Progress of mitochondrial and endoplasmic reticulum-associated signaling and its regulation of chronic liver disease by Chinese medicine.

The endoplasmic reticulum (ER) is connected to mitochondria through mitochondria-associated ER membranes (MAMs). MAMs provide a framework for crosstalk between the ER and mitochondria, playing a crucial role in regulating cellular calcium balance, lipid metabolism, and cell death. Dysregulation of MAMs is involved in the development of chronic liver disease (CLD). In CLD, changes in MAMs structure and function occur due to factors such as cellular stress, inflammation, and oxidative stress, leading to abnormal interactions between mitochondria and the ER, resulting in liver cell injury, fibrosis, and impaired liver function. Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD. This paper reviews the literature on the association between mitochondria and the ER, as well as the intervention of traditional Chinese medicine in regulating CLD.

Clinicopathological factors predict residual lymph node metastasis in locally advanced rectal cancer with ypT0-2 after neoadjuvant chemoradiotherapy.

PURPOSE: Residual lymph node metastases (RLNM) remained a great concern in the implementation of organ-preserving strategies and led to poor prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to identify the clinicopathological factors correlated with RLNM in LARC patients with ypT0-2 after neoadjuvant chemoradiotherapy (NCRT). METHODS: We retrospectively analyzed 417 patients histologically diagnosed middle-low LARC after NCRT and total mesorectal excision (TME), whose pathological staging was ypT0-2. All patients received pelvic magnetic resonance imaging (MRI) before NCRT. The radiation doses were 50-50.6 Gy for the planning gross tumor volume and 41.8-45 Gy for the planning target volume, respectively. A nomogram for predicting RLNM was constructed using a binary logistic regression. Nomogram performance was assessed by receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC). RESULTS: After surgery, 191 patients (45.8%) were ypT0, 43 patients (10.3%) were ypT1 and 183 patients (43.9%) were ypT2, and a total of 49 patients (11.8%) were found the presence of RLNM. Multivariable analyses identified MRI-defined mesorectal fascia (MRF)-positive, high-grade histopathology at biopsy, advanced ypT-category, and the presence of perineural invasion (PNI) as the predictive factors. The nomogram, incorporating all these predictors, showed good discrimination and calibration efficacy, with the areas under the ROC curve of 0.690 (95% CI: 0.610-0.771). Both DCA and CIC demonstrated that this nomogram has good clinical usefulness. CONCLUSION: The nomogram model can predict RLNM in patients with ypT0-2 tumors. It can help select suitable patients for performing organ-preserving strategies after NCRT.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

[Research progress of the regulation of orphan nuclear receptors on chronic liver diseases].

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.

Molecular basis of inherited protein C deficiency results from genetic variations in the signal peptide and propeptide regions.

BACKGROUND: Inherited protein C deficiency (PCD) caused by mutations in protein C (PC) gene (PROC) increases the risk of thrombosis. Missense mutations in PC's signal peptide and propeptide have been reported in patients with PCD, but their pathogenic mechanisms, except mutations in R42 residue, remain unclear. OBJECTIVES: To investigate the pathogenic mechanisms of inherited PCD caused by 11 naturally occurring missense mutations in PC's signal peptide and propeptide. METHODS: Using cell-based assays, we evaluated the impact of these mutations on various aspects such as activities and antigens of secreted PC, intracellular PC expression, subcellular localization of a reporter protein, and propeptide cleavage. Additionally, we investigated their effect on pre-messenger RNA (pre-mRNA) splicing using a minigene splicing assay. RESULTS: Our data revealed that certain missense mutations (L9P, R32C, R40C, R38W, and R42C) disrupted PC secretion by impeding cotranslational translocation to the endoplasmic reticulum or causing endoplasmic reticulum retention. Additionally, some mutations (R38W and R42L/H/S) resulted in abnormal propeptide cleavage. However, a few missense mutations (Q3P, W14G, and V26M) did not account for PCD. Using a minigene splicing assay, we observed that several variations (c.8A>C, c.76G>A, c.94C>T, and c.112C>T) increased the incidence of aberrant pre-mRNA splicing. CONCLUSION: Our findings suggest that variations in PC's signal peptide and propeptide have varying effects on the biological process of PC, including posttranscriptional pre-mRNA splicing, translation, and posttranslational processing. Additionally, a variation could affect the biological process of PC at multiple levels. Except for W14G, our results provide a clear understanding of the relationship between PROC genotype and inherited PCD.

