Subcarrier modulation based phase-coded coherent lidar.

This paper presents a lean subcarrier modulation-based phase-coded coherent lidar system with a non-quadrature receiver and sampling ratio lower than the Nyquist sampling ratio. Specifically, by utilizing the drawbacks of low Doppler tolerance in encoding signals, phase information can be obtained after pulse compression, and the mirror frequency introduced by real sampling can be negligible. Validation experiments based on inverse synthetic aperture lidar are performed, with the corresponding imaging results having a resolution superior to 4 cm, demonstrating our system's efficiency in phase acquisition that is free from frequency aliasing.

An atypical case of incontinentia pigmenti with a hypomorphic variant.

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects skin, hair, teeth, eyes and central nervous system. We present the case of a female patient with mild IP caused by a hypomorphic pathogenic variant of the inhibitor of the kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG) gene. This is the first report of a female IP patient with the hypomorphic variant, NM_001099856.6: c.1423dup, which is causative of anhidrotic ectodermal dysplasia with immune deficiency in males.

MWDNs: reconstruction in multi-scale feature spaces for lensless imaging.

Lensless cameras, consisting of only a sensor and a mask, are small and flexible enough to be used in many applications with stringent scale constraints. These mask-based imagers encode scenes in caustic patterns. Most existing reconstruction algorithms rely on multiple iterations based on physical model for deconvolution followed by deep learning for perception, among which the main limitation of reconstruction quality is the mismatch between the ideal and the real model. To solve the problem, we in this work learned a class of multi Wiener deconvolution networks (MWDNs), deconvoluting in multi-scale feature spaces with Wiener filters to reduce the information loss and improving the accuracy of the given model by correcting the inputs. A comparison between the proposed and the state-of-the-art algorithms shows that ours achieves much better images and performs well in real-world environments. In addition, our method takes greater advantage of the computational time due to the abandonment of iterations.

KRT5 mutation regulate melanin metabolism through notch signalling pathway between keratinocytes and melanocytes.

Dowling-Degos disease (DDD) is an autosomal dominant hereditary skin disease characterized by acquired reticular hyperpigmentation in flexural sites, and one of its causative genes is KRT5 gene. But the effect of KRT5, expressed only in keratinocytes, on melanocytes is unclear. Other pathogenic genes of DDD include POFUT1, POGLUT1 and PSENEN genes, which is involved in posttranslational modification of Notch receptor. In this study, we aim to determine the ablation of keratinocyte KRT5 affect melanogenesis in melanocyte through Notch signalling pathway. Here we found that KRT5 downregulation decreased the expression of the Notch ligand in keratinocytes and Notch1 intracellular domain in melanocytes, by establishing two cell models of ablation of KRT5 in keratinocytes based on CRISPR/Cas9 site-directed mutation and lentivirus-mediated shRNA. Treatment of melanocytes with Notch inhibitors had same effects with ablation of KRT5 on increase of TYR and decrease of Fascin1. Activation of Notch signalling reverses the effect of ablation of KRT5 on melanogenesis. Immunohistochemistry of DDD lesions with KRT5 gene mutation confirmed changes in the expression of relevant molecules in Notch signalling. Our research elucidates molecular mechanism of KRT5-Notch signalling pathway in the regulation of melanocytes by keratinocytes, and preliminary reveal the mechanism of DDD pigment abnormality caused by KRT5 mutation. These findings identify potential therapeutic targets of the Notch signalling pathway for the treatment of skin pigment disorders.

Ultrasound-Guided Capsular Thyroid Injection Therapy With Dexamethasone and Lidocaine Mixture for Subacute Thyroiditis: A Single-Center Study.

OBJECTIVES: Subacute thyroiditis (SAT) is a self-limiting, inflammatory thyroid disease possibly caused by viral infection. In recent years, the incidence of SAT is increasing, especially during the pandemic of the COVID-19. This study aimed to evaluate the efficacy, safety, and recovery time of capsular thyroid injection therapy under ultrasound guidance for SAT. METHODS: A total of 73 patients with SAT were divided into two groups. Patients in group A (n = 48) received an ultrasound-guided capsular injection consisting of dexamethasone (DEX) and lidocaine in the thyroid lesion area, while patients in group B (n = 25) received oral prednisolone (PSL). The two groups were compared for pain relief and treatment duration, the recovery time of thyroid function, recurrence rates, hypothyroidism incidence, and drug-related side effects. RESULTS: The follow-up time was 1 year. In group A, the duration of pain relief, treatment, and recovery time of thyroid function were significantly shorter than that in group B (P < .05), and no statistically significant differences in recurrence rate or incidence of hypothyroidism were observed (P > .05). Weight gain was significantly higher in group A at the end of treatment (P < .001). CONCLUSIONS: Compared with oral PSL treatment, ultrasound-guided local injection of DEX and lidocaine into the capsular thyroid is a safe and effective procedure that can significantly reduce the treatment time of SAT.

