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BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimers disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.

The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (Aβ) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aβ retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE ε3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine Aβ retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for Aβ transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness., Introduction The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) has led to a global pandemic, with more than 35 million cases as of [...]

In this paper, we explore the potentialities and interconnections between existing and hypothetical community energy systems and the concept of generative justice. New York State’s more recent official energy plan, for instance, includes provisions for community-scale microgrids, and several European nations offer significant financial support to citizens interested in building micro and intermediate-scale renewable energy systems. Such efforts and technologies appear to promise some degree of generative justice, returning much of the value generated by distributed renewable energy back to the community producing it. However, most currently conceived and implemented community energy systems recirculate value in very narrow and limited ways. Building upon an analysis of New York energy policy and on-the-ground cases, we explore community energy’s potential. What kinds of value are being generated by community energy systems and for whom? How could such efforts be more generative of justice across a broad range of values, not just electrons and dollars? Through the attempt to broaden thinking not only about community energy systems but also the concept of generative justice, we connect technological and organizational configurations of community energy systems and the forms of value they have the potential to generate: including, the production of grassroots energy and organizational expertise, the capacity for local and personal autonomy in energy planning and decision-making, and the enhancement of an affective sense and embodied experience of community. Finally, we examine some of the barriers to realizing more generatively just community energy systems.

The emergence of microreactor technology has helped to drive supporting nuclear materials qualification and acceptance processes. One essential component in these small reactors is a solid moderator, which typically consists of metal hydride and cladding. While the behavior and performance of metal-hydride moderators go back to early advanced reactor development for nuclear-powered aviation and space propulsion, there remains a knowledge gap in the understanding of hydrogen transport--related phenomena and irradiation performance for hydride moderators. This impacts the acceptance/qualification of hydride moderators for microreactors. The goal of this technical note is to lay out a potential path forward for advanced moderator qualification and acceptance for designers and developers of microreactors. The proposed approach has benefited from a model microreactor core with the design parameters of a hydride moderator. Based on the model core and design parameters, a simple chart was developed for the major challenges of hydride moderators where potential incidents, causes, effects, and resolutions are described. The relation between the offered resolutions and the maturity of the metal-hydride moderator technology was emphasized using technological readiness. Technological readiness levels (TRLs) were clustered to three sets: physical phenomena related, reactor irradiations, and system demonstration. Some essential needs to fill the knowledge gaps are discussed for physical phenomena--related TRLs. For reactor irradiations, the importance of identifying goals and priorities is stressed to reach certain TRLs. For system demonstration, it is noted that metal-hydride moderator qualification must comply with the overall microreactor design. [ABSTRACT FROM AUTHOR]

As microreactors evolve to become a more affordable and efficient worldwide energy source, the development of moderator material within the system to decrease the required mass of low-enriched uranium fuel is important. The use of low- instead of high-enriched uranium in small nuclear reactors stems from recent national policies associated with nonproliferation. New designs are being developed for a range of applications and nuclear space systems in particular. Using system geometries such as those described in this paper, the next step is to advance the technology readiness level of moderator material such as delta-yttrium hydride (YHx,x = 1.6--2.0) so that it can be qualified for use in a microreactor system. Although characterization of unirradiated material has been documented previously, to fully understand the performance of this material, behavior in relevant irradiation environments must occur. This paper describes the fabrication of yttrium hydride samples through innovative techniques and how these samples were tested in two relevant neutron environments. These two experiments include (1) a critical experiment performed at the National Criticality Experiments Research Center (NCERC) to evaluate reactivity changes in a neutron-critical environment and (2) irradiation in the Advanced Test Reactor (ATR) to assess structural integrity/material form, thermophysical data, hydrogen permeability, and other features post irradiation. For this purpose, hundreds of samples were fabricated for the NCERC and ATR experiments and are described within this paper. [ABSTRACT FROM AUTHOR]

Immune cells have been implicated in idiopathic pulmonary fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We performed mass cytometry to quantify immune cell subsets in lungs of 12 patients with IPF and 15 organ donors without chronic lung disease and used existing single-cell RNA-sequencing data to investigate transcriptional profiles of immune cells overrepresented in IPF. Among myeloid cells, we found increased numbers of alveolar macrophages (AMØs) and dendritic cells (DCs) in IPF, as well as a subset of monocyte-derived DCs. In contrast, monocyte-like cells and interstitial macrophages were reduced in IPF. Transcriptomic profiling identified an enrichment for IFN-γ response pathways in AMØs and DCs from IPF, as well as antigen processing in DCs and phagocytosis in AMØs. Among T cells, we identified three subsets of memory T cells that were increased in IPF, including CD4+ and CD8+ resident memory T cells (TRM) and CD8+ effector memory cells. The response to the IFN-γ pathway was enriched in CD4 TRM and CD8 TRM cells in IPF, together with T cell activation and immune response–regulating signaling pathways. Increased AMØs, DCs, and memory T cells were present in IPF lungs compared with control subjects. In IPF, these cells possess an activation profile indicating increased IFN-γ signaling and upregulation of adaptive immunity in the lungs. Together, these studies highlight critical features of the immunopathogenesis of IPF. [ABSTRACT FROM AUTHOR]

