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The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8+ T cell invasion into BEC. CD8+ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8+ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8+ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin+ CD8+ T cells formed ß-catenin-associated interactions with BEC, were larger than E-cadherin- CD8+ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin+ CD103+ CD69+ CD8+ T cells into BEC.

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Tropical peatlands are globally significant in the terrestrial carbon cycle as they are comprised of a large forest carbon sink and a large peat carbon store-both of which can potentially be exchanged with the atmosphere on decadal time frames. Greenhouse gas emissions from fire-disturbance and development of tropical peatlands over the last few decades, and the potential for ongoing emissions, highlights the need for policy to slow or halt emissions and to activate mechanisms to sequester carbon through restoration of degraded peatlands. The UN REDD + scheme provides a means for developing countries to receive payments for avoided deforestation and forest degradation, but the steps to achieve REDD+ compliance are rigorous and the details required can be a barrier to activating benefits-especially for peatlands where repeated cycles of fire interrupt forest recovery and create a range of recovery classes. Therefore, to improve estimates of peat fire emissions and of carbon balance of tropical peatlands, the biomass and combustion factor parameters need to be developed and applied according to forest recovery stage. In this study we use published activity data from the extensive 1997 fires in the peatlands of Indonesian Borneo to detail a transparent and accountable way to estimate and report emissions from tropical peatland fires. This example for estimating and reporting emissions is provided to assist REDD+ countries to efficiently develop their capacity for improving emissions estimates from fire-impacted tropical peatlands.

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ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.

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INTRODUCTION: Operation Bushmaster is a high-fidelity military medical field practicum for fourth-year medical students at the Uniformed Services University. During Operation Bushmaster, students treat live-actor and mannequin-based simulated patients in wartime scenarios throughout the five-day practicum. This study explored the impact of participating in Operation Bushmaster on students' decision-making in a high-stress, operational environment, a crucial aspect of their future role as military medical officers. MATERIALS AND METHODS: A panel of emergency medicine physician experts used a modified Delphi technique to develop a rubric to evaluate the participants' decision-making abilities under stress. The participants' decision-making was assessed before and after participating in either Operation Bushmaster (control group) or completing asynchronous coursework (experimental group). A paired-samples t-test was conducted to detect any differences between the means of the participants' pre- and posttest scores. This study was approved by the Institutional Review Board at Uniformed Services University #21-13079. RESULTS: A significant difference was detected in the pre- and posttest scores of students who attended Operation Bushmaster (P < .001), while there was no significant difference in the pre- and posttest scores of students who completed online, asynchronous coursework (P = .554). CONCLUSION: Participating in Operation Bushmaster significantly improved the control group participants' medical decision-making under stress. The results of this study confirm the effectiveness of high-fidelity simulation-based education for teaching decision-making skills to military medical students.

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BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced tumor necrosis factor-α/interleukin-6 production and T-cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment, but not interstitial lung- and tissue-resident synovial lining macrophages. Here, we assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n = 22), chronic liver disease (n = 8), non-cirrhotic portal hypertension (n = 4), and healthy controls (n = 4). Phenotype and function of isolated primary human liver macrophages were characterized by flow cytometry (cirrhosis, n = 11; control, n = 14) ex vivo. Also, AXL expression was assessed on peritoneal (n = 29) and gut macrophages (n = 16) from cirrhotic patients. Regulation of AXL expression was analyzed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells, and GAS6 in co-culture experiments. RESULTS: AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (healthy, 90.2%; Child-Pugh A, 76.1%; Child-Pugh B, 64.5%; and Child-Pugh C, 18.7%; all P < .05) and negatively correlated with Model for End-Stage Liver Disease and C-reactive protein (all P < .05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSC-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

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Disturbance trends over recent decades indicate that climate change is resulting in increased fire severity and extent in Australia's temperate Eucalyptus forests. As disturbance cycles become shorter and more severe, empirical measurements are required to identify potential change in forest carbon (C) stock and emissions. However, such estimates are rare in the literature. The 2019-2020 wildfires burnt through 6 to 7 million ha of mainly temperate open Eucalyptus forest in south-east Australia, with top down emission estimates ranging from 97 to 130 tonnes CO2 ha-1. Study sites that had been assessed for all aboveground C pools prior to the wildfires, were burnt in January 2020 by wildfire that varied in severity. Here we quantify the impact of high and low/moderate fire severities on tree mortality, C loss and C redistribution and assess implications for future C storage in these temperate Eucalyptus forests. Higher fire severity resulted in greater overstorey tree mortality but not understorey or loss of dead standing trees than in low/moderate severity fires. High severity fires combusted almost twice as much C from live trees (42 Mg C ha-1) as low/moderate severity fires (25 Mg C ha-1), while C loss from dead standing trees was similar among fire severity classes (average 17 Mg C ha-1). Total aboveground C lost across study sites was 42 Mg C ha-1 for high and 47 Mg C ha-1 for low/moderate severity, with an average of 45 Mg C ha-1 equivalent to 15 % (high severity) and 14 % (low/moderate severity) of AGC. Extrapolating our findings to other tall to medium open Eucalyptus forests across Victoria revealed that 37.33 ± 12.25 Tg C (mean ± s.e.) or 152 ± 50 Mg CO2 ha-1 was lost to the atmosphere from the 0.9 million ha of these productive forests, equating to about 20 % of Australia's total net annual emissions.

