Sangju Cold Granule exerts anti-viral and anti-inflammatory activities against influenza A virus in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Sangju Cold Granule (SJCG) is a classical traditional Chinese medicine (TCM) prescription described in "Item Differentiation of Warm Febrile Diseases". Historically, SJCG was employed to treat respiratory illnesses. Despite its popular usage, the alleviating effect of SJCG on influenza A virus infection and its mechanisms have not been fully elucidated. AIM OF THE STUDY: Influenza is a severe respiratory disease that threatens human health. This study aims to assess the therapeutic potential of SJCG and the possible molecular mechanism underlying its activity against influenza A virus in vitro and in vivo. MATERIALS AND METHODS: Ultrahigh-performance liquid chromatography (UPLC)-Q-Exactive was used to identify the components of SJCG. The 50% cytotoxic concentration of SJCG in MDCK and A549 cells were determined using the CCK-8 assay. The activity of SJCG against influenza A virus H1N1 was evaluated in vitro using cytopathic effect inhibition and progeny virus titer reduction assays. RT-qPCR was performed to obtain the expression levels of inflammatory mediators and the transcriptional regulation of RIG-I and MDA5 in H1N1-infected A549 cells. Then, the mechanism of SJCG effect on viral replication and inflammation was further explored by measuring the expressions of proteins of the RIG-I/NF-kB/IFN(I/III) signaling pathway by western blot. The impact of SJCG was explored in vivo in an intranasally H1N1-infected BALB/c mouse pneumonia model treated with varying doses of SJCG. The protective role of SJCG in this model was evaluated by survival, body weight monitoring, lung viral titers, lung index, lung histological changes, lung inflammatory mediators, and peripheral blood leukocyte count. RESULTS: The main SJCG chemical constituents were flavonoids, carbohydrates and glycosides, amino acids, peptides, and derivatives, organic acids and derivatives, alkaloids, fatty acyls, and terpenes. The CC50 of SJCG were 24.43 mg/mL on MDCK cells and 20.54 mg/mL on A549 cells, respectively. In vitro, SJCG significantly inhibited H1N1 replication and reduced the production of TNF-α, IFN-ß, IL-6, IL-8, IL-13, IP-10, RANTES, TRAIL, and SOCS1 in infected A549 cells. Intracellularly, SJCG reduced the expression of RIG-I, MDA5, P-NF-κB P65 (P-P65), P-IκBα, P-STAT1, P-STAT2, and IRF9. In vivo, SJCG enhanced the survival rate and decreased body weight loss in H1N1-infected mice. Mice with H1N1-induced pneumonia treated with SJCG showed a lower lung viral load and lung index than untreated mice. SJCG effectively alleviated lung damage and reduced the levels of TNF-α, IFN-ß, IL-6, IP-10, RANTES, and SOCS1 in lung tissue. Moreover, SJCG significantly ameliorated H1N1-induced leukocyte changes in peripheral blood. CONCLUSIONS: SJCG significantly reduced influenza A virus and virus-mediated inflammation through inhibiting the RIG-I/NF-kB/IFN(I/III) signaling pathway. Thus, SJCG could provide an effective TCM for influenza treatment.

Design of novel chiral self-assembling peptides to explore the efficiency and mechanism of mRNA-FIPV vaccine delivery vehicles.