Multi-Omics Research Strategies for Psoriasis and Atopic Dermatitis.

Psoriasis and atopic dermatitis (AD) are multifactorial and heterogeneous inflammatory skin diseases, while years of research have yielded no cure, and the costs associated with caring for people suffering from psoriasis and AD are a huge burden on society. Integrating several omics datasets will enable coordinate-based simultaneous analysis of hundreds of genes, RNAs, chromatins, proteins, and metabolites in particular cells, revealing networks of links between various molecular levels. In this review, we discuss the latest developments in the fields of genomes, transcriptomics, proteomics, and metabolomics and discuss how they were used to identify biomarkers and understand the main pathogenic mechanisms underlying these diseases. Finally, we outline strategies for achieving multi-omics integration and how integrative omics and systems biology can advance our knowledge of, and ability to treat, psoriasis and AD.

Constrained least-squares algorithm for active optics correction of a primary mirror.

Active optics technology improves the performance and image quality of large telescopes. To effectively compensate for optical aberrations, the constrained least-squares (CLS) algorithm, which considers the characteristics of the resultant moment, the force budget, and the local force smoothness, is proposed to optimize the force distribution. First, the constraint of the resultant moment is used to decouple the shape control and location control. Then, through the force budget, the surface residual and force amplitude can be balanced. At last, the local smooth constraint is proposed to reduce the mirror's internal stress. Simulations were conducted on a 4 m thin mirror to compare the force distributions obtained by the least-squares, bending modes (BMs), and CLS algorithms. The results show that under equivalent residuals, the proposed algorithm is superior to the BM algorithm and performs better on local force smoothness.

Modeling and optimal control of mutated COVID-19 (Delta strain) with imperfect vaccination.

As people around the world work to stop the COVID-19 pandemic, mutated COVID-19 (Delta strain) that are more contagious are emerging in many places. How to develop effective and reasonable plans to prevent the spread of mutated COVID-19 is an important issue. In order to simulate the transmission of mutated COVID-19 (Delta strain) in China with a certain proportion of vaccination, we selected the epidemic situation in Jiangsu Province as a case study. To solve this problem, we develop a novel epidemic model with a vaccinated population. The basic properties of the model is analyzed, and the expression of the basic reproduction number R 0 is obtained. We collect data on the Delta strain epidemic in Jiangsu Province, China from July 20, to August 5, 2021. The weighted nonlinear least square estimation method is used to fit the daily asymptomatic infected people, common infected people and severe infected people. The estimated parameter values are obtained, the approximate values of the basic reproduction number are calculated R 0 ≈ 1.378 . Through the global sensitivity analysis, we identify some parameters that have a greater impact on the prevalence of the disease. Finally, according to the evaluation results of parameter influence, we consider three control measures (vaccination, isolation and nucleic acid testing) to control the spread of the disease. The results of the study found that the optimal control measure is to dynamically adjust the three control measures to achieve the lowest number of infections at the lowest cost. The research in this paper can not only enrich theoretical research on the transmission of COVID-19, but also provide reliable control suggestions for countries and regions experiencing mutated COVID-19 epidemics.

Optimal control and cost-effectiveness analysis of a new COVID-19 model for Omicron strain.

Omicron, a mutant strain of COVID-19, has been sweeping the world since November 2021. A major characteristic of Omicron transmission is that it is less harmful to healthy adults, but more dangerous for people with underlying disease, the elderly, or children. To simulate the spread of Omicron in the population, we developed a new 9-dimensional mathematical model with high-risk and low-risk exposures. Then we analyzed its dynamic properties and obtain the basic reproduction number R 0 . With the data of confirmed cases from March 1, 2022 published on the official website of Shanghai, China, we used the weighted nonlinear least square estimation method to estimate the parameters, and get the basic reproduction number R 0 ≈ 1 . 5118 . Finally, we considered three control measures (isolation, detection and treatment), and studied the optimal control strategy and cost-effectiveness analysis of the model. The control strategy G is determined to be the optimal control strategy from the purpose of making fewer people infected. In strategy G, the three human control measures contain six control variables, and the control strength of these variables needs to be varied according to the pattern shown in Figure 11, so that the number of infections can be minimized and the percentage of reduction of infections can reach more than 95%.

