Propensity score matching enables batch-effect-corrected imputation in single-cell RNA-seq analysis.

Developments of single-cell RNA sequencing (scRNA-seq) technologies have enabled biological discoveries at the single-cell resolution with high throughput. However, large scRNA-seq datasets always suffer from massive technical noises, including batch effects and dropouts, and the dropout is often shown to be batch-dependent. Most existing methods only address one of the problems, and we show that the popularly used methods failed in trading off batch effect correction and dropout imputation. Here, inspired by the idea of causal inference, we propose a novel propensity score matching method for scRNA-seq data (scPSM) by borrowing information and taking the weighted average from similar cells in the deep sequenced batch, which simultaneously removes the batch effect, imputes dropout and denoises data in the entire gene expression space. The proposed method is testified on two simulation datasets and a variety of real scRNA-seq datasets, and the results show that scPSM is superior to other state-of-the-art methods. First, scPSM improves clustering accuracy and mixes cells of the same type, suggesting its ability to keep cell type separation while correcting for batch. Besides, using the scPSM-integrated data as input yields results free of batch effects or dropouts in the differential expression analysis. Moreover, scPSM not only achieves ideal denoising but also preserves real biological structure for downstream gene-based analyses. Furthermore, scPSM is robust to hyperparameters and small datasets with a few cells but enormous genes. Comprehensive evaluations demonstrate that scPSM jointly provides desirable batch effect correction, imputation and denoising for recovering the biologically meaningful expression in scRNA-seq data.

Antifungal and anti-biofilm activities of patchouli alcohol against Candida albicans.

The opportunistic fungal pathogen Candida albicans could cause severe clinical outcomes which could be exacerbated by the scarcity of antifungals. The capacity of C. albicans to form biofilms on medical devices that are hard to eradicate, further deepen the need to develop antifungal agents. In this study, we, for the first time, showed that patchouli alcohol (PA) can inhibit the growth of multiple C. albicans strains, as well as four other Candida species, with MICs of 64 µg/mL and MFCs from 64 to 128 µg/mL. The biofilm formation and development, adhesion, yeast-to-hyphal transition and extracellular polysaccharide of C. albicans can be inhibited by PA in a concentration-dependent manner. Confocal microscopy analyses of cells treated with PA showed that PA can increase the membrane permeability and intracellular reactive oxygen species (ROS) production. In C. elegans, PA did not influence the survival below 64 µg/mL. In this study PA demonstrated antifungal and antibiofilm activity against C. albicans and our results showed the potential of developing PA to fight Candida infections.

Combined effects of toxic Microcystis aeruginosa and high pH on antioxidant responses, immune responses, and apoptosis of the edible freshwater bivalve Corbicula fluminea.

Due to increasing anthropogenic perturbation and water eutrophication, cyanobacterial blooms (CYBs) have become a global ecological and environmental problem. Toxic CYBs and elevated pH are considered to be the two key stressors associated with eutrophication in natural waters, particularly in the event of CO2 depletion induced by dense blooms. However, previous research has been focused on investigating the impacts of toxic CYBs or pH changes in isolation, whereas the interactive effects of such stressors on edible bivalves that inhabit CYB waters still lack information. In this study, the combined effects of toxic Microcystis aeruginosa and pH shifts on the antioxidant responses, immune responses, and apoptosis of the edible freshwater bivalve Corbicula fluminea were explored. The results showed that the activity of antioxidant enzymes was significantly impacted by the interactive effects between toxic M. aeruginosa exposure and time course, yet pH shifts showed no significant effects on the activities of these antioxidant enzymes, implying that the antioxidant response in C. fluminea was mainly triggered by toxic M. aeruginosa exposure. Toxic M. aeruginosa also induced an increased production of reactive oxygen species and malondialdehyde in treated clams, particularly under high pH settings. The elevated lysosomal enzyme activity helped C. fluminea defend against toxic M. aeruginosa exposure under high pH conditions. The principal component analysis (PCA) and the integrated biomarker response (IBR) results suggested that the treated clams were subjected to the elevated toxicity of toxic M. aeruginosa in conditions of high pH. The heat shock proteins-related genes might be triggered to resist the oxidative damage in treated clams. Moreover, the upregulation of TNF and casp8 genes indicated the potential activation of the caspase8-mediated apoptotic pathway through TNF receptor interaction, potentially resulting in apoptosis. The TUNEL assay results further confirmed that apoptosis appeared in treated clams. These findings improve our understanding of the combined toxicological effects of harmful algae and pH shifts on bivalves, which will provide insights into a comprehensive ecological risk assessment of toxic CYBs to edible bivalve species.