The enhancement of conventional liposome and lipid nanoparticle (LNP) methodologies in the formulation and deployment of messenger RNA (mRNA) vaccines necessitates further refinement to augment both their effectiveness and biosafety profiles. Additionally, researching these innovative delivery carrier materials represents both a prominent focus and a significant challenge in the current scientific landscape. Here we designed new chiral self-assembling peptides as the delivery carrier for RNA vaccines to study the underlying mechanisms in the feline infectious peritonitis virus (FIPV) model system. Firstly, we successfully transcribed mature enhanced green fluorescent protein (EGFP) mRNA and feline infectious peritonitis virus nucleocapsid (FIPV N) mRNA in vitro from optimized vectors. Subsequently, we developed chiral self-assembling peptide-1 (CSP-1) and chiral self-assembling peptide-2 (CSP-2) peptides, taking into account the physical and chemical characteristics of nucleic acid molecules as well as the principles of self-assembling peptides, with the aim of improving the delivery efficiency of mRNA molecule complexes. We determined the optimal coating ratio between CSP and mRNA by electrophoretic mobility shift assay. We found that the peptides and mRNA complexes can protect the mRNA from RNase A enzyme and efficiently deliver mRNA into cells for target antigen proteins expression. Animal experiments confirmed that CSP-1/mRNA complex can effectively trigger immune response mechanisms involving IFN-γ and T cell activation. It can also stimulate CD4+ and CD8+ T cell proliferation and induce serum antibody titers up to 10,000 times higher. And no pathological changes were observed by immunohistochemistry in liver, spleen, and kidney, indicating that CSP-1 may be a safe and promising delivery system for mRNA vaccines. Methodologically, this research represents a novel endeavor in the utilization of chiral self-assembling peptides within the realm of mRNA vaccines. This approach not only introduces fresh prospects for employing such nanomaterials in various mRNA vaccines but also expands the potential for developing small molecules, proteins, and antibodies. Furthermore, it paves the way for new clinical applications of existing pharmaceuticals.

The Impact of Medical Resources and Oral Antiviral Drugs on SARS-CoV-2 Mortality - Hong Kong SAR, China, 2022.

Introduction: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrates increased transmissibility compared to earlier strains, contributing to a significant number of fatalities in Hong Kong Special Administrative Region (HKSAR), China. Adequate medical resources and medications are essential in mitigating these deaths. This study evaluates the effects of supplementary resources from the Chinese mainland during the fifth wave of the pandemic in HKSAR. Methods: Vector autoregression (VAR) was employed to analyze data from the Oxford coronavirus disease 2019 (COVID-19) Government Response Tracker to assess the effectiveness of control measures during five waves of the pandemic in HKSAR. Additionally, a transmission dynamics model was created to investigate the influence of supplementary medical resources from the Chinese mainland and oral medications on mortality. Results: In the initial four waves, workplace closures, restrictions on public events, international travel bans, and shielding the elderly significantly influenced pandemic management. Contrarily, during the fifth wave, these measures showed no notable effects. When comparing a situation without extra medical resources or COVID-19 oral medication, there was a 17.7% decrease in COVID-19 fatalities with mainland medical resources and an additional 10.2% reduction with oral medications. Together, they contributed to a 26.6% decline in fatalities. Discussion: With the rapid spread of the virus, regional reallocation of medical resources may reduce mortality even when the local healthcare system is overstretched.

Loss of ADAR1 induces ferroptosis of breast cancer cells.

Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.

Depressive Symptoms among Psychiatric Nurses in a Hospital: An Analytical Research.

BACKGROUND: Psychiatric nurses are vulnerable to the menace of negative emotions due to the nature of their work and the closed environment in which they work. In this study, we aimed to investigate the incidence and influencing factors of depression among psychiatric nurses. METHODS: A cross-sectional survey method was adopted to investigate 64 nurses working in the psychiatric department of a hospital from June 2022 to June 2023. The Beck Depression Inventory (BDI) questionnaire was administered to all included respondents, who were divided into depressed group (>4 points) and non-depressed group (≤4 points) according to the BDI scores. General sociological and disease-related characteristics of these two groups were measured, and items with significant differences were analyzed by logistic regression to derive factors that have an impact on the occurrence of depression among psychiatric nurses. RESULTS: Twelve psychiatric nurses in the surveyed hospital exhibited signs of depressive symptoms, with a rate of 18.75%. The univariate analysis unveiled differences between the depressed group and the non-depressed group in terms of daily sleep time, weekly working hours, professional title, working pressure, physical exercise, length of service, and physical condition. Further analysis through logistic regression revealed that daily sleep time, weekly working hours, and physical condition were factors affecting the occurrence of depression among psychiatric nurses. CONCLUSION: The vulnerability of psychiatric nurses to depression, which are potentially influenced by daily sleep hours, weekly working hours, and physical condition, deserves clinical attention so that countermeasures can be developed for early intervention.