Study on Enhancing the Thermoelectric Stability of the ß-Cu2Se Phase by Mn Doping.

Cu2Se is a promising thermoelectric (TE) material due to its low cost, Earth abundance, and high thermoelectric properties. However, the biggest problem of Cu2Se is its unstable chemical properties. In particular, under the action of an electric field or gradient temperature field, the chemical potential of copper ions inside the material increases. When the external field is strong enough, the chemical potential of copper ions at the negative end of the material reaches the chemical potential of elemental copper. Under these conditions, copper ions must precipitate out, causing Cu2Se to be unstable, and making it unsuitable for use in applications. In this study, we prepared Cu2-xMnxSe (x = 0, 0.02, 0.04 and 0.06) series bulk materials by vacuum melting-annealing and sintered by spark plasma sintering (SPS). We investigated the effects of Mn doping on the composition, microstructure, band structure, scattering mechanism, thermoelectric properties, and stability of Cu2Se. The results show that Mn doping can adjust the carrier concentration, promote the stabilization of the ß-phase structure and improve the electrical properties of Cu2Se. When x = 0.06, the highest power factor (PF) value of Cu1.94Mn0.06Se at 873 K was 1.62 mW m-1 K-2. The results of carrier scattering mechanism analysis based on the conductivity ratio method show that the sample doped with Mn and pure Cu2Se had the characteristics of ionization impurity scattering, and the scattering factor was 3/2. However, the deterioration in thermal conductivity was large, and a superior zT value needs to be obtained. The cyclic test results of high-temperature thermoelectric properties show that Mn doping can hinder Cu+ migration and improve its thermoelectric stability, which preliminarily verifies the feasibility of using the stable zirconia mechanism to improve the thermoelectric stability of Cu2Se.

Sudden death of a child associated with invasive non-typeable Haemophilus influenzae infection with underlying IgG2 subclass deficiency.

Haemophilus influenzae can be divided into typeable and non-typeable strains. Although non-typeable Haemophilus influenzae (NTHi) is less likely to be a fatal bacterium, invasive NTHi infection has been reported to increase worldwide. This study presents a case of sudden death of a child with invasive NTHi infection and underlying immunoglobulin G2 (IgG2) deficiency. A two years seven months male child with a high fever was found unresponsive in bed, lying face down on a soft pillow. Later, the hospital declared the subject dead. An autopsy revealed that the only noteworthy finding was tissue congestion. The histopathological findings disclosed neutrophils within blood vessels of major organs. Meanwhile, the formation of the micro abscess was not visible, which indicated bacteremia. The bacterial blood culture was positive for Haemophilus Influenzae. Polymerase chain reaction assay revealed the absence of an entire capsule locus. The transmission electron microscopy showed that the colonies did not have polysaccharide capsules. Based on the above findings, the strain was identified as NTHi. Furthermore, the value of serum IgG2 was deficient, indicating the presence of IgG2 subclass deficiency. The subject eventually died from asphyxia by smothering due to a comorbid condition with a high fever brought on by NTHi-induced bacteremia and lying face down. IgG2 subclass deficiency contributed to the development of invasive NTHi infection. The invasive NTHi infection might present a risk of sudden death, particularly for immunocompromised children. As forensic pathologists and pediatricians may encounter such a problematic clinical condition, they should be aware of this.

Role of miR-143 and miR-146 in Risk Evaluation of Coronary Artery Diseases in Autopsied Samples.

