Lipocalin 10 is essential for protection against inflammation-triggered vascular leakage by activating LDL receptor-related protein 2-slingshot homologue 1 signalling pathway.

AIMS: Systemic inflammation occurs commonly during many human disease settings and increases vascular permeability, leading to organ failure, and lethal outcomes. Lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin family, is remarkably altered in the cardiovascular system of human patients with inflammatory conditions. Nonetheless, whether Lcn10 regulates inflammation-induced endothelial permeability remains unknown. METHODS AND RESULTS: Systemic inflammation models were induced using mice by injection of endotoxin lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) surgery. We observed that the expression of Lcn10 was dynamically altered only in endothelial cells (ECs), but not in either fibroblasts or cardiomyocytes isolated from mouse hearts following the LPS challenge or CLP surgery. Using in vitro gain- and loss-of-function approaches and an in vivo global knockout mouse model, we discovered that Lcn10 negatively regulated endothelial permeability upon inflammatory stimuli. Loss of Lcn10 augmented vascular leakage, leading to severe organ damage and higher mortality following LPS challenge, compared to wild-type controls. By contrast, overexpression of Lcn10 in ECs displayed opposite effects. A mechanistic analysis revealed that both endogenous and exogenous elevation of Lcn10 in ECs could activate slingshot homologue 1 (Ssh1)-Cofilin signalling cascade, a key axis known to control actin filament dynamics. Accordingly, a reduced formation of stress fibre and increased generation of cortical actin band were exhibited in Lcn10-ECs, when compared to controls upon endotoxin insults. Furthermore, we identified that Lcn10 interacted with LDL receptor-related protein 2 (LRP2) in ECs, which acted as an upstream factor of the Ssh1-Confilin signalling. Finally, injection of recombinant Lcn10 protein into endotoxic mice showed therapeutic effects against inflammation-induced vascular leakage. CONCLUSION: This study identifies Lcn10 as a novel regulator of EC function and illustrates a new link in the Lcn10-LRP2-Ssh1 axis to controlling endothelial barrier integrity. Our findings may provide novel strategies for the treatment of inflammation-related diseases.

Drivers of nematode diversity in forest soils across climatic zones.

Nematodes are the most abundant multi-cellular animals in soil, influencing key processes and functions in terrestrial ecosystems. Yet, little is known about the drivers of nematode abundance and diversity in forest soils across climatic zones. This is despite forests covering approximately 30% of the Earth's land surface, providing many crucial ecosystem services but strongly varying in climatic conditions and associated ecosystem properties across biogeographic zones. Here, we collected nematode samples from 13 forests across a latitudinal gradient. We divided this gradient into temperate, warm-temperate and tropical climatic zones and found that, across the gradient, nematode abundance and diversity were mainly influenced by soil organic carbon content. However, mean annual temperature and total soil phosphorus content in temperate zones, soil pH in warm-temperate zones, and mean annual precipitation in tropical zones were more important in driving nematode alpha-diversity, biomass and abundance. Additionally, nematode beta-diversity was higher in temperate than in warm-temperate and tropical zones. Together, our findings demonstrate that the drivers of nematode diversity in forested ecosystems are affected by the spatial scale and climatic conditions considered. This implies that high resolution studies are needed to accurately predict how soil functions respond if climate conditions move beyond the coping range of soil organisms.

Efficacy and safety of umbilical cord mesenchymal stem cells for the treatment of patients with COVID-19.

OBJECTIVES: The coronavirus disease (COVID-19) outbreak has catastrophically threatened public health worldwide and presented great challenges for clinicians. To date, no specific drugs are available against severe acute respiratory syndrome coronavirus 2. Mesenchymal stem cells (MSCs) appear to be a promising cell therapy owing to their potent modulatory effects on reducing and healing inflammation-induced lung and other tissue injuries. The present pilot study aimed to explore the therapeutic potential and safety of MSCs isolated from healthy cord tissues in the treatment of patients with COVID-19. METHODS: Twelve patients with COVID-19 treated with MSCs plus conventional therapy and 13 treated with conventional therapy alone (control) were included. The efficacy of MSC infusion was evaluated by changes in oxygenation index, clinical chemistry and hematology tests, immunoglobulin (Ig) levels, and pulmonary computerized tomography (CT) imaging. The safety of MSC infusion was evaluated based on the occurrence of allergic reactions and serious adverse events. RESULTS: The MSC-treated group demonstrated significantly improved oxygenation index. The area of pulmonary inflammation decreased significantly, and the CT number in the inflammatory area tended to be restored. Decreased IgM levels were also observed after MSC therapy. Laboratory biomarker levels at baseline and after therapy showed no significant changes in either the MSC-treated or control group. CONCLUSION: Intravenous infusion of MSCs in patients with COVID-19 was effective and well tolerated. Further studies involving a large cohort or randomized controlled trials are warranted.