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Prescribed fire to reduce forest fuels has been routinely applied to reduce wildfire risk in many parts of the world. It has also been proposed that prescribed fire can be used to mitigate greenhouse gas (GHG) emissions. Although prescribed fire creates emissions, if the treatment also decreases the incidence of subsequent wildfires, it is possible for the net outcome to be an emissions decline. Previous studies have suggested prescribed fire, at the frequencies required to materially impact wildfire occurrence, generally leads to net emissions increases. A focus on emissions means any change in carbon storage within the ecosystem remains unaccounted for; because living, dead, and soil carbon pools are characterized by different residence times, a re-distribution of carbon amongst these pools may either reduce or increase long-term ecosystem carbon stores. A full ecosystem carbon model has been developed to investigate the implications of prescribed fire management on total Net Ecosystem Carbon Balance (NECB), inclusive of both emissions and carbon storage. Consistent with previous work, the results suggested limited potential for reducing net GHG emissions through applying prescribed fire, with higher emissions from prescribed fire approximately offset by lower emissions and avoided carbon losses from the subsequent reduction in wildfire frequency. For example, shortening the prescribed fire interval from 25 to 10 years resulted in a NECB sequestration that was typically less than ±0.4 Mg C ha-1 yr-1, or less than approximately 0.1% of the total ecosystem carbon storage. Hence, whilst there was limited opportunity for achieving emission abatement outcomes from changing prescribed fire management, there were no significant emission penalties for doing so. These results suggest land managers should be free to adopt prescribed fire regimes to target specific management outcomes, without significantly impacting net emissions or total ecosystem carbon storage over the long term.

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Accurate assessment of tropical peat forest carbon stocks and impact of fires on carbon pools is required to determine the magnitude of emissions to the atmosphere and to support emissions reduction policies. We assessed total aboveground carbon (AGC) in biomass pools including trees, shrubs, deadwood, litter and char, and peat carbon to develop empirical estimates of peat swamp forest carbon stocks in response to fire and disturbance. In contrast to the common assumption that peat fires combust all AGC, we observed that about half of undisturbed forest AGC, equivalent to about 70 Mg C ha-1, remains after one or two recent fires - mainly in dead trees, woody debris and pyrogenic carbon. Both recently burnt and repeatedly burnt peat forests store similar amounts of carbon in the top 10 cm of peat when compared with undisturbed forests (70 Mg C ha-1), mainly due to increased peat bulk density after fires that compensates for their lower peat C%. The proportion of fuel mass consumed in fire, or combustion factor (CF), is required to make accurate estimates of peat fire emissions for both AGC and peat carbon. This study estimated a CF for AGC (CFAGC) of 0.56, comparable to the default value of the Intergovernmental Panel on Climate Change (IPCC). This study estimated a varying CF for peat (CFPEAT) that ranged from 0.4 to 0.68 as depth of burn increased. This revised CFPEAT is one third to one half of the IPCC default value of 1.0. The current assumption of complete combustion of peat (CF = 1.0) is widely acknowledged in the literature as oversimplification and is not supported by our field observations or data. This study provides novel empirical data to improve estimates of peat forests carbon stocks and emissions from tropical peat fires.