Coronary artery disease (CAD) is a common and fatal cardiovascular disease. Among known CAD risk factors, miRNA polymorphisms, such as Has-miR-143 (rs41291957 C>G) and Has-miR-146a (rs2910164 G>A), have emerged as important genetic markers of CAD. Despite many genetic association studies in multiple populations, no study assessing the association between CAD risk and SNPs of miR-143 and miR-146 was documented in the Japanese people. Therefore, using the TaqMan SNP assay, we investigated two SNP genotypes in 151 subjects with forensic autopsy-proven CAD. After pathological observation, we used ImageJ software to assess the degree of coronary artery atresia. Moreover, the genotypes and miRNA content of the two groups of samples with atresia <10% and >10% were analyzed. The results showed that the CC genotype of rs2910164 was more frequent in patients with CAD than in controls, which was associated with the risk of CAD in the study population. However, Has-miR-143 rs41291957 genotype did not show a clear correlation with the risk of CAD.

A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase.

Vitamin K is a vital micronutrient implicated in a variety of human diseases. Warfarin, a vitamin K antagonist, is the most commonly prescribed oral anticoagulant. Patients overdosed on warfarin can be rescued by administering high doses of vitamin K because of the existence of a warfarin-resistant vitamin K reductase. Despite the functional discovery of vitamin K reductase over eight decades ago, its identity remained elusive. Here, we report the identification of warfarin-resistant vitamin K reductase using a genome-wide CRISPR-Cas9 knockout screen with a vitamin K-dependent apoptotic reporter cell line. We find that ferroptosis suppressor protein 1 (FSP1), a ubiquinone oxidoreductase, is the enzyme responsible for vitamin K reduction in a warfarin-resistant manner, consistent with a recent discovery by Mishima et al. FSP1 inhibitor that inhibited ubiquinone reduction and thus triggered cancer cell ferroptosis, displays strong inhibition of vitamin K-dependent carboxylation. Intriguingly, dihydroorotate dehydrogenase, another ubiquinone-associated ferroptosis suppressor protein parallel to the function of FSP1, does not support vitamin K-dependent carboxylation. These findings provide new insights into selectively controlling the physiological and pathological processes involving electron transfers mediated by vitamin K and ubiquinone.

Hypothalamic Hnscr regulates glucose balance by mediating central inflammation and insulin signal.

OBJECTIVES: Hypothalamic dysfunction leads to glucose metabolic imbalance; however, the mechanisms still need clarification. Our current study was to explore the role of hypothalamic Hnscr in glucose metabolism. MATERIALS AND METHODS: Using Hnscr knockout or htNSC-specific Hnscr overexpression mice, we evaluated the effects of Hnscr on glucose metabolism through GTTs, ITTs, serum indicator measurements, etc. Immunofluorescence staining and Western blotting were performed to test inflammation levels and insulin signalling in hypothalamus. Conditioned medium intervene were used to investigate the effects of htNSCs on neuronal cell line. We also detected the glucose metabolism of mice with htNSCs implantation. RESULTS: Hnscr expression decreased in the hypothalamus after high-fat diet feed. Hnscr-null mice displayed aggravated systematic insulin resistance, while mice with htNSC-specific Hnscr overexpression had the opposite phenotype. Notably, Hnscr-null mice had increased NF-κB signal in htNSCs, along with enhanced inflammation and damaged insulin signal in neurons located in arcuate nucleus of hypothalamus. The secretions, including sEVs, of Hnscr-deficient htNSCs mediated the detrimental effects on the CNS cell line. Locally implantation with Hnscr-depleted htNSCs disrupted glucose homeostasis. CONCLUSIONS: This study demonstrated that decreased Hnscr in htNSCs led to systematic glucose imbalance through activating NF-κB signal and dampening insulin signal in hypothalamic neurons.

[Clinical effect of Corail femoral prosthesis with different offset in total hip arthroplasty].