Modeling and dynamic analysis of novel coronavirus pneumonia (COVID-19) in China.

Although novel coronavirus pneumonia (COVID-19) was widely spread in mainland China in early 2020, it was soon controlled. To study the impact of government interventions on the spread of disease during epidemics, a differential equation system is established to simulate the process of virus propagation in this paper. We first analyze its basic properties, basic reproduction number R 0 and existence of equilibria. Then we prove that the disease-free equilibrium (DFE) is Globally Asymptotically Stable when R 0 is less than 1. Through the analysis of the daily epidemic data from January 10, 2020 to March 11, 2020, combined with the implementation of the national epidemic policy, we divide the whole process into three stages: the first stage (natural state), the second stage (isolation state), the third stage (isolation, detection and treatment). By using the weighted nonlinear least square method to fit the data of three stages, the parameters are obtained, and three basic reproduction numbers are calculated, which are: R 01 = 2.6735 , R 02 = 0.85077 , R 03 = 0.18249 . Sensitivity analysis of threshold parameters and corresponding graphical results were also performed to examine the relative importance of various model parameters to the spread and prevalence of COVID-19. Finally, we simulate the trend of three stages and verify the theory of Global Asymptotic Stability of DFE. The conclusion of this paper proves theoretically that the Chinese government's epidemic prevention measures are effective in the fight against the spread of COVID-19. This study can not only provide a reference for research methods to simulate COVID-19 transmission in other countries or regions, but also provide recommendations on COVID-19 prevention measures for them.

Comparing quality of life between patients undergoing trans-areola endoscopic thyroid surgery and trans-oral endoscopic thyroid surgery.

BACKGROUND: Compared with conventional open surgery, endoscopic thyroidectomy via the oral vestibular approach (ETVOA) and endoscopic thyroidectomy via the areola approach (ETAA) avoided scarring of the skin, which may help patients achieve a better quality of life (QOL). However, the benefit of the QOL from this technique has not been adequately investigated, therefore this study compared the QOL outcomes between ETVOA and ETAA. METHODS: 131 patients were enrolled in this study. ETAA surgery and ETVOA surgery were performed in 74 patients and 57 patients, respectively. These patients were followed up at 2 weeks, 4 weeks, and 8 weeks, and their QOL was evaluated using a thyroid surgery-specific questionnaire and a short-form health survey (SF-36). RESULTS: There were no differences in clinical characteristics such as gender, age, body mass index (BMI), and tumor size between the two groups. The volume of intraoperative blood loss, cost of hospitalization, and complications between the two procedures showed no differences. Compared with ETAA, ETVOA has a longer operation time, no drainage, and shorter hospital stay. In the QOL questionnaire, several parameters in ETVOA were better. The satisfaction scores of patients undergoing ETVOA were higher. In addition, the cosmetic satisfaction in patients who received ETOVA was significantly better than that of patients who underwent ETAA. The degree of neck movement disorder in patients with ETVOA was milder. Patients who received ETVOA had higher score on the SF-36. CONCLUSIONS: The trans-oral endoscopic approach can acquire better cosmetic results and achieved high-level QOL.

Sub-Millisecond Phase Retrieval for Phase-Diversity Wavefront Sensor.

We propose a convolutional neural network (CNN) based method, namely phase diversity convolutional neural network (PD-CNN) for the speed acceleration of phase-diversity wavefront sensing. The PD-CNN has achieved a state-of-the-art result, with the inference speed about 0.5 ms, while fusing the information of the focal and defocused intensity images. When compared to the traditional phase diversity (PD) algorithms, the PD-CNN is a light-weight model without complicated iterative transformation and optimization process. Experiments have been done to demonstrate the accuracy and speed of the proposed approach.

Technique for endoscopic thyroidectomy with selective lateral neck dissection via a chest-breast approach.

