Biology subjects

Bingham, E.

Publications and source records attributed to Bingham, E..

6 recordsLinked to original sources

bioRxiv2026

Alfalfa varieties can weakly choose beneficial nitrogen-fixing bacteria from a population isolated from a single field

O_LIIn natural and agricultural systems, legumes recruit rhizobia from diverse soil populations to fix nitrogen in root nodules. A few legumes, including the model legume Medicago truncatula, can select and enrich beneficial rhizobia. Here, we investigated whether its perennial relative, Medicago sativa (alfalfa), a globally important forage crop, also possesses this ability. C_LIO_LIWe developed a genetically variable collection of 117 Sinorhizobium meliloti strains sampled from three field-grown alfalfa varieties, performed multi-strain and single-strain inoculations in a nitrogen-free greenhouse experiment across the same hosts, and evaluated plant benefits and relative strain fitness in nodules. C_LIO_LIAlfalfa varieties differed in which strains best promoted plant growth and which strains had high fitness in nodules. Regressing strain fitness and host benefit revealed that two of three alfalfa varieties selected and enriched more beneficial strains during symbiosis, though the strength of selection was weak. In alignment with these results, no variety produced as much biomass in mixed inoculation as it did with the best-performing single strain. C_LIO_LILegumes ability to enrich beneficial rhizobial populations from field-representative strain diversity warrants further study to develop optimized varieties. Ultimately, identifying crop varieties that naturally select for beneficial bacteria could reduce the need for repeated inoculant applications. C_LI

Plant Biology↗

bioRxiv2025

NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control

CAR-T cells have yet to show widespread efficacy in solid tumors due in part to their poor persistence and loss of function in the tumor microenvironment. Further, heterogenous expression of most CAR target antigens in solid tumors can lead to escape of antigen-null tumors that resist CAR-T killing. Strategies to cooperatively boost both CAR-T and endogenous anti-tumor immunity could curb tumor escape and may be critical for achieving durable efficacy in cancer patients. NKTR-255 is a polymer-conjugated IL-15 with extended half-life that can boost endogenous T and NK cells, as well as CD19 CAR-T activity in B cell malignancies. However, whether NKTR-255 is sufficient to overcome CAR-T dysfunction in the suppressive solid tumor microenvironment, and how NKTR-255 and CAR-Ts together re-shape endogenous anti-tumor immunity, is not known. Using an autochthonous mouse model of ROR1+ lung adenocarcinoma, we show that NKTR-255 significantly boosted accumulation, reduced exhaustion, and improved function of tumor-infiltrating CAR-T cells. Compared with NKTR-255 or CAR-T treatment alone, combination of NKTR-255 and CAR-T therapy synergistically increased tumor-infiltrating CD11b+ cytotoxic NK cells, activated dendritic cells, and endogenous tumor-specific T cells that preserved a PD-1+Tcf1+ stem-like phenotype. Consequently, NKTR-255 and CAR-T combination therapy induced complete elimination of ROR1+ tumor and significantly improved survival, with enhanced tumor control dependent on activity of both CAR-Ts and endogenous T cells. Altogether, our data suggest that combining NKTR-255 with CAR-T therapy is a promising strategy to enhance both CAR-T and endogenous anti-tumor immunity to promote coordinated control of aggressive tumors.

immunology↗

bioRxiv2025

Cover crop microbiomes affect legume cash crop growth but not consistently through enriching nitrogen-fixing rhizobia

Harnessing plant-microbe interactions offers a promising path to reduce chemical inputs and enhance crop resilience in agricultural systems. However, microbial inoculants often fail to persist or function consistently across soils, which limits their broad utility. Here, we explore whether legume cover crops can be used to create microbial legacies that improve nodulation and nitrogen fixation in downstream legume cash crops. In a greenhouse experiment, we inoculated four cash crops with rhizosphere and nodule microbiomes derived from different legume cover crops, then used 16S rRNA and nifH amplicon sequencing to profile bacterial and diazotroph communities, respectively. Host identity shaped cover crop rhizosphere and nodule microbial communities, and specific taxa within these communities predicted nodulation and growth in some cash crops. Host specificity varied widely across cash crops, with alfalfa narrowly dependent on a specific symbiont and common bean and fava bean forming more permissive, taxonomically diverse nodule communities. Increased nodulation did not consistently improve biomass, and outcomes in some cash crops depended on more than symbiont compatibility alone. In particular, common bean growth was predicted by both rhizobial and non-rhizobial taxa, while soybean nodulation was shaped by its compatible symbiont as well as a mismatched rhizobial taxon associated with other hosts. Together, these results suggest that cover crops can shape cash crop microbiomes and productivity in host-specific ways, requiring precise symbiont matching in selective hosts but offering more flexible, multi-taxon management opportunities in permissive hosts.