Effect of veno-arterial extracorporeal membrane oxygenation lower-extremity cannulation on intra-arterial flow characteristics, oxygen content, and thrombosis risk.

PURPOSE: This study aimed to investigate the effects of lower-extremity cannulation on the intra-arterial hemodynamic environment, oxygen content, blood damage, and thrombosis risk under different levels of veno-arterial (V-A) ECMO support. METHODS: Computational fluid dynamics methods were used to investigate the effects of different levels of ECMO support (ECMO flow ratios supplying oxygen-rich blood 100-40 %). Flow rates and oxygen content in each arterial branch were used to determine organ perfusion. A new thrombosis model considering platelet activation and deposition was proposed to determine the platelet activation and thrombosis risk at different levels of ECMO support. A red blood cell damage model was used to explore the risk of hemolysis. RESULTS: Our study found that partial recovery of cardiac function improved the intra-arterial hemodynamic environment, with reduced impingement of the intra-arterial flow field by high-velocity blood flow from the cannula, a flow rate per unit time into each arterial branch closer to physiological levels, and improved perfusion in the lower extremities. Partial recovery of cardiac function helps reduce intra-arterial high shear stress and residence time, thereby reducing blood damage. The overall level of hemolysis and platelet activation in the aorta decreased with the gradual recovery of cardiac contraction function. The areas at high risk of thrombosis under V-A ECMO femoral cannulation support were the aortic root and the area distal to the cannula, which moved to the descending aorta when cardiac function recovered to 40-60 %. However, with the recovery of cardiac contraction function, hypoxic blood pumped by the heart is insufficient in supplying oxygen to the front of the aortic arch, which may result in upper extremity hypoxia. CONCLUSION: We developed a thrombosis risk prediction model applicable to ECMO cannulation and validated the model accuracy using clinical data. Partial recovery of cardiac function contributed to an improvement in the aortic hemodynamic environment and a reduction in the risk of blood damage; however, there is a potential risk of insufficient perfusion of oxygen-rich blood to organs.

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma.

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

Analysis of non-physiological shear stress-induced red blood cell trauma across different clinical support conditions of the blood pump.

Systematic research into device-induced red blood cell (RBC) damage beyond hemolysis, including correlations between hemolysis and RBC-derived extracellular vesicles, remains limited. This study investigated non-physiological shear stress-induced RBC damage and changes in related biochemical indicators under two blood pump clinical support conditions. Pressure heads of 100 and 350 mmHg, numerical simulation methods, and two in vitro loops were utilized to analyze the shear stress and changes in RBC morphology, hemolysis, biochemistry, metabolism, and oxidative stress. The blood pump created higher shear stress in the 350-mmHg condition than in the 100-mmHg condition. With prolonged blood pump operation, plasma-free hemoglobin and cholesterol increased, whereas plasma glucose and nitric oxide decreased in both loops. Notably, plasma iron and triglyceride concentrations increased only in the 350-mmHg condition. The RBC count and morphology, plasma lactic dehydrogenase, and oxidative stress across loops did not differ significantly. Plasma extracellular vesicles, including RBC-derived microparticles, increased significantly at 600 min in both loops. Hemolysis correlated with plasma triglyceride, cholesterol, glucose, and nitric oxide levels. Shear stress, but not oxidative stress, was the main cause of RBC damage. Hemolysis alone inadequately reflects overall blood pump-induced RBC damage, suggesting the need for additional biomarkers for comprehensive assessments.