Baseline characteristics and changes of biomarkers in disease course predict prognosis of patients with COVID-19.

The outbreak of coronavirus disease (COVID-19) has brought great challenges to the world. The objectives of this study were to describe the baseline characteristics and changes of biomarkers of these COVID-19 patients and identify predictive value of the above markers for patient death. Using patient death as the observational endpoints, clinical data of inpatients in a special ward for COVID-19 in Wuhan, China were retrospectively collected. Univariate and multivariate Cox regression analyses were used to evaluate prognostic value of baseline characteristics and laboratory data changes. This study included clinical data of 75 patients. Age, c-reactive protein (CRP) and interleukin-6 levels were independent predictors of patient death. Survivors were characterized as having declining neutrophil counts, D-dimer, N-terminal pronatriuretic peptide, troponin I (TnI) and c-reactive protein levels, while counts of lymphocyte gradually came back. Non-survivors were characterized with increasing white blood cell counts (WBC) and neutrophil counts. Changes of WBC, TnI and interleukin-6 were also independently associated with patient death. Older age, baseline CRP and IL-6 levels may be used as meaningful predictors to identify patients with poor prognosis. Changes of biomarkers should be closely monitored in the management of patients with COVID-19, while constantly increasing levels of WBC, TnI and interleukin-6 in the disease course also predict patient death.

3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model.

3,4-Dihydroxyphenylethanol (DOPET) is a polyphenol found in olive oil. The present study evaluated the protective role of DOPET on LPS provoked septic cardiac injury in a murine model. Four groups were used in the study (n = 3): control, LPS, DOPET alone, and DOPET + LPS. LPS (15 mg/kg; i.p.); they were used to induce cardiac sepsis. The cardiac markers like LDH, CK-MB, and troponin-T, as well as inflammatory cytokines like TNF-α and IL-6 were measured in the serum. The antioxidants and oxidative stress parameters were measured in cardiac tissues. RT-PCR and western blot methods were done to evaluate the expression of inflammatory mediators and apoptotic markers. DOPET significantly decreased the cardiac markers (LDH, CK-MB, and troponin-T) and TNF-α and IL-6 level in the serum. DOPET effectively reduced the levels of MDA and NO in LPS intoxicated rats. DOPET also increased the levels of antioxidants like SOD, CAT, GPx, and GSH in LPS intoxicated rats. The mRNA levels of TNF-α, IL-6, and NF-κB were significantly downregulated by DOPET in cardiac tissues of LPS rats. The protein expression of Bcl-2 was upregulated, and Bax and caspase-3 were downregulated by DOPET. DOPET effectively attenuates LPS-induced cardiac dysfunction through its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Efficacy and safety of umbilical cord mesenchymal stem cells for the treatment of patients with COVID-19

OBJECTIVES: The coronavirus disease (COVID-19) outbreak has catastrophically threatened public health worldwide and presented great challenges for clinicians. To date, no specific drugs are available against severe acute respiratory syndrome coronavirus 2. Mesenchymal stem cells (MSCs) appear to be a promising cell therapy owing to their potent modulatory effects on reducing and healing inflammation-induced lung and other tissue injuries. The present pilot study aimed to explore the therapeutic potential and safety of MSCs isolated from healthy cord tissues in the treatment of patients with COVID-19. METHODS: Twelve patients with COVID-19 treated with MSCs plus conventional therapy and 13 treated with conventional therapy alone (control) were included. The efficacy of MSC infusion was evaluated by changes in oxygenation index, clinical chemistry and hematology tests, immunoglobulin (Ig) levels, and pulmonary computerized tomography (CT) imaging. The safety of MSC infusion was evaluated based on the occurrence of allergic reactions and serious adverse events. RESULTS: The MSC-treated group demonstrated significantly improved oxygenation index. The area of pulmonary inflammation decreased significantly, and the CT number in the inflammatory area tended to be restored. Decreased IgM levels were also observed after MSC therapy. Laboratory biomarker levels at baseline and after therapy showed no significant changes in either the MSC-treated or control group. CONCLUSION: Intravenous infusion of MSCs in patients with COVID-19 was effective and well tolerated. Further studies involving a large cohort or randomized controlled trials are warranted.

