Thrombomodulin Improves Cognitive Deficits in Heat-Stressed Mice.

BACKGROUND: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice. METHODS: Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. RESULTS: Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. CONCLUSIONS: The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.

Clotting Blood into an Adhesive Gel by Hemostatic Powder Based on Cationic/Anionic Polysaccharides and Laponite.

Hemostatic powder is widely employed for emergency bleeding control due to its ability to conform to irregularly shaped wounds, ease of use, and stable storage. However, current powders exhibit limited tissue adhesion and insufficient support for thrombus formation, making them easily washed away by blood. In this study, a hybrid powder (QAL) was produced by mixing quaternized chitosan (QCS) powder, catechol-modified alginate (Cat-SA) powder, and laponite (Lap) powder. Upon addition of QAL, the blood quickly transformed to a robust and adhesive blood gel. The adhesion strength of the blood gel was up to 31.33 ± 1.56 kPa. When compared with Celox, QAL showed superior performance in promoting hemostasis. Additionally, QAL exhibited effectiveness in eliminating bacteria while also demonstrating outstanding biocompatibility with cells and blood. These favorable properties, including strong coagulation, adhesion to wet tissue, antibacterial activity, biosafety, ease of use, and stable storage, make QAL a promising emergency hemostatic agent.

Extraction and Validation of Biomechanical Gait Parameters with Contactless FMCW Radar.

A 77 GHz frequency-modulated continuous wave (FMCW) radar was utilized to extract biomechanical parameters for gait analysis in indoor scenarios. By preprocessing the collected raw radar data and eliminating environmental noise, a range-velocity-time (RVT) data cube encompassing the subjects' information was derived. The strongest signals from the torso in the velocity and range dimensions and the enveloped signal from the toe in the velocity dimension were individually separated for the gait parameters extraction. Then, six gait parameters, including step time, stride time, step length, stride length, torso velocity, and toe velocity, were measured. In addition, the Qualisys system was concurrently utilized to measure the gait parameters of the subjects as the ground truth. The reliability of the parameters extracted by the radar was validated through the application of the Wilcoxon test, the intraclass correlation coefficient (ICC) value, and Bland-Altman plots. The average errors of the gait parameters in the time, range, and velocity dimensions were less than 0.004 s, 0.002 m, and 0.045 m/s, respectively. This non-contact radar modality promises to be employable for gait monitoring and analysis of the elderly at home.

Sensitive Electrochemical Sensor for Glycoprotein Detection Using a Self-Serviced-Track 3D DNA Walker and Catalytic Hairpin Assembly Enzyme-Free Signal Amplification.

Approaches for the detection of targets in the cellular microenvironment have been extensively developed. However, developing a method with sensitive and accurate analysis for noninvasive cancer diagnosis has remained challenging until now. Here, we reported a sensitive and universal electrochemical platform that integrates a self-serviced-track 3D DNA walker and catalytic hairpin assembly (CHA) triggering G-Quadruplex/Hemin DNAzyme assembly signal amplification. In the presence of a target, the aptamer recognition initiated the 3D DNA walker on the cell surface autonomous running and releasing DNA (C) from the triple helix. The released DNA C as the target-triggered CHA moiety, and then G-quadruplex/hemin, was formed on the surface of electrode. Eventually, a large amount of G-quadruplex/hemin was formed on the sensor surface to generate an amplified electrochemical signal. Using N-acetylgalactosamine as a model, benefiting from the high selectivity and sensitivity of the self-serviced-track 3D DNA walker and the CHA, this designed method showed a detection limit of 39 cell/mL and 2.16 nM N-acetylgalactosamine. Furthermore, this detection strategy was enzyme free and exhibited highly sensitive, accurate, and universal detection of a variety of targets by using the corresponding DNA aptamer in clinical sample analysis, showing potential for early and prognostic diagnostic application.

Promoted Photothermal Catalytic CO Hydrogenation by Using TiC-Supported Co-Fe5 C2 Catalysts.

