Cinnamaldehyde Alleviates Bone Loss by Targeting Oxidative Stress and Mitochondrial Damage via the Nrf2/HO-1 Pathway in BMSCs and Ovariectomized Mice.

Osteoporosis (OP) is typically brought on by disruption of bone homeostasis. Excessive oxidative stress and mitochondrial dysfunction are believed to be the primary mechanisms underlying this disorder. Therefore, in order to restore bone homeostasis effectively, targeted treatment of oxidative stress and mitochondrial dysfunction is necessary. Cinnamaldehyde (CIN), a small molecule that acts as an agonist for the nuclear factor erythroid 2-related factor (Nrf2), has been found to possess antiapoptotic, anti-inflammatory, and antioxidant properties. We found that CIN, while rescuing apoptosis, can also reduce the accumulation of reactive oxygen species (ROS) to improve mitochondrial dysfunction and thus restore the osteogenic differentiation potential of BMSCs disrupted by hydrogen peroxide (H2O2) exposure. The role of CIN was preliminarily considered to be a consequence of Nrf2/HO-1 axis activation. The ovariectomized mice model further demonstrated that CIN treatment ameliorated oxidative stress in vivo, partially reversing OVX-induced bone loss. This improvement was seen in the trabecular microarchitecture and bone biochemical indices. However, when ML385 was concurrently injected with CIN, the positive effects of CIN were largely blocked. In conclusion, this study sheds light on the intrinsic mechanisms by which CIN regulates BMSCs and highlights the potential therapeutic applications of these findings in the treatment of osteoporosis.

Study of Dietary Emodin on Immune Defense in Megalobrama amblycephala against Aeromonas hydrophila.

This experiment aimed to investigate the effects of emodin on the total bacterial count and immune response in various tissues of Wuchang bream infected with A. hydrophila. The experimental diets were made by supplementing emodin at 0, 30, 100, and 150 mg kg-1 to basal (control) diet, respectively, and fed to fish with an initial weight of 50.4 ± 2.35 g. All fish were divided into five experimental groups: uninfected fish fed with basal control diet (negative control, NC), infected fish fed with the diet supplemented with 0 (positive control group, PC), 30 (30), 100 (100), and 150 mg/kg (150) of emodin. The fish were reared for 14 days and sampled at different time points. The results showed that the total bacterial count in the kidney, blood, and liver tissues of Wuchang bream infected with A. hydrophila was significantly affected by the supplementation and feeding time of emodin. At the beginning of the experiment, the difference in total bacterial count among the groups was not significant. On day 1, the total bacterial count in all groups was significantly higher (p < 0.05) than that in the negative control group. On day 4, the total bacterial count in all the emodin groups was significantly reduced, and the best bactericidal effect was observed in the 100 mg kg-1 group. In addition, emodin had a significant effect on the immune response of Wuchang bream after infection with A. hydrophila (p < 0.05). Compared with the other groups, the respiratory burst activity, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) content, and white blood cell count (WBC) in the 100 and 150 mg kg-1 groups could be restored to normal levels in the shortest time (p < 0.05). Furthermore, this study also measured the complement alternative pathway activity (ACH50), plasma superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content of the fish. The results showed that supplying 100 mg kg-1 emodin to the diet could significantly (p < 0.05) increase the ACH50 activity of the fish. Compared with the positive control (PC) group, the addition of emodin to the diet can inhibit the decrease in SOD activity and the increase in MDA content in the plasma of infected Wuchang bream. In conclusion, supplying 100 mg kg-1 emodin to the diet can enhance the ability of Wuchang bream to resist A. hydrophila infection by reducing the total bacterial count in tissues, increasing the activity of related immune enzymes, and promoting the secretion of cytokines. This provides a theoretical basis for production practice.

Longitudinal surveillance of three biomarkers to predict recurrence of hepatocellular carcinoma after radical resection.

