Comparison of Fracture Behavior in Single-Edge Notched Beams Reinforced with Steel Bars or CFRP Bars.

To explore and compare the failure modes, deformation behaviors, and load-bearing capacities of single-edge notched (SEN) beams strengthened with carbon fiber-reinforced polymer (CFRP) and steel bars, static and dynamic three-point bending tests on both types of concrete beams have been carried out in this study. During the static tests, the electro-hydraulic servo machine served as a loading device to apply pressure to CFRP beams and reinforced concrete (RC) beams. During the impact experiments, different impact velocities were imparted by adjusting the drop hammer's height. Thus, information regarding crack propagation, energy absorption, and deformation was obtained. The results from the static tests showed that the RC beams predominantly experienced shear failure. In contrast, the CFRP beams primarily exhibited bending-shear failure, attributed to the relatively weaker bond strength between the bars and the concrete. Impact tests were conducted at three different velocities in this study. As the impact velocity increased, both types of concrete beams transitioned from bending failure to bending-shear failure. At the lowest velocity, the difference in energy absorption between beams reinforced with different materials was insignificant during the bending process. However, at the highest velocity, CFRP beams absorbed less energy than RC beams. The study of structures' impact failure modes and their mechanical characteristics offers valuable references for the anti-collision design and protection of structures.

Abnormal expression of CXCL13, MIF and IL-35 in patients with primary Sjögren's syndrome and its relationship with disease severity.

Introduction: The aim of the study was to detect the saliva chemokine (C-X-C motif) ligand 13 (CXCL13), macrophage migration inhibitory factor (MIF), and interleukin 35 (IL-35) levels in patients with primary Sjögren's syndrome (pSS) and pSS-associated interstitial lung disease (pSS-ILD), and to explore the relationship between CXCL13, MIF, IL-35 levels, and disease severity. Material and methods: ESSDAI score was used to evaluate the disease activity of pSS patients, and the levels of CXCL13, MIF and IL-35 in saliva of subjects were detected and analyzed, and the relationship between CXCL13, MIF, IL-35 and the occurrence of pSS was evaluated. Pearson's correlation coefficient was used to analyze the correlation between CXCL13, MIF, IL-35 and ESSDAI score. ROC curve analysis was conducted to assess the diagnostic value of CXCL13, MIF, IL-35 and their combined application in pSS. Results: The levels of CXCL13, MIF, and IL-35 in saliva were positively correlated with ESSDAI score. Saliva CXCL13 and IL-35 are risk factors for the development of pSS into pSS-ILD. The ROC curve shows that the combination of saliva CXCL13, MIF and IL-35 has the highest diagnostic efficiency for pSS-ILD. Conclusions: CXCL13, MIF and IL-35 are related to the activity of pSS, and the combined diagnosis of these three indexes is expected to be an important method to predict the occurrence and development of pSS.

Mechanism-based target therapy in primary biliary cholangitis: opportunities before liver cirrhosis?

Primary biliary cholangitis (PBC) is an immune-mediated liver disease characterized by cholestasis, biliary injuries, liver fibrosis, and chronic non-suppurative cholangitis. The pathogenesis of PBC is multifactorial and involves immune dysregulation, abnormal bile metabolism, and progressive fibrosis, ultimately leading to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are currently used as first- and second-line treatments, respectively. However, many patients do not respond adequately to UDCA, and the long-term effects of these drugs are limited. Recent research has advanced our understanding the mechanisms of pathogenesis in PBC and greatly facilitated development of novel drugs to target mechanistic checkpoints. Animal studies and clinical trials of pipeline drugs have yielded promising results in slowing disease progression. Targeting immune mediated pathogenesis and anti-inflammatory therapies are focused on the early stage, while anti-cholestatic and anti-fibrotic therapies are emphasized in the late stage of disease, which is characterized by fibrosis and cirrhosis development. Nonetheless, it is worth noting that currently, there exists a dearth of therapeutic options that can effectively impede the progression of the disease to its terminal stages. Hence, there is an urgent need for further research aimed at investigating the underlying pathophysiology mechanisms with potential therapeutic effects. This review highlights our current knowledge of the underlying immunological and cellular mechanisms of pathogenesis in PBC. Further, we also address current mechanism-based target therapies for PBC and potential therapeutic strategies to improve the efficacy of existing treatments.

Neural oscillations after acute large artery atherosclerotic cerebral infarction during resting state and sleep spindles.