The imbalance between Bregs, Tfh, and Tregs in patients with anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To detect the alteration of regulatory B cells (Bregs), follicular helper T cells (Tfh), and regulatory T cells (Tregs) frequencies in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Analyze their association with clinical severity and activity, and explore the effects of different immunotherapies on those immune cell subsets. METHODS: We enrolled 21 patients with anti-NMDAR encephalitis, 22 patients with neuromyelitis optica spectrum disorder (NMOSD), 14 patients with idiopathic intracranial hypertension (IIH), and 20 healthy controls (HC) in our study. The frequencies of various immune cell subsets were determined using flow cytometry. RESULTS: Compared to patients with IIH and HC, the frequencies of CD24hiCD38hi transitional B cells as well as Tregs were significantly lower while the frequency of Tfh was significantly higher in patients with anti-NMDAR encephalitis. The frequency of CD24hiCD38hi transitional B cells was significantly lower in the acute stage than in the recovery stage, and was negatively correlated with the modified Rankin scale (mRS) and the clinical assessment scale for autoimmune encephalitis (CASE). The frequency of CD24hiCD38hi transitional B cells at the last follow-up after rituximab (RTX) treatment was significantly higher than those treated with oral immunosuppressants or untreated. There was no clear difference between anti-NMDAR encephalitis and NMOSD in the above immune cell subsets. CONCLUSION: We suggested that the frequencies of CD24hiCD38hi transitional B cells and Tregs were decreased while the frequency of Tfh was increased in patients with anti-NMDAR encephalitis. CD24hiCD38hi transitional B cells frequency may be a potential indicator to estimate the disease activity and severity.

Integrating regular and transcriptomic analyses reveal resistance mechanisms in Corbicula fluminea (Müller, 1774) in response to toxic Microcystis aeruginosa exposure.

The frequent occurrence of cyanobacterial blooms (CYBs) caused by toxic Microcystis aeruginosa poses a great threat to aquatic organisms. Although freshwater benthic bivalves have proven to be capable of uptake high levels of microcystins (MCs) due to their filter-feeding habits, there is a paucity of information concerning their systemic resistance mechanisms to MCs. In this study, the resistance mechanisms in Corbicula fluminea (O. F. Müller, 1774) in response to the exposure of toxic M. aeruginosa were explored through transcriptional analysis combined with histopathological and biochemical phenotypic analysis. Toxic M. aeruginosa exposure caused dose-dependent histological damage in the hepatopancreas. The conjugation reaction catalyzed by glutathione S-transferases was vulnerable to being activated by high concentrations of M. aeruginosa (10 ×105 cells mL-1). Additionally, reactive oxygen species scavenging processes mediated by superoxide dismutase and catalase were active in the initial stage of toxic M. aeruginosa exposure. The results of the integrated biomarker response index suggested that the biotransformation and antioxidant defense system in C. fluminea could be continuously activated after acute exposure to the high concentration of toxic M. aeruginosa. The eggNOG and GO analysis of the differentially expressed genes (DEGs) indicated that DEGs were significantly enriched in transporter activity, oxidant detoxification and response to oxidative stress categories, which were consistent with the alterations of biochemical indices. Besides, DEGs were significantly annotated in a few KEGG pathways involved in biotransformation (oxidation, cooxidation and conjugation) and immunoreaction (lysosome and phagosome responses), which could be responsible for the tolerance of C. fluminea to toxic M. aeruginosa. These findings improve our understanding of potential resistance mechanisms of freshwater bivalves to MCs.

Influencing factors of urban innovation and development: a grounded theory analysis.