The Impact of Rotor Axial Displacement Variation on Simulation Accuracy of Fully Magnetic Levitation Centrifugal Blood Pump.

The rotor axial displacement of the full magnetic levitation blood pump varies with the operating conditions. The effect of rotor axial displacement on simulation results is unclear. This study aimed to evaluate the effect of rotor axial displacement on the predicted blood pump flow field, hydraulic performance, and hemocompatibility through simulation. This study used the CentriMag blood pump as a model, and conducted computational fluid dynamics simulations to assess the impact of rotor displacement. Considering rotor axial displacement leads to opposite results regarding predicted residence time and thrombotic risk compared with not considering rotor axial displacement. Not considering rotor axial displacement leads to deviations in the predicted values, where the effects on the flow field within the blood pump, ratio of secondary flow, and amount of shear stress >150 Pa are significant. The variation in the back clearance of the blood pump caused by the ideal and actual rotor displacements is the main cause of the above phenomena. Given that the rotor axial displacement significantly impacts the simulation accuracy, the effect of rotor axial displacement must be considered in the simulation.

Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Pan-genome insights into adaptive evolution of bacterial symbionts in mixed host-microbe symbioses represented by human gut microbiota Bacteroides cellulosilyticus.

Animal hosts harbor diverse assemblages of microbial symbionts that play crucial roles in the host's lifestyle. The link between microbial symbiosis and host development remains poorly understood. In particular, little is known about the adaptive evolution of gut bacteria in host-microbe symbioses. Recently, symbiotic relationships have been categorized as open, closed, or mixed, reflecting their modes of inter-host transmission and resulting in distinct genomic features. Members of the genus Bacteroides are the most abundant human gut microbiota and possess both probiotic and pathogenic potential, providing an excellent model for studying pan-genome evolution in symbiotic systems. Here, we determined the complete genome of an novel clinical strain PL2022, which was isolated from a blood sample and performed pan-genome analyses on a representative set of Bacteroides cellulosilyticus strains to quantify the influence of the symbiotic relationship on the evolutionary dynamics. B. cellulosilyticus exhibited correlated genomic features with both open and closed symbioses, suggesting a mixed symbiosis. An open pan-genome is characterized by abundant accessory gene families, potential horizontal gene transfer (HGT), and diverse mobile genetic elements (MGEs), indicating an innovative gene pool, mainly associated with genomic islands and plasmids. However, massive parallel gene loss, weak purifying selection, and accumulation of positively selected mutations were the main drivers of genome reduction in B. cellulosilyticus. Metagenomic read recruitment analyses showed that B. cellulosilyticus members are globally distributed and active in human gut habitats, in line with predominant vertical transmission in the human gut. However, existence and/or high abundance were also detected in non-intestinal tissues, other animal hosts, and non-host environments, indicating occasional horizontal transmission to new niches, thereby creating arenas for the acquisition of novel genes. This case study of adaptive evolution under a mixed host-microbe symbiosis advances our understanding of symbiotic pan-genome evolution. Our results highlight the complexity of genetic evolution in this unusual intestinal symbiont.

An Optimized Method for Evaluating the Preparation of High-Quality Fuel from Various Types of Biomass through Torrefaction.

The pretreatment for torrefaction impacts the performance of biomass fuels and operational costs. Given their diversity, it is crucial to determine the optimal torrefaction conditions for different types of biomass. In this study, three typical solid biofuels, corn stover (CS), agaric fungus bran (AFB), and spent coffee grounds (SCGs), were prepared using fluidized bed torrefaction. The thermal stability of different fuels was extensively discussed and a novel comprehensive fuel index, "displacement level", was analyzed. The functional groups, pore structures, and microstructural differences between the three raw materials and the optimally torrefied biochar were thoroughly characterized. Finally, the biomass fuel consumption for household heating and water supply was calculated. The results showed that the optimal torrefaction temperatures for CS, AFB, and SCGs were 240, 280, and 280 °C, respectively, with comprehensive quality rankings of the optimal torrefied biochar of AFB (260) > SCG (252) > CS (248). Additionally, the economic costs of the optimally torrefied biochar were reduced by 7.03-19.32%. The results indicated that the displacement level is an index universally applicable to the preparation of solid fuels through biomass torrefaction. AFB is the most suitable solid fuel to be upgraded through torrefaction and has the potential to replace coal.