OBJECTIVE: To explore the early clinical efficacy of primary total hip arthroplasty(THA) with Corail standard stems (KS type) and high offset stems (KHO type), by analyzing the postoperative radiographic parameters of different offset of femoral components with Corail stem which has a neck-shaft angle of 135 ° in unilateral primary THA, by comparing the measurement results on both sides and analyzing the reconstruction of the postoperative femoral offset and the hip joint function recovery. METHODS: A retrospective analysis was made of 186 patients with unilateral hip joint lesions who underwent the first total hip arthroplasty with Johnson & Johnson Corail prostheses from January 2015 to June 2017. According to the use of femoral prostheses with different eccentricities during the operation, the patients were divided into high eccentricity group and standard eccentricity group. In the high eccentricity group, there were 52 cases of Corail high eccentricity prosthesis(KHO type), including 20 females and 32 males;aged 21 to 71 years old with an average of(50.6±13.2) years;body mass index(BMI) was (26.0±4.1) kg/m2. The standard eccentricity group included 134 Corail standard femoral stem prostheses(KS type), 57 females and 77 males;aged 18 to 77 years old with an average of (47.3±14.0) years;BMI was (25.3±3.5) kg/m2. The abduction arm, femoral eccentricity, acetabular eccentricity and the length difference of lower limbs were measured on the postoperatively positive X-ray film of the hip joint. Harris score and related complications were recorded before and after the operation, and the stability of the prosthesis was analyzed. RESULTS: There were significant differences in femoral eccentricity, joint eccentricity and abduction arm between the affected side and the healthy side in the high eccentricity group(P<0.05). There were significant differences in femoral eccentricity and acetabular eccentricity between the affected side and the healthy side in the standard eccentricity group(P<0.05). There were significant differences in combined eccentricity, abduction arm and length of lower limbs between two groups(P<0.05). In the high eccentricity group, the abduction arm of the affected hip joint was positively correlated with the femoral eccentricity, acetabular eccentricity and joint eccentricity(r=0.633, P<0.001;r=0.384, P=0.005;r=0.690, P<0.001). The same results were also obtained in the healthy side(r=0.688, P<0.001;r=0.574, P<0.001;r=0.765, P<0.001). In the standard eccentricity group, the abduction arm of the affected hip joint was positively correlated with the femoral eccentricity, acetabular eccentricity and combined eccentricity(r=0.734, P<0.001;r=0.418, P<0.001;r=0.749, P<0.001). The same results were also obtained in the healthy side(r=0.775, P<0.001;r=0.397, P<0.001;r=0.773, P<0.001). The difference of the length of both lower limbs was significantly correlated with the difference of bilateral joint eccentricity and bilateral abduction arm (r=0.376, P=0.006;r=-0.346, P=0.012). There was no significant correlation between the difference of the length of both lower limbs and the difference of bilateral joint eccentricity and bilateral abduction arm (r=-0.009, P=0.919;r=-0.036, P=0.682). There was no significant difference in Harris score between two groups at the last follow-up(P>0.05). At the last follow-up, Trendelenburg was negative in all patients in both groups, and the prostheses were stable. CONCLUSION: Both Corail standard stem and high offset stem may be effectively reconstruct the femoral offset, reconstruct the anatomical structure and biomechanics of the hip joint, and maintain the length of lower limbs and the stability of the hip joint in the unilateral primary total hip arthroplasty. Although the offset of the femur was not reconstructed normally in some cases, the stability of the components and postoperative function were not affected.

Early patellar tendon rupture after total knee arthroplasty: A direct repair method.