Photothermal catalytic CO hydrogenation offers the potential to synthesize light hydrocarbons by using solar energy. However, the selectivity and activity of the reaction are still far below those achieved in conventional thermal catalytic processes. Herein, we report that the Co-modified Fe5 C2 on TiC catalyst promotes photothermal catalytic CO hydrogenation with a 59 % C2+ selectivity in the produced hydrocarbons and a 30 % single-pass CO conversion at a high gas hourly space-time velocity of 12 000 mL g-1 h-1 . Using in-situ-irradiated XPS, we show that light-induced hot electron injection from TiC to Fe5 C2 modulates the chemical state of Fe, thereby increasing the CO-to-C2+ conversion. This work suggests that it is possible for plasmon-mediated surface chemistry to enhance the activity and selectivity of photothermal catalytic reactions.

Electroactive poly(thionine) as imprinted polymer and reference probe simultaneously for ratiometric ion imprinted electrochemical Pb2+sensor.

In this work, an electrochemical sensor based on ion-imprinted polymer/Au nanoparticles/porous biochar (IIP/AuNPs/PBC) composite was proposed for the highly selective and sensitive detection of Pb2+. In this work, poly (thionine) (pTHI) served simultaneously as imprinted polymer and reference probe. It could not only realize the specific detection of Pb2+, but also provide an internal reference signal to eliminate the influence of human and environmental factors on the detection signal and further improve the stability of the sensor. In addition, the AuNPs/PBC composite with large specific surface area, excellent electron transport and electrocatalytic performance could effectively enhance the detection signal as a carrier material. At the same time, the AuNPs on the PBC surface would promote the formation of uniform and stable IIP through Au-S bonds. The synergistic effect between IIP, AuNPs/PBC and ratiometric signal mode gave the Pb2+sensor excellent performance, including a wide linear range (0.1-1000µg l-1), low detection limit (0.03µg l-1, S/N = 3), excellent selectivity and stability. All these results indicate that the proposed sensor could provide a meaningful reference for highly selective detection of heavy metal ions (HMIs).

Efficient Adsorption and Electrochemical Detection of Cd2+ with a Ternary MgZnFe-Layered Double Hydroxides Engineered Porous Biochar Composite.

Their unique layered structure, large specific surface area, good stability, high negative charge density between layers, and customizable composition give layered double hydroxides (LDHs) excellent adsorption and detection performance for heavy metal ions (HMIs). However, their easy aggregation and low electrical conductivity limit the practical application of untreated LDHs. In this work, a ternary MgZnFe-LDHs engineered porous biochar (MgZnFe-LDHs/PBC) heterojunction was proposed as a sensing and adsorption material for the effective detection and removal of Cd2+ from wastewater. The growth of MgZnFe-LDHs in the PBC pores not only reduces the accumulation of MgZnFe-LDHs, but also improves the electrical conductivity of the composite. The synergistic effect between MgZnFe-LDHs and PBC enables the composite to achieve a maximum adsorption capacity of up to 293.4 mg/g for Cd2+ in wastewater. Meanwhile, the MgZnFe-LDHs/PBC-based electrochemical sensor shows excellent detection performance for Cd2+, presenting a wide linear range (0.01 ng/L-1 mg/L), low detection limit (3.0 pg/L), good selectivity, and stability. The results indicate that MgZnFe-LDHs/PBC would be a potential material for detecting and removing Cd2+ from wastewater.

A Molecularly Imprinted Electrochemical Sensor Based on TiO2@Ti3C2Tx for Highly Sensitive and Selective Detection of Chlortetracycline.