Urban innovation and development are a core driver for promoting the industrial, economic, and social development of cities. However, the factors that affect the innovation and development of cities lack systematic analysis as well as interaction analysis. Based on a multidimensional perspective, this study suggests that natural, economic, and social factors are three major factors conditioning urban innovation and development. A grounded theoretical qualitative method is further adopted to code relevant research literatures, news reports and interview materials, resulting in an onion factors model. We find that natural factors-including environmental quality, geographic location, and city scale-are prerequisite for conditioning urban innovation and development. Economic factors are also key, including economic level, industrial structure, industrial agglomeration, and technological innovation. Social factors are guarantee factors, including administrative hierarchy, cultural environment, population structure, and government management and services, i.e., they are essential for cities to become adaptable in the current dynamic situation. The study provides theoretical support and practical directions for the formulation of policies for urban innovation development.

Differential translation elongation directs protein synthesis in response to acute glucose deprivation in yeast.

Protein synthesis is energetically expensive and its rate is influenced by factors such as cell type and environment. Suppression of translation is a canonical response to stressful changes in the cellular environment. In particular, inhibition of the initiation step of translation has been highlighted as the key control step in stress-induced translational suppression as mechanisms that quickly suppress initiation are well-conserved. However, cells have evolved complex regulatory means to control translation apart from initiation. Here, we examine the role of the elongation step of translation in yeast subjected to acute glucose deprivation. The use of ribosome profiling and in vivo reporter assays demonstrated elongation rates slow progressively following glucose removal. We observed that ribosome distribution broadly shifts towards the downstream ends of transcripts after both acute and gradual glucose deprivation but not in response to other stressors. Additionally, on assessed mRNAs, a correlation existed between ribosome occupancy and protein production pre-stress but was lost after stress. These results indicate that stress-induced elongation regulation causes ribosomes to slow down and build up on a considerable proportion of the transcriptome in response to glucose withdrawal. Finally, we report ribosomes that built up along transcripts are competent to resume elongation and complete protein synthesis after readdition of glucose to starved cells. This suggests that yeast has evolved mechanisms to slow translation elongation in response to glucose starvation which do not preclude continuation of protein production from those ribosomes, thereby averting a need for new initiation events to take place to synthesize proteins.Abbreviations: AUG: start codon, bp: base pair(s), CDS: coding sequence, CHX: cycloheximide, eEF2: eukaryotic elongation factor 2, LTM: lactimidomycin, nt: nucleotide, PGK1: 3-phosphoglycerate kinase, ribosomal biogenesis: ribi, RO: ribosome occupancy, RPF: ribosome protected fragment, TE: translational efficiency.

Profiling of widely targeted metabolomics for the identification of chemical composition in epidermis, xylem and pith of Gleditsiae Spina.

Gleditsiae Spina, the thorn of Gleditsia sinensis Lam., has a long history of being used as a traditional medicine in East Asian countries. However, only a few biologically active substances have been identified from it. In this study, the epidermis, xylem and pith of Gleditsiae Spina, respectively Gs-E, Gs-X and Gs-P, were studied. We used a widely targeted metabolomics method to investigate the chemical composition of Gs-E, Gs-X and Gs-P. A total of 728 putative metabolites were identified from Gleditsiae Spina, including 211 primary metabolites and 517 secondary metabolites. These primary and secondary metabolites could be categorized into more than 10 different classes. Flavonoids, phenolic acids, lipids, amino acids and derivatives, and organic acids constituted the main metabolite groups. Multivariate statistical analysis showed that the Gs-E, Gs-X and Gs-P samples could be clearly separated. Differential accumulated metabolite (DAM) analysis revealed that more than half of the DAMs exhibited the highest relative concentrations in Gs-E, and most of the DAMs showed the lowest relative concentrations in Gs-X. Moreover, 11 common differential primary metabolites and 79 common differential secondary metabolites were detected in all comparison groups. These results further our understanding of chemical composition and metabolite accumulation of Gleditsiae Spina.

Spatial and temporal distribution characteristics of carbon emissions and their drivers in shrinking cities in China: Empirical evidence based on the NPP/VIIRS nighttime lighting index.

Shrinking cities are a category of cities characterized by population loss, and the environmental problems of these cities are often neglected. Using panel data from 2012 to 2019, this paper investigates the spatial and temporal distribution characteristics of carbon emissions in shrinking cities in China and the driving factors. The results find that: (1) From 2012 to 2019, carbon emissions tend to increase in shrinking cities and decrease in non-shrinking cities. Due to earlier industrial development and ecological neglect, shrinking cities in Northeast China have higher carbon emissions than other regions. (2) Population size, industrial structure and public services promote the growth of carbon emissions in shrinking cities. The influence of living environment on carbon emissions in shrinking cities is not significant. There is an environmental Kuznets curve (EKC) relationship between economic level and carbon emission. (3) In shrinking cities, the increase in commuting time and distance due to spatial expansion promotes the growth of carbon emissions. Foreign investment decreases with the loss of population, which reduces carbon emissions. Technological progress gradually declines as investment in science and technology decreases, which makes carbon emissions grow. This paper clarifies the driving factors of carbon emissions in shrinking cities in China, and therefore, the findings of this paper have important reference value for the formulation of carbon reduction policies in shrinking cities in developing countries.