Performance of quick sequential organ failure assessment (qSOFA) score for prognosis of heat-related hospitalized patients.

BACKGROUND: Heat-related illnesses pose significant threats to human health. OBJECTIVES: (1) To evaluate the use of qSOFA score for prognosis of heat-related hospitalized patients; and (2) identify other predictors for patient prognosis. METHODS: Using 28-day mortality as the primary endpoint, a retrospective, observational study of patients hospitalized between June 2013 and September 2018 was conducted. RESULTS: The qSOFA score from 84 patients was identified as an independent predictor of patient prognosis. The area under the receiver operating characteristic curves for qSOFA score was 0.702, and a sensitivity of 100.00% and a specificity of 47.06% were found for qSOFA score greater than or equal to 2. Other predictors included bilirubin, urea nitrogen, and troponin I levels. CONCLUSIONS: qSOFA score can be used as a parameter to distinguish patients with severe heat-related illness prior to further clinical analyses. In addition to that, multiple organ impairment should be considered when assessing patient prognosis.

Smoking Attenuates Efficacy of Penehyclidine Hydrochloride in Acute Respiratory Distress Syndrome Induced by Lipopolysaccharide in Rats.

BACKGROUND Penehyclidine hydrochloride is a novel drug for acute respiratory distress syndrome. The aim of the study was to reveal the impact of smoking on the efficacy of the drug in rats with acute respiratory distress syndrome. MATERIAL AND METHODS A 132 Sprague-Dawley rats were used in this study; 72 rats were used in the smoking models. Penehyclidine hydrochloride (3 mg/kg) was injected to induce acute respiratory distress syndrome. Rats were divided into the smoking group and the non-smoking group; these 2 groups were subdivided according to different treatments. The arterial blood gas analysis (PaO2/FiO2) and extent of pneumonedema (wet-to-dry weight ratio) was analyzed to evaluate disease severity. Expressions of mitogen-activated protein kinases (p-p38MAPK, p38MAPK, p-ERK, ERK, p-JNK, and JNK) in lung tissue were measured using western blot assay. RESULTS Penehyclidine hydrochloride improved the pneumonedema (wet-to-dry weight ratio) and hyoxemia (PaO2/FiO2) of the disease in non-smoking group (P<0.001, P<0.001 respectively), but not in smoking group (P=0.244, P=0.424 respectively). The drug inhibited the expressions of phospho-p38MAPK and phospho-ERK in non-smoking group (P<0.001, P<0.001 respectively), but not in smoking group (P=0.350, P=0.507 respectively). In the smoking group, blocking the phospho-p38MAPK or phospho-ERK signal pathway by their inhibitors showed a better therapeutic effect on the pneumonedema and hyoxemia compared with the use of penehyclidine hydrochloride (phospho-p38MAPK: P=0.004, P=0.010 respectively; phospho-ERK: P=0.022, P=0.004 respectively). CONCLUSIONS The study confirmed the protective effect of penehyclidine hydrochloride in acute respiratory distress syndrome, mainly in the non-smoking group, which might be explained by the fact that phospho-p38MAPK and phospho-ERK signal pathways were difficult to inhibit by the drug in the smoking group.

Increased Serum Concentrations of TNF-Like Weak Inducer of Apoptosis Predict Higher 28-Day Mortality in Patients with Sepsis.

We performed the current study to explore potential predictive value of serum Tumor Necrosis Factor- (TNF-) like weak inducer of apoptosis (TWEAK) concentrations for 28-day mortality in patients with sepsis. Adult septic patients (age≥18 years) admitted to a general ICU between November 2016 and October 2017 were consecutively included in our prospective observational study. TWEAK concentrations were detected in septic patients and healthy controls. Dynamic changes of TWEAK concentrations between 1st day and 3rd day of admission to ICU (ΔTWEAK concentrations) were also measured. A total of 79 septic patients were included and 19 of them (24.1%) died after a follow-up period of 28 days. We identified arterial lactate, NT-proBNP, and male gender as independent factors for 28-day mortality of patients with sepsis. The serum levels of TWEAK were significantly lower in septic patients compared to controls (417.4 ± 196.7 pg/ml versus 1243.8 ± 174.3 pg/ml, p<0.001). We found a positive correlation between TWEAK concentrations and SOFA score (Spearman correlation coefficient 0.235, p=0.037). Area under the receiver operating characteristic curve (AUROC) of ΔTWEAK concentrations for 28-day mortality was 0.754 (95% CI 0.645-0.844). We also evaluated the diagnostic performance of combinative index (ΔTWEAK concentrations and lactate) and obtained an AUROC of 0.860 (95% CI 0.763-0.928). In conclusion, our study found lower TWEAK concentrations in septic patients than those in healthy controls. Furthermore, the increased TWEAK concentrations during disease process predict higher 28-day mortality in septic patients. Dynamic changes of TWEAK should be an important supplement for current prognostic markers.