BACKGROUND: Radical resection is a curative treatment for patients with hepatocellular carcinoma (HCC), but the incidence of recurrence remains high. We aimed to explore the performance of predicting HCC recurrence by longitudinal surveillance of the protein induced by vitamin K absence (PIVKA-II), alpha- fetoprotein (AFP), and lectin-reactive AFP (AFP-L3) during postoperative follow-up. METHODS: Patients who underwent radical resection for HCC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and December 2020 were included. All enrolled patients regularly monitor PIVKA-II, AFP, AFP-L3 every 3 months during postoperative follow-up. The surveillance performance of PIVKA-II, AFP, AFP-L3 during follow-up for the prediction of HCC recurrence was compared in patients. The generalized estimation equation (GEE) was used to analyze the trends of the tumor biomarkers and interactions with time. Area under the receiver operator characteristic (AUROC) curves, the optimal cut-off value, the sensitivity and specificity were calculated to evaluate the performance of the three biomarkers. The recurrence-free survival (RFS) and overall survival (OS) of patients with any of the elevated biomarkers was analyzed by Kaplan-Meier curves and the log-rank test. Multivariate logistic regression models were used to analyze potential risk factors for recurrence. RESULTS: The GEE analysis indicated that PIVKA-II, AFP, AFP-L3 in the recurrence patients were higher than the no recurrence patients during follow-up, PIVKA-II and AFP showed increasing trends from 6 months before recurrence. In predicting recurrence, the AUROCs for PIVKA-II, AFP, AFP-L3 and their combination were 0.885, 0.754, 0.781 and 0.885 respectively, the optimal cut-off value for PIVKA-II, AFP, AFP-L3 was 29.5 mAU/ml, 10.7 ng/L, 1.5% respectively. The sensitivity in predicting recurrence for PIVKA-II, AFP, AFP-L3 and combination were 75.0, 54.7, 57.8 and 79.7% respectively. The RFS and the OS of patients with any of the biomarkers elevated during the follow-up was significantly shorter than that without elevated biomarkers ( P  < 0.001). Multivariate analysis showed that any of the biomarkers elevated was the independent risk factor of recurrence. CONCLUSION: Longitudinal surveillance of PIVKA-II, AFP and AFP-L3 can effectively predict recurrence of HCC after operation.

Carcinosarcoma of common bile duct: A case report.

BACKGROUND: Carcinosarcomas of the common bile duct (CBD) are an extremely rare finding in the clinical setting. Based on a review of 12 literatures, 3 cases had the imaging features of ossification. Carcinosarcomas are prone to distant metastasis, as they possess clinical features of both carcinoma and sarcoma, and generally have with a poor prognosis. Due to the small number of cases reported, clinical experience in the diagnosis and treatment of the disease is lacking. CASE SUMMARY: The patient was a 75-year-old woman who had experienced recurrent chills with nausea and vomiting for 3 mo. Computed tomography, magnetic resonance imaging, endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography led to the diagnosis of malignant tumor of the CBD. The patient ultimately underwent cholecystectomy, CBD resection, and choledochojejunostomy. Postoperative pathological examination revealed carcinosarcoma of the CBD, and the latest follow-up showed that the patient is recovering well. Based on previous case reports, some carcinosarcoma has ossification characteristics in imaging. If it is misdiagnosed as biliary calculi, the use of laser lithotripsy in surgery may lead to tumor diffusion. Choledochoscopy and narrow band staining of mucosa are very important for diagnosis. CONCLUSION: We herein present a rare case of carcinosarcomas of the CBD, we found the tumours may have imaging features of polypoid growth and ossification only when the sarcomal components are bone differentiation, while show soft tissue shadow when non bone differentiation. Confirmation of diagnosis depends greatly upon postoperative pathological examination and the adjuvant treatment has not been established, which leads to the poor prognosis.

The nuclear receptor REV-ERBα integrates circadian clock and energy metabolism.