Growth and photosynthesis responses of microcystin (MC)- and non-MC-producing Microcystis strains during co-culture with the submerged macrophyte Myriophyllum spicatum.

The growth and photosynthetic responses of microcystin (MC)- and non-MC-producing Microcystis to the submerged macrophyte Myriophyllum spicatum were investigated under plant-Microcystis co-culture conditions (PMC + , PMC-), in comparison with their corresponding mono-culture controls (SMC + , SMC-). The OJIP chlorophyll a fluorescence transient was recorded and analyzed using JIP-test parameters. In comparison with the corresponding mono-culture controls, the quantum efficiencies of the electron transport chain expressed as parameters Ψo and φEo decreased by more than 25% in the PMC- group, much higher than those in the PMC+ group (p < 0.05). The decreasing extent of the electron transport flux ratio ETo/RC was significantly larger in the PMC- group than in the PMC+ group (p < 0.05). The performance index (PIABS) decreased by 26.98% in the PMC- group and by 16.25% in the PMC+ group. These results indicated that the non-MC-producing Microcystis was more sensitive than the MC-producing strain when co-cultured with M. spicatum, and the efficiency and energy flux of electron transport might be the main targets of Photosystem II. Future research should focus on the intraspecific composition and toxigenic levels of Microcystis populations interacting with submerged macrophytes to guide the use of submerged vegetation restoration.

Elevated Circulating Levels of Glycoprotein Non-Metastatic Melanoma Protein B as a Predictor of Gestational Diabetes Mellitus.

BACKGROUND: The current study aims to investigate the differences of glycoprotein non-metastatic melanoma protein B (GPNMB) levels between gestational diabetes mellitus (GDM) women and normal blood glucose women during pregnancy to provide the basis for early intervention and treatment of GDM. METHODS: The level of GPNMB was detected using an enzyme-linked immunosorbent assay (ELISA). Pearson's correlation assay was performed to analyze the correlation between serum GPNMB and fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c). The receiver operating characteristic (ROC) curve was carried out to analyze the diagnostic value of serum GPNMB. RESULTS: Our data showed that the serum GPNMB level in GDM group was higher than that in normal blood glucose group at 5 - 12 weeks, 13 - 23 weeks, and 24 - 28 weeks of gestation, but there was no significant difference at 29 - 37 weeks of gestation. Meanwhile, the total level of serum GPNMB in GDM group was significantly higher than that in normal blood glucose group. Further study indicated that serum GPNMB positively correlated with FPG (r = 0.562, p < 0.0001) or HbA1c (r = 0.652, p < 0.0001). ROC analysis showed that serum GPNMB level at 13 - 23 weeks of gestation had a good predictive effect on predicting GDM at 24 weeks of gestation and beyond. When the cutoff value of serum GPNMB level was 2.46 µg/L, the sensitivity and specificity were 80% and 72%, respectively. CONCLUSIONS: The serum GPNMB level at 13 - 23 weeks of gestation is an independent risk factor for GDM in 24 weeks and beyond, and early inhibition with GPNMB may provide a preventive measure in GDM women.

The correlations between Th1 and Th2 cytokines in human alveolar echinococcosis.

BACKGROUND: Alveolar echinococcosis (AE) is a zoonotic parasitic disease caused by Echinococcus multilocularis larval tapeworm infections in humans that severely impairs the health of affected patients in the northern hemisphere. METHODS: The expression levels of 20 cytokines associated with AE infection were measured by enzyme-linked immunosorbent assay, and the correlations between these cytokines were analysed in the R programming language. RESULTS: Serum cytokine levels differed among individuals in both the AE patient and healthy control groups. The results of the correlations among the cytokines showed obvious differences between the two groups. In the AE patients group, Th1 and Th2 cytokines formed a more complicated network than that in the healthy control group. CONCLUSIONS: The altered correlations between Th1 and Th2 cytokines may be closely associated with AE infection, which may provide a new explanation for the essential differences between AE patients and healthy individuals.