Electroencephalogram-microstate analysis was conducted using low-resolution electromagnetic tomography (LORETA)-KEY to evaluate dynamic brain network changes in patients with acute large artery atherosclerotic cerebral infarction (LAACI) during the rest and sleep stages. This study included 35 age- and sex-matched healthy controls and 34 patients with acute LAACI. Each participant performed a 3-h, 19-channel video electroencephalogram test. Subsequently, 20 epochs of 2-s sleep spindles during stage N2 sleep and five epochs of 10-s electroencephalogram data in the resting state for each participant were obtained. In both the resting state and sleep spindles, patients with LAACI displayed altered neural oscillations. The parameters of microstate A (coverage, occurrence, and duration) increased during the resting state in the patients with LAACI compared with healthy controls. The coverage and occurrence of microstate B and D were reduced in the LAACI group compared with the healthy controls (p < 0.05). Moreover, during sleep spindles, the duration of microstate A and the transition probability from microstate A and B to C decreased, but the coverage of microstate B and the transition rate from microstate B to D increased (p < 0.05) in the LAACI group compared with the healthy controls. These results enable better understanding of how neural oscillations are modified in patients with LAACI during the resting state and sleep spindles. Following LAACI, the dynamic brain network undergoes changes during sleep spindles and the resting state. Continued long-term investigations are required to determine how well these changes in brain dynamics reflect the clinical characteristics of patients with LAACI.

Spatio-temporal dynamics of resting-state brain networks are associated with migraine disability.

OBJECTIVE: The changes in resting-state functional networks and their correlations with clinical traits remain to be clarified in migraine. Here we aim to investigate the brain spatio-temporal dynamics of resting-state networks and their possible correlations with the clinical traits in migraine. METHODS: Twenty Four migraine patients without aura and 26 healthy controls (HC) were enrolled. Each included subject underwent a resting-state EEG and echo planar imaging examination. The disability of migraine patients was evaluated by Migraine Disability Assessment (MIDAS). After data acquisition, EEG microstates (Ms) combining functional connectivity (FC) analysis based on Schafer 400-seven network atlas were performed. Then, the correlation between obtained parameters and clinical traits was investigated. RESULTS: Compared with HC group, the brain temporal dynamics depicted by microstates showed significantly increased activity in functional networks involving MsB and decreased activity in functional networks involving MsD; The spatial dynamics were featured by decreased intra-network FC within the executive control network( ECN) and inter-network FC between dorsal attention network (DAN) and ECN (P < 0.05); Moreover, correlation analysis showed that the MIDAS score was positively correlated with the coverage and duration of MsC, and negatively correlated with the occurrence of MsA; The FC within default mode network (DMN), and the inter-FC of ECN- visual network (VN), ECN- limbic network, VN-limbic network was negatively correlated with MIDAS. However, the FC of DMN-ECN was positively correlated with MIDAS; Furthermore, significant interactions between the temporal and spatial dynamics were also obtained. CONCLUSIONS: Our study confirmed the notion that altered spatio-temporal dynamics exist in migraine patients during resting-state. And the temporal dynamics, the spatial changes and the clinical traits such as migraine disability interact with each other. The spatio-temporal dynamics obtained from EEG microstate and fMRI FC analyses may be potential biomarkers for migraine and with a huge potential to change future clinical practice in migraine.

[Tianma Gouteng Decoction regulates MFN2 expression to delay vascular aging in spontaneously hypertensive rats].

We studied the effect of Tianma Gouteng Decoction on vascular aging in spontaneously hypertensive rats(SHRs) to explore the molecular mechanism of the decoction in improving arterial vascular aging by regulating the expression of mitofusin 2(MFN2).Twenty 64-weeks-old SHRs were randomly assigned into the aging group and the treatment group(Tianma Gouteng Decoction 5.48 mg·kg~(-1)).Wistar-Kyoto(WKY) rats of 64 weeks old were taken as the normal group and SHR rats of 14 weeks old as the young group.The intervention with Tianma Gouteng Decoction lasted for 12 weeks.We then employed HE staining and Masson staining to observe the morphology of thoracic aorta under an electron microscope and measured the malondialdehyde(MDA) content, superoxide dismutase(SOD) activity, respiratory chain complex Ⅲ level, and thioredoxin peroxidase(TPX) activity.The vascular aging was detected via the biomarker senescence-associated beta-galactosidase(SA-ß-Gal).The expression levels of MFN2 and aging marker proteins silent information regulator 1(SIRT1), Klotho, p21, and p53 in thoracic aorta were detected by immunohistochemistry/fluorescence, qRT-PCR, and Western blot.Compared with the young group and the normal group, the aging group had risen blood pressure, lumen stenosis caused by thickened intima of blood vessels, decreased SOD and TPX activities, increased MDA and mitochondrial respiratory chain complex Ⅲ levels, down-regulated expression of MFN2, SIRT1, and Klotho, and up-regulated expression of p21 and p53(P<0.01 or P<0.05).The treatment with Tianma Gouteng Decoction significantly lowered blood pressure, mitigated vascular intimal thickening, increased SOD and TPX activities, and decreased MDA and mitochondrial respiratory chain complex Ⅲ levels, thus alleviating vascular aging.At the same time, the decoction up-regulated the expression of MFN2, SIRT1, and Klotho, while down-regulated that of p21 and p53(P<0.01 or P<0.05).In summary, Tianma Gouteng Decoction can significantly delay the vascular aging in hypertension.Specifically, it may up-regulate the expression of MFN2 and regulate the expression of aging-related proteins to alleviate oxidative stress.