Building a better foundation: improving root-trait measurements to understand and model plant and ecosystem processes.

Trait-based approaches provide a useful framework to investigate plant strategies for resource acquisition, growth, and competition, as well as plant impacts on ecosystem processes. Despite significant progress capturing trait variation within and among stems and leaves, identification of trait syndromes within fine-root systems and between fine roots and other plant organs is limited. Here we discuss three underappreciated areas where focused measurements of fine-root traits can make significant contributions to ecosystem science. These include assessment of spatiotemporal variation in fine-root traits, integration of mycorrhizal fungi into fine-root-trait frameworks, and the need for improved scaling of traits measured on individual roots to ecosystem-level processes. Progress in each of these areas is providing opportunities to revisit how below-ground processes are represented in terrestrial biosphere models. Targeted measurements of fine-root traits with clear linkages to ecosystem processes and plant responses to environmental change are strongly needed to reduce empirical and model uncertainties. Further identifying how and when suites of root and whole-plant traits are coordinated or decoupled will ultimately provide a powerful tool for modeling plant form and function at local and global scales.

Similar below-ground carbon cycling dynamics but contrasting modes of nitrogen cycling between arbuscular mycorrhizal and ectomycorrhizal forests.

Compared with ectomycorrhizal (ECM) forests, arbuscular mycorrhizal (AM) forests are hypothesized to have higher carbon (C) cycling rates and a more open nitrogen (N) cycle. To test this hypothesis, we synthesized 645 observations, including 22 variables related to below-ground C and N dynamics from 100 sites, where AM and ECM forests co-occurred at the same site. Leaf litter quality was lower in ECM than in AM trees, leading to greater forest floor C stocks in ECM forests. By contrast, AM forests had significantly higher mineral soil C concentrations, and this result was strongly mediated by plant traits and climate. No significant differences were found between AM and ECM forests in C fluxes and labile C concentrations. Furthermore, inorganic N concentrations, net N mineralization and nitrification rates were all higher in AM than in ECM forests, indicating 'mineral' N economy in AM but 'organic' N economy in ECM trees. AM and ECM forests show systematic differences in mineral vs organic N cycling, and thus mycorrhizal type may be useful in predicting how different tree species respond to multiple environmental change factors. By contrast, mycorrhizal type alone cannot reliably predict below-ground C dynamics without considering plant traits and climate.

De-escalation of empiric antibiotics in patients with severe sepsis or septic shock: A meta-analysis.

OBJECTIVE: To evaluate the impact of de-escalation therapy on clinical outcomes in patients with severe sepsis and/or septic shock. METHODS: We performed a systematic literature search in PubMed, EMBASE, Web of Science, and CENTRAL on The Cochrane Library. The search terms used were "sepsis," "septic shock" and "de-escalation." The relative risk (RR) with 95% confidence intervals (CI) was used to evaluate the impact of de-escalation therapy on clinical outcomes. RESULTS: Nine individual studies (1873 patients) were included. Mortality trended lower in the de-escalation group as compared with the continuation of broad-spectrum antibiotics group. However, the results were not statistically significant (RR = 0.74, 95% CI 0.54-1.03). CONCLUSION: Antibiotic de-escalation therapy has no detrimental impact on mortality in patients with severe sepsis and/or septic shock, as compared to the continuation of broad-spectrum antibiotics. Since de-escalation affords an opportunity to limit overuse of broad-spectrum antibiotics, it should be considered as an option in clinical practice.

The Value of BISAP Score for Predicting Mortality and Severity in Acute Pancreatitis: A Systematic Review and Meta-Analysis.

