TRAP-induced PAR1 expression with its mechanism during AMI in a rat model.

BACKGROUND AND OBJECTIVE: Protease-activated receptor 1 (PAR1) is crucial in individuals with acute myocardial infarction (AMI). The continuous and prompt PAR1 activation mainly dependent on PAR1 trafficking is essential for the role of PAR1 during AMI in which cardiomyocytes are in hypoxia. However, the PAR1 trafficking in cardiomyocytes specially during the hypoxia is still unclear. METHODS AND RESULT: A rat AMI model was created. PAR1 activation with thrombin-receptor activated peptide (TRAP) had a transient effect on cardiac function in normal rats but persistent improvement in rats with AMI. Cardiomyocytes from neonatal rats were cultured in a normal CO2 incubator and a hypoxic modular incubator chamber. The cells were then subjected to western blot for the total protein expression and staining with fluorescent reagent and antibody for PAR1 localization. No change in total PAR1 expression following TRAP stimulation was observed; however, it led to increased PAR1 expression in the early endosomes in normoxic cells and decreased expression in the early endosomes in hypoxic cells. Under hypoxic conditions, TRAP restored the PAR1 expression on both cell and endosomal surfaces within an hour by decreasing Rab11A (8.5-fold; 179.93 ± 9.82% of the normoxic control group, n = 5) and increasing Rab11B (15.5-fold) expression after 4 h of hypoxia. Similarly, Rab11A knockdown upregulated PAR1 expression under normoxia, and Rab11B knockdown downregulated PAR1 expression under both normoxic and hypoxic conditions. Cardiomyocytes knocked out of both Rab11A, and Rad11B lost the TRAP-induced PAR1 expression but still exhibited the early endosomal TRAP-induced PAR1 expression under hypoxia. CONCLUSIONS: TRAP-mediated activation of PAR1 in cardiomyocytes did not alter the total PAR1 expression under normoxic conditions. Instead, it triggers a redistribution of PAR1 levels under normoxic and hypoxic conditions. TRAP reverses the hypoxia-inhibited PAR1 expression in cardiomyocytes by downregulating Rab11A expression and upregulating Rab11B expression.

Interpersonal matching of autistic trait levels in typically developed individuals is associated with spontaneous gaze following and initiation during face-to-face social interaction.

OBJECTIVES: People with autism spectrum disorders (ASD) usually exhibit typical behaviours and thoughts that are called autistic traits. Autistic traits are widely and continuously distributed among typically developed (TD) and ASD populations. Previous studies have found that people with ASD have difficulty in following the eye gaze of social peers. However, it remains unknown whether TD adults with high or low autistic traits also differ in spontaneous gaze following and initiation in face-to-face social interactions. To fill this gap, this study used a novel and naturalistic gaze-cueing paradigm to examine this research question. DESIGN: A 4 (group: high-high, high-low, low-high or low-low autistic traits) × 3 (congruency: congruent, neutral, or incongruent) mixed-measures design was used. METHODS: Typically developed adults who were high or low in autistic traits completed a visual search task while a confederate who was high or low in autistic traits sat facing them. Critically, the match of autistic traits within a participant-confederate pair was manipulated. The confederate gazed at (congruent) or away from (incongruent) the location of the target prior to the appearance of the target. Participants were not explicitly instructed to follow the confederate's gaze. RESULTS: Autistic traits were associated with spontaneous gaze following and initiation in face-to-face social interactions. Specifically, only when both the participant and confederate were low in autistic traits did the incongruent gaze cues of confederates interfere with the participants' responses. CONCLUSIONS: Autistic traits impeded gaze following and initiation by TD adults. This study has theoretical and practical implications regarding autistic trait-induced social deficits and indicates a new approach for social skill interventions.

[Advances in Modeling of Multiple Myeloma in Mice].

Multiple myeloma(MM)is a systemic malignancy of plasma cells.Nowadays,the basic research on MM is flourishing with the continuous optimization and innovation of mouse models of MM.Heterologous mouse models of MM established with human-derived cells and immunodeficient mice have been applied in assessing drug efficacy,exploring drug resistance mechanisms,and observing tumor-bone marrow microenvironment interactions.In the last decades,the homologous mouse models of MM established with murine-derived cells or gene-editing technologies have been widely used in the research on the pathogenesis and drug development.Additionally,the stable modeling of targeted organ injury will be a key problem to be tackled in this field.This review summarizes the characteristics and application progress of mouse models of MM.

C-Reactive Protein and Inflammatory Cytokines during Percutaneous Coronary Intervention.