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Many chronic inflammatory diseases are treated by administration of "biological" therapies in terms of fully human and humanized monoclonal antibodies or Fc fusion proteins. These tools have widespread efficacy and are favored because they generally exhibit high specificity for target with a low toxicity. However, the design of clinically applicable humanized antibodies is complicated by the need to circumvent normal antibody clearance mechanisms to maintain therapeutic dosing, whilst avoiding development of off target antibody dependent cellular toxicity. Classically, professional phagocytic immune cells are responsible for scavenging and clearance of antibody via interactions with the Fc portion. Immune cells such as macrophages, monocytes, and neutrophils express Fc receptor subsets, such as the FcγR that can then clear immune complexes. Another, the neonatal Fc receptor (FcRn) is key to clearance of IgG in vivo and serum half-life of antibody is explicitly linked to function of this receptor. The liver is a site of significant expression of FcRn and indeed several hepatic cell populations including Kupffer cells and liver sinusoidal endothelial cells (LSEC), play key roles in antibody clearance. This combined with the fact that the liver is a highly perfused organ with a relatively permissive microcirculation means that hepatic binding of antibody has a significant effect on pharmacokinetics of clearance. Liver disease can alter systemic distribution or pharmacokinetics of antibody-based therapies and impact on clinical effectiveness, however, few studies document the changes in key membrane receptors involved in antibody clearance across the spectrum of liver disease. Similarly, the individual contribution of LSEC scavenger receptors to antibody clearance in a healthy or chronically diseased organ is not well characterized. This is an important omission since pharmacokinetic studies of antibody distribution are often based on studies in healthy individuals and thus may not reflect the picture in an aging or chronically diseased population. Therefore, in this review we consider the expression and function of key antibody-binding receptors on LSEC, and the features of therapeutic antibodies which may accentuate clearance by the liver. We then discuss the implications of this for the design and utility of monoclonal antibody-based therapies.

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Point-of-care ultrasound (POCUS) can help the clinician diagnose different ocular pathologies including retinal detachment, vitreous detachment, lens dislocation, and intraocular foreign bodies. Ocular pathologies such as blurry vision, double vision, loss of vision, and eye trauma are common chief complaints and require a comprehensive evaluation in order to determine the etiology and choose the correct treatment. Specifically ultrasound can help the clinician decide whether an urgent ophthalmology consult is appropriate. We present a case in which a lens dislocation was diagnosed using POCUS and review the available literature.

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Tropical peatlands are areas of high carbon density that are important in biosphere-atmosphere interactions. Drainage and burning of tropical peatlands releases about 5% of global greenhouse gas (GHG) emissions, yet there is great uncertainty in these estimates. Our comprehensive literature review of parameters required to calculate GHG emissions from burnt peat forests, following the international guidelines, revealed many gaps in knowledge of carbon pools and few recent supporting studies. To improve future estimates of the total ecosystem carbon balance and peatfire emissions this study aimed to account for all carbon pools: aboveground, deadwood, pyrogenic carbon (PyC) and peat of single and repeatedly burnt peat forests. A further aim was to identify the minimum sampling intensity required to detect with 80% power significant differences in these carbon pools among long unburnt, recently burnt and repeatedly burnt peat swamp forests. About 90 Mg C ha-1 remains aboveground as deadwood after a single fire and half of this remains after a second fire. One fire produces 4.5 ± 0.6 Mg C ha-1 of PyC, with a second fire increasing this to 7.1 ± 0.8 Mg C ha-1. For peat swamp forests these aboveground carbon pools are rarely accounted in estimates of emissions following multiple fires, while PyC has not been included in the total peat carbon mass balance. Peat bulk density and peat carbon content change with fire frequency, yet these parameters often remain constant in the published emission estimates following a single and multiple fires. Our power analysis indicated that as few as 12 plots are required to detect meaningful differences between fire treatments for the major carbon pools. Further field studies directed at improving the parameters for calculating carbon balance of disturbed peat forest ecosystems are required to better constrain peatfire GHG emission estimates.