PURPOSE: The Bedside Index for Severity in Acute Pancreatitis (BISAP) score has been developed to identify patients at high risk for mortality or severe disease early during the course of acute pancreatitis. We aimed to undertake a meta-analysis to quantify the accuracy of BISAP score for predicting mortality and severe acute pancreatitis (SAP). MATERIALS AND METHODS: We searched the databases of Pubmed, Embase, and the Cochrane Library to identify studies using the BISAP score to predict mortality or SAP. The pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were calculated from each study and were compared with the traditional scoring systems. RESULTS: Twelve cohorts from 10 studies were included. The overall sensitivity of a BISAP score of ≥3 for mortality was 56% (95% CI, 53%-60%), with a specificity of 91% (95% CI, 90%-91%). The positive and negative likelihood ratios were 5.65 (95% CI, 4.23-7.55) and 0.48 (95% CI, 0.41-0.56), respectively. Regarding the outcome of SAP, the pooled sensitivity was 51% (43%-60%), and the specificity was 91% (89%-92%). The pooled positive and negative likelihood ratios were 7.23 (4.21-12.42) and 0.56 (0.44-0.71), respectively. Compared with BISAP score, the Ranson criteria and APACHEⅡscore showed higher sensitivity and lower specificity for both outcomes. CONCLUSIONS: The BISAP score was a reliable tool to identify AP patients at high risk for unfavorable outcomes. Compared with the Ranson criteria and APACHEⅡscore, BISAP score outperformed in specificity, but having a suboptimal sensitivity for mortality as well as SAP.

Leaf economics and hydraulic traits are decoupled in five species-rich tropical-subtropical forests.

Leaf economics and hydraulic traits are critical to leaf photosynthesis, yet it is debated whether these two sets of traits vary in a fully coordinated manner or there is room for independent variation. Here, we tested the relationship between leaf economics traits, including leaf nitrogen concentration and leaf dry mass per area, and leaf hydraulic traits including stomatal density and vein density in five tropical-subtropical forests. Surprisingly, these two suites of traits were statistically decoupled. This decoupling suggests that independent trait dimensions exist within a leaf, with leaf economics dimension corresponding to light capture and tissue longevity, and the hydraulic dimension to water-use and leaf temperature maintenance. Clearly, leaf economics and hydraulic traits can vary independently, thus allowing for more possible plant trait combinations. Compared with a single trait dimension, multiple trait dimensions may better enable species adaptations to multifarious niche dimensions, promote diverse plant strategies and facilitate species coexistence.

Leading dimensions in absorptive root trait variation across 96 subtropical forest species.

Absorptive root traits show remarkable cross-species variation, but major root trait dimensions across species have not been defined. We sampled first-order roots and measured 14 root traits for 96 angiosperm woody species from subtropical China, including root diameter, specific root length, stele diameter, cortex thickness, root vessel size and density, mycorrhizal colonization rate, root branching intensity, tissue density, and concentrations of carbon and nitrogen ([N]). Root traits differed in the degree of variation and phylogenetic conservatism, but showed predictable patterns of cross-trait coordination. Root diameter, cortex thickness and stele diameter displayed high variation across species (coefficient of variation (CV)=0.51-0.69), whereas the stele:root diameter ratio and [N] showed low variation (CV<0.32). Root diameter, cortex thickness and stele diameter showed a strong phylogenetic signal across species, whereas root branching traits did not, and these two sets of traits were segregated onto two nearly orthogonal (independent) principal component analysis (PCA) axes. Two major dimensions of root trait variation were found: a diameter-related dimension potentially integrating root construction, maintenance, and persistence with mycorrhizal colonization, and a branching architecture dimension expressing root plastic responses to the environment. These two dimensions may offer a promising path for better understanding root trait economics and root ecological strategies world-wide.

Acquisition of ephemeral module in roots: a new view and test.

The terminal root branch orders composed mainly of primarily-developed tissues are increasingly recognized as an ephemeral module specialized for resource absorption. This root module is crucial in driving a range of ecosystem processes such as belowground productivity, carbon and nutrient cycling. Traditionally, acquisition of the ephemeral root module is achieved by separating these primarily-developed branch orders with forceps. However, obtaining this root segment with forceps approach is labor-intensive which may not be applicable for studies with an appreciable amount of root samples. To address this challenge, we developed a new idea to obtain the ephemeral root module. In this new view, root samples were tenderly kneaded by hand and the detached roots are considered as the ephemeral root module. To test this idea, four species with contrasting growing environment were selected and a range of chemicals were determined including C, N, P, Ca, S, Mg, Ba, Zn, Mn, Pb, Cu, V and Li. We found no or little difference of these chemicals in roots by hand-kneading approach from roots by forceps approach. These results suggested that hand-kneading method could be a convenient way to acquire ephemeral root module.