Search

Pyroptosis signifies a significant form of programmed neuronal demise subsequent to ischemic stroke. In our prior investigations, we demonstrated that the Elabela (ELA)–Apelin receptor (APJ) axis alleviated neuronal death by improving collateral circulation and mitigating ferroptosis in a murine model of middle cerebral artery occlusion (MCAO). However, the connection between ELA and neuronal pyroptosis remains further elucidation. Here, we observed an upregulation of ELA and APJ expression in both murine brain specimens and cultured HT-22 hippocampal neurons exposed to experimental ischemic stroke. ELA administration markedly diminished the infarct size in comparison to controls. ELA treatment ameliorated neurological deficits and anxiety-like symptoms in mice with stroke, concurrently inhibiting pyroptosis and mitochondria fission in neurons. Conversely, ELA knockdown yielded the opposite effects. Utilizing RNA-sequencing analysis, we identified a candidate for pyroptosis priming, Z -DNA-binding protein 1 (ZBP1), which was suppressed in ELA-treated HT-22 neurons during oxygen-glucose deprivation/reperfusion (OGD/R). Subsequent co-immunoprecipitation analyses demonstrated the binding between APJ and ZBP1. Specifically, APJ suppressed ZBP1 to inhibit NLRP3 inflammasome activation and dynamin-related protein 1-mediated mitochondrial fission in neurons. In summary, our findings suggest that ELA functions as a stroke-induced signal limiting neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling, thereby underscoring ELA as a potential therapeutic target for ischemic stroke treatment. • ELA and APJ were elevated in neurons following ischemic stroke. • ELA-32 delivery alleviated ischemic brain injury and anxiety-like behavior after MCAO. • ELA-APJ signaling mitigated GSDMD-mediated neuronal pyroptosis and mitochondrial fission in ischemic stroke. • APJ interacted with ZBP1 to inhibit NLRP3 inflammasome activation and Drp 1 mitochondrial translocation in neurons post stroke. [ABSTRACT FROM AUTHOR]

Abstract Residual phenylalanine hydroxylase (PAH) activity is the main determinant of the metabolic phenotype in phenylketonuria (PKU). The genotypic heterogeneity of PKU, involving >1000 PAH variants and over 2500 different genotypes, makes genotype-based phenotype prediction challenging. While a relationship between PAH variants and the metabolic phenotype is well established, we questioned the importance of PAH expression and residual in vitro activity for the metabolic phenotype. Thirty-four PAH variants (p.F39 L, p.A47V, p.D59Y, p.I65S, p.R68G, p.R68S, p.E76G, p.A104D, p.D143G, p.R155H, p.R176L, p.V190A, p.G218 V, p.R241C, p.R243Q, p.P244L, p.R252W, p.R261Q, p.E280K, p.R297H, p.A300S, p.I306V, p.A309V, p.L311P, p.A313T, p.L348 V, p.V388 M, A403V, p.R408Q, p.R408W, p.R413P, p.D415N, p.Y417H, and p.A434D) were transiently transfected into COS-7 cells, and expression of PAH was investigated. Expression patterns were compared with in vitro PAH activity and allelic phenotype values (APVs). In vitro PAH activity was significantly higher (p <.01) in variants associated with mild hyperphenylalaninemia (PAH activity = 52.1 ± 8.5%; APV = 6.7–10.0) than that in classic PKU variants (PAH activity = 21.1 ± 7.0%; APV = 0–2.7). Mild PKU variants (PAH activity = 40.2 ± 7.6%; APV = 2.8–6.6) were not significantly different from mild hyperphenylalaninemia, but there was a difference (p <.048) compared with classic PKU phenotypes. [ABSTRACT FROM AUTHOR]