The physiological processes of mammals show rhythmic changes in a 24-h cycle. Circadian rhythms are under the subtle control of the autonomous circadian clock, and dysregulation of the circadian system can lead to health problems such as metabolic disorders. REV-ERBα, a member of the nuclear receptor superfamily, is an important component of the mammalian circadian clock. REV-ERBα regulates various physiological processes, including the regulation of metabolism, inflammation and immunity as well as the circadian rhythm, making it a potential therapeutic target for metabolic syndrome, inflammatory diseases and cancers. In recent years, an array of new REV-ERBα ligands have been discovered, most of which have potential applications in the treatment of diseases. In this review, we focus on the regulatory role of nuclear receptor REV-ERBα in energy metabolism and inflammation, in order to provide new strategies for the therapy of metabolic syndrome and its related diseases.

A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis.

Type 2 diabetic osteoporosis (T2DOP) is a chronic bone metabolic disease. Compared with traditional menopausal osteoporosis, the long-term high glucose (HG) microenvironment increases patients' risk of fracture and osteonecrosis. We were accumulating evidence that implicated ferroptosis as a pivotal mechanism of glucolipotoxicity-mediated death of osteocytes and osteoblast, a novel form of programmed cell death resulting from uncontrolled lipid peroxidation depending on iron. Vitamin K2 (VK2), a fat-soluble vitamin, is clinically applied to prevent osteoporosis and improve coagulation. This study aimed to clarify the role and mechanism of VK2 in HG-mediated ferroptosis. We established the mouse T2DOP model by intraperitoneal injection of streptozotocin solution and a high-fat and high-sugar diet. We also cultured bone marrow mesenchymal stem cells (BMSCs) in HG to simulate the diabetic environment in vitro. Based on our data, VK2 inhibited HG-mediated bone loss and ferroptosis, the latter manifested by decreased levels of mitochondrial reactive oxygen species, lipid peroxidation, and malondialdehyde and increased glutathione in vitro. In addition, VK2 treatment was capable of restoring bone mass and strengthening the expression of SIRT1, GPX4, and osteogenic markers in the distal femurs. As for further mechanism exploration, we found that VK2 could activate AMPK/SIRT1 signaling, and knockdown of SIRT1 by siRNA prevented the VK2-mediated positive effect in HG-cultured BMSCs. Summarily, VK2 could ameliorate T2DOP through the activation of the AMPK/SIRT1 signaling pathway to inhibit ferroptosis.

Predictive Value of the TP53 p.G245S Mutation Frequency for the Short-Term Recurrence of Hepatocellular Carcinoma as Detected by Pyrophosphate Sequencing.

Aims: We explored the relationship between the mutation at the p.G245S site in TP53 and the short-term recurrence of hepatocellular carcinoma (HCC). Materials and Methods: 101 HCC patients were included in this study. The TP53 p.G245S mutation frequency spectrum was examined by direct sequencing of genomic DNA from tissue specimens of HCC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the independent prognostic factors of tumor recurrence. ROC curve analysis was applied to determine the cut-off value for the p.G245S mutation frequency and to verify the predictive ability of the Cox model compared with single risk factor indices. Results: A multivariate Cox regression analysis showed that TP53 p.G245S mutation frequency (HR = 1.231, 95% CI: 1.006-1.505, p = 0.043), AFP (HR = 2.432, 95% CI: 1.297-4.561, p = 0.006), MTM (HR = 2.656, 95% CI: 0.930-7.583, p = 0.068), and PVTT (HR = 14.297, 95% CI: 3.085-66.243, p = 0.001) were independent prognostic factors for short-term recurrence. The cut-off value for the TP53 p.G245S mutation frequency (18.5%) was determined by ROC analysis. A predictive model integrating the TP53 p.G245S mutation frequency with PVTT, MTM, and AFP values appears to an excellent predictive indicator of short-term recurrence in HCC patients (AUC = 0.849, 95% CI = 0.748-0.950, p = 0.000001). Survival analysis indicated that the probability of short-term recurrence-free survival was significantly different among different TP53 p.G245S mutation frequency, MTM, PVTT, and AFP risk groups (p < 0.05). Conclusion: The mutation frequency of the p.G245S site is a novel prognostic risk factor for the short-term recurrence of HCC.