plant biology↗

bioRxiv2025

Modulating AP-1 enables CAR-T cells to establish an intratumoral PD-1+Tcf1+ stem-like reservoir and overcomes resistance to PD-1 axis blockade

PD-1+Tcf1+ stem-like cells are critical mediators of endogenous T cell responses to PD-1/PD-L1 blockade and are maintained by MHC-dependent interactions with professional antigen-presenting cells (APCs). Unlike conventional T cells, CAR-T cells are activated by intact antigen expressed on tumors, not by peptide/MHC expressed on APCs, restricting their activation to the hostile tumor microenvironment (TME) that may impair preservation of this critical stem-like subset. Indeed, in an autochthonous model of ROR1+ lung cancer that we developed, CAR-T cells targeting the tumor-associated antigen ROR1 were uniformly Tcf1+ prior to infusion but rapidly downregulated Tcf1 in vivo and became terminally exhausted, similar to observations in patients, resulting in faster attrition and no enhancement in response to PD-L1 blockade. We hypothesized that overexpression of AP-1 family transcription factors, which can regulate T cell exhaustion, could enable CAR-Ts to maintain this critical PD-1+Tcf1+ subset within tumors independently of APCs and sensitize them to PD-1/PD-L1 blockade. Overexpression of the AP-1 TF c-Jun, but not BATF, improved preservation of PD-1+Tcf1+ CAR-T cells within tumors in a cell-intrinsic manner that correlated with increased persistence deeper within tumors. Notably, c-Jun overexpression alone was insufficient to prevent CAR-T exhaustion in the lung TME, in contrast to prior work in xenograft models, with progressive CAR-T dysfunction correlated with PD-1-dependent downregulation of c-Jun. However, c-Jun overexpression dramatically sensitized CAR-Ts to PD-L1 blockade, which restored c-Jun levels in CAR-Ts, drove log-fold expansion of CAR-Ts within tumors, and induced nearly complete eradication of ROR1+ tumor in highly aggressive models of lung cancer. Altogether, our data show that combination with PD-L1 blockade is necessary to unleash the full potential of c-Jun-overexpressing CAR-T cells in aggressive solid tumors like lung cancer and suggest that strategies to enhance formation of intratumoral PD-1+Tcf1+ reservoirs can overcome CAR-T resistance to PD-1 blockade.

immunology↗

bioRxiv2024

Metabolically-driven flows enable exponential growth in macroscopic multicellular yeast

The ecological and evolutionary success of multicellular lineages is due in no small part to their increased size relative to unicellular ancestors. However, large size also poses biophysical challenges, especially regarding the transport of nutrients to all cells; these constraints are typically overcome through multicellular innovations (e.g., a circulatory system). Here we show that an emergent biophysical mechanism -- spontaneous fluid flows arising from metabolically-generated density gradients -- can alleviate constraints on nutrient transport, enabling exponential growth in nascent multicellular clusters of yeast lacking any multicellular adaptations for nutrient transport or fluid flow. Surprisingly, beyond a threshold size, the metabolic activity of experimentally-evolved snowflake yeast clusters drives large-scale fluid flows that transport nutrients throughout the cluster at speeds comparable to those generated by the cilia of extant multicellular organisms. These flows support exponential growth at macroscopic sizes that theory predicts should be diffusion limited. This work demonstrates how simple physical mechanisms can act as a biophysical scaffold to support the evolution of multicellularity by opening up phenotypic possibilities prior to genetically-encoded innovations. More broadly, our findings highlight how cooption of conserved physical processes is a crucial but underappreciated facet of evolutionary innovation across scales.

evolutionary biology↗

bioRxiv2022

Pyro-Velocity: Probabilistic RNA Velocity inference from single-cell data

Single-cell RNA Velocity has dramatically advanced our ability to model cellular differentiation and cell fate decisions. However, current preprocessing choices and model assumptions often lead to errors in assigning developmental trajectories. Here, we develop, Pyro-Velocity, a Bayesian, generative, and multivariate RNA Velocity model to estimate the uncertainty of cell future states. This approach models raw sequencing counts with the synchronized cell time across all expressed genes to provide quantifiable and improved information on cell fate choices and developmental trajectory dynamics.

bioinformatics↗