BACKGROUND: Endoscopic thyroidectomy has been widely accepted because it can effectively avoid neck scarring. However, there are seldom reports concerning completely endoscopic lateral neck dissection approaches. In this study, we introduced a technique for performing endoscopic thyroidectomy with lateral neck dissection via a chest-breast approach. METHODS: We retrospectively reviewed 18 patients who underwent endoscopic total thyroidectomy along with levels II, III, IV, and VI dissection. All major outcomes, such as cosmetic effect, operative time and complications, etc., were analyzed. In addition, another 20 patients who underwent traditional open surgery (open group) were enrolled in the study to conduct a contrasting analysis between patients treated with the endoscopic technique (endoscopic group) and open group patients, in terms of demographic data and main operative outcomes, to evaluate the feasibility of this technique. RESULTS: All 18 endoscopic surgery cases were successfully performed, and no patient was converted to the open procedure intra-operatively. There were no significant differences between the two groups regarding age (P = 0.209), Body Mass Index (P = 0.479), sex (P = 0.218), drainage time (P = 0.153), operation time (P = 0.065), intra-operative blood loss (P = 0.139), post-operative pain (P = 0.114), and number of dissected lateral lymph nodes (II: P = 0.201; III + IV: P = 0.107). The mean total and lateral lymph nodes dissection (LLND) time in the endoscopic group were longer than those of the open group (P = 0.002; 235 ± 35 vs. 182 ± 20 min, P = 0.000; 125 ± 21 vs. 80 ± 14 min, P = 0.000). The primary lesion diameter of the endoscopic group was smaller than that of the open group (1.7 ± 0.8 vs. 2.9 ± 1.3 cm, P = 0.002). The scores for cosmetic satisfaction in the endoscopic group were higher than those in the open group (8.3 ± 0.7 vs. 4.4 ± 0.9, P = 0.000). Among the complications, there was no significant difference between the two approaches in transient vocal cord paresis (1/18 vs. 0/20, P = 0.474), transient hypoparathyroidism (4/18 vs. 4/20, P = 1.000), post-operative lymphatic leakage (1/18 vs. 3/20, P = 0.606), and intra-operative large blood vessel injury (2/18 vs. 0/20, P = 0.218). There was no incidence of uncontrolled bleeding, mental nerve injury, permanent hypoparathyroidism, permanent recurrent laryngeal nerve (RLN) injury, skin bruise on the neck, asphyxia/dyspnea or other complications like tracheal injury, esophageal injury, etc., nor was there any death or recurrence in either of the two groups during the short follow-up period. CONCLUSION: It is feasible to perform LLND (levels II, III, IV, and VI) with endoscopic thyroidectomy via a chest-breast approach. In particular, this technique avoids a large scar on the patient's neck and has well operative outcomes compared with open surgery. Accordingly, this technique may offer one more option for selective patients.

Surgical drainage of lactational breast abscess with ultrasound-guided Encor vacuum-assisted breast biopsy system.

Lactational breast abscess is a serious complication of mastitis and commonly diagnosed in breast-feeding women. The traditional drainage of breast abscess was often performed with incisive technique which may result in prolonged healing time, regular dressings, dressing pain, interfering with breastfeeding and unsatisfactory cosmetic outcome. As minimal invasive alternatives to incisive drainage, needle aspiration or percutaneous catheter placement cannot completely replace incisive drainage for the inability to treat large, multiloculated or chronic abscess. Vacuum-assisted breast biopsy system (VABB) has been successfully applied in the treatment of benign breast diseases with satisfactory cosmetic outcomes. Among VABB devices, EnCor system has some distinctive features that make it an appropriate candidate for the treatment of lactational breast abscesses. In this study, for the first time, we investigated the feasibility, efficacy, and cosmetic results of surgical drainage of lactational breast abscess with US-guided Encor VABB system. Our data suggests this procedure could serve as a promising alternative for women with lactational breast abscess who require incisive intervention with high cure rate, relatively short healing time, low recurrence rate, few complications, satisfactory cosmetics outcome and without interfering with breastfeeding.

Kallistatin attenuates endothelial senescence by modulating Let-7g-mediated miR-34a-SIRT1-eNOS pathway.