Development of a nomogram to predict surgical site infection after closed comminuted calcaneal fracture.

BACKGROUND: Compared with open comminuted calcaneal fractures, less emphasis is placed on postoperative surgical site infection (SSI) of closed comminuted calcaneal fractures. This study aimed to identify the risk factors associated with SSI and build a nomogram model to visualize the risk factors for postoperative SSI. METHODS: We retrospectively collected patients with closed comminuted calcaneal fractures from the Second Affiliated Hospital of Wenzhou Medical University database from 2017 to 2020. Risk factors were identified by logistics regression analysis, and the predictive value of risk factors was evaluated by ROC (receiver operating characteristic curve). Besides, the final risk factors were incorporated into R4.1.2 software to establish a visual nomogram prediction model. RESULTS: The high-fall injury, operative time, prealbumin, aspartate aminotransferase (AST), and cystatin-C were independent predictors of SSI in calcaneal fracture patients, with OR values of 5.565 (95%CI 2.220-13.951), 1.044 (95%CI 1.023-1.064), 0.988 (95%CI 0.980-0.995), 1.035 (95%CI 1.004-1.067) and 0.010 (95%CI 0.001-0.185) (Ps < 0.05). Furthermore, ROC curve analysis showed that the AUC values of high-fall injury, operation time, prealbumin, AST, cystatin-C, and their composite indicator for predicting SSI were 0.680 (95%CI 0.593-0.766), 0.756 (95%CI 0.672-939), 0.331 (95%CI 0.243-0.419), 0.605 (95%CI 0.512-0.698), 0.319 (95%CI 0.226-0.413) and 0.860 (95%CI 0.794-0.926), respectively (Ps < 0.05). Moreover, the accuracy of the nomogram to predict SSI risk was 0.860. CONCLUSIONS: Our study findings suggest that clinicians should pay more attention to the preoperative prealbumin, AST, cystatin C, high-fall injury, and operative time for patients with closed comminuting calcaneal fractures to avoid the occurrence of postoperative SSI. Furthermore, our established nomogram to assess the risk of SSI in calcaneal fracture patients yielded good accuracy and can assist clinicians in taking appropriate measures to prevent SSI.

Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.

T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies.

A Biparatopic Antibody-Drug Conjugate to Treat MET-Expressing Cancers, Including Those that Are Unresponsive to MET Pathway Blockade.

Lung cancers harboring mesenchymal-to-epithelial transition factor (MET) genetic alterations, such as exon 14 skipping mutations or high-level gene amplification, respond well to MET-selective tyrosine kinase inhibitors (TKI). However, these agents benefit a relatively small group of patients (4%-5% of lung cancers), and acquired resistance limits response durability. An antibody-drug conjugate (ADC) targeting MET might enable effective treatment of MET-overexpressing tumors (approximately 25% of lung cancers) that do not respond to MET targeted therapies. Using a protease-cleavable linker, we conjugated a biparatopic METxMET antibody to a maytansinoid payload to generate a MET ADC (METxMET-M114). METxMET-M114 promotes substantial and durable tumor regression in xenografts with moderate to high MET expression, including models that exhibit innate or acquired resistance to MET blockers. Positron emission tomography (PET) studies show that tumor uptake of radiolabeled METxMET antibody correlates with MET expression levels and METxMET-M114 efficacy. In a cynomolgus monkey toxicology study, METxMET-M114 was well tolerated at a dose that provides circulating drug concentrations that are sufficient for maximal antitumor activity in mouse models. Our findings suggest that METxMET-M114, which takes advantage of the unique trafficking properties of our METxMET antibody, is a promising candidate for the treatment of MET-overexpressing tumors, with the potential to address some of the limitations faced by the MET function blockers currently in clinical use.

Inhibition of Histone Deacetylases 1, 2, and 3 Enhances Clearance of Cholesterol Accumulation in Niemann-Pick C1 Fibroblasts.