In view of the serious side effects of chlortetracycline (CTC) on the human body, it is particularly important to develop rapid, sensitive, and selective technologies for the detection of CTC in food. In this work, a molecularly imprinted electrochemical sensor with [Fe(CN)6]3-/4- as signal probe was proposed for the highly sensitive and selective detection of CTC. For this purpose, TiO2, which acts as an interlayer scaffold, was uniformly grown on the surface of Ti3C2Tx sheets through a simple two-step calcination process using Ti3C2Tx as the precursor to effectively avoid the stacking of Ti3C2Tx layers due to hydrogen bonding and van der Waals forces. This endowed TiO2@Ti3C2Tx with large specific surface, abundant functional sites, and rapid mass transfer. Then, polypyrrole molecularly imprinted polymers (MIPs) with outstanding electrical conductivity were modified on the surface of TiO2@Ti3C2Tx via simple electro-polymerization, where the pyrrole was employed as a polymeric monomer and the CTC provided a source of template molecules. This will not only provide specific recognition sites for CTC, but also facilitate electron transport on the electrode surface. The synergistic effects between TiO2@Ti3C2Tx and polypyrrole MIPs afforded the TiO2@Ti3C2Tx/MIP-based electrochemical sensor excellent detection properties toward CTC, including ultra-low limits of detection (LOD) (0.027 nM), a wide linear range (0.06-1000 nM), and outstanding stability, reproducibility, selectivity, and feasibility in real samples. The results indicate that this strategy is feasible and will broaden the horizon for highly sensitive and selective detection of CTC.

Nitrogen Doped Porous Biochar/ß-CD-MOFs Heterostructures: Bi-Functional Material for Highly Sensitive Electrochemical Detection and Removal of Acetaminophen.

Acetaminophen (AC) is one of the most common over-the-counter drugs, and its pollutant in groundwater has attracted more attention due to its serious risk to human health. Currently, the research on AC is mainly focused on its detection, but few are concerned about its removal. In this work, for the first time, nitrogen-doped Soulangeana sepals derived biochar/ß-cyclodextrin-Metal-organic frameworks (N-SC/ß-CD-MOFs) composite was proposed for the simultaneous efficient removal and detection of AC. N-SC/ß-CD-MOFs combined the properties of host-guest recognition of ß-CD-MOFs and porous structure, high porosity, and large surface area of N-SC. Their synergies endowed N-SC/ß-CD-MOFs with a high adsorption capacity toward AC, which was up to 66.43 mg/g. The adsorption type of AC on the surface of N-SC/ß-CD-MOFs conformed to the Langmuir adsorption model, and the study of the adsorption mechanism showed that AC adsorption on N-SC was mainly achieved through hydrogen bonding. In addition, the high conductivity, large specific surface area and abundant active sites of N-SC/ß-CD-MOFs were of great significance to the high-performance detection of AC. Accordingly, the sensor prepared with N-SC/ß-CD-MOFs presented a wide linear range (1.0-30.0 µM) and a low limit of detection of 0.3 nM (S/N = 3). These excellent performances demonstrate that N-SC/ß-CD-MOFs could act as an efficient dual-functional material for the detection and removal of AC.

An Electrochemical Sensor Based on a Porous Biochar/Cuprous Oxide (BC/Cu2O) Composite for the Determination of Hg(II).

Mercuric ion (Hg2+) in aqueous media is extremely toxic to the environment and organisms. Therefore, the ultra-trace electrochemical determination of Hg2+ in the environment is of critical importance. In this work, a new electrochemical Hg2+ sensing platform based on porous activated carbon (BC/Cu2O) modified with cuprous oxide was developed using a simple impregnation pyrolysis method. Differential pulse anodic stripping voltammetry (DPASV) was used to investigate the sensing capability of the BC/Cu2O electrode towards Hg2+. Due to the excellent conductivity and large specific surface area of BC, and the excellent catalytic activity of Cu2O nanoparticles, the prepared BC/Cu2O electrode exhibited excellent electrochemical activity. The high sensitivity of the proposed system resulted in a low detection limit of 0.3 ng·L-1 and a wide linear response in the ranges from 1.0 ng·L-1 to 1.0 mg·L-1. In addition, this sensor was found to have good accuracy, acceptable precision, and reproducibility. All of these results show that the BC/Cu2O composite is a promising material for Hg2+ electrochemical detection.

Can the Sci-Tech Innovation Increase the China's Green Brands Value?-Evidence from Threshold Effect and Spatial Dubin Model.

