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Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs function as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.

Animals can capitalize on invariance in the environment by learning and automating highly consistent actions; however, they must also remain flexible and adapt to environmental changes. It remains unclear how primary motor cortex (M1) can drive precise movements, yet also support behavioral exploration when faced with consistent errors. Using a reach-to-grasp task in rats, along with simultaneous electrophysiological monitoring in M1 and dorsolateral striatum (DLS), we find that behavioral exploration to overcome consistent task errors is closely associated with tandem increases in M1 and DLS neural variability; subsequently, consistent ensemble patterning returns with convergence to a new successful strategy. We also show that compared to reliably patterned intracranial microstimulation in M1, variable stimulation patterns result in significantly greater movement variability. Our results thus indicate that motor and striatal areas can flexibly transition between two modes, reliable neural pattern generation for automatic and precise movements versus variable neural patterning for behavioral exploration.

Abstract Glioma represents the most common central nervous system neoplasm in adults. Current classification scheme utilizes molecular alterations, particularly IDH1.R132H, to stratify lesions into distinct prognostic groups. Identification of the single nucleotide variant through traditional tissue biopsy assessment poses procedural risks and does not fully reflect the heterogeneous and evolving tumor landscape. Here, we introduce a liquid biopsy assay, mt-IDH1dx. The blood-based test allows minimally invasive detection of tumor-derived extracellular vesicle RNA using only 2 ml plasma volume. We perform rigorous, blinded validation testing across the study population (n = 133), comprising of IDH1.R132H patients (n = 80), IDH1 wild-type gliomas (n = 44), and age matched healthy controls (n = 9). Results from our plasma testing demonstrate an overall sensitivity of 75.0% (95% CI: 64.1%–84.0%), specificity 88.7% (95% CI: 77.0%–95.7%), positive predictive value 90.9%, and negative predictive value 70.1% compared to the tissue gold standard. In addition to fundamental diagnostic applications, the study also highlights the utility of mt-IDH1dx platform for blood-based monitoring and surveillance, offering valuable prognostic information. Finally, the optimized workflow enables rapid and efficient completion of both tumor tissue and plasma testing in under 4 hours from the time of sampling.

Abstract Today, more than 70 carbon pricing schemes have been implemented around the globe, but their contributions to emissions reductions remains a subject of heated debate in science and policy. Here we assess the effectiveness of carbon pricing in reducing emissions using a rigorous, machine-learning assisted systematic review and meta-analysis. Based on 483 effect sizes extracted from 80 causal ex-post evaluations across 21 carbon pricing schemes, we find that introducing a carbon price has yielded immediate and substantial emission reductions for at least 17 of these policies, despite the low level of prices in most instances. Statistically significant emissions reductions range between –5% to –21% across the schemes (–4% to –15% after correcting for publication bias). Our study highlights critical evidence gaps with regard to dozens of unevaluated carbon pricing schemes and the price elasticity of emissions reductions. More rigorous synthesis of carbon pricing and other climate policies is required across a range of outcomes to advance our understanding of “what works” and accelerate learning on climate solutions in science and policy.

Abstract Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs function as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.

Abstract Bacteriophages are ubiquitous viral predators that have primarily been studied using fast-growing laboratory cultures of their bacterial hosts. However, microbial life in nature is mostly in a slow- or non-growing, dormant state. Here, we show that diverse phages can infect deep-dormant bacteria and suspend their replication until the host resuscitates (“hibernation”). However, a newly isolated Pseudomonas aeruginosa phage, named Paride, can directly replicate and induce the lysis of deep-dormant hosts. While non-growing bacteria are notoriously tolerant to antibiotic drugs, the combination with Paride enables the carbapenem meropenem to eradicate deep-dormant cultures in vitro and to reduce a resilient bacterial infection of a tissue cage implant in mice. Our work might inspire new treatments for persistent bacterial infections and, more broadly, highlights two viral strategies to infect dormant bacteria (hibernation and direct replication) that will guide future studies on phage-host interactions.

Abstract The recent emergence of a causal link between Epstein-Barr virus (EBV) and multiple sclerosis has generated considerable interest in the development of an effective vaccine against EBV. Here we describe a vaccine formulation based on a lymph node targeting Amphiphile vaccine adjuvant, Amphiphile-CpG, admixed with EBV gp350 glycoprotein and an engineered EBV polyepitope protein that includes 20 CD8+ T cell epitopes from EBV latent and lytic antigens. Potent gp350-specific IgG responses are induced in mice with titers >100,000 in Amphiphile-CpG vaccinated mice. Immunization including Amphiphile-CpG also induces high frequencies of polyfunctional gp350-specific CD4+ T cells and EBV-specific CD8+ T cells that are 2-fold greater than soluble CpG and are maintained for >7 months post immunization. This combination of broad humoral and cellular immunity against multiple viral determinants is likely to provide better protection against primary infection and control of latently infected B cells leading to protection against the development of EBV-associated diseases.