Importance of baseline musculoskeletal ultrasound findings in the prognosis of rheumatoid arthritis.

OBJECTIVES: To investigate the prognostic value of baseline musculoskeletal ultrasound (MSUS) findings for rheumatoid arthritis (RA). METHOD: We retrospectively analyzed 138 patients with RA. Patients' first MSUS record was considered as the baseline expression. The subsequent MSUS changes that showed alleviation or progression were regarded as the cutoff point. Grayscale ultrasound (GSUS) synovitis, power Doppler ultrasound (PDUS) synovitis, PDUS tenosynovitis (TS), and bone erosion were scored using a semi-quantitative scale. According to the ultrasound (US) results of the cutoff point, patients were divided into the alleviation group and the progression group. Laboratory results (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], rheumatoid factor [RF], anticyclic citrullinated peptide [anti-CCP] antibody, and anti-keratin antibody [AKA]), disease activity score in 28 joints (DAS28)-ESR, and US scores were compared between the two groups to analyze the prognostic value of US findings in RA. RESULTS: The alleviation group had higher levels of CRP, synovitis, TS, GSUS synovitis, PDUS synovitis, PDUS TS, and US total scores at baseline than the progression group (p < 0.05). The alleviation group received more aggressive treatment in their initial approach than the progression group (p < 0.05). The frequency of US examinations in the alleviation group was more than that in the progression group at follow-up (p < 0.05). Presence of baseline synovitis (OR 0.248, p = 0.006) and a higher GSUS synovitis score (OR 0.521, p = 0.006) were negatively correlated with RA progression. CONCLUSIONS: Presence of baseline synovitis and higher GSUS synovitis score do not always indicate worse prognosis of RA, which can be improved with aggressive treatment. Regular MSUS follow-up may have positive influences on prognosis. Key Points • The presence of synovitis at baseline and higher GSUS synovitis score do not necessarily imply poor prognosis of RA. • Prompt and powerful therapy and regular ultrasound follow-up can slow down the progression of RA and improve its prognosis. • Patients with slight and less arthritis at baseline might be ignored and get worse prognosis due to mild treatment strategies and irregular MSUS examination.

[Corrigendum] Astragaloside IV attenuates hypoxia­induced pulmonary vascular remodeling via the Notch signaling pathway.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 4A on p. 6, the 'T' and 'DAPT' data panels appeared to contain some of the same data, although one of the panels appeared to have been rotated through 180° relative to the other. The authors have re­examined their original data, and have realized that this figure was assembled incorrectly. Subsequently, the authors have reperformed the experiments that were concerned with the immunohistochemical detection of PCNA in rat lung tissue samples, and the new results for Fig. 4A are shown in a corrected version of Fig. 4 on the next page. Note that the errors made in assembling the original version of this figure did not quantitatively affect either the results or the overall conclusions reported in this paper. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them this opportunity to publish a Corrigendum; furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 23: Article no. 89, 2021; DOI: 10.3892/mmr.2020.11726].

Comparative transcriptomic analysis revealed novel potential therapeutic targets of traditional Chinese medicine (Pinggan-Qianyang decoction) on vascular remodeling in spontaneously hypertensive rats.

BACKGROUND: Both experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics. METHODS: In this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin-eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis. RESULTS: After PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change > 1.3 and P-value < 0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell autophagy. The cellular signaling pathways involved in autophagy may be AGE-RAGE/PI3K/Akt/mTOR signaling pathway. CONCLUSION: The present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE-RAGE/PI3K/Akt/mTOR signal pathway in cell autophagy biology.