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OBJECTIVES: A proof of concept cross-sectional study investigating changes in myocardial abnormalities across stages of chronic kidney disease (CKD). Characterizing noninvasive markers of myocardial fibrosis on cardiac magnetic resonance, echocardiography, and correlating with biomarkers of fibrosis, myocardial injury, and functional correlates including exercise tolerance. BACKGROUND: CKD is associated with an increased risk of cardiovascular death. Much of the excess mortality is attributed to uremic cardiomyopathy, defined by increased left ventricular hypertrophy, myocardial dysfunction, and fibrosis. The prevalence of these abnormalities across stages of CKD and their impact on cardiovascular performance is unknown. METHODS: A total of 134 nondiabetic, pre-dialysis subjects with CKD stages 2 to 5 without myocardial ischemia underwent cardiac magnetic resonance (1.5-T) including; T1 mapping (biomarker of diffuse fibrosis), T2 mapping (edema), late gadolinium enhancement, and assessment of aortic distensibility. Serum biomarkers including collagen turnover (P1NP, P3NP), troponin T, and N-terminal pro-B-type natriuretic peptide were measured. Cardiovascular performance was quantified by bicycle cardiopulmonary exercise testing and echocardiography. RESULTS: Native myocardial T1 times increased incrementally from stage 2 to 5 (966 ± 21 ms vs. 994 ± 33 ms; p < 0.001), independent of hypertension and aortic distensibility. Left atrial volume, E/e', N-terminal pro-B-type natriuretic peptide, P1NP, and P3NP increased with CKD stage (p < 0.05), while effort tolerance (% predicted VO2Peak, %VO2VT) decreased (p < 0.001). In multivariable linear regression models, estimated glomerular filtration rate was the strongest predictor of native myocardial T1 time (p < 0.001). Native myocardial T1 time, left atrial dilatation, and high-sensitivity troponin T were independent predictors of % predicted VO2Peak (p < 0.001). CONCLUSIONS: Imaging and serum biomarkers of myocardial fibrosis increase with advancing CKD independent of effects of left ventricular afterload and might be a key intermediary in the development of uremic cardiomyopathy. Further studies are needed to determine whether these changes lead to the increased rates of heart failure and death in CKD. (Left Ventricular Fibrosis in Chronic Kidney Disease [FibroCKD]; NCT03176862).

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Acetaminophen (APAP) is the main cause of acute liver failure in the West. Specific efficacious therapies for acute liver failure (ALF) are limited and time-dependent. The mechanisms that drive irreversible acute liver failure remain poorly characterized. Here we report that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage after toxic liver injury. Our data demonstrate that blocking platelet CLEC-2 signalling enhances liver recovery from acute toxic liver injuries (APAP and carbon tetrachloride) by increasing tumour necrosis factor-α (TNF-α) production which then enhances reparative hepatic neutrophil recruitment. We provide data from humans and mice demonstrating that platelet CLEC-2 influences the hepatic sterile inflammatory response and that this can be manipulated for therapeutic benefit in acute liver injury. Since CLEC-2 mediated platelet activation is independent of major haemostatic pathways, blocking this pathway represents a coagulopathy-sparing, specific and novel therapy in acute liver failure.

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Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.

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Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro. Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception.

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More frequent hot and windy weather in fire prone forested landscapes requires that a full suite of fuel reduction measures be investigated for effectiveness in fuel hazard reduction, environmental impact and carbon (C) outcomes. Although prescribed fire and thinning are routinely applied in forests of North America to reduce fuel loads, there are few detailed studies from Australia. We report the impacts of fuel reduction treatments including burning, mechanical thinning and the combination of both on forest C and fuel hazard in open forests dominated by Eucalyptus sieberi in south-eastern Australia. Carbon losses to the atmosphere and redistribution within the forest were calculated from stocks within each fuel category before and after treatment. Mechanical thinning + burning was the most effective treatment for reducing aboveground C and fuel hazard, with major reductions in dead trees, stumps and understorey, as well as stems removed for sale as pulpwood. However forest floor fuel loads increased in thinned treatments relative to control forests. The overall fuel hazard rating in the burn only treatment was significantly reduced from extreme to low immediately following burning. In thinned only stands, the overall fuel hazard rating did not change from the pre-treatment rating of extreme, due to high surface and forest floor fuel loads and loose and flammable bark on the retained overstorey trees. This result suggests the current fuel hazard guide in use in Australia should be revised to enable it to better describe the benefits of thinning for fuel reduction - in this case the removal of about 50% of aboveground C mostly as overstorey trees, and a significant reduction in understorey, dead trees and stumps.

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Syphilis, caused by Treponema pallidum subsp. pallidum (TPA), remains an important public health problem with an increasing worldwide prevalence. Despite recent advances in in vitro cultivation, genetic variability of this pathogen during infection is poorly understood. Here, we present contemporary and geographically diverse complete treponemal genome sequences isolated directly from patients using a methyl-directed enrichment prior to sequencing. This approach reveals that approximately 50% of the genetic diversity found in TPA is driven by inter- and/or intra-strain recombination events, particularly in strains belonging to one of the defined genetic groups of syphilis treponemes: Nichols-like strains. Recombinant loci were found to encode putative outer-membrane proteins and the recombination variability was almost exclusively found in regions predicted to be at the host-pathogen interface. Genetic recombination has been considered to be a rare event in treponemes, yet our study unexpectedly showed that it occurs at a significant level and may have important impacts in the biology of this pathogen, especially as these events occur primarily in the outer membrane proteins. This study reveals the existence of strains with different repertoires of surface-exposed antigens circulating in the current human population, which should be taken into account during syphilis vaccine development.

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Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.

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