A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors.

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.

Lung Cancer Prevalence in Virginia: A Spatial Zipcode-Level Analysis via INLA.

BACKGROUND: Examining lung cancer (LC) cases in Virginia (VA) is essential due to its significant public health implications. By studying demographic, environmental, and socioeconomic variables, this paper aims to provide insights into the underlying drivers of LC prevalence in the state adjusted for spatial associations at the zipcode level. METHODS: We model the available VA zipcode-level LC counts via (spatial) Poisson and negative binomial regression models, taking into account missing covariate data, zipcode-level spatial association and allow for overdispersion. Under latent Gaussian Markov Random Field (GMRF) assumptions, our Bayesian hierarchical model powered by Integrated Nested Laplace Approximation (INLA) considers simultaneous (spatial) imputation of all missing covariates through elegant prediction. The spatial random effect across zip codes follows a Conditional Autoregressive (CAR) prior. RESULTS: Zip codes with elevated smoking indices demonstrated a corresponding increase in LC counts, underscoring the well-established connection between smoking and LC. Additionally, we observed a notable correlation between higher Social Deprivation Index (SDI) scores and increased LC counts, aligning with the prevalent pattern of heightened LC prevalence in regions characterized by lower income and education levels. On the demographic level, our findings indicated higher LC counts in zip codes with larger White and Black populations (with Whites having higher prevalence than Blacks), lower counts in zip codes with higher Hispanic populations (compared to non-Hispanics), and higher prevalence among women compared to men. Furthermore, zip codes with a larger population of elderly people (age ≥ 65 years) exhibited higher LC prevalence, consistent with established national patterns. CONCLUSIONS: This comprehensive analysis contributes to our understanding of the complex interplay of demographic and socioeconomic factors influencing LC disparities in VA at the zip code level, providing valuable information for targeted public health interventions and resource allocation. Implementation code is available at GitHub.

[Retracted] Human HLA­F adjacent transcript 10 promotes the formation of cancer initiating cells and cisplatin resistance in bladder cancer.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the cellular morphological data in Fig. 1C, the immunofluorescence data shown in Fig. 1E, and certain of the scratch­wound assay data shown in Fig. 2A were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 308­314, 2018; DOI: 10.3892/mmr.2018.9005].

CRP inhibits the osteoblastic differentiation of OPCs via the up-regulation of primary cilia and repression of the Hedgehog signaling pathway.

Inflammation disrupts bone metabolism and leads to bone damage. C-reactive protein (CRP) is a typical inflammation marker. Although CRP measurement has been conducted for many decades, how osteoblastic differentiation influences molecular mechanisms remains largely unknown. The present study attempted to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) while elucidating the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after recombinant C-reactive protein treatment. In a series of experiments, CRP inhibited OPC proliferation, osteoblastic differentiation, and the OPC gene expression of the hedgehog (Hh) signaling pathway. The inhibitory effect of CRP on OPC proliferation occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of proto cilium on osteoblastic differentiation was analyzed using the bioinformatics p. This revealed the primary cilia activation of recombinant CRP effect on OPCs through in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblastic differentiation inhibited by recombinant CRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the Suppressor of Fused (SUFU) formation and blocked Gli2 degradation. This counteracted osteogenesis inhibition caused by CRP. Therefore, these data depict that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism could be associated with primary cilia activation and Hh pathway repression.