BACKGROUND: Patellar tendon rupture after total knee arthroplasty (TKA) is a catastrophic complication. Although the occurrence of this injury is rare, it can lead to significant dysfunction for the patient and is very tricky to deal with. There has been no standard treatment for early patella tendon rupture after TKA, and long-term follow-up data are lacking. AIM: To introduce a direct repair method for early patella tendon rupture following TKA and determine the clinical outcomes and complications of this method. METHODS: During the period of 2008 to 2021, 3265 consecutive TKAs were retrospectively reviewed. Twelve patients developed early patellar tendon rupture postoperatively and were treated by a direct repair method. Mean follow-up was 5.7 years. Demographic, operative, and clinical data were collected. The clinical outcomes were assessed using the Western Ontario and McMaster Universities (WOMAC) score, the Hospital for Special Surgery (HSS) score, knee range of motion, extensor lag, and surgical complications. Descriptive statistics and paired t test were employed to analyze the data. RESULTS: For all 12 patients who underwent direct repair for early patellar tendon rupture, 3 patients failed: One (8.3%) for infection and two (17.6%) for re-fracture. The two patients with re-fracture both underwent reoperation to reconstruct the extensor mechanism and the patient with infection underwent revision surgery. The range of motion was 109.2° ± 10.6° preoperatively to 87.9° ± 11° postoperatively, mean extensor lag was 21° at follow-up, and mean WOMAC and HSS scores were 65.8 ± 30.9 and 60.3 ± 21.7 points, respectively. CONCLUSION: This direct repair method of early patellar tendon rupture is not an ideal therapy. It is actually ineffective for the recovery of knee joint function in patients, and is still associated with severe knee extension lag and high complication rates. Compared with the outcomes of other repair methods mentioned in the literature, this direct repair method shows poor clinical outcomes.

Variability of Target Volumes and Organs at Risk Delineation in Breast Cancer Radiation Therapy: Quality Assurance Results of the Pretrial Benchmark Case for the POTENTIAL Trial.

PURPOSE: To estimate the variations in clinical target volumes (CTVs) and organs at risk delineation within the quality assurance (QA) program of the POTENTIAL trial, which is a multicenter, randomized phase 3 trial evaluating postmastectomy radiation therapy (RT), with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. METHODS AND MATERIALS: The simulating computed tomography scan data set of a benchmark case was sent to the participating centers, and the delineation of CTVs and organs at risk was required to be completed by the investigators following protocol guidelines. All submitted contours were reviewed and compared with the reference contours created by the QA team, using quantitative geometric analysis regarding volume and the Jaccard Index (JCI), Dice similarity coefficient, Geographic Miss Index, Discordance Index, and mean distance to agreement. In addition to the whole-volume analysis of all structures, the combination contour of the supraclavicular fossa and level III and II axilla (CTVsc + axIII + axII) was further analyzed on a slice-by-slice basis. RESULTS: The contours from 26 centers were reviewed and variations were observed between submission and reference. The variations of the CTV of the chest wall, contralateral breast, and heart were small, for which the mean JCI values were 0.62, 0.68, and 0.87, respectively. However, the mean JCI values of the CTV of the internal mammary nodal region, ipsilateral brachial plexus, left anterior descending coronary artery, and right coronary artery were 0.38, 0.21, 0.29, and 0.18, respectively, suggesting marked variations. In addition, marked under- and overoutlining variations were identified on 4 slices of CTVsc + axIII + axII on slice-by-slice analysis. CONCLUSIONS: There were residual contouring variations despite a detailed protocol being provided, confirming the importance of pretrial QA in RT and highlighting the need for education and consideration of a real-time central review of the target delineation before the trial participants begin RT.

Different squatting positions after total knee arthroplasty: A retrospective study.

BACKGROUND: Total knee arthroplasty (TKA) has been shown to improve quality of life and reduce pain. High-flexion activities such as squatting, kneeling, and floor transfers are mainly listed as demanding tasks. Among them, squatting is an important position. AIM: To provide a new squat position classification and evaluate the different squatting positions of a series of patients after primary TKA. METHODS: From May 2018 to October 2019, we retrospectively reviewed 154 video recordings of the squatting-related motions of patients after TKA. Among the included patients, 119 were women and 35 were men. Their mean age at the index surgery was 61.4 years (range, 30 to 77). RESULTS: The median follow-up was 12 mo (range, 6 to 156 mo). We classified those squatting-related motions into three major variations according to squatting depth: Half squat, parallel squat, and deep squat. The angles of hip flexion, knee flexion, and ankle dorsiflexion were measured in the screenshots captured from the videos at the moment of squatting nadir. A total of 26 patients were classified as half squats, 75 as parallel squats, and 53 as deep squats. The angles of hip flexion, knee flexion, and ankle dorsiflexion all differed significantly among the three squatting positions (P < 0.001). In the parallel squat group, the mean knee flexion angle (°) was 116.5 (SD, 8.1; range, 97 to 137). In the deep squat group, the mean knee flexion angle (°) was 132.5 (SD, 9.3; range, 116 to 158). CONCLUSION: Among the three squatting positions, deep squat showed the highest hip, knee, and ankle flexion angles, followed by the parallel squat. With the improvement of squatting ability, the patient's postoperative satisfaction rate was also significantly enhanced. However, the different squatting abilities of the patients cannot be effectively distinguished from the scoring results (P > 0.05). Our squatting position classification offers a pragmatic approach to evaluating patients' squatting ability after TKA.