Niemann-Pick disease type C1 (NPC1) is a rare genetic cholesterol storage disorder caused by mutations in the NPC1 gene. Mutations in this transmembrane late endosome protein lead to loss of normal cholesterol efflux from late endosomes and lysosomes. It has been shown that broad spectrum histone deacetylase inhibitors (HDACi's) such as Vorinostat correct the cholesterol accumulation phenotype in the majority of NPC1 mutants tested in cultured cells. In order to determine the optimal specificity for HDACi correction of the mutant NPC1s, we screened 76 HDACi's of varying specificity. We tested the ability of these HDACi's to correct the excess accumulation of cholesterol in patient fibroblast cells that homozygously express NPC1 I1061T , the most common mutation. We determined that inhibition of HDACs 1, 2, and 3 is important for correcting the defect, and combined inhibition of all three is needed to achieve the greatest effect, suggesting a need for multiple effects of the HDACi treatments. Identifying the specific HDACs involved in the process of regulating cholesterol trafficking in NPC1 will help to focus the search for more specific druggable targets.

Evaluation of the clinical efficacy of 3D Printing technology assisted surgery combined with early postoperative comprehensive rehabilitation in the treatment of Senile Intertrochanteric Fractures.

OBJECTIVES: To observe the clinical value of 3D printing technology assisted surgery combined with early postoperative comprehensive rehabilitation in elderly patients with intertrochanteric fractures. METHODS: Sixty elderly patients with intertrochanteric fractures of the femur who were treated in our hospital from January 2018 to January 2020 were selected and randomly divided into two groups. In the experimental group, 3D printing technology assisted surgery combined with early postoperative comprehensive rehabilitation was used for treatment. While in the control group, traditional open reduction and dynamic hip screw internal fixation combined with postoperative conventional treatment was utilized. The duration of surgery, intraoperative blood loss, postoperative hospital stay, weight bearing time, fracture healing time and other surgical indicators were recorded respectively, and hip joint function recovery was evaluated prior to and 2 weeks after surgery. All patients were followed up for six months to observe the occurrence of complications within half a year, including deep vein thrombosis, incision infection, avascular necrosis of femoral head, hip joint stiffness, delayed fracture healing, etc. Subsequently, the differences in postoperative complications between the two groups were compared and analyzed. RESULTS: The operation time, blood loss, postoperative hospital stay, weight bearing time and fracture healing time of the experimental group were better than those of the control group, and the difference was statistically significant (p<0.05). After treatment, the hip joint function of the experimental group was significantly improved compared with the control group, with a statistically significant difference(p=0.03). The incidence of operative complications in the experimental group was 10% (3/30) within six months postoperatively, significantly lower than the 33% (10/30) in the control group, with statistical significance (p=0.03). CONCLUSION: 3D printing with early rehab proved to be effective treatment in our study. Such a combined treatment has the advantages of precise operative reduction, fast postoperative recovery, and certain safety and effectiveness.

Antibody drug conjugates of cleavable amino-benzoyl-maytansinoids.

ADCs based on the natural product maytansine have been successfully employed clinically. In a previous report, ADCs based on hydrophilic non-cell permeable maytansinoids was presented. The authors in this report further explore the maytansine scaffold to develop tubulin inhibitors capable of cell permeation. The research resulted in amino-benzoyl-maytansinoid payloads that were further elaborated with linkers for conjugating to antibodies. This approach was applied to MUC16 tumor targeting antibodies for ovarian cancers. A positive control ADC was evaluated alongside the amino-benzoyl-maytansinoid ADC and the efficacy observed was equivalent while the isotype control ADCs had no effect.

Improved hybrid de novo genome assembly and annotation of African wild rice, Oryza longistaminata, from Illumina and PacBio sequencing reads.