Systematic analysis of MASP-1 serves as a novel immune-related biomarker in sepsis and trauma followed by preliminary experimental validation.

Background: Dysregulated immune response in trauma and sepsis leads to the abnormal activation of the complement and coagulation systems. Mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) activates the lectin pathway of the complement system and mediates proinflammatory and procoagulant reactions. However, the potential effects of MASP-1 in trauma and sepsis have not yet been explored. Methods: We obtained five sepsis, two trauma, and one sepsis and trauma RNA-sequencing dataset from the Gene Expression Omnibus (GEO) database and conducted a comprehensive evaluation of the expression pattern, biological functions, and diagnostic value of MASP-1 in trauma and sepsis. Additionally, we investigated the association between MASP-1 expression and clinicopathological characteristics of trauma and sepsis. Furthermore, we collected clinical specimens to preliminarily validate the expression level and diagnostic efficacy of MASP-1 as well as the correlation of MASP-1 with clinical features of trauma and sepsis. Subsequently, we conducted a correlation analysis among MASP-1, immune cell infiltration, and immune and molecular pathways. Finally, we mechanistically analyzed the relationship among MASP-1, specific immune cells, and pivotal molecular pathways. Results: MASP-1 expression was significantly upregulated in the trauma/sepsis samples compared to the control samples in the GEO datasets. MASP-1 exhibited excellent diagnostic values (AUC > 0.7) in multiple datasets and at multiple time points and could efficiently distinguish trauma/sepsis samples from the control samples. Moreover, MASP-1 expression was significantly positively correlated with the severity of the disease (APACHE-II, CRP, and neutrophil levels). These results were further validated by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Functional enrichment analysis revealed that MASP-1 primarily promotes trauma and sepsis via the immune-related signaling pathway. MASP-1 was significantly correlated with the infiltration of specific immune cells (such as B cells, CD8 T cells, neutrophils, macrophages, and infiltrating lymphocytes) and immune and molecular pathways (such as checkpoint, HLA, IL6/JAK/STAT3 signaling, necrosis, T-cell co-inhibition, and T-cell co-stimulation). Finally, analysis of the transcription and single-cell data revealed that MASP-1 was specifically expressed in T cells, and further correlation analysis revealed a close correlation between MASP-1 expression, proportion of CD8 T cells, and IL6/JAK/STAT3 signaling scores. Conclusion: Our results suggest that MASP-1 can serve as an immune-related biomarker for the diagnosis and disease severity of trauma and sepsis. It may activate the IL6 JAK-STAT3 signaling pathway and promote CD8 T-cell depletion to trigger traumatic sepsis.

Socioeconomic status as a predictor of post-operative mortality and outcomes in carotid artery stenting vs. carotid endarterectomy.

Background: The association between low socioeconomic status (SES) and worse surgical outcomes has become an emerging area of interest. Literature has demonstrated that carotid artery stenting (CAS) poses greater risk of postoperative complications, particularly stroke, than carotid endarterectomy (CEA). This study aims to compare the impact of low SES on patients undergoing CAS vs. CEA. Methods: The National Inpatient Sample (NIS) was queried for patients undergoing CAS and CEA from 2010 to 2015. Patients were stratified by highest and lowest median income quartiles by zip code and compared through demographics, hospital characteristics, and comorbidities defined by the Charlson Comorbidity Index (CCI). Primary outcome was in-hospital mortality. Secondary outcomes included acute kidney injury (AKI), post-operative stroke, sepsis, and bleeding requiring reoperation.Multivariable logistic regression was used to determine the effect of SES on outcomes. Results: Five thousand four hundred twenty-five patients underwent CAS (Low SES: 3,516 (64.8%); High SES: 1,909 (35.2%) and 38,399 patients underwent CEA (Low SES: 22,852 (59.5%); High SES: 15,547 (40.5%). Low SES was a significant independent predictor of mortality [OR = 2.07 (1.25-3.53); p = 0.005] for CEA patients, but not for CAS patients [OR = 1.21 (CI 0.51-2.30); p = 0.68]. Stroke was strongly associated with low SES, CEA patients (Low SES = 1.5% vs. High SES = 1.2%; p = 0.03), while bleeding was with high SES, CAS patients (Low SES = 5.3% vs. High SES = 7.1%; p = 0.01). CCI was a strong predictor of mortality for both procedures [CAS: OR1.45 (1.17-1.80); p < 0.001. CEA: OR1.60 (1.45-1.77); p < 0.001]. Advanced age was a predictor of mortality post-CEA [OR = 1.03 (1.01-1.06); p = 0.01]. While not statistically significant, advanced age and increased mortality trended towards a positive association in CAS [OR = 1.05 (1.00-1.10); p = 0.05]. Conclusions: Low SES is a significant independent predictor of post-operative mortality in patients who underwent CEA, but not CAS. CEA is also associated with higher incidence of stroke in low SES patients. Findings demonstrate the impact of SES on outcomes for patients undergoing carotid revascularization procedures. Prospective studies are warranted to further evaluate this disparity.