Enabling High Quality Factor and Enhanced Thermoelectric Performance in BiBr3-Doped Sn0.93Mn0.1Te via Band Convergence and Band Sharpening.

Lead-free SnTe-based materials are expected to replace PbTe and have gained much attention from the thermoelectric community. In this work, a maximum ZT of ∼1.31 at 873 K is attained in SnTe via promoting a high quality factor resulting from Mn alloying and BiBr3 doping. The results show that Mn alloying in SnTe converges the L band and the ∑ band in valence bands to supply enhanced valley degeneracy and the density of states effective mass, giving rise to a high power factor of ∼21.67 µW cm-1 K-2 at 723 K in Sn0.93Mn0.1Te. In addition, the subsequent BiBr3 doping can sharpen the top of the valence band to coordinate the contradiction between the band effective mass and the carrier mobility, thus enhancing the carrier mobility while maintaining a relatively large density of states effective mass. Consequently, a maximum power factor of 23.85 µW cm-1 K-2 at 873 K is achieved in Sn0.93Mn0.1Te-0.8 atom % BiBr3. In addition to band sharpening, BiBr3 doping can also effectively suppress the bipolar effect at elevated temperatures and reduce the lattice thermal conductivity by strengthening the point defect phonon scattering. Benefitting from doping BiBr3 in Sn0.93Mn0.1Te optimizes the carrier mobility and suppresses the lattice thermal conductivity, resulting in a dramatically enhanced quality factor. Accordingly, an average ZT of ∼0.62 in the temperature range of 300-873 K is obtained in Sn0.93Mn0.1Te-0.8 atom % BiBr3, ∼250% increase compared with that in Sn1.03Te.

[Application of high offset Corail femoral stem prosthesis in unilateral primary total hip arthroplasty].

OBJECTIVE: To investigate the application of high offset femoral stem prosthesis in primary total hip arthroplasty. METHODS: From January 2015 to June 2017, 51 patients with unilateral hip diseases who underwent primary total hip arthroplasty with Corail high offset femoral stem prosthesis(KHO type) were selected for retrospective study, including 20 females and 31 males;the age ranged from 21 to 71 years old with an average of(50.8±13.3) years old. The abduction arm, femoral offset, acetabular offset and the length of lower limbs were measured on the positive X-ray film of hip joint after operation. Harris scores before and after operation and related complications were recorded, and the stability of prosthesis was analyzed. RESULTS: The femoral offset, combined offset and abduction arm of the affected side were significantly greater than those of the healthy side(P<0.05). There was no significant difference in acetabular offset between the affected side and the healthy side (P>0.05). The femoral offset of 17 hips (33.3%) was reconstructed normally, of which 15 cases (88.2%) had equal length of both lower limbs. The femoral offset of 34 hips (66.7%) was greater than that of the healthy side, and 34 cases (100%) had equal length of both lower limbs. All 51 patients were followed up for(42.3±7.3) months. The Harris score increased from 38.0±7.6 before operation to 92.1±3.1 at the final follow-up(P<0.001). CONCLUSION: Although the high offset Corail prosthesis can not normally reconstruct the femoral offset in unilateral primary total hip arthroplasty, it does not affect the reconstruction of the length of lower limbs and the stability of the prosthesis.

A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis.

Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health.

[Research progress on role of traditional Chinese medicine in hepatic fibrosis based on miRNA-mediated activation of NLRP3 inflammasome].

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1ß and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.

[Study on mechanism of curcumol against liver fibrosis based on autophagy and apoptosis of hepatic stellate cells].