Abstract Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in major innate immunity signaling components, we found that signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS signaling, persistent infection leads to focal myocarditis and vasculitis of the large vessels attached to the base of the heart. Large vessel vasculitis was observed for up to 60 days post infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.

Abstract Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context.

Here, the authors report on the discovery of physiological vasculogenic fibroblasts capable of forming functional blood vessels. In vivo tissue reprogramming triggered by topical tissue nanotransfection (TNT) of a single anti-miR-200b oligonucleotide achieved therapeutic tissue vascularization.

Abstract The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

The authors investigate whether strong light-matter coupling can alter the nonlinear optical response of molecules inside a microcavity. Focusing on electroabsorption as a model third order nonlinearity, they find that apparent discrepancies between experiment and classical transfer matrix modeling arise from dark states in the system and are not a sign of new physics in the strong coupling regime.

Fibrosis of the skin plays an important role in scleroderma. Here the authors demonstrate genetic and epigenetic abnormalities at the centromere that affect the replication of the chromosomes, resulting in activation of pathways involved in inflammation and fibrosis

Chimeric antigen receptors (CAR) are a promising option for cell-based immunotherapy for cancer and other immune diseases. Here the authors develop speedingCARs, an integrated CAR design and screening platform based on modular signaling domain shuffling and single cell transcriptomic analyses, and test its potential for identifying and validating novel CAR designs.

The T cell response to SARS-CoV-2 is important in protection from infection. Here the authors show by concentrating on a specific HLA haplotype that mutations in SARS-CoV-2 as new variants emerge can affect T cell recognition and reduce T cell responses to the virus.

It is not fully understood how behavioral flexibility is established in the context of automatic performance of a complex motor skill. Here the authors show that corticostriatal activity can flexibly transition between two modes during a reach to-grasp task in rats: reliable neural pattern generation for precise, automatic movements versus variable neural patterning for behavioral exploration.

Neural sampling machines make use of noise to perform learning. Here, Dutta et al. present a hybrid stochastic synapse composed out of a ferroelectric transistor combined with a stochastic selector exhibiting multiplicative synaptic noise required for implementing a neural sample machine.

The authors study a cohort of healthcare workers in India who received two doses of the ChAdOx-1-nCoV19 vaccine during the Delta wave. Using serological data, they infer that 25% of the cohort were infected within 60 days of vaccination, although there were no severe infections leading to hospitalisations.

Neurological complications are frequently observed in severe Hand, Foot and Mouth Disease but the underlying causes are unknown. Here, the authors report infected astrocytes release CXCL1 which activates neuronal CXCR2 to cause neuropathogenesis.

Acquired resistance limits the efficacy of PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Here, the authors show that inhibition of RNA polymerase I transcription using CX-5461 increases the therapeutic efficacy of PARPi and overcomes PARPi resistance in PDX models of HGSOC.

Mycobacterium tuberculosis (Mtb) modern strains emerged from a common progenitor after the loss of Mtb-specific deletion 1 region (TbD1). Here, the authors show that deletion of TbD1 correlates with enhanced Mtb virulence in animal models, mirroring the development of hypoxic granulomas in human disease progression.

Chromosome arm-level aneuploidies (CAAs) are frequently observed in cancer. Here, the authors analyse CAA landscapes across different tumour types, relating these chromosome arm gains and losses to tumour evolution, metastasis, patient survival and response to a range of anti-cancer therapies.

Designing alternative paradigms for bio-inspired analog computing that harnesses collective dynamics remains a challenge. Here, the authors exploit the synchronization dynamics of coupled vanadium dioxide-based insulator-to-metal phase-transition nano-oscillators for adaptive locomotion control.

Antibodies are generated through remote genomic interactions involving immunoglobulin variable (VH), diversity (DH) and joining (JH) gene segments. Here the authors develop a strategy to track VH-DHJH motion in B-lymphocytes and provide evidence that chromosome organisation near the sol-gel phase transition dictates the timing of genomic interactions to orchestrate gene expression and somatic recombination.