Based on the perspective of the innovation value chain, sci-tech innovation is divided into two stages: R&D and achievement transformation. This paper uses panel data from 25 provinces in China as the sample. We utilize a two-way fixed effect model, spatial Dubin model, and panel threshold model to discuss the impact of two-stage innovation efficiency on the value of the green brand, the spatial effect of this impact, and the threshold role of intellectual property protection in the process. The results indicate that: (1) the two stages of innovation efficiency have a positive impact on the value of green brands, and the effect of the eastern region is significantly better than that of the central and western regions. (2) The spatial spillover effect of the two stages of regional innovation efficiency on the value of green brands is evident, especially in the eastern region. (3) The innovation value chain has a pronounced spillover effect. (4) The single threshold effect of intellectual property protection is significant. When the threshold is crossed, the positive impact of the two stages of innovation efficiency on the value of green brands is significantly enhanced. (5) The influence of economic development level, openness, market size, and marketization degree on the value of green brands shows remarkable regional differences. In conclusion, this study contributes to understanding green brands' growth and provides important implications for developing independent brands in various regions of China.

Evaluation of the reliability of the upper lip bite test and the modified mallampati test in predicting difficult intubation under direct laryngoscopy in apparently normal patients: a prospective observational clinical study.

BACKGROUND AND AIMS: Difficult endotracheal intubation is one of the most challenging operations in anesthesia. How to better predict difficult airway and make corresponding preparations to reduce the occurrence of accidents is a difficult task faced by anesthesiologists every day. This study decide to evaluate the value of the Upper Lip Bite Test (ULBT) and the Modified Mallampati Test (MMT) in predicting difficult intubation under direct laryngoscopy and find out the most intuitive and simple method to predict difficult intubation under direct laryngoscopy in apparently normal patients. PATIENTS AND METHODS: This descriptive-analytical study was performed on 450 patients for elective surgery under general anesthesia requiring endotracheal intubation. The ULBT and MMT grading were evaluated preoperatively and Cormack and Lehane's (CL) classification was recorded on the day of surgery during intubation under direct laryngoscopy. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio (LR), Youden index and area under ROC curve of ULBT and MMT respectively and in combination were calculated and compared. And the consistency between the total scores of ULBT and MMT combined in different ways and CL grading was counted. RESULTS: Of the 450 patients, 69 (15.3%) were classified as difficult cases of direct laryngoscopy. The accuracy, sensitivity, specificity, PPV and NPV of ULBT were 81.33, 11.59, 93.96, 25.81, 85.44%; and those the corresponding values for MMT were 66.22, 62.32, 69.29, 26.88 and 91.03%. A combination of ULBT and MMT did not improve the sensitivity in the sample tested. The combined total scores of ULBT and MMT in both ways were less consistent with CL grading in predicting difficult intubation under direct laryngoscopy. CONCLUSION: Based on findings of current study, we conclude that ULBT and MMT for difficult intubation have only poor to moderate discriminative power when used alone. The combination of the two tests in fractional form is also not a good predictor of difficult intubation under direct laryngoscopy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100052987, Registered 07 November 2021, http://www.chictr.org.cn.

ncDLRES: a novel method for non-coding RNAs family prediction based on dynamic LSTM and ResNet.

BACKGROUND: Studies have proven that the same family of non-coding RNAs (ncRNAs) have similar functions, so predicting the ncRNAs family is helpful to the research of ncRNAs functions. The existing calculation methods mainly fall into two categories: the first type is to predict ncRNAs family by learning the features of sequence or secondary structure, and the other type is to predict ncRNAs family by the alignment among homologs sequences. In the first type, some methods predict ncRNAs family by learning predicted secondary structure features. The inaccuracy of predicted secondary structure may cause the low accuracy of those methods. Different from that, ncRFP directly learning the features of ncRNA sequences to predict ncRNAs family. Although ncRFP simplifies the prediction process and improves the performance, there is room for improvement in ncRFP performance due to the incomplete features of its input data. In the secondary type, the homologous sequence alignment method can achieve the highest performance at present. However, due to the need for consensus secondary structure annotation of ncRNA sequences, and the helplessness for modeling pseudoknots, the use of the method is limited. RESULTS: In this paper, a novel method "ncDLRES", which according to learning the sequence features, is proposed to predict the family of ncRNAs based on Dynamic LSTM (Long Short-term Memory) and ResNet (Residual Neural Network). CONCLUSIONS: ncDLRES extracts the features of ncRNA sequences based on Dynamic LSTM and then classifies them by ResNet. Compared with the homologous sequence alignment method, ncDLRES reduces the data requirement and expands the application scope. By comparing with the first type of methods, the performance of ncDLRES is greatly improved.