Modelling of the in-stent thrombus formation by dissipative particle dynamics.

BACKGROUND: Stent implantation is a highly efficacious intervention for the treatment of coronary atherosclerosis. Nevertheless, stent thrombosis and other post-operative complications persist, and the underlying mechanism of adverse event remains elusive. METHODS: In the present study, a dissipative particle dynamics model was formulated to simulate the motion, adhesion, activation, and aggregation of platelets, with the aim of elucidating the mechanisms of in-stent thrombosis. FINDINGS: The findings suggest that stent thrombosis arises from a complex interplay of multiple factors, including endothelial injury resulting from stent implantation and alterations in the hemodynamic milieu. Furthermore, the results suggest a noteworthy association between in-stent thrombosis and both the length of the endothelial injured site and the degree of stent malposition. Specifically, the incidence of stent thrombosis appears to rise in tandem with the extent of the injured site, while moderate stent malposition is more likely to result in in-stent thrombosis compared to severe or minor malposition. INTERPRETATION: This study offers novel research avenues for investigating the plasticity mechanism of stent thrombosis, while also facilitating the clinical prediction of stent thrombosis formation and the development of more precise treatment strategies.

Multi-Method Investigation of Blood Damage Induced By Blood Pumps in Different Clinical Support Modes.

To investigate the effects of blood pumps operated in different modes on nonphysiologic flow patterns, cell and protein function, and the risk of bleeding, thrombosis, and hemolysis, an extracorporeal blood pump (CentriMag) was operated in three clinical modalities including heart failure (HF), venous-venous (V-V) extracorporeal membrane oxygenation (ECMO), and venous-arterial (V-A) ECMO. Computational fluid dynamics (CFD) methods and coupled hemolysis models as well as recently developed bleeding and thrombosis models associated with changes in platelet and von Willebrand factor (vWF) function were used to predict hydraulic performance and hemocompatibility. The V-A ECMO mode had the highest flow losses and shear stress levels, the V-V ECMO mode was intermediate, and the HF mode was the lowest. Different nonphysiologic flow patterns altered cell/protein morphology and function. The V-A ECMO mode resulted in the highest levels of platelet activation, receptor shedding, vWF unfolding, and high molecular weight multimers vWF (HMWM-vWF) degradation, leading to the lowest platelet adhesion and the highest vWF binding capacity, intermediate in the V-V ECMO mode, and opposite in the HF mode. The V-A ECMO mode resulted in the highest risk of bleeding, thrombosis, and hemolysis, with the V-V ECMO mode intermediate and the HF mode lowest. These findings are supported by published experimental or clinical statistics. Further studies found that secondary blood flow passages resulted in the highest risk of blood damage. Nonphysiologic blood flow patterns were strongly associated with cell and protein function changing, blood damage, and complications.