Antiplatelet effects of the CEACAM1-derived peptide QDTT.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) restricts platelet activation via platelet collagen receptor GPVI/FcRγ-chain. In this study, screening against collagen-induced platelet aggregation was performed to identify functional CEACAM1 extracellular domain fragments. CEACAM1 fragments, including Ala-substituted peptides, were synthesized. Platelet assays were conducted on healthy donor samples for aggregation, cytotoxicity, adhesion, spreading, and secretion. Mice were used for tail bleeding and FeCl3-induced thrombosis experiments. Clot retraction was assessed using platelet-rich plasma. Extracellular segments of CEACAM1 and A1 domain-derived peptide QDTT were identified, while N, A2, and B domains showed no involvement. QDTT inhibited platelet aggregation. Ala substitution for essential amino acids (Asp139, Thr141, Tyr142, Trp144, and Trp145) in the QDTT sequence abrogated collagen-induced aggregation inhibition. QDTT also suppressed platelet secretion and "inside-out" GP IIb/IIIa activation by convulxin, along with inhibiting PI3K/Akt pathways. QDTT curtailed FeCl3-induced mesenteric thrombosis without significantly prolonging bleeding time, implying the potential of CEACAM1 A1 domain against platelet activation without raising bleeding risk, thus paving the way for novel antiplatelet drugs.

What is the context? The study focuses on Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its role in platelet activation, particularly through the GPVI/FcRγ-chain pathway.The research aims to identify specific fragments of CEACAM1's extracellular domain that could restrict platelet activation, without increasing bleeding risk.What is new? The researchers identified a peptide called QDTT derived from the A1 domain of CEACAM1's extracellular segment. This peptide demonstrated the ability to inhibit platelet aggregation, secretion, and GP IIb/IIIa activation.The study also revealed that specific amino acids within the QDTT sequence were essential for its inhibitory effects on collagen-induced aggregation.What is the impact? The findings suggest that the A1 domain-derived peptide QDTT from CEACAM1 could serve as a potential basis for developing novel antiplatelet drugs. This peptide effectively limits platelet activation and aggregation without significantly prolonging bleeding time, indicating a promising approach to managing thrombosis and related disorders while minimizing bleeding risks.

The association between hepatitis B virus and semen quality: a systematic review and meta-analysis.

BACKGROUND: Some studies have suggested that hepatitis B virus (HBV) infection had a negative association with semen quality, but the conclusions have been inconsistent. The purpose of our study was to systematically assess the association between HBV infection and semen parameters. METHODS: We searched electronic databases for studies published from January 1980 to August 2023. Eleven studies were included in the analysis. Primary outcomes were semen volume, sperm concentration, sperm morphology, sperm motility and sperm progressive motility. We also conducted a subgroup analysis between China and other countries. RESULT: Compared with the semen quality of HBV-negative men, HBV infection had a negative association with semen volume (MD: -0.20 mL, 95%CI: -0.32 to - 0.09, P = 0.0004), sperm concentration (MD: -4.46 × 106/mL, 95%CI: -7.09 to - 1.84, P = 0.0009), sperm morphology (MD: -2.49%, 95%CI: -4.35 to - 0.64, P = 0.008), sperm motility (MD: -6.85%, 95%CI: -11.53 to - 2.18, P = 0.004), and sperm progressive motility (MD: -6.63%, 95%CI: -10.24 to - 3.02, P = 0.0003). However, HBV infection had no significant association with total sperm count (MD: -31.50 × 106, 95%CI: -74.11 to 11.10, P = 0.15). The association between HBV and semen quality were inconsistent between the subgroups. CONCLUSION: HBV infection had a negative association with sperm concentration, motility, morphology, and semen volume. However, The association between HBV and total sperm count remain unclear. This metaanalysis suggests that we should pay attention to the adverse effect of HBV on sperm quality, and several studies have reported the relevant mechanisms. But due to the significant heterogeneity among studies on some semen parameters, further large and well-designed researches are needed before introducing clinical management recommendations.