A novel end-to-end method to predict RNA secondary structure profile based on bidirectional LSTM and residual neural network.

BACKGROUND: Studies have shown that RNA secondary structure, a planar structure formed by paired bases, plays diverse vital roles in fundamental life activities and complex diseases. RNA secondary structure profile can record whether each base is paired with others. Hence, accurate prediction of secondary structure profile can help to deduce the secondary structure and binding site of RNA. RNA secondary structure profile can be obtained through biological experiment and calculation methods. Of them, the biological experiment method involves two ways: chemical reagent and biological crystallization. The chemical reagent method can obtain a large number of prediction data, but its cost is high and always associated with high noise, making it difficult to get results of all bases on RNA due to the limited of sequencing coverage. By contrast, the biological crystallization method can lead to accurate results, yet heavy experimental work and high costs are required. On the other hand, the calculation method is CROSS, which comprises a three-layer fully connected neural network. However, CROSS can not completely learn the features of RNA secondary structure profile since its poor network structure, leading to its low performance. RESULTS: In this paper, a novel end-to-end method, named as "RPRes, was proposed to predict RNA secondary structure profile based on Bidirectional LSTM and Residual Neural Network. CONCLUSIONS: RPRes utilizes data sets generated by multiple biological experiment methods as the training, validation, and test sets to predict profile, which can compatible with numerous prediction requirements. Compared with the biological experiment method, RPRes has reduced the costs and improved the prediction efficiency. Compared with the state-of-the-art calculation method CROSS, RPRes has significantly improved performance.

A propensity-matched study of the association between pre-pregnancy maternal underweight and perinatal outcomes of singletons conceived through assisted reproductive technology.

RESEARCH QUESTION: Is pre-pregnancy maternal underweight associated with perinatal outcomes of singletons who were conceived through assisted reproductive technology (ART)? DESIGN: A 10-year (2006-2015) Chinese sample of 6538 women and their singleton infants who were conceived through ART was used to examine the association between pre-pregnancy maternal underweight and perinatal outcomes. Propensity scores for underweight were calculated for each participant using multivariable logistic regression, which was used to match 740 (91.36% of 810) underweight women with 740 normal weight women; the effects of underweight on birth weight and gestational age were then assessed by generalized estimating equation model. RESULTS: After propensity score matching, the birth weight was lower (difference -136.83 g, 95% CI -184.11 to -89.55 g) in the underweight group than in the normal weight group. The risks of low birth weight (LBW) and small for gestational age (SGA) were increased in the underweight group compared with those in the normal weight group (LBW: RR 1.64, 95% CI 1.01 to 2.67; SGA: RR 1.46, 95% CI 1.06 to 2.02). The risks of fetal macrosomia and being large for gestational age (LGA) were decreased in the underweight group compared with those in the normal weight group (macrosomia: RR 0.39, 95% CI 0.26 to 0.61; LGA: RR 0.36, 95% CI 0.24 to 0.53). The associations between underweight, gestational age and preterm birth were not statistically significant. CONCLUSIONS: Among women undergoing ART, pre-pregnancy maternal underweight was associated with lower birth weight, increased LBW and SGA risks, and decreased fetal macrosomia and LGA risks in singleton infants.

A Regularized Weighted Smoothed L0 Norm Minimization Method for Underdetermined Blind Source Separation.