Lung organogenesis requires precise timing and coordination to effect spatial organization and function of the parenchymal cells. To provide a systematic broad-based view of the mechanisms governing the dynamic alterations in parenchymal cells over crucial periods of development, we performed a single-cell RNA-sequencing timeseries yielding 102,571 epithelial, endothelial and mesenchymal cells across nine time points from embryonic day 12 to postnatal day 14 in mice. Combining computational fate-likelihood prediction with RNA in situ hybridization and immunofluorescence, we explore lineage relationships during the saccular to alveolar stage transition. The utility of this publicly searchable atlas resource (www.sucrelab.org/lungcells) is exemplified by discoveries of the complexity of type 1 pneumocyte function and characterization of mesenchymal Wnt expression patterns during the saccular and alveolar stages - wherein major expansion of the gas-exchange surface occurs. We provide an integrated view of cellular dynamics in epithelial, endothelial and mesenchymal cell populations during lung organogenesis. [ABSTRACT FROM AUTHOR]

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection. Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients. [ABSTRACT FROM AUTHOR]

The current technology for hydrogen isotope separation requires enormous capital investment and energy consumption. Palladium-based membranes exhibit hydrogen isotope selectivity and provide a continuous method of isotope enrichment but have high material costs. Here, the authors investigate the potential of titanium carbide thin films coated on vanadium as a low-cost alternative, which enabled operation at high temperatures. Protium and deuterium exhibited nominally identical solubility in TiC coated vanadium over a range of 500–700 °C. Permeation tests from 600 to 700 °C revealed that protium permeated faster than deuterium, with the separation factor decreasing from 1.34 to 1.15 with increasing temperature. XPS depth-profiling showed a distinct interface between the TiC layer and the V foil in as-fabricated membranes. However, post-test analysis revealed significant V diffusion through TiC and segregation to the surface. Surface limitations resulting from this degradation accounted for changes in flux and may explain why the separation factor was lower than the value of 1.42 expected from high temperature interstitial diffusion of protium/deuterium in vanadium. [ABSTRACT FROM AUTHOR]

R3669 --> 760.5 --> Breathing is essential to life and can be easily disrupted by many adverse events. Disorders such as high cervical spinal cord injury (SCI) and sleep apnea can decrease quality of life and enhance the ill effects of comorbidities like Alzheimer's disease (AD). Previous studies have shown an increase in cognitive impairments in subjects with both sleep apnea and AD. Apolipoprotein E (ApoE) is a protein found throughout the body and central nervous system (CNS) that is involved in the regulation and transport of cholesterol and lipids. Out of the three APOE human alleles (E2, E3, and E4), the E4 allele has been implicated in the early onset and higher risk of AD when compared to E2 or E3. Previous research in our lab has shown that the interaction between APOE genotype and sex has different effects on breathing motor plasticity following a cervical SCI in mice. However, it is unknown how baseline respiratory pattern and capability differs between uninjured individuals expressing either ApoE4 or E3, specifically under hypoxic conditions. Unpublished data from our lab has examined these differences in male mice, showing that E4 male mice have high variation in respiratory pattern, as well as a less robust response to hypoxia. Using ApoE as our independent variable, we measured respiratory parameters of female C57/BL6 ApoE3 and ApoE4 humanized mice using whole body plethysmography (WBP), hypothesizing that ApoE3 animals would display a greater baseline respiratory rate and have a more adaptive, heightened response to hypoxic exposure than those expressing ApoE4. Preliminary data comparing E3 female animals (n=8) and E4 female animals (n=8) showed differences across several key measurements. Interestingly, ApoE4 humanized female mice had a more robust response to hypoxic exposure that failed to persist following cessation of hypoxia. However, at baseline, E4 female animals showed no differences in respiratory pattern in contrast to our previously collected male ApoE4 data. These results indicate a critical role of the APOE genotype in the regulation of breathing and response to hypoxic conditions which differs between males and females. To further understand this distinction, future experiments will examine differences in levels of brainstem and spinal cord serotonin expression between ApoE3 and E4 males and females, as well as plasticity following injury in areas high in ApoE expression. [ABSTRACT FROM AUTHOR]

