The rockefeller university

Esther Obeng is an attending physician and associate professor at Emory University School of Medicine, where she leads a research group focused on myelodysplastic syndromes (MDS). Esther's team is investigating how normal hematopoietic stem cells develop into cancerous cells, as well as developing targeted therapies for MDS patients. We recently spoke to Esther about her move from St. Jude Children's Research Hospital to Emory, how her patients inform her research, as well as the joys and struggles of having running as a hobby.

Animals sense their metabolic needs to guide adaptive behaviors partly through serotonin, a neurotransmitter associated with feeding in many species. Here we investigate the ability of the serotonin system to evaluate and interpret diverse diets by studying long-term foraging behaviors of the nematode C. elegans on bacteria. Behavioral screens on a genome-wide collection of E coli strains identified 22 metabolic mutants that induce behavioral aversion and stress responses in C. elegans. We show that different classes of serotonergic neurons promote aversion to non-preferred E. coli diets and retention on preferred E. coli diets, respectively, through different serotonin receptors. Serotonin is integrated with dopamine and octopamine signals across distributed circuits to direct opposing behavioral responses to preferred and aversive diets. These results reveal interacting neuromodulatory circuits that guide context-dependent evaluation of dietary quality.

The loss and mutation of Topoisomerase 3 beta (TOP3B), the only known eukaryotic topoisomerase with the ability to catalyze RNA strand passage reactions, is linked to schizophrenia, autism, and intellectual disability. Uniquely, TOP3B primarily localizes to the cytoplasm and has been shown to regulate translation and stability of a subset of mRNA transcripts. Three neurological disease-linked de novo TOP3B point mutations outside of the active site have been identified but their impact on TOP3B activity in cells remains poorly understood. Upon establishing a new Neuro2A cell-based TOP3B activity assay, we provide genetic and biochemical evidence that the autism-linked C666R mutation causes accumulation of unresolved TOP3B center dot mRNA covalent intermediates by directly disrupting metal coordination via an atypical D1C3-type metal binding motif within the zinc finger domain. Furthermore, we show that primary neurons are sensitive to TOP3B center dot mRNA covalent intermediates, including those formed by the C666R mutant TOP3B, and that such adducts are capable of causing ribosome collisions. Together, these data identify a previously underappreciated role of the zinc finger domain and how non-active site disease-linked mutations affect TOP3B activity and neuronal toxicity.

Cell cycle events are ordered by cyclin-dependent kinases (CDKs), which phosphorylate hundreds of substrates. Multiple phosphatases oppose these CDK substrates, yet their collective role in regulating phosphorylation timing in vivo remains unclear. Here, we show that four phosphatases (PP2A-B55, PP2A-B56, CDC14, and PP1) each target distinct subsets of CDK substrate sites in vivo in fission yeast, influencing when phosphorylation occurs during G2 and mitosis. On average, sites dephosphorylated by CDC14 and PP2A-B56 are phosphorylated earlier during G2, followed by sites dephosphorylated by PP1 and PP2A-B55. This suggests that these phosphatases set different phosphorylation thresholds at the G2/M transition. Consistent with this, depleting PP2A-B55 or CDC14 accelerates mitotic onset, likely by advancing phosphorylation of their respective CDK substrates, suggesting these phosphorylation thresholds are important for regulating mitotic onset. Our findings establish in vivo phosphatase substrate specificity as a key factor regulating the timing of CDK substrate phosphorylation throughout the cell cycle.

How are systems supporting high-level cognition organized in the human brain? We hypothesize that cognitive processes involved in understanding people and places are implemented by distinct neural systems with parallel anatomical organization. We test this hypothesis using precision neuroimaging of individual human brains on diverse tasks involving perception and cognition in the domains of familiar people, places, and objects. We find that thinking about people and places elicits responses in distinct areas of high-level association cortex within the default mode network, spanning the frontal, parietal, and temporal lobes. Person-and place-preferring brain regions are systematically spatially adjacent across cortical zones. These areas have strongly domain-specific response profiles across visual, semantic, and episodic tasks and are specifically functionally connected to other parts of association cortex with like domain preference. Social and spatial networks remain anatomically separated at the apex of a unimodal-to-transmodal gradient across cortex and include regions with anatomical connections to the hippocampal formation. These results demonstrate the existence of parallel, domain-specific networks reaching the cortical apex.

