The rockefeller university

Intravenous immunoglobulin (IVIG) administered at high doses is used to treat a wide array of autoimmune diseases. Studies in murine models have identified that the anti-inflammatory activity of IVIG is dependent on sialylation of the N-linked glycan on the CH2 domain of immunoglobulin G (IgG), the type I IgG inhibitory Fc receptor Fc gamma RIIB, and the type II Fc receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). We hypothesized that DC-SIGN, a C-type lectin, may directly interact with glycans on Fc gamma RIIB, augmenting its ability to bind sialylated IgG. We found that Fc-engineering sialylated IgG1 to enhance its affinity for Fc gamma RIIB resulted in a molecule that was more potent than IVIG in reducing the inflammatory sequelae of antibody or T cell-mediated autoimmune diseases, providing the basis for a class of potent anti-inflammatory therapeutics.

Transcription in bacteria is a multi-step process. In the first step, contacts between RNA polymerase and the promoter DNA must be established for transcription initiation to begin, but then these contacts must be broken for the enzyme to transition into the elongation phase. Single-molecule and biochemical observations report that promoter escape is a highly regulated and sometimes rate-limiting step in the transcription cycle; however, the structural mechanisms of promoter escape remain obscure. Promoter escape also serves as the target for the clinically important antibiotic rifampicin, used to treat tuberculosis. Here, we present seven distinct intermediates showing the structural details of M. tuberculosis RNA polymerase initial transcribing complexes and promoter escape, using a de novo cryo-electron microscopy approach. We describe the structural rearrangements that RNA polymerase undergoes to clear the promoter, including those required to release the initiation factor, sigma, providing a structural account for decades of biochemical observations. These structures and supporting biochemistry provide a model of promoter escape, a universal step in the transcription cycle, with conformations that may be used to develop Rifampicin alternatives.

Gut microbiota editing represents a promising therapeutic strategy for dysbiosis-associated diseases. Bacteriophages (phages), with their host specificity, enable precise microbial manipulation but face challenges such as environmental vulnerability and low bioavailability, which limit their in vivo efficacy. Here, we develop double-responsive hydrogel microspheres (HMs) via electrohydrodynamic spraying to enhance oral phage delivery. Composed of sodium alginate, hyaluronic acid, and Eudragit S100, these HMs achieve 90% encapsulation efficiency for a Salmonella-targeting phage cocktail. Such formulation significantly protects phages from gastric conditions, prolongs their intestinal retention, and enables responsive payload release in the colon. In a murine model of Salmonella Typhimurium (STm)-induced colitis, HMs-encapsulated phages (HMs-Phages) reduce intestinal STm burden by nearly 2000-fold and lower levels of proinflammatory cytokines (TNF-alpha, IL-6, IL-1 beta) to 60% of those in infected group. Notably, HMs-Phages achieve potent antibacterial efficacy comparable to ciprofloxacin while selectively targeting STm. This targeted strategy circumvents antibiotics-associated microbiota dysbiosis and diarrhea, thereby effectively restoring gut homeostasis and improving host physical health. By integrating targeted pathogen eradication with microbiota conservation, this work provides a precise toolkit for gut microbiota editing and phage therapy, offering substantial advantages over antibiotics for managing dysbiosis-related diseases.

The study of foraging is central to a renewed interest in naturalistic behavior in neuroscience. Applying a foraging framework grounded in behavioral ecology has enabled probing of the mechanisms underlying cognitive processes such as decision-making within a more ecological context. Yet, foraging also involves myriad other aspects, including navigation of complex environments, sensory processing, and social interactions. Here, we first provide a brief overview of the neuroscience of foraging decisions, and then combine insights from behav-ioral ecology and neuroscience to review the role of these additional dimensions of foraging. We conclude by highlighting four opportunities for the continued de-velopment of foraging as an ethological framework for neuroscience: integrating normative and implementation-level models, developing new tools, enabling cross-species comparisons, and fostering interdisciplinary collaboration.

Likelihood-free inference for simulator-based statistical models has developed rapidly from its infancy to a useful tool for practitioners. However, models with more than a handful of parameters still generally remain a challenge for the Approximate Bayesian Computation (ABC) based inference. To advance the possibilities for performing likelihood-free inference in higher dimensional parameter spaces, we introduce an extension of the popular Bayesian optimisation based approach to approximate discrepancy functions in a probabilistic manner which lends itself to an efficient exploration of the parameter space. Our approach achieves computational scalability for higher dimensional parameter spaces by using separate acquisition functions, discrepancies, and associated summary statistics for distinct subsets of the parameters. The efficient additive acquisition structure is combined with exponentiated loss-likelihood to provide a misspecification-robust characterisation of posterior distributions for subsets of model parameters. The method successfully performs computationally efficient inference in a moderately sized parameter space and compares favourably to existing modularised ABC methods. We further illustrate the potential of this approach by fitting a bacterial transmission dynamics model to a real data set, which provides biologically coherent results on strain competition in a 30-dimensional parameter space.

Quaternary climatic fluctuations had a substantial influence on ecosystems, species distribution, phenology and genetic diversity, driving extinction, adaptation and demographic shifts during glacial periods and postglacial expansions. Integration of genomic data and environmental niche modelling can provide valuable insights on how organisms responded to past environmental variations and contribute to assessing vulnerability and resilience to ongoing climatic challenges. Among vertebrates, turtles are particularly vulnerable to habitat changes because of distinctive life history traits and the effect of environmental conditions on physiology and survival. We estimated contemporary heterozygosity (H) and effective population size (N e) using a high-quality chromosome-level reference genome we produced for the European pond turtle (Emys orbicularis) and reference genomes and whole genome sequence data available for 21 species of tortoises and freshwater turtles. We implemented environmental niche modelling (ENM) to estimate past habitat dynamics. We found recurrent cycles of population expansion and contraction over the last 10 Mya in all species, with a general pattern of decrease in N e correlated with temperature reduction after the last interglacial period. No correlation was found between habitat fluctuations during the Quaternary and past N e. Moreover, neither H nor mean N e was correlated to threat status as defined by IUCN Red List categories. Our results add to studies on other vertebrates showing the extent to which genetic parameters can aid the assessment of conservation status, and although genomic data may not always be consistent indicators of the level of threat, investigations of which genomic parameters could best represent essential biodiversity variables should be consistently supported.

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.