Kallistatin, a plasma protein, protects against vascular and organ injury. This study is aimed to investigate the role and mechanism of kallistatin in endothelial senescence. Kallistatin inhibited H2 O2 -induced senescence in human endothelial cells, as indicated by reduced senescence-associated-ß-galactosidase activity, p16INK4a and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked H2 O2 -induced superoxide formation, NADPH oxidase levels and VCAM-1, ICAM-1, IL-6 and miR-34a synthesis. Kallistatin reversed H2 O2 -mediated inhibition of endothelial nitric oxide synthase (eNOS), SIRT1, catalase and superoxide dismutase (SOD)-2 expression, and kallistatin alone stimulated the synthesis of these antioxidant enzymes. Moreover, kallistatin's anti-senescence and anti-oxidant effects were attributed to SIRT1-mediated eNOS pathway. Kallistatin, via interaction with tyrosine kinase, up-regulated Let-7g, whereas Let-7g inhibitor abolished kallistatin's effects on miR-34a and SIRT1/eNOS synthesis, leading to inhibition of senescence, oxidative stress and inflammation. Furthermore, lung endothelial cells isolated from endothelium-specific kallistatin knockout mice displayed marked reduction in mouse kallistatin levels. Kallistatin deficiency in mouse endothelial cells exacerbated senescence, oxidative stress and inflammation compared to wild-type mouse endothelial cells, and H2 O2 treatment further magnified these effects. Kallistatin deficiency caused marked reduction in Let-7g, SIRT1, eNOS, catalase and SOD-1 mRNA levels, and elevated miR-34a synthesis in mouse endothelial cells. These findings indicate that endogenous kallistatin through novel mechanisms protects against endothelial senescence by modulating Let-7g-mediated miR-34a-SIRT1-eNOS pathway.

Solar multi-conjugate adaptive optics based on high order ground layer adaptive optics and low order high altitude correction.

Multi-conjugate adaptive optics (MCAO) is the most promising technique currently developed to enlarge the corrected field of view of adaptive optics for astronomy. In this paper, we propose a new configuration of solar MCAO based on high order ground layer adaptive optics and low order high altitude correction, which result in a homogeneous correction effect in the whole field of view. An individual high order multiple direction Shack-Hartmann wavefront sensor is employed in the configuration to detect the ground layer turbulence for low altitude correction. Furthermore, the other low order multiple direction Shack-Hartmann wavefront sensor supplies the wavefront information caused by high layers' turbulence through atmospheric tomography for high altitude correction. Simulation results based on the system design at the 1-meter New Vacuum Solar Telescope show that the correction uniform of the new scheme is obviously improved compared to conventional solar MCAO configuration.

Kallistatin induces breast cancer cell apoptosis and autophagy by modulating Wnt signaling and microRNA synthesis.

Kallistatin is an endogenous protein that regulates differential signaling pathways and biological functions. Our previous studies showed that kallistatin gene therapy inhibited angiogenesis, tumor growth and metastasis in mice, and kallistatin protein suppressed Wnt-mediated growth, migration and invasion by blocking Wnt/ß-catenin signaling pathway in breast cancer cells. In this study, we show that kallistatin reduced cell viability, and increased apoptotic cell death and caspase-3 activity in MDA-MB-231 breast cancer cells. Kallistatin also induced cancer cell autophagy, as evidenced by increased LC3B levels and elevated Atg5 and Beclin-1 expression; however, co-administration of Wnt or PPARγ antagonist GW9662 abolished these effects. Moreover, kallistatin via its heparin-binding site antagonized Wnt3a-induced cancer cell proliferation and increased PPARγ expression. Kallistatin inhibited oncogenic miR-21 synthesis associated with reduced Akt phosphorylation and Bcl-2 synthesis, but increased BAX expression. Kallistatin via PKC-ERK activation reduced miR-203 levels, leading to increased expression of suppressor of cytokine signaling 3 (SOCS3), a tumor suppressor. Conversely, kallistatin stimulated expression of the tumorigenic suppressors miR-34a and p53. Kallistatin's active site is essential for suppressing miR-21 and miR-203, and stimulating miR-34a and SOCS3 expression. This is the first study to demonstrate that kallistatin's heparin-binding site is essential for inhibiting Wnt-mediated effects, and its active site plays a key role in regulating miR-21, miR-203, miR-34a and SOCS3 synthesis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in inducing apoptosis and autophagy in breast cancer cells, thus inhibiting tumor progression by regulation of Wnt/PPARγ signaling, as well as miR-21, miR-203 and miR-34a synthesis.

First on-sky demonstration of the piezoelectric adaptive secondary mirror.

We propose using a piezoelectric adaptive secondary mirror (PASM) in the medium-sized adaptive telescopes with a 2-4 m aperture for structure and control simplification by utilizing the piezoelectric actuators in contrast with the voice-coil adaptive secondary mirror. A closed-loop experimental setup was built for on-sky demonstration of the 73-element PASM developed by our laboratory. In this Letter, the PASM and the closed-loop adaptive optics system are introduced. High-resolution stellar images were obtained by using the PASM to correct high-order wavefront errors in May 2016. To the best of our knowledge, this is the first successful on-sky demonstration of the PASM. The results show that with the PASM as the deformable mirror, the angular resolution of the 1.8 m telescope can be effectively improved.