The spatiotemporal regulation of morphogenetic signals, along with local tissue mechanics, guides morphogenesis and determines the shape of the embryo. However, how these signals integrate into developmental circuits remains poorly understood. Here, we developed a light-inducible strategy to induce BMP4 signaling with precise spatial coordinates in human pluripotent stem cells. Light-controlled BMP4 induces SMAD1-5 phosphorylation, resulting in amnion differentiation, and relies on a tension-dependent induction of WNT and NODAL for mesoderm differentiation. In response to BMP4 signaling, the mechanosensitive transcription factor YAP1 accumulates in the nucleus, where it represses WNT3 mRNA, regulating the induction of the three germ layers. Based on these findings, we developed a mathematical model that integrates tissue mechanics into morphogen dynamics, quantitatively explaining tissue-scale responses to BMP4 signaling. Thus, light induction of the morphogen BMP4 in human stem cell models elucidated the interplay between tissue mechanics and signaling at the onset of gastrulation.

Background: Polymicrobial sepsis is an infectious disease characterized by excessive inflammation and coagulation that is linked to more severe disease pathology, organ failure, and fatality. The plasma contact system is a protein cascade in the blood that can be activated by bacteria and contributes to both inflammation and coagulation. Objectives: To determine if inhibiting the plasma contact system by targeting highmolecular-weight kininogen (HK) can exert a protective effect on bacteria-induced coagulation. Methods: Polymicrobial cecal slurry (CS) was prepared from donor mice and used for ex vivo and in vivo experiments. CS was used in vivo to establish a murine model of polymicrobial sepsis. CS was incubated with mouse or human plasma ex vivo. Contact system activation was assessed by Western blot, and clotting was assessed spectroscopically. Our monoclonal antihuman HK antibody, 3E8, was used to determine how contact system inhibition could delay CS-induced coagulation ex vivo. Results: Polymicrobial CS activated the plasma contact system in vivo in mice and ex vivo in both mouse and human plasma. CS promoted coagulation in mouse and human plasma ex vivo. Treatment with our 3E8 anti-HK antibody protected against CS-induced contact system activation and coagulation. Conclusion: The plasma contact system was activated in the CS model of polymicrobial sepsis. Targeting HK in polymicrobial sepsis may have beneficial effects in limiting excessive coagulation and could represent a novel therapeutic avenue to promote survival in sepsis.

Myeloid cells-including monocytes, macrophages, dendritic cells, and granulocytes-are critical architects of the tumor microenvironment, in which they exert diverse functions ranging from immunosuppressive to immunostimulatory. Advances in single-cell omics and high-dimensional immune profiling have unveiled the remarkable heterogeneity and plasticity of these cells, revealing lineage-specialized functions that shape cancer immunity. These discoveries have sparked growing interest in therapeutically targeting myeloid cells as a next-generation strategy in cancer immunotherapy. As a complementary or alternative approach to T cell-centered immunotherapies, myeloid-directed therapies offer unique opportunities to reprogram the immune landscape, enhance antitumor responses, and overcome resistance mechanisms. In this review, we highlight recent discoveries in myeloid cell biology in cancer and discuss emerging therapeutic targets, with an emphasis on antibody-based therapies that have reached clinical development. We further provide perspective on translational challenges to implement these approaches into the clinic and discuss how Fc-engineering and rational antibody design can optimize myeloid cell engagement and amplify their immune effector functions. Together, these advances position myeloid-directed immunotherapies as a promising approach to enhance the efficacy and durability of cancer treatment.

The gut conveys nutritional, mechanical, and microbial signals to the brain to regulate physiology and behavior. Writing in Nature, Liu et al. reveal a colonic neuropod-vagus circuit that senses bacterial flagellin, highlighting microbial input as a rapid driver of feeding control and expanding paradigms of communication between the gut and the brain.

Mosquitoes, the world's deadliest animal, exemplify single-mating systems where females mate only once in their lifetime, making mate choice critically important for reproductive success and mosquito control. Despite this importance, the mechanisms behind mosquito mating and what prevents the female from mating again remain poorly understood. To address this gap, we developed a dual-color fluorescent sperm system in invasive Aedes aegypti mosquitoes and quantified mating patterns, confirming that 86%-96% of females mate only once. Using behavioral tracking of mating pairs, deep learning, and quantitative analysis at increasing resolution, we discovered that females actively control mating initiation through a previously undescribed behavior: genital tip elongation. This female response is triggered by rapidly evolving male genital structures, creating a lock-and-key mechanism that determines mating success. Comparative analysis revealed that Aedes albopictus, separated from Aedes aegypti by similar to 35 million years of evolution, employs a similar female-controlled system. Strikingly, we found that Aedes albopictus males bypass female control when attempting cross-species matings with Aedes aegypti females, but not with conspecific females. This "lock-picking" ability, combined with the known sterility induced by cross-species matings, could explain how Aedes albopictus competitively displaces Aedes aegypti populations in overlapping territories. Our findings redefine mosquito reproduction as a female-controlled process and establish a quantitative framework for investigating the molecular and neurobiological mechanisms underlying mating control and species competition in these globally important disease vectors.