The present study clarified the molecular mechanism of curcumol against liver fibrosis based on its effects on the autopha-gy and apoptosis of hepatic stellate cells. The hepatic stellate cells were divided into a blank control group, a transforming growth factor-ß1(TGF-ß1)(10 ng·mL~(-1)) group, and low-(12.5 mg·L~(-1)), medium-(25 mg·L~(-1)), and high-dose(50 mg·L~(-1)) curcumol groups. The effect of curcumol on the viability of hepatic stellate cells induced by TGF-ß1 was detected by the MTT assay kit. The apo-ptosis in each group was determined by flow cytometry. Real-time fluorescence-based quantitative PCR(RT-PCR) was employed for the detection of mRNA expression of α-smooth muscle actin(α-SMA), type Ⅰ collagen(collagen Ⅰ), and type Ⅲ collagen(collagen Ⅲ). Western blot was used to detect the protein expression of p62, microtubule-associated protein 1 light chain 3(LC3), beclin1, B cell lymphoma 2(Bcl-2), and Bcl-2-associated X protein(Bax). Transmission electron microscopy(TEM) was used to observe cell morphology and autophagosome formation in each group. The autophagic flux was observed after cell infection with adenovirus under double fluorescence labeling. The cell viability assay revealed that compared with the TGF-ß1 group, the curcumol groups showed significantly decreased cell viability. The apoptosis assay showed that the apoptosis rates of the curcumol groups were significantly higher than that of the TGF-ß1 group. RT-PCR indicated that the mRNA expression of α-SMA, collagenⅠ, and collagen Ⅲ in the curcumol groups was significantly lower than that of the TGF-ß1 group. Western blot showed that the expression of p62, LC3, beclin1, Bcl-2, and Bax in the curcumol groups was significantly different from that in the TGF-ß1 group. As demonstrated by TEM, compared with the TGF-ß1 group, the curcumol groups showed significantly increased autophagosomes. The detection of autophagic flow by the adenovirus under double fluorescence labeling showed that autolysosomes in the curcumol groups were significantly increased compared with those in the TGF-ß1 group. Curcumol can induce the autophagy and apoptosis of hepatic stellate cells, which may be one of its anti-liver fibrosis mechanisms.

Alkbh1-mediated DNA N6-methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging.

OBJECTIVES: DNA N6-methyladenine (N6-mA) demethylase Alkbh1 participates in regulating osteogenic differentiation of mesenchymal stem cell (MSCs) and vascular calcification. However, the role of Alkbh1 in bone metabolism remains unclear. MATERIALS AND METHODS: Bone marrow mesenchymal stem cells (BMSCs)-specific Alkbh1 knockout mice were used to investigate the role of Alkbh1 in bone metabolism. Western blot, qRT-PCR, and immunofluorescent staining were used to evaluate the expression of Alkbh1 or optineurin (optn). Micro-CT, histomorphometric analysis, and calcein double-labeling assay were used to evaluate bone phenotypes. Cell staining and qRT-PCR were used to evaluate the osteogenic or adipogenic differentiation of BMSCs. Dot blotting was used to detect the level of N6-mA in genomic DNA. Chromatin immunoprecipitation (Chip) assays were used to identify critical targets of Alkbh1. Alkbh1 adeno-associated virus was used to overexpress Alkbh1 in aged mice. RESULTS: Alkbh1 expression in BMSCs declined during aging. Knockout of Alkbh1 promoted adipogenic differentiation of BMSCs while inhibited osteogenic differentiation. BMSC-specific Alkbh1 knockout mice exhibited reduced bone mass and increased marrow adiposity. Mechanistically, we identified optn as the downstream target through which Alkbh1-mediated DNA m6A modification regulated BMSCs fate. Overexpression of Alkbh1 attenuated bone loss and marrow fat accumulation in aged mice. CONCLUSIONS: Our findings demonstrated that Alkbh1 regulated BMSCs fate and bone-fat balance during skeletal aging and provided a potential target for the treatment of osteoporosis.