Kallistatin inhibits TGF-ß-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression.

Kallistatin, an endogenous protein, consists of two structural elements: active site and heparin-binding domain. Kallistatin exerts beneficial effects on fibrosis by suppressing transforming growth factor (TGF)-ß synthesis in animal models. TGF-ß is the most potent inducer of endothelial-mesenchymal transition (EndMT), which contributes to fibrosis and cancer. MicroRNA (miR)-21 is an important player in organ fibrosis and tumor invasion. Here we investigated the potential role of kallistatin in EndMT via modulation of miR-21 in endothelial cells. Human kallistatin treatment blocked TGF-ß-induced EndMT, as evidenced by morphological changes as well as increased endothelial and reduced mesenchymal marker expression. Kallistatin also inhibited TGF-ß-mediated reactive oxygen species (ROS) formation and NADPH oxidase expression and activity. Moreover, kallistatin antagonized TGF-ß-induced miR-21 and Snail1 synthesis, Akt phosphorylation, NF-κB activation, and matrix metalloproteinase 2 (MMP2) synthesis and activation. Kallistatin via its heparin-binding site blocked TGF-ß-induced miR-21, Snail1 expression, and ROS formation, as wild-type kallistatin, but not heparin-binding site mutant kallistatin, exerted the effect. Conversely, kallistatin through its active site stimulated the synthesis of endothelial nitric oxide synthase (eNOS), sirtuin 1 (Sirt1) and forkhead box O1 (FoxO1); however, these effects were blocked by genistein, a tyrosine kinase inhibitor. This is the first study to demonstrate that kallistatin's heparin-binding site is crucial for preventing TGF-ß-induced miR-21 and oxidative stress, while its active site is key for stimulating the expression of antioxidant genes via interaction with an endothelial surface tyrosine kinase. These findings reveal novel mechanisms of kallistatin in protection against fibrosis and cancer by suppressing EndMT.

Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis.

INTRODUCTION: Kallistatin levels in the circulation are reduced in patients with sepsis and liver disease. Transgenic mice expressing kallistatin are resistant to lipopolysaccharide (LPS)-induced mortality. Here, we investigated the effect of kallistatin on survival and organ damage in mouse models of established sepsis. METHODS: Mice were rendered septic by cecal ligation and puncture (CLP), or endotoxemic by LPS injection. Recombinant human kallistatin was administered intravenously six hours after CLP, or intraperitoneally four hours after LPS challenge. The effect of kallistatin treatment on organ damage was examined one day after sepsis initiation, and mouse survival was monitored for four to six days. RESULTS: Human kallistatin was detected in mouse serum of kallistatin-treated mice. Kallistatin significantly reduced CLP-induced renal injury as well as blood urea nitrogen, serum creatinine, interleukin-6 (IL-6), and high mobility group box-1 (HMGB1) levels. In the lung, kallistatin decreased malondialdehyde levels and HMGB1 and toll-like receptor-4 (TLR4) synthesis, but increased suppressor of cytokine signaling-3 (SOCS3) expression. Moreover, kallistatin attenuated liver injury, serum alanine transaminase (ALT) levels and hepatic tumor necrosis factor-α (TNF-α) synthesis. Furthermore, delayed kallistatin administration improved survival in CLP mice by 38%, and LPS-treated mice by 42%. In LPS-induced endotoxemic mice, kallistatin attenuated kidney damage in association with reduced serum creatinine, IL-6 and HMGB1 levels, and increased renal SOCS3 expression. Kallistatin also decreased liver injury in conjunction with diminished serum ALT levels and hepatic TNF-α and TLR4 expression. In cultured macrophages, kallistatin through its active site increased SOCS3 expression, but this effect was blocked by inhibitors of tyrosine kinase, protein kinase C and extracellular signal-regulated kinase (ERK), indicating that kallistatin stimulates a tyrosine-kinase-protein kinase C-ERK signaling pathway. CONCLUSIONS: This is the first study to demonstrate that delayed human kallistatin administration is effective in attenuating multi-organ injury, inflammation and mortality in mouse models of polymicrobial infection and endotoxemia. Thus, kallistatin therapy may provide a promising approach for the treatment of sepsis in humans.