Astragaloside IV attenuates hypoxia­induced pulmonary vascular remodeling via the Notch signaling pathway.

The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS­IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS­IV on hypoxia­induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O2); iii) treatment, hypoxia + intragastrical administration of AS­IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS­IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS­IV treatment on the development of hypoxia­induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS­IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS­IV treatment, 5 mmol/l γ­secretase inhibitor [N­[N­(3,5­difluorophenacetyl)­L­alanyl]­S­phenylglycine t­butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch­3, Jagged­1, hes family bHLH transcription factor 5 (Hes­5) and PCNA were measured via reverse transcription­quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia­induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS­IV treatment alleviated PAH and prevented RV hypertrophy. AS­IV also inhibited hypoxia­induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia­induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS­IV treatment inhibited hypoxia­induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia­treated PAH model rats and cultured PASMCs, AS­IV treatment reduced the expression levels of Jagged­1, Notch­3 and Hes­5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS­IV in vitro and in vivo. Collectively, the results indicated that AS­IV effectively reversed hypoxia­induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS­IV for treatment of vascular diseases, such as PAH.

Clinical significance of progranulin correlated with serum soluble Oxford 40 ligand in primary Sjögren's syndrome.

The present study aimed to investigate the association between the expressions of serum progranulin (PGRN) and serum soluble Oxford 40 ligand (sOX40L) and determine their clinical significances in primary Sjögren's syndrome (pSS).The present study included a total of 68 patients with pSS and 50 healthy controls. Demographic data and clinical basic information were collected. Enzyme-linked immunosorbent assay (ELISA) was performed to determine serum levels of PGRN, sOX40L and interleukins. Spearman's correlation coefficient and Mann-Whitney U test were used to determine the correlation between PGRN, and sOX40L and the association between PGRN and sOX40L and disease activity and disease severity.Serum interleukin (IL)-4, IL-6, IL-10, PGRN, and sOX40L levels were significantly higher in pSS patients as compared to the healthy controls. A positive correlation was observed between PGRN and sOX40L. Patients with elevated levels of PGRN or sOX40L exhibited higher disease activity compared to those with lower levels. Patients with III to IV stages of pSS or multiple system damage showed higher serum levels of PGRN and sOX40L.Elevated serum PGRN, and sOX40L levels were relevant with disease activity and severity in patients with pSS.

Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics.

BACKGROUND: Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension (PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown. METHODS: To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1α (HIF-1α) on pulmonary arterial smooth muscle cell (PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1α in the development and progression of PH using HIF-1α gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1 (Drp1). RESULTS: We found that HIF-1α expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1α also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1. CONCLUSIONS: In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.

Integral tau methods for stiff stochastic chemical systems.

Tau leaping methods enable efficient simulation of discrete stochastic chemical systems. Stiff stochastic systems are particularly challenging since implicit methods, which are good for stiffness, result in noninteger states. The occurrence of negative states is also a common problem in tau leaping. In this paper, we introduce the implicit Minkowski-Weyl tau (IMW-τ) methods. Two updating schemes of the IMW-τ methods are presented: implicit Minkowski-Weyl sequential (IMW-S) and implicit Minkowski-Weyl parallel (IMW-P). The main desirable feature of these methods is that they are designed for stiff stochastic systems with molecular copy numbers ranging from small to large and that they produce integer states without rounding. This is accomplished by the use of a split step where the first part is implicit and computes the mean update while the second part is explicit and generates a random update with the mean computed in the first part. We illustrate the IMW-S and IMW-P methods by some numerical examples, and compare them with existing tau methods. For most cases, the IMW-S and IMW-P methods perform favorably.

[Spectral analysis of electromyography of low back muscle fatigue induced by simulated driving].

OBJECTIVE: To evaluate the effects of different vibration frequency on the back muscle fatigue during simulated driving. METHODS: Thirty-six subjects performed three simulated driving experiments under three vertical vibration frequencies which were 1.8, 4.0, 6.0 Hz respectively and the driving time was 90 minutes. At the same time the electromyography of low back was recorded. RESULTS: The median frequencies calculated from the power spectrum were decreased exponentially under three vertical vibration frequencies, especially under 4.0 Hz vibration frequency. CONCLUSION: The 4.0 Hz vibration frequency has the most important effect on the back muscle fatigue under simulated driving condition.