BACKGROUND: C-reactive protein (CRP) is significantly associated with cardiovascular diseases; however, whether CRP plays a causal role in coronary artery disease has yet to be determined. In addition, the relationship between CRP, atherosclerosis, and inflammation remains controversial. METHODS AND RESULTS: Serum interleukin (IL)-6, IL-1ß, and CRP levels were determined in 160 patients at time points around percutaneous coronary intervention (PCI) with drug-eluting stent implantation. The levels were found to be at peak at 24 h post-PCI and gradually declined to the level before PCI at day 30 post-PCI. These inflammation markers around PCI have no statistical difference in the different postdilation pressures (≤14, 14-18, and ≥18 atm) and stent number (1 and ≥2 stents) groups. Treatment of cultured human vascular smooth muscle cells (VSMCs) with a combination of IL-6 and IL-1ß at concentrations associated with PCI did not result in any significant change in the CRP mRNA levels. The IL-6-augmented CRP expression in human internal mammary arteries (IMAs) stretched with a mechanical strength of 3 g was blocked by the nuclear factor-κB (NF-κB) peptide inhibitor SN50 and not by the inactive SN50 analog SN50M. IL-6 treatment increased NF-κB activity in human IMAs stretched with 3 g, and this effect was further blocked by stretch-activated channel (SAC) inhibitors (streptomycin or GdCl3) and SN50. CONCLUSIONS: The current study provides evidence that increased serum IL-6, IL-1ß, and CRP levels around PCI are not different between different postdilation pressure and stent number groups. The combination of IL-6 and IL-1ß at concentrations associated with PCI cannot induce CRP expression in human VSMCs, but they can augment mechanical strain-induced CRP synthesis via the SAC-NF-κB pathway in human IMAs.

Controllable optical transitions of amorphous Mg and Mg-Ni films via electrochemical methods.

Amorphous Mg and MgNix (0.03 ≤ x ≤ 0.30) thin films capped with Pd were prepared by magnetron co-sputtering, and their hydrogen-induced optical transitions were investigated via electrochemical charging and discharging in KOH electrolyte solution. Repetitive transitions, up to dozens of times between the mirror state and transparent state, are achieved in these amorphous Mg and MgNix thin films even though some performance degeneration occurs during cycling. These deteriorations are mainly attributed to the breakdown of the film structure, which is caused by both a large change in film volume during cycling and the corrosive attack of the KOH electrolyte. In addition, calculations based on the electrochemical stripping method indicate that the hydrogen diffusion coefficient is significantly increased by amorphization; however, it is only slightly improved by the addition of Ni. Among the prepared amorphous films, MgNi0.09 film shows the largest hydrogen diffusion coefficient, namely, 2.64 × 10(-13) cm(2) s(-1). More importantly, the optical properties of the amorphous Mg and MgNix films are readily manipulated in the charging process, especially under a small charging current density, where there is a linear correlation between charging capacity and transmittance. The tunable optical properties obtained in the present study will greatly expand the application fields of Mg-based thin films.

Optimal timing and drug combination of selinexor in multiple myeloma: a systematic review and meta-analysis.

OBJECTIVES: Multiple myeloma (MM) remains an incurable disease despite advances in treatment options. Recently, selinexor has shown promising efficacy for relapsed/refractory multiple myeloma (RRMM), whereas its optimal timing and drug combination remain unclear. In order to assess the various regimens that incorporate selinexor, a systematic review and meta-analysis was conducted. METHODS: Clinical trials and real-world studies involving MM patients treated with selinexor were included. Pooled risk ratio (RR) was calculated to compare the rates, along with a 95% confidence interval (CI) and concurrent p-value assessment. A random-effects model was employed to provide a more conservative evaluation. RESULTS: A total of 16 studies enrolling 817 patients were reviewed. The usage of selinexor as the fifth-line or prior therapy achieved a higher objective response rate (ORR) (65.9% versus 23.4%, p < 0.01) and longer pooled progression-free survival (PFS) (median: 12.5 months versus 2.9 months, p < 0.01) than those after the fifth-line usage. In addition, early usage also resulted in a consistent trend of pooled overall survival (median: 22.7 months versus 8.9 months, p = 0.26), compared with post-fifth-line usage. Selinexor and dexamethasone (Xd) plus either protease inhibitors (PIs) or immunomodulatory drugs (IMiDs) achieved better ORRs than the Xd-only regimen for RRMM, with ORRs of 56.1%, 52.5% and 24.6%, respectively (p < 0.01). CONCLUSION: In conclusion, using selinexor as the fifth-line or prior therapy had a beneficial impact on RRMM. The regimen of Xd plus PIs or IMiDs was recommended.

Phosphate solubilizing microorganisms: a sustainability strategy to improve urban ecosystems.