Gut-liver crosstalk in sepsis-induced liver injury.

Sepsis is characterized by a dysregulated immune response to infection leading to life-threatening organ dysfunction. Sepsis-induced liver injury is recognized as a powerful independent predictor of mortality in the intensive care unit. During systemic infections, the liver regulates immune defenses via bacterial clearance, production of acute-phase proteins (APPs) and cytokines, and metabolic adaptation to inflammation. Increased levels of inflammatory cytokines and impaired bacterial clearance and disrupted metabolic products can cause gut microbiota dysbiosis and disruption of the intestinal mucosal barrier. Changes in the gut microbiota play crucial roles in liver injury during sepsis. Bacterial translocation and resulting intestinal inflammation lead to a systemic inflammatory response and acute liver injury. The gut-liver crosstalk is a potential target for therapeutic interventions. This review analyzes the underlying mechanisms for the gut-liver crosstalk in sepsis-induced liver injury.

Mitochondria in Sepsis-Induced AKI.

AKI is a common clinical condition associated with the risk of developing CKD and ESKD. Sepsis is the leading cause of AKI in the intensive care unit (ICU) and accounts for nearly half of all AKI events. Patients with AKI who require dialysis have an unacceptably high mortality rate of 60%-80%. During sepsis, endothelial activation, increased microvascular permeability, changes in regional blood flow distribution with resulting areas of hypoperfusion, and hypoxemia can lead to AKI. No effective drugs to prevent or treat human sepsis-induced AKI are currently available. Recent research has identified dysfunction in energy metabolism as a critical contributor to the pathogenesis of AKI. Mitochondria, the center of energy metabolism, are increasingly recognized to be involved in the pathophysiology of sepsis-induced AKI and mitochondria could serve as a potential therapeutic target. In this review, we summarize the potential role of mitochondria in sepsis-induced AKI and identify future therapeutic approaches that target mitochondrial function in an effort to treat sepsis-induced AKI.

Metal-Free Carbon Quantum Dots Implant Graphitic Carbon Nitride: Enhanced Photocatalytic Dye Wastewater Purification with Simultaneous Hydrogen Production.

The use of photocatalysts to purify wastewater and simultaneously convert solar energy into clean hydrogen energy is of considerable significance in environmental science. However, it is still a challenge due to their relatively high costs, low efficiencies, and poor stabilities. In this study, a metal-free carbon quantum dots (CQDs) modified graphitic carbon nitride photocatalyst (CCN) was synthesized by a facile method. The characterization and theoretical calculation results reveal that the incorporation of CQDs into the g-C3N4 matrix significantly improves the charge transfer and separation efficiency, exhibits a redshift of absorption edge, narrows the bandgap, and prevents the recombination of photoexcited carriers. The hydrogen production and simultaneous degradation of methylene blue (MB) or rhodamine B (RhB) in simulated wastewaters were further tested. In the simulated wastewater, the CCN catalyst showed enhanced photodegradation efficiency, accompanied with the increased hydrogen evolution rate (1291 µmol·h-1·g-1). The internal electrical field between the g-C3N4 and the CQDs is the main reason for the spatial separation of photoexcited electron-hole pairs. Overall, this work could offer a new protocol for the design of highly efficient photocatalysts for dye wastewater purification with simultaneous hydrogen production.

[Randomized double-blind parallel controlled multicenter trial of Reyanning Mixture in treatment of acute tonsillitis].