African wild rice Oryza longistaminata, one of the eight AA- genome species in the genus Oryza, possesses highly valued traits, such as the rhizomatousness for perennial rice breeding, strong tolerance to biotic and abiotic stresses, and high biomass production on poor soils. To obtain the high-quality reference genome for O. longistaminata we employed a hybrid assembly approach through incorporating Illumina and PacBio sequencing datasets. The final genome assembly comprised only 107 scaffolds and was approximately ∼363.5 Mb, representing ∼92.7% of the estimated African wild rice genome (∼392 Mb). The N50 lengths of the assembled contigs and scaffolds were ∼46.49 Kb and ∼6.83 Mb, indicating ∼3.72-fold and ∼18.8-fold improvement in length compared to the earlier released assembly (∼12.5 Kb and 364 Kb, respectively). Aided with Hi-C data and syntenic relationship with O. sativa, these assembled scaffolds were anchored into 12 pseudo-chromosomes. Genome annotation and comparative genomic analysis reveal that lineage-specific expansion of gene families that respond to biotic- and abiotic stresses are of great potential for mining novel alleles to overcome major diseases and abiotic adaptation in rice breeding programs. This reference genome of African wild rice will greatly enlarge the existing database of rice genome resources and unquestionably form a solid base to understand genomic basis underlying highly valued phenotypic traits and search for novel gene sources in O. longistaminata for the future rice breeding programs.

Draft genomes of two outcrossing wild rice, Oryza rufipogon and O. longistaminata, reveal genomic features associated with mating-system evolution.

Oryza rufipogon and O. longistaminata are important wild relatives of cultivated rice, harboring a promising source of novel genes for rice breeding programs. Here, we present de novo assembled draft genomes and annotation of O. rufipogon and O. longistaminata. Our analysis reveals a considerable number of lineage-specific gene families associated with the self-incompatibility (SI) and formation of reproductive separation. We show how lineage-specific expansion or contraction of gene families with functional enrichment of the recognition of pollen, thus enlightening their reproductive diversification. We documented a large number of lineage-specific gene families enriched in salt stress, antifungal response, and disease resistance. Our comparative analysis further shows a genome-wide expansion of genes encoding NBS-LRR proteins in these two outcrossing wild species in contrast to six other selfing rice species. Conserved noncoding sequences (CNSs) in the two wild rice genomes rapidly evolve relative to selfing rice species, resulting in the reduction of genomic variation owing to shifts of mating systems. We find that numerous genes related to these rapidly evolving CNSs are enriched in reproductive structure development, flower development, and postembryonic development, which may associate with SI in O. rufipogon and O. longistaminata.

[Scientificity of traditional commodity grade of Chinese medicinal materials--taking Lonicerae Japonicae Flos as example].

Taking Lonicerae Japonicae Flos as an example, the method of "expert consensus of different regions" was used to screen the representative samples and evaluate their commodity grades. The correlation analysis, hierarchical cluster analysis and partial least squares discriminant analysis(PLS-DA) of "commodity grade-appearance characteristic-component content" were carried out to reveal the scientificity of traditional commodity grade of Chinese medicinal material. By referring to the existing literature and the grade investigation from the sample collection regions, 78 "initial grade" samples were screened out from 118 collected samples. Authoritative experts from four regions(n=4) including Linyi(Shangdong province), Bozhou(Anhui province), Anguo(Hebei province) and Beijing were organized to evaluate their commodity grades, separately. Based on the grade consistency rate(R_i≥70%), 69 "local grade" samples were screened out from the "initial grade" samples. Based on the average grade consistency rate ■ "authoritative grade" samples were screened out from the "local grade" samples, including15 first-grade samples, 9 second-grade samples, 11 third-grade samples and 17 fourth-grade samples. For these "authoritative grade" samples, the main appea-rance characteristics were quantified and the contents of 13 components were determined by ultra performance liquid chromatography(UPLC). Furthermore, the total contents of 6 phenolic acids, 4 flavonoids and 3 iridoids were calculated, respectively. The results of correlation analysis showed that 4 appearance characteristics indices were correlated with the commodity grades: color, rate of yellow bars(including blooming flowers), rate of black heads(including black bars), and rate of stems and leaves(including bud debris). Five component content indices were correlated with the commodity grades: chlorogenic acid, isochlorogenic acid C, sweroside, loganin and the total contents of six phenolic acids. Furthermore, chlorogenic acid, loganin and the total contents of six phenolic acids showed significantly negative correlation with the main appearance characteristics, indicating that the appearance characteristics of Lonicerae Japonicae Flos can reflect its internal quality, and these 3 indices can be used as quality markers(Q-markers). The results of hierarchical cluster analysis showed that the samples of four grades were classified into four categories, and the samples with the same grades and the same categories accounted for 80.8% of the total samples, while the samples with the different grades were obviously classified into different categories. The results of PLS-DA analysis showed that the samples of different grades showed obvious intragroup aggregation and intergroup dispersion. The above results indicated that it was feasible to evaluate the traditional commodity grade of Lonicerae Japonicae Flos by the method of "expert consensus of different regions". For the evaluation of traditional commodity grade of Chinese medicinal material, the samples should be representative, expert conclusions should have enough consensuses, and grade determination should be authoritative. As the crystallization of clinical experience, traditional commodity grade can scientifically reflect the internal quality of Chinese medicinal material.

Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid.

Niemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. The most prevalent disease-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking from the endoplasmic reticulum to the LE/Ly compartments. We now show that the FDA-approved histone deacetylase inhibitor (HDACi) valproic acid (VPA) corrects the folding and trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis, an effect that is largely driven by a reduction in HDAC7 expression. The VPA-mediated trafficking correction is in part associated with an increase in the acetylation of lysine residues in the cysteine-rich domain of NPC1. The HDACi-mediated correction is synergistically improved by combining it with the FDA-approved anti-malarial, chloroquine, a known lysosomotropic compound, which improved the stability of the LE/Ly-localized fraction of the I1061T variant. We posit that combining the activity of VPA, to modulate epigenetically the cellular acetylome, with chloroquine, to alter the lysosomal environment to favor stability of the trafficked I1061T variant protein can have a significant therapeutic benefit in patients carrying at least one copy of the I1061T variant of NPC1, the most common disease-associated mutation leading to NPC disease. Given its ability to cross the blood-brain barrier, we posit VPA provides a potential mechanism to improve the response to 2-hydroxypropyl-ß-cyclodextrin, by restoring a functional NPC1 to the cholesterol managing compartment as an adjunct therapy.

Characteristics of within-household varicella transmission events associated with school outbreaks in Shanghai, China, 2009-2018.

Transmission of varicella occurs frequently in schools and households. We investigated the characteristics of varicella cases derived from within-household transmission and the modes of varicella transmission between school and household settings in Shanghai, China, from 2009 to 2018. Within-household transmission occurred in 278 households, of which 134 transmission events were between children. Sixty-one household varicella transmission events may be attributed to isolation procedures for infected students during school outbreaks, and 7.6% of school outbreaks were caused by schoolchildren cases derived from within-household transmission. The frequency of 'school-household-school' transmission adds an additional layer of complexity to the control of school varicella outbreaks. Administration of varicella vaccine as post-exposure prophylaxis after exposure is considered to be an effective measure to control varicella spread within households and schools.

Quality of life in caregivers of young children with Prader-Willi syndrome.

BACKGROUND: This study aimed to measure quality of life (QOL) in primary caregivers of young childrenwith Prader-Willi syndrome (PWS). METHODS: The caregivers of 32 children aged from 6.1 to 71.2 months completed the Chinese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF). We also evaluated the social adaption capacity of these children with Infants-Junior Middle School Students' Social-Life Abilities Scale. Correlation test was used to explore the related factors to caregivers' QOL. RESULTS: Caregivers of young children with PWS had significantly lower QOL. The correlation analyses revealed that caregivers' QOL was lower in children with young age, combined diseases or symptoms or poor social adaption, or caregivers having concerns about the child. CONCLUSIONS: Rearing a chilld with PWS may lead to decreased QOL. Psychological status of caregivers should be highlighted and social support should be given to families with PWS children.