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Recent studies have provided insights into the pathology of and immune response to COVID-19 1 – 8 . However, a thorough investigation of the interplay between infected cells and the immune system at sites of infection has been lacking. Here we use high-parameter imaging mass cytometry 9 that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses—possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general. Imaging mass cytometry of the human lung reveals the cellular composition and spatial architecture during COVID-19 and other acute injuries, enabling the characterization of lung pathophysiology from structural, immunological and clinical perspectives.

Multiple sclerosis (MS) is characterized by demyelinated and inflammatory lesions in the brain and spinal cord that are highly variable in terms of cellular content. Here, we used imaging mass cytometry (IMC) to enable the simultaneous imaging of 15+ proteins within staged MS lesions. To test the potential for IMC to discriminate between different types of lesions, we selected a case with severe rebound MS disease activity after natalizumab cessation. With post-acquisition analysis pipelines we were able to: (1) Discriminate demyelinating macrophages from the resident microglial pool; (2) Determine which types of lymphocytes reside closest to blood vessels; (3) Identify multiple subsets of T and B cells, and (4) Ascertain dynamics of T cell phenotypes vis-à-vis lesion type and location. We propose that IMC will enable a comprehensive analysis of single-cell phenotypes, their functional states and cell-cell interactions in relation to lesion morphometry and demyelinating activity in MS patients. It takes an army of immune cells to defend the body against infection. But sometimes the body’s immune system mistakenly attacks its own cells and chronic inflammatory conditions develop. In multiple sclerosis – also known as “MS” – a horde of immune cells infiltrate the brain and spinal cord, forming lesions which strip nerve cells of their insultation, a protective fatty material called myelin. Nerve cells become damaged, scarred and exposed, and this interferes with messages between the brain and other parts of the body. Advanced imaging techniques have revolutionized the diagnosis of multiple sclerosis by capturing lesions as they develop in the brain and spinal cord. Researchers have also focused their efforts on understanding how immune cells activated in the blood stream invade the central nervous system. To better understand how a mistaken immune response leads to nerve damage in multiple sclerosis, a forensic examination of which immune cells accumulate in brain tissue to form lesions is needed. Standard techniques for analyzing whole tissue samples are however limited by design, capable of detecting only a few cell markers in one section of tissue. Ramaglia et al. have now validated a new imaging technique for looking at an array of cell types in brain tissue in a single sample. The technique – called imaging mass cytometry (or IMC for short) – was used to look at post-mortem brain tissue from a multiple sclerosis patient with an acute form of the illness. The tissue examined had multiple sclerosis lesions present. Different types of immune cells were simultaneously identified and characterized using a panel of antibodies which recognize the signature proteins each immune cell makes when active. The state of the underlying myelin content of the tissue was also characterized. The imaging approach could distinguish between the immune cells of the brain (known as resident microglia) and a type of white blood cell summoned as part of the immune response (infiltrating macrophages). The analysis showed that, in the particular patient examined, microglia are abundant in active lesions in multiple sclerosis; also, different subsets of white blood cells were detected. Measuring how far different immune cells had migrated from nearby blood vessels added insights as to how immune cells move through the brain and which cells may have arrived first. Altogether, Ramaglia et al. have shown that IMC can be used as a discovery tool to gain a deeper understanding of multiple sclerosis lesions and immune cells active in the inflamed brain. Further work will apply this now validated imaging approach to large cohorts of multiple sclerosis patients.

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled two active MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In the acutely demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In the post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.

Recent studies have provided insights into the pathology of and immune response to COVID-19[1,2,3,4,5,6,7,8]. However, a thorough investigation of the interplay between infected cells and the immune system at sites of infection has been lacking. Here we use high-parameter imaging mass cytometry[9] that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses—possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general.