High-frequency global navigation satellite system (GNSS) is one of the most effective means for structural health monitoring. At present, most of the GNSS-based structural health monitoring research focuses on the positioning method, however, the unmodeled error caused by the complex monitoring environment and the receiver are always ignored by such technology. Most of the displacement extraction algorithms based on GNSS kinematic positioning are based on the Kalman filter and its variants, and the research on the effective determination of the process noise matrix and the measurement noise matrix is still limited. This paper aims to explore a displacement extraction method with automatic parameter tuning for structural health monitoring. An auto-tuning Kalman smoother has been introduced for extracting vibration displacement from GNSS kinematic positioning. Specifically, we divide the GNSS kinematic positioning results into a training set and a validation set, then use non-convex optimization to obtain the hyperparameters of the Kalman smoother. Finally, we extract the displacement from Kalman smoother with the tuned hyperparameters. Simulation and field experiments were carried out to verify the proposed method. The results show the feasibility and effectiveness of the method for vibration displacement extraction. For real-time kinematic positioning, the displacement extraction accuracy is improved by 9.58% compared to the traditional Kalman smoother; for precise point positioning, the displacement extraction accuracy is improved by 15.36%. The influence of the proportion of training set on the proposed method is discussed, and suggestion for the training set proportion is given. [ABSTRACT FROM AUTHOR]

Background In phenylketonuria (PKU) patients, the combination of two phenylalanine hydroxylase ( PAH ) alleles is the main determinant of residual enzyme activity in vivo and in vitro . Inconsistencies in genotype-phenotype correlations have been observed in compound heterozygous patients and a particular combination of two PAH alleles may produce a phenotype that is different from the expected one, possibly due to interallelic complementation. Methods A dual eukaryotic vector system with two distinct PAH proteins N-terminally fused to different epitope tags was used to investigate the co-expression of PAH alleles reported in patients with inconsistent phenotypes. PAH variant proteins were transiently co-transfected in COS-7 cells. PAH activity was measured by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS), and protein expression was measured by Western blot. Genotypes were compared with predicted PAH activity from the PAH locus-specific database ( PAH vdb) and with phenotypes and tetrahydrobiopterin (BH 4 ) responsiveness from more than 10,000 PKU patients (BIOPKU database). Results Through the expression and co-expression of 17 variant alleles we demonstrated that interallelic interaction could be both positive and negative. The co-expressions of p.[I65T];[R261Q] (19.5% activity; predicted 43.5%) and p.[I65T];[R408W] (15.0% vs. 26.8% activity) are examples of genotypes with negative interallelic interaction. The co-expressions of p.[E178G];[Q232E] (55.0% vs. 36.4%) and p.[P384S];[R408W] (56.1% vs. 40.8%) are examples of positive subunit interactions. Inconsistencies of PAH residual enzyme activity in vitro and of PKU patients' phenotypes were observed as well. The PAH activity of p.[R408W];[A300S] is 18.0% of the wild-type activity; however, 88% of patients with this genotype exhibit mild hyperphenylalaninemias (MHPs). Conclusion The co-expression of two distinct PAH variants revealed possible dominance effects (positive or negative) by one of the variants on residual PAH activity as a result of interallelic complementation. [ABSTRACT FROM AUTHOR]

The mitogenic effects of periodic mechanical stress on nucleus pulpous cells have been studied extensively but the mechanisms whereby nucleus pulpous cells sense and respond to mechanical stimulation remain a matter of debate. We explored this question by performing cell culture experiments in our self-developed periodic stress field and perfusion culture system. Under periodic mechanical stress, rat nucleus pulpous cell proliferation was significantly increased ( p < 0.05 for each) and was associated with increases in the phosphorylation and activation of EGFR, Rac1, and ERK1/2 ( p < 0.05 for each). Pretreatment with the ERK1/2 selective inhibitor PD98059 reduced periodic mechanical stress-induced nucleus pulpous cell proliferation ( p < 0.05 for each), while the activation levels of EGFR and Rac1 were not inhibited. Proliferation and phosphorylation of ERK1/2 were inhibited after pretreatment with the Rac1 inhibitor NSC23766 in nucleus pulpous cells in response to periodic mechanical stress ( p < 0.05 for each), while the phosphorylation site of EGFR was not affected. Inhibition of EGFR activity with AG1478 abrogated nucleus pulpous cell proliferation ( p < 0.05 for each) and attenuated Rac1 and ERK1/2 activation in nucleus pulpous cells subjected to periodic mechanical stress ( p < 0.05 for each). These findings suggest that periodic mechanical stress promotes nucleus pulpous cell proliferation in part through the EGFR-Rac1-ERK1/2 signaling pathway, which links these three important signaling molecules into a mitogenic cascade. [ABSTRACT FROM AUTHOR]