R4661 --> 760.7 --> Breathing is vital for life and is both uniquely complex and vulnerable to disruption. Disorders of breathing such as those that occur in sleep apnea and even high cervical spinal cord injury (SCI) can impair quality of life and potentiate the ill effects of comorbidities like Alzheimer's disease (AD). Indeed, studies have shown greater cognitive and cardiovascular impairments in subjects with sleep apnea and AD. Apolipoprotein E (ApoE) is a ubiquitous protein found throughout the body and CNS which aids in the regulation and transport of cholesterol and lipids. Moreover, the E4 allele confers a higher risk of early onset AD than either the E2 or E3 alleles. Previous research in our lab has shown the interaction between ApoE genotype and sex differentially affects breathing motor plasticity following SCI in mice. However, it is unknown how baseline respiratory pattern and capability during hypoxic challenge may differ between uninjured individuals expressing APOE4 and E3 alleles. Thus, with APOE genotype as our independent variable, we measured the respiratory parameters of male E3 and E4 targeted replacement mice using whole body plethysmography (WBP), hypothesizing that E3 animals would display a more adaptive, heightened response to hypoxic exposure than those expressing E4. Preliminary data comparing E3 animals (n=9) and E4 animals (n=8) demonstrated differences across several key measurements. At baseline, E4 animals were shown to breathe in an energy inefficient manner as exemplified high measures in tidal volume and frequency. During sustained hypoxia, frequency, tidal volume, and minute volume initially increased across all animals, but APOE3 animals mounted a much more robust and sustained response with APOE4 values falling well below baseline measures prior to termination of hypoxia. These preliminary results suggest a critical role of the APOE genotype in regulation of baseline breathing and in response to hypoxic conditions and that possessing the APOE4 allele may confer vulnerabilities in respiratory function and during environmental challenges leading to cognitive decline. Future directions include examining anatomically critical CNS respiratory regions and neural cell function. [ABSTRACT FROM AUTHOR]

Background: Tumor metastasis is responsible for 90% of cancer-related deaths. Recently, a strong link between microRNA dysregulation and human cancers has been established. However, the molecular mechanisms through which microRNAs regulate metastasis and cancer progression remain unclear. Methods: We analyzed the reciprocal expression regulation of miR-31 and SOX4 in esophageal squamous and adenocarcinoma cell lines by qRT-PCR and Western blotting using overexpression and shRNA knock-down approaches. Furthermore, methylation studies were used to assess epigenetic regulation of expression. Functionally, we determined the cellular consequences using migration and invasion assays, as well as proliferation assays. Immunoprecipitation and ChIP were used to identify complex formation of SOX4 and co-repressor components. Results: Here, we report that SOX4 promotes esophageal tumor cell proliferation and invasion by silencing miR-31 via activation and stabilization of a co-repressor complex with EZH2 and HDAC3. We demonstrate that miR-31 is significantly decreased in invasive esophageal cancer cells, while upregulation of miR-31 inhibits growth, migration and invasion of esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) cell lines. miR-31, in turn, targets SOX4 for degradation by directly binding to its 3'-UTR. Additionally, miR-31 regulates EZH2 and HDAC3 indirectly. SOX4, EZH2 and HDAC3 levels inversely correlate with miR-31 expression in ESCC cell lines. Ectopic expression of miR-31 in ESCC and EAC cell lines leads to down regulation of SOX4, EZH2 and HDAC3. Conversely, pharmacologic and genetic inhibition of SOX4 and EZH2 restore miR-31 expression. We show that SOX4, EZH2 and HDAC3 form a co-repressor complex that binds to the miR-31 promoter, repressing miR-31 through an epigenetic mark by H3K27me3 and by histone acetylation. Clinically, when compared to normal adjacent tissues, esophageal tumor samples show upregulation of SOX4, EZH2, and HDAC3, and EZH2 expression is significantly increased in metastatic ESCC tissues. Conclusions: Thus, we identified a novel molecular mechanism by which the SOX4, EZH2 and miR-31 circuit promotes tumor progression and potential therapeutic targets for invasive esophageal carcinomas. [ABSTRACT FROM AUTHOR]

