, immune synapses, DNA repair, transcriptional activation, and the functions of nuclear pores, the nucleolus and centrosomes. In this perspective article, the laureates of the award take us on their personal and professional trip that led to their scientific discoveries. Their stories are a celebration of the interdisciplinary essence of Natural Sciences and the potential unlocked when scientists from different fields work together to solve mysteries.

A phase 1 trial of D2C7-it in combination with an Fc-engineered anti-CD40 monoclonal antibody (2141-V11) administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma (MG).

e14015 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR wild-type and mutant-specific (EGFRvIII) monoclonal antibody (Ab) fragment and a genetically engineered form of the Pseudomonas exotoxin. When injected directly into the tumor by convection enhanced delivery (CED), immunotoxins induce both direct tumor killing and secondary immune responses by activation of CD4+ and CD8+ T-cells. Tumor-associated macrophages (TAMs) are the most prominent glioma-infiltrating immune cells and constitute up to 40% of the tumor mass. Upon binding of D2C7-IT to EGFR and cellular internalization, the Pseudomonas exotoxin moiety of the D2C7-IT kills residual GBM cells, upregulates proinflammatory CD40, and induces pattern recognition receptor pathway transcriptome expression. This potentially creates a proinflammatory glioma microenvironment where TAM activation may be further stimulated by sequential CED of 2141-V11, an Fc engineered anti-human CD40 agonist antibody developed at Rockefeller University. We are conducting a first in human trial of the combination of D2C7-IT + 2141-V11 administered via CED in recurrent MG patients. Methods: Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade 3 or 4 MG; ≥ 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing levels of 2141-V11 to determine the maximum tolerated dose (MTD) of the compound administered intratumorally in conjunction with D2C7-IT. Dose escalation and de-escalation are managed using a modified Bayesian optimal interval (BOIN) design to identify the MTD. Intratumoral administration of D2C7-IT via CED (4612 ng/mL over 72 hours) is followed by a 7-hour infusion of 2141-V11, both infused at 0.5 mL/hr. 2141-V11 is dose-escalated to determine the MTD when combined with D2C7-IT. Four dose levels (DL) are planned: #1: 0.70 mg; #2: 2.0 mg; #3: 7.0 mg; #4: 21.0 mg. Results: As of February 7, 2022, three patients were treated at DL1 and DL2, and two patients at DL3. No DLTs have been observed, and all eight patients remain alive and in observation on study after 7.0, 6.5, 6.0, 4.4, 2.8, 2.4, 0.9 and 0.5 months. Early signs of tumor response have been observed, with one patient at DL1 and 2 patients at DL2 without radiographic evidence of active tumor. Grade 2 or higher AEs due to D2C7-IT and/or 2141-V11 include: headache (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1; grade 2, n = 1); dysphasia (grade 3, n = 1); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 1); and depressed level of consciousness (grade 2, n = 1). Enrollment is ongoing. Conclusions: Intratumoral administration of D2C7-IT + 2141-V11 via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT04547777.