Displacement is an important parameter in engineering analysis in structural mechanics and geomechanics. For decades, displacement detection based on the Global navigation satellite system (GNSS) has increasingly been important for a wide range of applications, from landslide monitoring, subsidence survey, to industrial measurement. However, due to the influence of measurement noise, it is still a challenge to identify and extract displacement from GNSS kinematic positioning results. To resolve this, we propose a novel displacement detection approach with the purpose of identifying and extracting displacement from GNSS kinematic positioning. Specifically, we use the Bayesian inference to obtain the displacement change time from the coordinate time series of GNSS kinematic positioning. By investigating the posterior distribution of the designed change point parameter, we can identify the change points. Furthermore, we derive the mean value from the posterior distribution of the mean parameter, and further obtain the displacement. Results from simulation and field experiments have demonstrated the effectiveness and flexibility of the proposed method. For significant displacement, it can be clearly identified; for small displacement, it can be identified by adding an interval constraint prior. The accuracy of vertical displacement extraction from GNSS real-time kinematic positioning can reach within 2 mm in 15 min. • A displacement detection method based on Bayesian inference from GNSS kinematic positioning is presented. • A new probability model of displacement detection is developed. • Bayesian inference is implemented by Markov Chain Monte Carlo sampling. • Displacement detection is achieved by posterior samples of parameters. [ABSTRACT FROM AUTHOR]

Abstract: The function of synaptotagmin as a Ca2+ sensor in neurotransmitter release involves Ca2+-dependent phospholipid binding to its two C2 domains, but this activity alone does not explain why Ca2+ binding to the C2B domain is more critical for release than Ca2+ binding to the C2A domain. Synaptotagmin also binds to SNARE complexes, which are central components of the membrane fusion machinery, and displaces complexins from the SNAREs. However, it is unclear how phospholipid binding to synaptotagmin is coupled to SNARE binding and complexin displacement. Using supported lipid bilayers deposited within microfluidic channels, we now show that Ca2+ induces simultaneous binding of synaptotagmin to phospholipid membranes and SNARE complexes, resulting in an intimate quaternary complex that we name SSCAP complex. Mutagenesis experiments show that Ca2+ binding to the C2B domain is critical for SSCAP complex formation and displacement of complexin, providing a clear rationale for the preponderant role of the C2B domain in release. This and other correlations between the effects of mutations on SSCAP complex formation and their functional effects in vivo suggest a key role for this complex in release. We propose a model whereby the highly positive electrostatic potential at the tip of the SSCAP complex helps to induce membrane fusion during release. [Copyright &y& Elsevier]

• Displacement is a good descriptor of the structural behavior. • Displacement is not the direct output of the accelerometer. • Online displacement extraction by the interaction of multiple simple models. • Interaction multiple model Kalman filter for significant displacement extraction. • Segmental integration of accelerometer for slight displacement extraction. Vibration detection and displacement extraction of structures are of great significance to structural health monitoring(SHM). Accelerometers are one of the most widely used sensors in SHM, but displacement is not the direct output of accelerometers. There has been substantial research undertaken on the state parameter estimation of structure. Most studies in the field of structural state estimation have only focused on offline structure analysis. Few empirical studies have focused on online displacement extraction and verification. The present study aimed to explore an adaptive online displacement extraction and vibration detection method with only acceleration measurement. The methodological approach taken in this study is a mixed methodology based on the interactive multiple model (IMM) Kalman filter. Vision-based displacement extraction and segmental integration based displacement extraction are designed as verification schemes. Four groups of experiments were carried out to verify the proposed method. The findings show that the damping vibration model is suitable for capturing obvious vibration, the constant acceleration model is suitable for capturing slight vibration, and the constant position model is suitable for static state tracking. For obvious vibration, the IMM Kalman filter can be effectively performed for displacement extraction and vibration detection. For slight vibration, the performance of the IMM segmental integration is good. It is hoped that this research will contribute to a deeper understanding of displacement extraction and vibration detection in SHM. [ABSTRACT FROM AUTHOR]