Activation of PI3K/AKT pathway correlates with poor prognosis in patients with neuroblastoma. Our previous studies have demonstrated that PI3K/AKT signaling is critical for the oncogenic transformations induced by gastrin-releasing peptide (GRP) and its receptor, GRP-R, in neuroblastoma. Moreover, PI3K/AKT-dependent oncogenic transformations require N-myc, an extensively studied oncogene in neuroblastoma. Whether AKT directly regulates the expression of N-myc oncogene is yet to be determined. Here, we report a novel finding that of the three AKT isoforms, AKT2 specifically regulated N-myc expression in neuroblastoma cells. We also confirmed that GRP-R is upstream of AKT2 and in turn, regulated N-myc expression via AKT2 in neuroblastoma cells. Functional assays demonstrated that attenuation of AKT2 impaired cell proliferation and anchorage-independent cell growth, and decreased the secretion of angiogenic factor VEGF in vitro. Furthermore, silencing AKT2 inhibited migration and invasion of neuroblastoma cells in vitro. Xenografts established by injecting AKT2 silenced human neuroblastoma cells into murine spleen expressed decreased levels of AKT2 and resulted in fewer liver metastases compared to controls in vivo. Hence, our study highlights the potential molecular mechanism(s) mediating the oncogenic role of GRP/GRP-R and demonstrates a novel role for AKT2 in neuroblastoma tumorigenesis, indicating that targeting the GRP/GRP-R/AKT2 axis may be important for developing novel therapeutics in the treatment of clinically aggressive neuroblastoma. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: SIX2 and CITED1 are transcriptional regulators that specify self-renewing nephronic progenitor cells of the embryonic kidney. We hypothesized that SIX2, which promotes and maintains this stem cell population, and CITED1 remain active in Wilms'' tumor (WT). Methods: To evaluate expression domains and the pathogenic significance of SIX2 and CITED1 across WT, the Children''s Oncology Group provided 40 WT specimens of stages I to IV (n = 10 per stage), which were enriched for unfavorable histology (n = 20) and treatment failure (relapse or death, n = 20). SIX2 and CITED1 protein expression was evaluated qualitatively (immunohistochemistry) and quantitatively (Western blot, or WB). Gene transcription was estimated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: SIX2 was visualized by immunohistochemistry in 36 (94.7%) of 38 specimens. Protein and messenger RNA expression of SIX2 were quantitatively similar across all stages of disease (P = .48 WB; P = 0.38 qPCR), in favorable or unfavorable histology (P = 0.51 WB; P = 0.58 qPCR), and in treatment failure or success (P = 0.86 WB; P = 0.49 qPCR). Although CITED1 expression paralleled SIX2 qualitatively, no quantitative correlation between SIX2 and CITED1 expression was observed (Spearman correlation coefficient, 0.28; P = 0.08). As in the fetal kidney, overlapping, but also distinct, WT cellular expression domains were observed between SIX2 and CITED1. Conclusion: SIX2 and CITED1 remain active across all disease characteristics of WT. Activity of these genes in WT potentially identifies a population of self-renewing cancer cells that exhibit an embryonic, stemlike phenotype. Taken together, these transcriptional regulators may be fundamental to WT cellular self-renewal and may represent targets for novel therapies that promote terminal differentiation. [Copyright &y& Elsevier]

The plasma-material interface and its impact on the performance of magnetically confined thermonuclear fusion plasmas are considered to be one of the key scientific gaps in the realization of nuclear fusion power. At this interface, high particle and heat flux from the fusion plasma can limit the material's lifetime and reliability and therefore hinder operation of the fusion device. Lithium-based surfaces are now being used in major magnetic confinement fusion devices and have observed profound effects on plasma performance including enhanced confinement, suppression and control of edge localized modes (ELM), lower hydrogen recycling and impurity suppression. The critical spatial scale length of deuterium and helium particle interactions in lithium ranges between 5-100 nm depending on the incident particle energies at the edge and magnetic configuration. Lithium-based surfaces also range from liquid state to solid lithium coatings on a variety of substrates (e.g., graphite, stainless steel, refractory metal W/Mo/etc., or porous metal structures). Temperature-dependent effects from lithium-based surfaces as plasma facing components (PFC) include magnetohydrodynamic (MHD) instability issues related to liquid lithium, surface impurity, and deuterium retention issues, and anomalous physical sputtering increase at temperatures above lithium's melting point. The paper discusses the viability of lithium-based surfaces in future burning-plasma environments such as those found in ITER and DEMO-like fusion reactor devices. [ABSTRACT FROM AUTHOR]

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κB ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells. Anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated pulmonary fibrosis. We conclude that silica induces differentiation of pulmonary osteoclast-like cells leading to progressive lung injury, likely due to sustained elaboration of boneresorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis. [ABSTRACT FROM AUTHOR]