Robust evidence reveals the reliable rate of normal/balanced embryos for identifying reciprocal translocation and Robertsonian translocation carriers.

We aimed to evaluate the reliable rate of normal/balanced embryos for reciprocal translocation and Robertsonian translocation carriers and to provide convincing evidence for clinical staff to conduct genetic counselling regarding common structural rearrangements to alleviate patient anxiety. The characteristics of 39,459 embryos that were sourced from unpublished data and literature were analyzed. The samples consisted of 17,536 embryo karyotypes that were not published and 21,923 embryo karyotypes obtained from the literature. Using the PubMed, Cochrane Library, Web of Science, and Embase databases, specific keywords were used to screen the literature for reciprocal translocation and Robertsonian translocation. The ratio of normal/balanced embryos in the overall data was calculated and analyzed, and we grouped the results according to gender to confirm if there were gender differences. We also divided the data into the cleavage stage and blastocyst stage according to the biopsy period to verify if there was a difference in the ratio of normal/balanced embryos. By combining the unpublished data and data derived from the literature, the average rates of normal/balanced embryos for reciprocal translocation and Robertsonian translocation carriers were observed to be 26.96% (7953/29,495) and 41.59% (4144/9964), respectively. Reciprocal translocation and Robertson translocation exhibited higher rates in male carriers than they did in female carriers (49.60% vs. 37.44%; 29.84% vs. 27.67%). Additionally, the data for both translocations exhibited differences in the normal/balanced embryo ratios between the cleavage and blastocyst stages of carriers for both Robertsonian translocation and reciprocal translocation (36.07% vs 43.43%; 24.88% vs 27.67%). The differences between the two location types were statistically significant (P < 0.05). The normal/balanced ratio of embryos in carriers of reciprocal and RobT was higher than the theoretical ratio, and the values ranged from 26.96% to 41.59%. Moreover, the male carriers possessed a higher number of embryos that were normal or balanced. The ratio of normal/balanced embryos in the blastocyst stage was higher than that in the cleavage stage. The results of this study provide a reliable suggestion for future clinic genetic consulting regarding the rate of normal/balanced embryos of reciprocal translocation and Robertsonian translocation carriers.

FUNDC1 modulates mitochondrial defects and pancreatic ß-cell dysfunction under lipotoxicity.

Insulin resistance and many metabolic disorders are causally linked to mitochondrial dysfunction or defective mitochondrial quality control. Mitophagy is a highly selective mechanism that recognizes and removes damaged mitochondria to maintain mitochondrial homeostasis. Here, we addressed the potential role of FUNDC1, a mediator of mitophagy, in pancreatic ß-cell dysfunction under lipotoxicity. In pancreatic MIN6 cells, FUNDC1 deficiency aggravated palmitate-induced mitochondrial dysfunction, which led to cell death and insulin insensitivity. Interestingly, FUNDC1 overexpression prevented these cellular harms brought on by palmitate. In mice models, pancreatic-specific FUNDC1 overexpression alleviated high-fat diet (HFD)-induced insulin resistance and obesity. Mechanistically, pancreatic-specific overexpression of FUNDC1 ameliorated mitochondrial defects and endoplasmic reticulum (ER) stress upon HFD. Our research indicates that FUNDC1 plays an essential role in apoptosis and dysfunction of pancreatic ß-cells via modulating lipotoxicity-induced mitochondrial defects.

Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviates atherosclerosis through the modulation of M1 polarization.