Understanding sheet erosion processes and improving estimates of soil erosion on biological soil crustal (biocrustal) slopes requires a deep understanding of the factors influencing sheet erosion and its detachment- and transport-limited processes. Simulated rainfall experiments were conducted on plots of biocrust to simultaneously measure the rates of splash detachment and sheet erosion with 0%, 20%, 40%, 50%, 60%, and 80% of coverage at 90 mm h−1 rainfall intensity and 15° slope. The splash detachment rate decreased rapidly during the first 5 min of rainfall and stabilised as rainfall continued, while the sheet erosion rate increased gradually and eventually became relatively stable. The rates of splash detachment and sheet erosion decreased substantially as biocrusts coverage increased and average values of them can be effectively weakened when biocrusts coverage increased from 20% to 40%. Transport-limited processes, dynamic equilibria between detachment- and transport-limited processes, and detachment-limited processes all occurred on biocrustal slope within the same rainfall event. The mean duration of transport-limited processes was longer (16.3 min vs. 9.1 min) when bare slopes were covered by biocrusts, and the latest change in the time from transport-limited to detachment-limited processes appeared at 40% biocrusts coverage. The existence of biocrusts could effectively affect the sheet erosion and its detachment- and transport-limited processes, especially when the coverage was close to 40%. These results can improve our understanding of impacts of biocrusts on sheet erosion processes, and aid an effective way of reducing sheet erosion in arid and semiarid regions. • The effects of biocrusts on sheet erosion were explored. • Detachment- and transport-limited processes occurred on biocrustal slope. • Increasing biocrusts coverage reduced rates of splash detachment and sheet erosion. • Biocrusts with a cover close to 40% effectively affected sheet erosion processes. [ABSTRACT FROM AUTHOR]

This study investigated the effects of different carbon sources on enriched Accumulibacter PAO cultures at high temperature (30 °C) and compared the carbon transformation with low temperature (20 °C) cases reported in literature, revealing several key metabolic differences. While PAOs seemed to prefer propionate anaerobically as compared to other VFAs at high temperature, high aerobic glycogen replenishment was realized with propionate as the anaerobic carbon source, a trait not previously observed at low temperatures. Therefore, it was found that propionate is not correlated with high P removal by Accumulibacter PAO at high temperatures. A combined substrate of acetate, propionate and perhaps butyrate seemed to be a better carbon source combination, since the total VFA uptake rate increased by up to 46%, and this increased the aerobic P-removal efficiency by up to 38.4% and reduced the glycogen recovery by more than 63% compared to the use of only propionate as substrate. This study improves our understanding of how to stimulate successful EBPR operation in warm climates by augmenting the P removal performance of PAOs. • High temperature affects PAO's kinetics but not its anaerobic stoichiometry. • PAO could utilize butyrate and iso-butyrate, hardly used valerate and iso-valerate. • Propionate as sole carbon source causes high aerobic glycogen replenishment. • A combination of acetate, propionate and perhaps butyrate may be a better for EBPR. • Multi-cycle operation may be crucial for PAOs outcompete GAOs at high temperature. [ABSTRACT FROM AUTHOR]

