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Motivation Single-cell transcriptomics profiling technologies enable genome-wide gene expression measurements in individual cells but can currently only provide a static snapshot of cellular transcriptional states. RNA velocity analysis can help infer cell state changes using such single-cell transcriptomics data. To interpret these cell state changes inferred from RNA velocity analysis as part of underlying cellular trajectories, current approaches rely on visualization with principal components, t-distributed stochastic neighbor embedding and other 2D embeddings derived from the observed single-cell transcriptional states. However, these 2D embeddings can yield different representations of the underlying cellular trajectories, hindering the interpretation of cell state changes. Results We developed VeloViz to create RNA velocity-informed 2D and 3D embeddings from single-cell transcriptomics data. Using both real and simulated data, we demonstrate that VeloViz embeddings are able to capture underlying cellular trajectories across diverse trajectory topologies, even when intermediate cell states may be missing. By considering the predicted future transcriptional states from RNA velocity analysis, VeloViz can help visualize a more reliable representation of underlying cellular trajectories. Availability and implementation Source code is available on GitHub (https://github.com/JEFworks-Lab/veloviz) and Bioconductor (https://bioconductor.org/packages/veloviz) with additional tutorials at https://JEF.works/veloviz/. Datasets used can be found on Zenodo (https://doi.org/10.5281/zenodo.4632471). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Introduction: Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed.Methods: To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model.Results: We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming.Conclusions: Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. [ABSTRACT FROM AUTHOR]

• Activation of the innate immune system drives outcomes after stroke. • PD-1+ monocytes in the blood of stroke patients correlate with cerebral edema. • PD-L1 administration decreases edema, improves survival, and promotes recovery. • Myeloid-specific PD-1 knockout abrogates the PD-L1 treatment effect. • PD-1 signaling skews blood monocytes away from an inflammatory phenotype prior to tissue infiltration. Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke. [ABSTRACT FROM AUTHOR]

The Student Curriculum Review Team (SCRT) was founded at the Johns Hopkins University School of Medicine (JHUSOM) in 2012 to refine pre-clinical courses. Since then, SCRT has provided a voice for student feedback – offering forums for discussion through 'Town Hall meetings' and confidential avenues for peer-to-peer comments. Here, we assess the perceived efficacy and utility of SCRT among the student body and faculty course directors. A cross-sectional analysis was conducted in 2019 using an anonymous survey distributed to second- (MS2) and third-year (MS3) medical students as well as faculty course directors at JHUSOM. A total of 113 student surveys and 13 faculty surveys were returned. The majority of students (97%) endorsed SCRT as effective in enabling them to express their concerns. Most faculty (69%) reported SCRT's impact on their respective course as positive and found SCRT suggestions to be 'realistic and actionable.' Students (84%) and faculty (62%) alike considered SCRT to meet needs not met by other curricular organizations at JHUSOM. Students and faculty find that SCRT satisfies an unfilled position in the landscape of curricular feedback at JHUSOM. This study may be beneficial for other academic institutions considering ways to better engage students in curricular reform. [ABSTRACT FROM AUTHOR]

Proper disinfection using adequate disinfecting agents will be necessary for infection control strategies against coronavirus disease 2019 (COVID-19). However, limited guidance exists on effective surface disinfectants or best practices for their use against severe acute respiratory coronavirus 2. We outlined a process of fully characterizing over 350 products on the Environmental Protection Agency List N, including pH, method of delivery, indication for equipment sterilization, and purchase availability. We then developed a streamlined set of guidelines to help rapidly evaluate and select suitable disinfectants from List N, including practicality, efficacy, safety, and cost/availability. This resource guides the evaluation of ideal disinfectants amidst practical considerations posed by the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo , by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications. [Display omitted] • Macrophages induce the MES-like state of glioblastoma cells • Induction is mediated by macrophage-derived OSM interacting with OSMR/LIFR-GP130 • Subsets of glioblastoma-associated macrophages express a related MES-like program • The MES-like state in glioblastoma is associated with cytotoxic T cells programs Hara et al. combine single-cell RNA sequencing and functional experiments to explore the crosstalk between glioblastoma and the microenvironment, revealing that macrophage-derived OSM induces the mesenchymal-like state of glioblastoma, a state associated with upregulation of major histocompatibility complex genes, and with potential implications for immunotherapy. [ABSTRACT FROM AUTHOR]