Intensification of urban construction has gradually destroyed human habitat ecosystems. Plants, which serve as the foundation of ecosystems, require green, low-cost, and effective technologies to sustain their growth in stressful environments. A total of 286 keywords and 10 clusters from the bibliometric analysis of 529 articles (1999-2023) indicate the increasing importance of research on microbial functionality in landscape ecosystems. Phosphate solubilizing microorganisms (PSMs) also improve plant disease resistance, adaptability, and survival. PSMs are widely used to promote plant growth and improve ecological quality. They can increase the availability of phosphorus in the soil and reduce the dependence of plants on chemical fertilizers. Microorganisms regulate phosphorus as key tools in landscape ecosystems. Most importantly, in urban and rural landscape practices, PSMs can be applied to green spaces, residential landscapes, road greening, and nursery planting, which play significant roles in improving vegetation coverage, enhancing plant resistance, improving environmental quality, and mitigating the heat island effect. PSMs are also helpful in restoring the ecological environment and biodiversity of polluted areas, such as brownfields, to provide residents with a more liveable living environment. Therefore, the multiple efficacies of PSM are expected to play increasingly important roles in the construction of urban and rural landscape ecosystems.

Characteristics of Adenosine-to-Inosine RNA editing-based subtypes and novel risk score for the prognosis and drug sensitivity in stomach adenocarcinoma.

Stomach adenocarcinoma (STAD) is always characterized by high mortality and poor prognosis with drug resistance and recrudescence due to individual genetic heterogeneity. Adenosine-to-Inosine RNA editing (ATIRE) has been reported associated with multiple tumors but the potential connection between ATIRE-related signatures and STAD remains unclear. In this study, we comprehensively elevated the genetic characteristics of ATIRE in STAD patients and first screened five vital survival-related ATIRE sites to identify a novel ATIRE-Risk score. Based on the risk scores, we further divided the patients into two different subtypes with diverse clinical characteristics and immune landscapes including immune cell infiltration (ICI), tumor microenvironment (TME), and immune checkpoint expression analysis. The low-risk subgroups, associated with better survival prognosis, were characterized by activated immune-cells, higher immune scores in TME, and down-expression of immunotherapy checkpoints. Moreover, different expressional genes (DEGs) between the above subtypes were further identified and the activation of immune-related pathways were found in low-risk patients. The stratified survival analysis further indicated patients with low-risk and high-tumor mutation burden (TMB) exhibited the best prognosis outcomes, implying the role of TMB and ATIRE-Risk scores was synergistic for the prognosis of STAD. Interestingly, anti-tumor chemotherapeutic drugs all exhibited lower IC50 values in low-risk subgroups, suggesting these patients might obtain a better curative response from the combined chemotherapy of STAD. Finally, combined with classical clinical features and ATIRE-Risk scores, we successfully established a promising nomogram system to accurately predict the 1/3/5-years survival ratio of STAD and this model was also estimated with high diagnostic efficiency and stable C-index with calibration curves. These significant ATIRE sites are promising to be further explored and might serve as a novel therapeutic target for STAD treatment.

Effects of thrombin and thrombin receptor activation on cardiac function after acute myocardial infarction.

Thrombin and thrombin receptor activation impact cardiomyocyte contraction and ventricular remodeling. However, there is some controversy regarding their effects in cardiac function, especially in cardiac dysfunction after acute myocardial infarction (AMI). A rat AMI model was created by left coronary artery ligation (LCA). Cardiac functional parameters, including the maximum left ventricular (LV) systolic pressure (LVSPmax), LV end-diastolic pressure (LVEDP), and the rise and fall rates in LV pressure (dp/dt max and dp/dt min, respectively), were measured. Hirudin decreased cardiac function within 120 minutes after AMI, whereas treatment with thrombin receptor-activating peptide (TRAP) reversed this hirudin-induced decrease in cardiac function. The mRNA and protein expression levels of inositol 1,4,5-trisphosphate receptor (IP3R) subtypes in infarct area tissues were analyzed by reverse transcription-polymerase chain reaction and immunoreaction. Hirudin decreased the expression levels of IP3R-1, -2, and -3 in the infarct area for up to 40 minutes after AMI, whereas TRAP treatment reversed these hirudin-induced effects. Treatment with the IP3R antagonist 2-aminoethoxydiphenyl borate (2.5 mg/kg) eliminated the effect of TRAP on the hirudin-induced decrease in cardiac function after AMI. Finally, TRAP increased the maximum binding capacity of the three IP3R subtypes, but only enhanced the affinity of IP3R-2. Thrombin and thrombin receptor activation improved cardiac function after AMI by an IP3R-mediated pathway, probably through the IP3R-2 subtype.