This study is a randomized controlled trial of Reyanning Mixture in the treatment of acute tonsillitis. According to the ratio of 1∶1∶1, a total of 144 patients were randomly divided into Reyanning Mixture group(RYN), Reyanning Mixture+Amoxicillin Capsules group(RYN+Amoxil) and Amoxicillin Capsules group(Amoxil), with 48 cases in each group, in order to evaluate the efficacy and safety of RYN alone or combined with Amoxil in the treatment of acute tonsillitis, and provided high-quality evidences for treatment of infectious diseases with traditional Chinese medicine and reduced use of antibiotics. The dosage of RYN was 20 mL, 3 times a day, 100 mL/bottle, oral for 7 days, and Amoxil dosage was 0.5 g, 3 times a day, 0.5 g×12 tablets/plate, oral for 7 days. A total of 144 cases were included, 3 cases were excluded(1 case was mistakenly included, 2 cases did not take drugs after inclu-ded), and a total of 141 cases were included in the full analysis set(FAS). The results showed statistical differences in the recovery time of the disease, the disappearance rate of fever on the 3 rd day and the disappearance rate of tonsillar redness and swelling between RYN and Amoxil. There were statistical differences in the cure rate of disease, recovery time of disease, body temperature recovery time, fever disappearance rate on the 3 rd day, pharynx swelling and pain disappearance rate and tonsil swelling disappearance rate between the RYN+Amoxil and Amoxil, but with no significant difference in the above aspects compared with RYN. The DDD of antibiotic use in RYN+Amoxil was significantly lower than that in Amoxil(P<0.01). According to the findings, when RYN was used alone in the treatment of acute tonsillitis, it was superior to Amoxil in time of recovery, short-term improvement of fever and redness and swelling of tonsil. Compared with RYN+Amoxil, there was no difference in cure rate of disease, recovery time of disease, body temperature recovery time, short-term improvement of fever, swelling of pharynx and swelling of tonsil, with a better efficacy than Amoxil. The clinical effect of RYN was similar to that of combined Amoxil in the treatment of acute tonsillitis, and RYN was superior to Amoxil in the time of recovery, short-term improvement of fever and redness and swelling of tonsil, with no adverse event or adverse reaction. RYN+Amoxil can significantly reduce the DDD value of antibiotics in the treatment of acute tonsillitis, with significant clinical advantages over Amoxil.

Synthesis, biological evaluation and molecular docking of 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs containing the piperazine moiety.

Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals' force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.

Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents.

A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.

Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice.

NephroCheck® is the commercial name of a combined product of two urinary biomarkers, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), expressed as [TIMP-2]·[IGFBP7], used to identify patients at high risk of acute kidney injury (AKI). AKI is a common and harmful complication especially in critically-ill patients, which can induce devastating short- and long-term outcomes. Over the past decade, numerous clinical studies have evaluated the utility of several biomarkers (e.g. neutrophil gelatinase-associated lipocalin, interleukin-18, liver-type fatty acid binding protein and kidney injury molecule-1, cystatin C) in the early diagnosis and risk stratification of AKI. Among all these biomarkers, [TIMP-2]·[IGFBP7] was confirmed to be superior in early detection of AKI, before the decrease of renal function is evident. In 2014, the US Food and Drug Administration permitted marketing of NephroCheck® (Astute Medical) (measuring urinary [TIMP-2]·[IGFBP7]) to determine if certain critically-ill patients are at risk of developing moderate to severe AKI. It has since been applied to clinical work in many hospitals of the United States and Europe to improve the diagnostic accuracy and outcomes of AKI patients. Now, more and more research is devoted to the evaluation of its application value, meaning and method in different clinical settings. In this review, we summarize the current research status of [TIMP-2]·[IGFBP7] and point out its future directions.

Extracorporeal techniques for the treatment of critically ill patients with sepsis beyond conventional blood purification therapy: the promises and the pitfalls.

Sepsis is one of the leading causes of morbidity and mortality worldwide. It is characterized by a dysregulated immune response to infections that results in life-threatening organ dysfunction and even death. Bacterial cell wall components (endotoxin or lipopolysaccharide), known as pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) released by host injured cells, are well-recognized triggers resulting in the elevation of both pro-inflammatory and anti-inflammatory cytokines. Understanding this complex pathophysiology has led to the development of therapeutic strategies aimed at restoring a balanced immune response by eliminating/deactivating these inflammatory mediators. Different extracorporeal techniques have been studied in recent years in the hope of maximizing the effect of renal replacement therapy in modulating the exaggerated host inflammatory response, including the use of high volume hemofiltration (HVHF), high cut-off (HCO) membranes, adsorption alone, and coupled plasma filtration adsorption (CPFA). These strategies are not widely utilized in practice, depending on resources and local expertise. The literature examining their use in septic patients is growing, but the evidence to support their use at this stage is considered of low level. Our aim is to provide a comprehensive overview of the technical aspects, clinical applications, and associated side effects of these techniques.