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Therapeutic efficacy with durable responses has been demonstrated with several antibody drugs that block key immune checkpoint receptors, including PD-1, PD-L1, and CTLA-4. Despite the success of these drugs, a substantial proportion of patients do not benefit. Targeting multiple inhibitory pathways simultaneously to augment anti-tumor immunity has proven to be a promising approach. The emergence of Repulsive Guidance Molecule b (RGMb), a ligand for PD-L2, as a novel co-inhibitory pathway in T cells, together with its regulation by the gut microbiome, encouraged the discovery and development of fully human anti-RGMb antibodies. Here, we describe phage display-derived monoclonal antibodies (mAbs) 2C11 and 5C10 that bind human RGMb with high affinities of 1.4 nM and 0.72 nM, respectively. Both mAbs 2C11 and 5C10 potently inhibited RGMb interaction with PD-L2. MAb 2C11 effectively inhibited RGMb interaction with bone morphogenetic proteins 2 and 4 (BMP2–4), while leaving RGMb interaction with Neogenin 1 (Neo1) unaffected. Conversely, mAb 5C10 disrupted RGMb interaction with Neo1 while maintaining RGMb binding to BMP2–4. These findings map the 2C11 epitope at the membrane-distal N-terminal region of RGMb, which coincides with both PD-L2- and BMP2–4-binding sites. The PD-L2 binding interface is likely positioned between RGMb’s N-terminal BMP-binding and C-terminal Neo1-binding regions. The in vivo activity of mAb 2C11 in combination with anti-PD-1 or anti-PD-L1 was tested in MC38 and B16-OVA cancer models and demonstrated synergistic effects by significantly enhancing anti-tumor responses. These properties make mAb 2C11 a promising candidate for therapeutic use to overcome immune checkpoint inhibitor resistances, warranting further exploration in clinical settings.

This qualitative study investigated high school student peer counselors' experience of a mind-body medicine curriculum incorporated into a peer counseling program following a school shooting. A series of focus groups were held with peer counselors in 10th-12th grade (n = 24, mean age = 16.5 [SD = 1.0]; 71% female) participating in the mind-body medicine curriculum. Data analysis was conducted using a thematic analysis. Peer counselors reported that the mind-body medicine curriculum decreased their stress and helped them regulate their emotions. Other interview themes included feeling closer to other students, improved relationships with their parents, increased resilience and self-confidence, working harder for their goals, not stressing over small things, and choosing supportive friends. The themes related to their peer counseling work were that the mind-body skills would help them be less reactive and more patient with other students and that the skills would also be helpful for these other students. This study has important implications for practitioners in the schools because the mind-body medicine curriculum can effectively complement the communication, problem-solving, and decision-making skills taught in peer counseling programs.

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.

If the received views on self-transformation in philosophical literature are correct, then either self-transformation (1) is caused by forces beyond oneself and beyond one's control, (2) is not rational to pursue, or (3) does not ever really happen. In this essay, James Gordon highlights the philosophical puzzle known as the "self-transformation puzzle," as raised by Ryan Kemp, who suggests that transformation of the sort educators are interested in cannot be self-caused: it is either something that happens to a person, or something that, if agent guided, is not full-fledged transformation. Next, Gordon turns to an alternative take on the puzzle that tries to recast the conceptual terrain and offer a new way of thinking about self-transformation, namely, the "aspirational" account of self-change offered by Agnes Callard. He argues that Callard's aspirational account of transformation shows that at least one of the premises of Kemp's argument is false. Finally, he suggests several ways that those interested in transformative education might appeal to the concept of aspiration to revise their educational practices.

Abstract The invasive Asian date mussel (Arcuatula senhousia) inhabits diverse global coastal environments, in some circumstances posing significant ecological and economic risks. Recently recorded in the Greater North Sea ecoregion, an established population has not previously been confirmed. Combining historical and field data, we provided baseline information from the UK and recorded colonisation in a variety of habitats. Gonadal development was assessed using the gonadosomatic index (GSI) to determine if an intertidal soft-sediment population is self-sustaining. Arcuatula senhousia records from subtidal muddy/mixed-sediment within a major estuarine system from 2007 to 2016 were also analysed. First detected in 2011, spatial distribution was variable across the years within the subtidal, with individuals found at 4–9 out of 25 sites, and densities per site varying from 10 to 290 individuals per m2. The intertidal population was, in part, associated with seagrass (Zostera spp.) and attached to bivalves. In marinas, individuals were attached to concrete tiles, associated with live Mytilus edulis, and to dead Ostrea edulis. Mean GSI from the intertidal population differed across months, peaking in July before declining in September/October, but with high inter-individual variability. Arcuatula senhousia is reproducing and maintaining viable populations. Using a natural capital approach, we identify the potential impacts on Europe’s functionally important habitats, fisheries and aquaculture if its spread continues.