Skin breakdown is a problem that affects many individuals with lower limb loss. Breakdown is caused most commonly by repetitive mechanical stresses that are imposed on the residual limb at its interface with the prosthetic socket. Skin can adapt to become more tolerant to these stresses, thus reducing the risk of breakdown, yet little is understood about this phenomenon and no methods exist for objectively determining if skin has become more load tolerant. These factors have limited the ability of clinicians to more fully understand the health of their patients’ skin and they have limited the ability of researchers to develop improved rehabilitation strategies and therapeutics to enhance the load tolerance of skin. At the root of these needs is the lack of understanding of how skin adapts to mechanical stress. In order to develop a better understanding, new methods are needed that can safely and accurately probe the cutaneous physiology of individuals with lower limb loss. The objective of this dissertation was to develop noninvasive methods to assess the structure and function of skin and then to determine the utility of the developed tools for the investigation of skin adaptation in individuals with lower limb loss. In Aim 1, novel noninvasive techniques were developed to measure key structural and functional features of the cutaneous microvasculature that may be involved in skin adaptation. In Aim 2, these tools were introduced to investigate skin adaptation to mechanical stress on eight able-bodied participants who wore a modified below-knee prosthetic socket for two weeks. Study results demonstrated good repeatability of the OCT-based measurement methods with the exception of some features. No statistically significant differences were found in any of the OCT measurements taken at different time points throughout the study or between the test site and a location-matched control site on the contralateral limb. It is believed that the limb skin was not stressed enough to induce adaptation in the participants. In Aim 3, a case study of three participants with unilateral transtibial limb loss was performed to investigate the skin of chronically-stressed regions of the residual limb using the measurement methods developed in Aim 1. Measurements were compared between a highly stressed region of the residual limb and a location-matched site on the intact contralateral limb. Notable differences in functional and structural characteristics of the microvasculature were found between the two limbs for each study participant and between the residual limbs of all study participants. The epidermis was also thicker in the residual limb versus the contralateral limb for all participants, a difference that was statistically significant. Taken together, this thesis introduced new noninvasive methods for investigating skin adaptation in users of lower limb prostheses, highlighted advantages and limitations related to the developed methods, and identified potential biomarkers for skin adaptation that are worth further investigation.

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled acute MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In a demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In a post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation. Footnotes * https://github.com/PittLab/IMC_Park_et_al_2019

Multiple Sclerosis (MS) is characterized by demyelinated and inflammatory lesions in the brain and spinal cord. Lesions contain immune cells with variable phenotypes and functions. Here we use imaging mass cytometry (IMC) to enable the simultaneous imaging of 15+ proteins within 11 staged MS lesions. Using this approach, we demonstrated that the majority of demyelinating macrophage-like cells in active lesions were derived from the resident microglial pool. Although CD8+ T cells predominantly infiltrated the lesions, CD4+ T cells were also abundant but localized closer to blood vessels. B cells with a predominant switched memory phenotype were enriched across all lesion stages and were found to preferentially infiltrate the tissue as compared to unswitched B cells which localized to the vasculature. We propose that IMC will enable a comprehensive analysis of single-cell phenotypes, their functional states and cell-cell interactions in relation to lesion morphometry and demyelinating activity in the MS brain.

According to standard macroeconomic models, the zero lower bound greatly reduces the effectiveness of monetary policy and increases the efficacy of fiscal policy. However, private-sector decisions depend on the entire path of expected future short-term interest rates, not just the current short-term rate. Put differently, longer-term yields matter. We show how to measure the zero bound's effects on yields of any maturity. Indeed, 1- and 2-year Treasury yields were surprisingly unconstrained throughout 2008 to 2010, suggesting that monetary and fiscal policy were about as effective as usual during this period. Only beginning in late 2011 did these yields become more constrained.

Respiratory syncytial virus is a major cause of illness in infants. In this randomized, double-blind, placebo-controlled trial, the safety and immunogenicity of a bivalent RSV prefusion F protein–based vaccine was assessed in pregnant women and their infants. Anti-RSV antibodies were elicited with efficient transplacental transfer.

Background Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. Methods The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). Results At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181. Conclusions Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. Trial registration ClinicalTrials.gov NCT01767311 .