BACKGROUND: Inflammation and immune dysfunction with classically activated macrophages(M1) infiltration are important mechanisms in the progression of atherosclerosis (AS). Dynamin-related protein 1 (DRP1)-dependent mitochondrial fission is a novel target for alleviating inflammatory diseases. This study aimed to investigate the effects of DRP1 inhibitor Mdivi-1 on AS. METHODS: ApoE-/- mice were fed with a high-fat diet supplemented with or without Mdivi-1. RAW264.7 cells were stimulated by ox-LDL, pretreated with or without MCC950, Mito-TEMPO, or Mdivi-1. The burden of plaques and foam cell formation were determined using ORO staining. The blood lipid profles and inflammatory cytokines in serum were detected by commercial kits and ELISA, respectively. The mRNA expression of macrophage polarization markers, activation of NLRP3 and the phosphorylation state of DRP1 were detected. Mitochondrial reactive oxygen species (mito-ROS), mitochondrial staining, ATP level and mitochondrial membrane potential were detected by mito-SOX, MitoTracker, ATP determination kit and JC-1 staining, respectively. RESULTS: In vivo, Mdivi-1 reduced the plaque areas, M1 polarization, NLRP3 activation and DRP1 phosphorylation at Ser616. In vitro, oxidized low-density lipoprotein (ox-LDL) triggered M1 polarization, NLRP3 activation and abnormal accumulation of mito-ROS. MCC950 and Mito-TEMPO suppressed M1 polarization mediated foam cell formation. Mito-TEMPO significantly inhibited NLRP3 activation. In addition, Mdivi-1 reduced foam cells by inhibiting M1 polarization. The possible mechanisms responsible for the anti-atherosclerotic effects of Mdivi-1 on reducing M1 polarization were associated with suppressing mito-ROS/NLRP3 pathway by inhibiting DRP1 mediated mitochondrial fission. In vitro, similar results were observed by DRP1 knockdown. CONCLUSION: Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviated atherogenesis via suppressing mito-ROS/NLRP3-mediated M1 polarization, indicating DRP1-dependent mitochondrial fission as a potential therapeutic target for AS.

Histones participate in base excision repair of 8-oxodGuo by transiently cross-linking with active repair intermediates in nucleosome core particles.

8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a biomarker of oxidative DNA damage and can be repaired by hOGG1 and APE1 via the base excision repair (BER) pathway. In this work, we studied coordinated BER of 8-oxodGuo by hOGG1 and APE1 in nucleosome core particles and found that histones transiently formed DNA-protein cross-links (DPCs) with active repair intermediates such as 3'-phospho-α,ß-unsaturated aldehyde (PUA) and 5'-deoxyribosephosphate (dRP). The effects of histone participation could be beneficial or deleterious to the BER process, depending on the circumstances. In the absence of APE1, histones enhanced the AP lyase activity of hOGG1 by cross-linking with 3'-PUA. However, the formed histone-PUA DPCs hampered the subsequent repair process. In the presence of APE1, both the AP lyase activity of hOGG1 and the formation of histone-PUA DPCs were suppressed. In this case, histones could catalyse removal of the 5'-dRP by transiently cross-linking with the active intermediate. That is, histones promoted the repair by acting as 5'-dRP lyases. Our findings demonstrate that histones participate in multiple steps of 8-oxodGuo repair in nucleosome core particles, highlighting the diverse roles that histones may play during DNA repair in eukaryotic cells.

Nucleosomes enter cells by clathrin- and caveolin-dependent endocytosis.

DNA damage and apoptosis lead to the release of free nucleosomes-the basic structural repeating units of chromatin-into the blood circulation system. We recently reported that free nucleosomes that enter the cytoplasm of mammalian cells trigger immune responses by activating cGMP-AMP synthase (cGAS). In the present study, we designed experiments to reveal the mechanism of nucleosome uptake by human cells. We showed that nucleosomes are first absorbed on the cell membrane through nonspecific electrostatic interactions between positively charged histone N-terminal tails and ligands on the cell surface, followed by internalization via clathrin- or caveolae-dependent endocytosis. After cellular internalization, endosomal escape occurs rapidly, and nucleosomes are released into the cytosol, maintaining structural integrity for an extended period. The efficient endocytosis of extracellular nucleosomes suggests that circulating nucleosomes may lead to cellular disorders as well as immunostimulation, and thus, the biological effects exerted by endocytic nucleosomes should be addressed in the future.

TCRα reporter mice reveal contribution of dual TCRα expression to T cell repertoire and function.

It is known that a subpopulation of T cells expresses two T cell receptor (TCR) clonotypes, though the extent and functional significance of this is not established. To definitively evaluate dual TCRα cells, we generated mice with green fluorescent protein and red fluorescent protein reporters linked to TCRα, revealing that ∼16% of T cells express dual TCRs, notably higher than prior estimates. Importantly, dual TCR expression has functional consequences, as dual TCR cells predominated response to lymphocytic choriomeningitis virus infection, comprising up to 60% of virus-specific CD4+ and CD8+ T cells during acute responses. Dual receptor expression selectively influenced immune memory, as postinfection memory CD4+ populations contained significantly increased frequencies of dual TCR cells. These data reveal a previously unappreciated contribution of dual TCR cells to the immune repertoire and highlight their potential effects on immune responses.

External sodium acetate improved Cr(VI) stabilization in a Cr-spiked soil during chemical-microbial reduction processes: Insights into Cr(VI) reduction performance, microbial community and metabolic functions.

Interest combined chemical and microbial reduction for Cr(VI) remediation in contaminated sites has greatly increased. However, the effect of external carbon sources on Cr(VI) reduction during chemical-microbial reduction processes has not been studied. Therefore, in this study, the role of external sodium acetate (SA) in improving Cr(VI) reduction and stabilization in a representative Cr(VI)-spiked soils was systemically investigated. The results of batch experiments suggested that the soil Cr(VI) content declined from 1000 mg/kg to 2.6-5.1 mg/kg at 1-5 g C/kg SA supplemented within 15 days of reaction. The external addition of SA resulted in a significant increase in the relative abundances of Cr(VI)-reducing microorganisms, such as Tissierella, Proteiniclasticum and Proteiniclasticum. The relative abundance of Tissierella increased from 9.1% to 29.8% with the SA treatment at 5 g C/kg soil, which was the main contributors to microbial Cr(VI) reduction. Redundancy analysis indicated that pH and SA were the predominant factors affecting the microbial community in the SA treatments at 2 g C/kg soil and 5 g C/kg soil. Functional prediction suggested that the addition of SA had a positive effect on the metabolism of key substances involved in Cr(VI) microbial reduction. This work provides new insightful guidance on Cr(VI) remediation in contaminated soils.

Effective Cr(VI) reduction and immobilization in chromite ore processing residue (COPR) contaminated soils by ferrous sulfate and digestate: A comparative investigation with typical reducing agents.

Chemical reduction combined with microbial stabilization is a green and efficient method for the remediation of hexavalent chromium (Cr(VI)) contaminated soil. In this study, the combination of ferrous sulfate with kitchen waste digestate was applied to reduce and immobilize Cr(VI) in chromite ore processing residue (COPR) contaminated soils, and systematically evaluated the remediation performance of Cr(VI) compared with several typical reducing agents (i.e., ferrous sulfate, zero valent iron, sodium thiosulfate, ferrous sulfide, and calcium polysulfide). The results showed that the combination of ferrous sulfate and digestate had superior advantages of a lower dosage of reducing agent and a long-term remediation effect compared to other single chemical reductants. Under an Fe(II):Cr(VI) molar ratio of 3:1% and 4% digestate (wt), the content of Cr(VI) in the soil decreased to 5.07 mg/kg after 60 days of remediation. Meanwhile, the leaching concentrations of Cr(VI) were below detection limit, which can meet the hazardous waste toxicity leaching standard. The risk level of Cr pollution was decreased from very high risk to low risk. The X-ray photoelectron spectroscopy (XPS) results further demonstrated that the combined treatments were beneficial to Cr(VI) reduction and stabilization. The abundance of bacteria with Cr(VI) reducing ability was higher than other treatments. Moreover, the high abundance of carbon and nitrogen metabolism in the combined treatments demonstrated that the addition of digestate was beneficial to the recovery and flourishing of Cr(VI)-reducing related microorganisms in COPR contaminated soils. This work provided an alternative way on Cr(VI) remediation in COPR contaminated soils.

Prognostic Significance of Serum Chloride Level Reduction in Patients with Chronic Heart Failure with Different Ejection Fractions.

Little is known regarding the prognostic value of serum chloride in patients with chronic heart failure (CHF) with different ejection fractions. We sought to determine the postdischarge outcomes associated with lower serum chloride between different CHF types.We reviewed the medical records of 1221 consecutive patients with CHF admitted to the First Affiliated Hospital of Kunming Medical University from January 2017 to October 2021. After excluding patients with in-hospital death, missing follow-up data, missing serum chloride level data, or chronic dialysis therapy, 791 patients were included. Of these patients, 343 had heart failure with reduced ejection fraction (HFrEF; i.e., left ventricular ejection fraction (LVEF) < 40%), and 448 had heart failure with preserved ejection fraction (HFpEF) or heart failure with median ejection fraction (HFmrEF; HFpEF plus HFmrEF; i.e., LVEF ≥40%). Over a median follow-up of 750 days, 344 patients (43.5%) had all-cause mortality. In the univariate analysis, serum sodium and chloride were strongly associated with mortality in both HF subgroups (P < 0.0001). A multivariable model including both serum sodium and chloride showed the highly significant association between serum chloride and survival (P < 0.0001), whereas the association between serum sodium and mortality was not reported (HFpEF plus HFmrEF, hazard ratio (HR) 0.975, 95% confidence interval [CI] 0.942-1.010, P = 0.158; HFrEF, HR 1.007, 95% CI 0.966-1.051, P = 0.734). Kaplan-Meier survival curve analysis revealed a significant difference in mortality risk with decreasing chloride levels in all patients with CHF. The optimal cutoff value of chloride in predicting all-cause mortality was 102.95 mmol/L with area under the curve value of 0.76 [HR 0.760, 95% CI 0.727-0.793, P < 0.0001], sensitivity of 60.2%, and specificity of 78.3%.Lower serum chloride is an independent predictor of death in CHF, regardless of heart failure subtype.

Tapping Into Skeletal Muscle Biomechanics for Design and Control of Lower Limb Exoskeletons: A Narrative Review.

Lower limb exoskeletons and exosuits ("exos") are traditionally designed with a strong focus on mechatronics and actuation, whereas the "human side" is often disregarded or minimally modeled. Muscle biomechanics principles and skeletal muscle response to robot-delivered loads should be incorporated in design/control of exos. In this narrative review, we summarize the advances in literature with respect to the fusion of muscle biomechanics and lower limb exoskeletons. We report methods to measure muscle biomechanics directly and indirectly and summarize the studies that have incorporated muscle measures for improved design and control of intuitive lower limb exos. Finally, we delve into articles that have studied how the human-exo interaction influences muscle biomechanics during locomotion. To support neurorehabilitation and facilitate everyday use of wearable assistive technologies, we believe that future studies should investigate and predict how exoskeleton assistance strategies would structurally remodel skeletal muscle over time. Real-time mapping of the neuromechanical origin and generation of muscle force resulting in joint torques should be combined with musculoskeletal models to address time-varying parameters such as adaptation to exos and fatigue. Development of smarter predictive controllers that steer rather than assist biological components could result in a synchronized human-machine system that optimizes the biological and electromechanical performance of the combined system.

Bladder Cancer Invasion Is Mediated by Mammalian Target of Rapamycin Complex 2-Driven Regulation of Nitric Oxide and Invadopodia Formation.

Bladder cancer invasion depends on mammalian target of rapamycin complex 2 (mTORC2) activity, although the downstream mTORC2 effectors that mediate this effect have not been fully defined. One potential downstream effector is the arginine derivative nitric oxide (NO). This study identified a stage-associated increase in the expression of the NO-generating enzymes endothelial NO synthase (eNOS) and inducible NOS (iNOS) in human bladder cancer. Reduction of NOS activity by pharmacologic inhibition or silencing of NOS enzymes reduced cancer cell invasion, with similar effects observed using the NO scavenger cobinamide. By contrast, enhanced invasion was seen with the NO donor Deta-NONOate and an analog of the downstream NO second messenger cGMP. Next, NOS expression was evaluated in invadopodia, which are cellular protrusions that form the invasive tips of cancer cells. Invadopodia were enriched in both iNOS protein and mTORC2 activity, and invadopodia formation was increased by Deta-NONOate and decreased by cobinamide and ablation of mTORC2 activity. Additionally, mTORC2 increased expression of iNOS. Using a zebrafish model, injection of iNOS- or rictor-silenced cells reduced the frequency of bladder cancer cell metastasis in zebrafish. These results indicate that mTORC2 can mediate bladder cancer cell invasion through increased iNOS expression, resulting in increased NO and cGMP production in invadopodia and further propagation of invadopodia formation.

Remediation of Cr(VI)-contaminated soil by combined chemical reduction and microbial stabilization: The role of biogas solid residue (BSR).

In this work, the use of chemical reduction combined with microbial stabilization to remediate Cr(VI) in contaminated soil was systematically investigated. The effectiveness, phytotoxicity and microbial diversity resulting from the combination of ferrous sulfate with microbial stabilization by biogas solid residue (BSR) were determined. The stabilization experiments showed that the optimum Cr(VI) conversion rate of 99.92% was achieved with an Fe (II)/Cr(VI) molar ratio of 3:1, a BSR dose of 5.2% (wt), and a water content of 40%. Under these conditions, the residual Cr(VI) content was 0.80 mg/kg, which satisfied the risk screening value (≤ 5.7 mg/kg) for soil contamination of land for general development in China. The remaining Cr(VI) level was stable for 90 days during the chemical reduction and biogenic stabilization process. Moreover, Zucconi test analysis suggested that the soil phytotoxicity to Brassica campestris L. disappeared. The results of microbial diversity analysis indicated that the bacterial community changed significantly during chemical reduction and microbial stabilization processes, and Bacillus, Pseudomonas and Psychrobacter may participate in the reduction of Cr(VI) into Cr(III).

Bioequivalence of a Generic Nateglinide Formulation in Healthy Chinese Volunteers under Fasting and Fed Conditions: A Randomized, Open-Label, Double-Cycle, Double-Crossover Study.

INTRODUCTION: Nateglinide or N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine is a drug with a rapid hypoglycemic effect that is mainly used in the treatment of type 2 diabetes. Very few studies have assessed bioequivalence based on feeding status. This study aimed to assess the pharmacokinetic bioequivalence and safety of nateglinide-containing tablets (0.12 g) in healthy Chinese volunteers under fasting and fed conditions. METHODS: The studies were performed in 2017-2018 in the Phase I Clinical Trial Ward of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China. Eligible Chinese volunteers received a single 0.12-g dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. Blood samples were collected at various time intervals, and plasma nateglinide concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Then, the adverse events, laboratory test results, vital signs, and physical exam findings were compared between the 2 groups. RESULTS: The ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf of the tested to reference preparations under fasting conditions were 105.03% (90% confidence interval [CI]: 99.53-110.83%), 104.02% (90% CI: 101.37-106.74%), and 104.04% (90% CI: 101.38-106.77%), respectively. The same ratios under fed conditions were 96.55% (90% CI: 85.80-108.65%), 103.08% (90% CI: 100.07-106.18%), and 103.07% (90% CI: 100.21-106.01%), respectively. The 90% CI values for Cmax, AUC0-t, and AUC0-inf fell within the accepted range of bioequivalence (80.00-125.0%). Common adverse events included hypoglycemia, heart rate increase, palpitation, sweating, dizziness, and diarrhea. CONCLUSIONS: The test formulation (0.12 g) met the CFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated by healthy Chinese subjects. TRIAL REGISTRATION: This trial has been registered in the Chinese Clinical trial registry (ChiCTR2000030694), March 10, 2020.

Gamma-Glutamyl Transpeptidase to Platelet Ratio: A New Inflammatory Marker Associated with Outcomes after Cardiac Arrest.

INTRODUCTION: In recent years, gamma-glutamyl transpeptidase to platelet ratio (GPR) has been proposed as a new inflammatory marker. We aimed to evaluate the association between GPR and outcomes after cardiac arrest (CA). METHODS: A total of 354 consecutive patients with CA were included in this retrospective study. Patients were divided into three groups according to tertiles of GPR (low, n = 119; middle, n = 117; and high, n = 118). To determine the relationship between GPR and prognosis, a logistic regression analysis was performed. The ability of GPR to predict the outcomes was evaluated by receiver operating characteristic (ROC) curve analysis. Two prediction models were established, and the likelihood ratio test (LRT) and the Akaike Information Criterion (AIC) were utilized for model comparison. RESULTS: Among the 354 patients (age 62 [52, 74], 254/354 male) who were finally included in the analysis, those in the high GPR group had poor outcomes. Multivariate logistic regression analysis revealed that GPR was independently associated with the three outcomes, for ICU mortality (odds ratios (OR) = 1.738, 95% confidence interval (CI): 1.221-2.474, P = 0.002), hospital mortality (OR = 1.676[1.164 - 2.413], P = 0.005), and unfavorable neurologic outcomes (OR = 1.623[1.121 - 2.351], P = 0.010). The area under the ROC curve was 0.611 (95% Cl: 0.558-0.662) for ICU mortality, 0.600 (95% CI: 0.547-0.651) for hospital mortality, and 0.602 (95% CI: 0.549-0.653) for unfavorable neurologic outcomes. Further, the LRT analysis showed that compared with the model without GPR, the GPR-combined model had a higher likelihood ratio χ 2 score and smaller AIC. CONCLUSION: GPR, as an inflammatory indicator, was independently associated with outcomes after CA. GPR is helpful in estimating the clinical outcomes of patients with CA.

Identification of Postural Controllers in Human Standing Balance.

Standing balance is a simple motion task for healthy humans but the actions of the central nervous system (CNS) have not been described by generalized and sufficiently sophisticated control laws. While system identification approaches have been used to extracted models of the CNS, they either focus on short balance motions, leading to task-specific control laws, or assume that the standing balance system is linear. To obtain comprehensive control laws for human standing balance, complex balance motions, long duration tests, and nonlinear controller models are all needed. In this paper, we demonstrate that trajectory optimization with the direct collocation method can achieve these goals to identify complex CNS models for the human standing balance task. We first examined this identification method using synthetic motion data and showed that correct control parameters can be extracted. Then, six types of controllers, from simple linear to complex nonlinear, were identified from 100 s of motion data from randomly perturbed standing. Results showed that multiple time-delay paths and nonlinear properties are both needed in order to fully explain human feedback control of standing balance.

Long noncoding RNA XIST regulates the EGF receptor to promote TGF-ß1-induced epithelial-mesenchymal transition in pancreatic cancer.

BACKGROUND: This study focuses on the lncRNA XIST (X inactive-specific transcript), an lncRNA involved in multiple human cancers, and investigates the functional significance of XIST and the molecular mechanisms underlying the epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC). METHODS: Clinical specimens from 25 patients as well as 5 human PC cell lines were analyzed for XIST, YAP, and microRNA(miR)-34a by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. To investigate how XIST influences cell proliferation, invasiveness, and apoptosis in PC, we performed the CCK-8 assays, Transwell assays, and flow cytometry. Luciferase reporter assays, qRT-PCR, and Western blot were applied to prove that miR-34a directly binds to XIST. RESULTS: Up-regulation of XIST and Yes associated protein (YAP) and down-regulation of miR-34a were consistently observed in the clinical specimens and PC cell lines. Silencing XIST reduced the expression of YAP and suppressed transforming growth factor (TGF)-ß1-induced EMT, while over-expression of XIST increased the expression of YAP and promoted EMT. In addition, inhibition of epidermal growth factor receptor (EGFR) hampered the XIST-promoted EMT. The results from the luciferase reporter assays confirmed that miR-34a directly targets XIST and suggested that XIST regulates cell proliferation, invasiveness, and apoptosis in PC by sponging miR-34a. CONCLUSIONS: XIST promotes TGF-ß1-induced EMT by regulating the miR-34a-YAP-EGFR axis in PC.

CEACAM1 Inhibited IκB-α/NF-κB Signal Pathway Via Targeting MMP-9/TIMP-1 Axis in Diabetic Atherosclerosis.

Atherosclerosis (AS) is the most common and serious complication in type 2 diabetes mellitus (T2DM). Recent studies have emphasized that inflammation is the main cause of atherosclerosis. Studies have shown that carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) regulates the expression of matrix metallopeptidase 9 (MMP-9) after ischemic stroke to reduce inflammation. The aim of this study was to elucidate potential molecular mechanism of CEACAM1 on the inflammatory response in atherosclerosis. The serum levels of CEACAM1, MMP-9, and tissue inhibitors of metalloproteinase 1 (TIMP-1) in T2DM patients and healthy control was detected. The results showed that the levels of CEACAM1 and TIMP-1 were significantly decreased, and the levels of MMP-9 were significantly higher than those in the control group. Moreover, we also observed the effect of CEACAM1 on atherosclerosis in T2DM rats. Hematoxylin & eosin (HE) staining and oil red staining showed that CEACAM1 recombinant protein reduced intima-media thickness and the area of atherosclerotic plaques. To further explore the molecular mechanism of CEACAM1 regulating MMP-9/TIMP-1, we conducted experiments in rat aorta vascular endothelial cells and rat aorta smooth muscle cells. The result showed that CEACAM1 inhibits inflammatory response via MMP-9/TIMP-1 axis. Taken together, CEACAM1 attenuates diabetic atherosclerosis by inhibition of IκB/NF-κB signal pathway via MMP-9/TIMP-1 axis, which indicate that CEACAM1 is potentially amenable to therapeutic manipulation for clinical application in atherosclerosis in T2DM.

The CEACAM1-derived peptide QLSN impairs collagen-induced human platelet activation through glycoprotein VI.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates collagen-mediated platelet activation through its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). However, the function of CEACAM1's extracellular cleavage fragments is currently unknown. In the present study, we used mass spectrometry (MS) to identify 9 cleavage fragments shed by matrix metallopeptidase 12 (MMP-12), and then we synthesized peptides with sequences corresponding to the fragments. QLSNGNRTLT (QLSN), a peptide from the A1-domain of CEACAM1, significantly attenuated collagen-induced platelet aggregation. QLSN also attenuated platelet static adhesion to collagen. Additionally, QLSN reduced human platelet secretion and integrin αIIbß3 activation in response to glycoprotein VI (GPVI)-selective agonist, convulxin. Correspondingly, QLSN treatment significantly decreased convulxin-mediated phosphorylation of Src, protein kinase B (Akt), spleen tyrosine kinase (Syk) and phospholipase Cγ2 (PLCγ2) in human platelets. These data indicate that the CEACAM1-derived peptide QLSN inhibits GPVI-mediated human platelet activation. QLSN could potentially be developed as a novel antiplatelet agent.