Explore the vast range of titles available.

Immunotherapy using checkpoint-blocking antibodies against PD-1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. We used noninvasive immuno-positron emission tomography (PET), using 89Zr-labeled PEGylated single-domain antibody fragments (nanobodies or VHHs), to explore the dynamics and distribution of intratumoral CD8⁺ T cells and CD11b⁺ myeloid cells in response to anti–PD-1 treatment in the MC38 colorectal mouse adenocarcinoma model. Responding and nonresponding tumors showed consistent differences in the distribution of CD8⁺ and CD11b⁺ cells. Anti–PD-1 treatment mobilized CD8⁺ T cells from the tumor periphery to a more central location. Only those tumors fully infiltrated by CD8⁺ T cells went on to complete resolution. All tumors contained CD11b⁺ myeloid cells from the outset of treatment, with later recruitment of additional CD11b⁺ cells. As tumors grew, the distribution of intratumoral CD11b⁺ cells became more heterogeneous. Shrinkage of tumors in responders correlated with an increase in the CD11b⁺ population in the center of the tumors. The changes in distribution of CD8⁺ and CD11b⁺ cells, as assessed by PET, served as biomarkers to gauge the efficacy of anti–PD-1 treatment. Single-cell RNA sequencing of RNA from intratumoral CD45⁺ cells showed that CD11b⁺ cells in responders and nonresponders were markedly different. The responders exhibited a dominant population of macrophages with an M1-like signature, while the CD45⁺ population in the nonresponders displayed an M2-like transcriptional signature. Thus, by using immuno-PET and single-cell RNA sequencing, we show that anti–PD-1 treatment not only affects interactions of CD8⁺ T cells with the tumor but also impacts the intratumoral myeloid compartment.

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.

This is a study protocol to co-create with knowledge users a core outcome set focused on middle-aged and older adults (40 years+) for use in social prescribing research. We will follow the Core Outcome Measures in Effectiveness Trials (COMET) guide and use modified Delphi methods, including collating outcomes reported in social prescribing publications, online surveys, and discussion with our team to finalize the core outcome set. We intentionally center this work on people who deliver and receive social prescribing and include methods to evaluate collaboration. Our three-part process includes: (1) identifying published systematic reviews on social prescribing for adults to extract reported outcomes; and (2) up to three rounds of online surveys to rate the importance of outcomes for social prescribing. For this part, we will invite people (n = 240) who represent the population experienced in social prescribing, including researchers, members of social prescribing organizations, and people who receive social prescribing and their caregivers. Finally, we will (3) convene a virtual team meeting to discuss and rank the findings and finalize the core outcome set and our knowledge mobilization plan. To our knowledge, this is the first study designed to use a modified Delphi method to co-create core outcomes for social prescribing. Development of a core outcome set contributes to improved knowledge synthesis via consistency in measures and terminology. We aim to develop guidance for future research, and specifically on the use of core outcomes for social prescribing at the person/patient, provider, program, and societal-level.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule-positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.

This is a study protocol to co-create with knowledge users a core outcome set focused on middle-aged and older adults (40 years+) for use in social prescribing research. We will follow the Core Outcome Measures in Effectiveness Trials (COMET) guide and use modified Delphi methods, including collating outcomes reported in social prescribing publications, online surveys, and discussion with our team to finalize the core outcome set. We intentionally center this work on people who deliver and receive social prescribing and include methods to evaluate collaboration. Our three-part process includes: (1) identifying published systematic reviews on social prescribing for adults to extract reported outcomes; and (2) up to three rounds of online surveys to rate the importance of outcomes for social prescribing. For this part, we will invite people (n = 240) who represent the population experienced in social prescribing, including researchers, members of social prescribing organizations, and people who receive social prescribing and their caregivers. Finally, we will (3) convene a virtual team meeting to discuss and rank the findings and finalize the core outcome set and our knowledge mobilization plan. To our knowledge, this is the first study designed to use a modified Delphi method to co-create core outcomes for social prescribing. Development of a core outcome set contributes to improved knowledge synthesis via consistency in measures and terminology. We aim to develop guidance for future research, and specifically on the use of core outcomes for social prescribing at the person/patient, provider, program, and societal-level.

Understanding how mutualisms evolve in response to a changing environment will be critical for predicting the long‐term impacts of global changes, such as increased N (nitrogen) deposition. Bacterial mutualists in particular might evolve quickly, thanks to short generation times and the potential for independent evolution of plasmids through recombination and/or HGT (horizontal gene transfer). In a previous work using the legume/rhizobia mutualism, we demonstrated that long‐term nitrogen fertilization caused the evolution of less‐mutualistic rhizobia. Here, we use our 63 previously isolated rhizobium strains in comparative phylogenetic and quantitative genetic analyses to determine the degree to which variation in partner quality is attributable to phylogenetic relationships among strains versus recent genetic changes in response to N fertilization. We find evidence of distinct evolutionary relationships between chromosomal and pSym genes, and broad similarity between pSym genes. We also find that nifD has a unique evolutionary history that explains much of the variation in partner quality, and suggest MoFe subunit interaction sites in the evolution of less‐mutualistic rhizobia. These results provide insight into the mechanisms behind the evolutionary response of rhizobia to long‐term N fertilization, and we discuss the implications of our results for the evolution of the mutualism. We investigate the evolution of partner quality in natural populations of symbiotic rhizobia using Sanger sequencing combined with quantitative genetic and phylogenetic analyses. We analyze whether the chromosome and symbiotic plasmid (pSym) show congruent evolution and whether phylogenies at these loci predict partner quality phenotypes. We find that partner quality traits are largely predicted by the pSym phylogeny, particularly nifD, an important symbiosis gene, and suggest horizontal gene transfer between these genomic elements.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1- positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule-positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.

In complex oxide heteroepitaxy, strain engineering is a powerful tool to obtain phases in thin films that may be otherwise unstable in bulk. A successful example of this approach is mixed phase bismuth ferrite (BiFeO3) epitaxial thin films. The coexistence of a tetragonal-like (T-like) matrix and rhombohedral-like (R-like) striations provides an enhanced electromechanical response, along with other attractive functional behaviors. In this paper, we compare the energetics associated with two thickness dependent strain relaxation mechanisms in this system: domain walls arising from monoclinic distortion in the T-like phase, and the interphase boundary between the host T-like matrix and tilted R-like phases. Combining x-ray diffraction measurements with scanning probe microscopy, we extract quantitative values using an empirical energy balance approach. The domain wall and phase boundary energies are found to be 113 \\(\\pm\\) 21 and 426 \\(\\pm\\) 23 mJ.m\\(^{-2}\\), respectively. These numerical estimates will help us realize designer phase boundaries in multiferroics, which possess colossal responses to external stimuli, attractive for a diverse range of functional applications.