• Two new unsaturated fatty acids (1 – 2) were isolated from the fungus P. javanicum HK1-22. • The relative configuration of 1 was assigned by NOE spectra of the acetonide derivative (1a). • Compound 5 showed significant antifungal activities against four strains of crop pathogens. Two new unsaturated fatty acids, 6 R ,8 R -dihydroxy-9 Z ,12 Z -octadecadienoic acid (1) and methyl-6 R ,8 R -dihydroxy-9 Z ,12 Z -octadecadienoate (2), and two known 9 Z ,12 Z -octadecadienoic acid analogues (3 , 4) together with a known sesquiterpenoid (5) were isolated from the mangrove rhizosphere soil-derived fungus Penicillium javanicum HK1-22. An acetonide derivative (1a) from 1 was also prepared. The relative configuration of 1 was determined by analysis of the 1D and 2D NOE spectra of 1a. The absolute configuration of 1 was assigned on the basis of biogenetic considerations. The antifungal activity of the high yield compound 5 was evaluated against four strains of crop pathogens and it showed significant antifungal activities against all the tested strains. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (ADs) are characterized by aberrant generation of autoreactive immune cells and persistent inflammation, leading to tissue destruction. Although common definitive pathogenesis mechanisms of ADs remain elusive, increasing recent evidence has found that non-coding RNAs (ncRNAs) are extensively involved in ADs and AD-related immune responses. Recent advances in the comprehension of biological functions of ncRNAs have greatly evolved the understandings of epigenetic regulation of autoimmunity and ADs. In general, ncRNAs are involved in proliferation, activation, differentiation, apoptosis, and functions of immune cells, promoting or inhibiting immune responses through multiple pathways. Aberrant expression of ncRNAs in immune cells dysregulates immune homeostasis, and has been implicated in a variety of ADs. Therefore, these ncRNAs are promising biomarkers of AD diagnosis and potential therapeutic targets for AD treatment. Clarification of the critical functions and mechanisms for ncRNAs may provide insights into understanding AD pathogenesis and treatment. In this review, we focus on recent studies on the involvement of ncRNAs in autoimmunity and ADs. • Non-coding RNAs are widely involved in the biological processes of both innate and adaptive immune cells. • Dysregulated non-coding RNAs are instrumental in the pathogenesis of autoimmune diseases. • Non-coding RNAs are promising biomarkers and potential therapeutic targets for autoimmune diseases. • Mechanistical studies on non-coding RNAs linking to autoimmune diseases may provide new insights for understanding the pathogenesis of autoimmune diseases. [ABSTRACT FROM AUTHOR]

In this report, by taking advantages of the competitive and synergistic effects of mixed-cations under the ionothermal conditions, a novel selenidostannate compound containing the mixed cations, namely (enH) 3 Na[Sn 3 Se 7 ] 2 ·1.5Me 2 NH·1.5H 2 O ( 1 , en=ethylenediamine, Me 2 NH=dimethylamine) was obtained in the presence of the ionic liquid (IL) [DAMS]I (4-N,N-Dimethylamino-4′-N′-methylstilbazolium iodide) with a bulky and more structurally rigid organic cation as the main solvent and en as the auxiliary solvent. The compound features anionic [ Sn 3 Se 7 ] n 2 n - layers that are interconnected by sodium ions to form a three-dimensional (3D) structure. The syntheses, structure, thermal, optical and electrochemical properties of 1 were investigated. 1 showed good thermal stability and a Na + ion storage property without capacity fading over 150 cycles. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) have recently been identified to be tightly linked to diverse human diseases. However, our knowledge of Systemic Lupus Erythematosus (SLE)-related lncRNAs remains limited. In the present study we investigated the contribution of the lncRNA NEAT1 to the pathogenesis of SLE. Here, we found NEAT1 expression was abnormally increased in SLE patients and predominantly expressed in human monocytes. Additionally, NEAT1 expression was induced by LPS via p38 activation. Silencing NEAT1 significantly reduced the expression of a group of chemokines and cytokines, including IL-6, CXCL10, etc., which were induced by LPS continuously and in late stages. Furthermore, it was identified the involvement of NEAT1 in TLR4-mediated inflammatory process was through affecting the activation of the late MAPK signaling pathway. Importantly, there was a positive correlation between NEAT1 and clinical disease activity in SLE patients. In conclusion, the increased NEAT1 expression may be a potential contributor to the elevated production of a number of cytokines and chemokines in SLE patients. Our findings suggest lncRNA contributes to the pathogenesis of lupus and provides potentially novel target for therapeutic intervention. [ABSTRACT FROM AUTHOR]