Compressed sensing (CS) theory has attracted widespread attention in recent years and has been widely used in signal and image processing, such as underdetermined blind source separation (UBSS), magnetic resonance imaging (MRI), etc. As the main link of CS, the goal of sparse signal reconstruction is how to recover accurately and effectively the original signal from an underdetermined linear system of equations (ULSE). For this problem, we propose a new algorithm called the weighted regularized smoothed L 0 -norm minimization algorithm (WReSL0). Under the framework of this algorithm, we have done three things: (1) proposed a new smoothed function called the compound inverse proportional function (CIPF); (2) proposed a new weighted function; and (3) a new regularization form is derived and constructed. In this algorithm, the weighted function and the new smoothed function are combined as the sparsity-promoting object, and a new regularization form is derived and constructed to enhance de-noising performance. Performance simulation experiments on both the real signal and real images show that the proposed WReSL0 algorithm outperforms other popular approaches, such as SL0, BPDN, NSL0, and L p -RLSand achieves better performances when it is used for UBSS.

The chemiluminescence immunoassay for aflatoxin B1 based on functionalized magnetic nanoparticles with two strategies of antigen probe immobilization.

A rapid and sensitive chemiluminescence immunoassay (CLIA) based on magnetic nanoparticles (MNPs) was developed to detect aflatoxin B1 (AFB1), which is a potent carcinogen in nature. We prepared monodisperse MNPs (300 nm in diameter) according to the solvothermal synthesis reaction and the MNPs were coated with silica by the Stöber method. Triethox was used as a one-step carboxylation reagent, and 3-aminopropyltriethoxysilane (APTES) an amination reagent, to modify the MNPs. We prepared two types of solid phase antigens using the above synthesized functionalized MNPs coupled with the later prepared AFB1-oxime active ester and the purchased BSA-AFB1 respectively. 2',6'-dimethylcarbonylphenyl-10-sulfopropylacridinium-9-carboxylate 4'-N-hydroxysuccinimide (4'-NHS) ester (NSP-DMAE-NHS), as a novel luminescent reagent, was used to label anti-AFB1 antibodies. The two CLIA calibration curves based on the two types of solid phase antigens were obtained and compared. The acquired limit of detection (LOD) was about 0.001 ng/mL for the two functionalized MNPs-based immunoassays, and the half maximal inhibitory concentration (IC50 ) was 0.51 ng/mL for the MNPs-AFB1-based method and 0.72 ng/mL for the MNPs-BSA-AFB1-based method.

Quantitative Real-Time Assessment for Feeding Skill of Preterm Infants.

Nutritive sucking is the approach of obtaining primary food for newborns within six months. However, completing the precise coordination of sucking-swallowing-respiratory actions under oral feeding is usually difficult for preterm infants and may affect the body and neural development of the premature infant. For this reason, how to obtain the quantitatively physiological information related to oral feeding is useful for physicians making more accurate clinical diagnoses for oral feeding disorders. However, there is still lack of monitoring systems for evaluating the feeding skill of infants quantitatively and objectively. The assessment of the feeding skill or the diagnosis of oral-feeding disorders still depends on the clinical experience of medical staffs. In this study, a novel wireless monitoring system is proposed to evaluate the feeding behavior of infants quantitatively and objectively and analyze the characteristics of these actions under oral feeding. Here, a specific feeding bottle and an optical probe are also designed and successfully applied to non-invasively monitor the sucking and respiratory actions, and a microphone is also applied to monitor the swallowing action. From the experimental results, the sucking and swallowing rate increases and the respiratory rate decreases with the increase of the infant age. Moreover, the duration increases and the interval of sucking-action sequence decreases with the increase of the infant age respectively. The proposed system successfully assesses the feeding behavior of preterm infants and may provide an objective evaluation tool for oral feeding ability and identifying the risk of infant developmental delay in the future.

CXCL5 signaling is a shared pathway of neuroinflammation and blood-brain barrier injury contributing to white matter injury in the immature brain.

BACKGROUND: In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood-brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. METHODS: Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. RESULTS: On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration. CONCLUSIONS: CXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain.