Erratum: Intrinsic Correlation between the Fraction of Liquidlike Zones and the ß Relaxation in High-Entropy Metallic Glasses [Phys. Rev. Lett. 129, 175501 (2022)].

This corrects the article DOI: 10.1103/PhysRevLett.129.175501.

Intrinsic Correlation between the Fraction of Liquidlike Zones and the ß Relaxation in High-Entropy Metallic Glasses.

Lacking the structural information of crystalline solids, the origin of the relaxation dynamics of metallic glasses is unclear. Here, we report the evolution of stress relaxation of high-entropy metallic glasses with distinct ß relaxation behavior. The fraction of liquidlike zones, determined at each temperature by the intensity of stress decay, is shown to be directly related to both the aging process and the spectrum of relaxation modes obtained by mechanical spectroscopy. The results shed light on the intrinsic correlation between the static and dynamic mechanical response in high-entropy and conventional metallic glasses, pointing toward a sluggish diffusion high-entropy effect in the liquid dynamics.

[Twelve-week of sofosbuvir/velpatasvir therapeutic regimen for chronic hepatitis C patients in northwest region of China: a real-world multicenter clinical study].

Objective: To study the real-world outcome of China FDA-approved Sofosbuvir (SOF)/Velpatasvir (VEL) in Northwest China. Methods: In this multicenter, prospective, real-world cohort study, we recruited patients from 10 sites from Northwest China, who were chronically infected with HCV GTs 1-6 from 06/2018 to 09/2019. Patients received SOF (400mg)/VEL (100mg) for 12 weeks, and with ribavirin 900-1200 mg for GT3 cirrhosis and for any genotype decompensated cirrhosis. The primary endpoint was sustained virological response at 12-weeks post-treatment (SVR12) and safety. The secondary endpoint was the change of liver function after the achievement of SVR12. Results: Totally, 143 patients were enrolled in the study, four patients were lost to follow-up and one died during the follow-up, 138 patients were included in per-protocol analysis. Of the 138 patients, the mean age 53 years, 53.6% male, 94.2% Han nationality, 53.6% liver cirrhosis, 10.1% HBsAg(+), 6.5% renal dysfunction, 5.1% treatment-experienced, and 16.7% patients received ribavirin treatment. The genotype distribution was as follows: 35.5% GT1, 42.8% GT2, 15.9% GT3, and 5.8% un-typed. The SVR12 rate was 96.5% (138/143, 95%CI: 93.5%-99.6%) for intention-to-treat analysis, and in per-protocol analysis, all 138 patients obtained SVR12 (100%). Compared with baseline, the serum total bilirubin, ALT and AFP levels decreased (all P < 0.05), as well as increased ALB and platelet count (all P < 0.001) at post-treatment 12-weeks. Overall adverse events (AEs) rate is 29.0%, and the most common AEs were anemia (14.5%) and fatigue (8.0%). Severe side effects (edema and fatigue) occurred in 2 patients, one of whom needed a short-term interruption of treatment due to fatigue. Conclusion: In this real-world cohort study, 12-week SOF/VEL regimen with or without ribavirin achieved high SVR12 rates (96.5%-100% overall) with excellent safety profile among patients with HCV GT1/2/3 infection including patients with GT3 and cirrhosis, and led to improvement of liver function.

[Research progress in studies on tooth development based on diphyodont mammals].

For decades, the molecular and cellular mechanisms that govern tooth development have been extensively investigated. However, most of the studies are based on mice, whose teeth are quite different from human teeth in morphological and developmental aspects. Mice are not the ideal model for understanding the development of permanent teeth as they have only one set of dentition. Thus, using of diphyodont mammals is a better model to study the deciduous and permanent tooth development and to understand the process of tooth replacement. Several diphyodont mammal models have been established including minipig, ferret, house shrew and rabbit. Studies based on the diphyodont mammals have characterized the morphological changes involved in tooth replacement and molecular mechanisms of tooth replacement. However, few developmental stages were studied on ferret due to the presence of seasonal estrus and the difficulty to obtain ferret embryos at the correct stage. The house shrew is limited as a model because their deciduous tooth germs become vestigial in the embryonic period. The main disadvantage of the rabbit is an incomplete dentition with the lack of canines. Compared to the above mentioned animal models, the miniature pig has proven to be a valuable animal model for diphyodont development due to its dentition similarities, including the morphology, number and size of teeth, to human's, and particularly its heterodont dentition consisting of incisors, canines, premolars and molars. The present article reviews the current knowledge on the development of the primary and successional teeth in minipig modle and briefly summarizes the studies based on other diphyodont mammal models.

Genome-wide association study of fleece traits in Inner Mongolia Cashmere goats.

Inner Mongolia Cashmere goat is a well-known local cashmere goat breed in China. It is famous for excellent fleece quality and a significant advantage in cashmere yield compared to other cashmere goat breeds. In this study, a genome-wide association study was used to investigate fiber length, fiber diameter, and cashmere yield of 192 Inner Mongolia Cashmere goats using the Illumina GoatSNP52K Beadchip panel. We discovered that four single nucleotide polymorphisms (SNPs) reached genome-wide significance levels. These SNPs were located in some genes, e.g. FGF12, SEMA3D, EVPL, and SOX5, possibly related to fleece traits in Inner Mongolia Cashmere goat. Gene ontology enrichment analysis revealed that these genes were enriched in several biological pathways that were involved in hair follicle development in cashmere goats. In summary, the identified significant SNPs and genes provide useful information to explore genetic mechanisms underlying the variation in fleece traits and genomic selection of Chinese cashmere goat.

[Detection of EDA gene mutation and phenotypic analysis in patients with hypohidrotic ectodermal dysplasia].

OBJECTIVE: To detect the ectodysplasin A (EDA) gene mutation in patients with hypohidro-tic ectodermal dysplasia (HED), and to analyze the distribution pattern of missing permanent teeth and the systemic manifestation of HED patients with EDA gene mutation. METHODS: Twelve HED families were enrolled from clinic for genetic history collection, systemic physical examination and oral examination. Peripheral blood or saliva samples were collected from the probands and the family members to extract genomic DNA. PCR amplification and Sanger sequencing were utilized to detect the EDA gene variations, which were compared with the normal sequence (NM_001399.5). The functional impact of EDA gene variants was then evaluated by functional prediction of mutation, conservation analysis and protein structure prediction. The pathogenicity of each EDA gene variation was assessed according to the stan-dards and guidelines of the American College of Medical Genetics and Genomics (ACMG). The systemic phenotype and missing permanent tooth sites of HED patients with EDA gene mutations were summarized, and the missing rate of each tooth position was analyzed and compared. RESULTS: Eight out of twelve HED families were identified to carry EDA gene mutations, including: c.164T>C(p.Leu55Pro); c.457C>T (p.Arg153Cys); c.466C>T(p.Arg156Cys); c. 584G>A(p.Gly195Glu); c.619delG(p.Gly207Profs*73); c.673C>T(p.Pro225Ser); c.676C>T(p.Gln226*) and c.905T>G(p.Phe302Cys). Among them, c.164T>C(p.Leu55Pro); c.619delG(p.Gly207Profs*73); c.673C>T(p.Pro225Ser); c.676C>T(p.Gln226*) and c.905T>G(p.Phe302Cys) were novel mutations. The HED patients with EDA gene mutations in this study were all male. Our results showed that the average number of missing permanent teeth was 13.86±4.49, the average number of missing permanent teeth in the upper jaw was 13.14±5.76, the missing rate was 73.02%. And in the lower jaw, the average number of missing permanent teeth was 14.57±3.05, the missing rate was 80.95%. There was no significant difference in the number of missing teeth between the left and right sides of the permanent dentition (P>0.05). Specifi-cally, the maxillary lateral incisors, the maxillary second premolars and the mandibular lateral incisors were more likely to be missing, while the maxillary central incisors, the maxillary and mandibular first molars had higher possibility of persistence. CONCLUSION: This study detected novel EDA gene pathogenic variants and summarized the distribution pattern of missing permanent teeth of HED patients, thus enriched the variation and phenotype spectrum of EDA gene, and provided new clinical evidence for genetic diagnosis and prenatal consultation.

Long non-coding RNA LINC00152 is up-regulated in ovarian cancer tissues and regulates proliferation and cell cycle of SKOV3 cells.

OBJECTIVE: To characterize functions of long non-coding RNA (lncRNA) in the progression of epithelial ovarian cancer. PATIENTS AND METHODS: Epithelial ovarian cancer tissues and matching normal tissues were collected from two individual patients for RNA microarray analysis. Besides, twenty-two ovarian cancer samples and ten healthy ovarian epithelial tissues were collected for Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). Microarray assay suggested that a list of cancer relating mRNAs and lncRNAs were upregulated. The identified lncRNAs were validated via RT-qPCR, which led to the identification of long intergenic non-protein coding RNA 152 (LINC00152). To determine the function of LINC00152 in ovarian cancer, we knocked down the expression of LINC00152 in epithelial ovarian cancer cell line SKOV3 with small interference RNAs (siRNAs). The effects of LIN00152 on the proliferation and cell cycle were determined by comparing the cell viability of SKOV3 cells with LIN00152 knockdown and the control cells with negative siRNA. The cell viability was assessed using Cell Counting Kit-8 (CCK-8) and flow cytometry assay. RNA microarray assay was used again in control and LINC00152 knockdown SKOV3 cells to identify downstream signaling pathways. RESULTS: Fourteen ovarian cancer relating lncRNAs were identified by RNA microarray assay. Up-regulation of LINC00152 was validated via RT-qPCR. A higher expression of LINC00152 in late cancer stage (III-IV) compared to the early stage tumors was also demonstrated. Inhibition of LINC00152 in SKOV3 cells inhibited cell proliferation and induced cell cycle arrest that involved prolonged G1 phase and shortened S phase. The microarray assay data of SKOV3 cells suggested that Cyclin-Dependent Kinase Inhibitor 1C (CDKN1C) was a potential downstream target of LINC00152. CONCLUSIONS: LINC00152 is upregulated in epithelial ovarian cancer tissues comparing to normal tissues. Knockdown of LINC00152 expression inhibits cell proliferation and induces cell cycle arrest. LINC00152 possibly interacts with Tumor Necrosis Factor (TNF) signaling pathway. CDKN1C is a potential downstream target of LINC00152.

Biological background of the genomic variations of cf-DNA in healthy individuals.

BACKGROUND: Cell-free DNA (cf-DNA)-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cf-DNA remains challenging, partially because of the undefined biological background of cf-DNA. MATERIALS AND METHODS: We investigated somatic mutations in the cf-DNA of 259 cancer-free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 × 10-7) and compared the variant allele frequencies (VAFs) of these mutations between the cf-DNA and the corresponding blood cell DNA. RESULTS: Sixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cf-DNA mutations were also present at similar VAFs in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely 'passenger mutations' of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors. CONCLUSION: Hematopoietic clone-derived mutations, including 'driver mutations' and 'passenger mutations', are prevalent in the cf-DNA of both healthy individuals and cancer patients and may be a potential source of false positives in the liquid biopsy. Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low VAF (≤0.1%) from tumor-derived mutations using conventional next-generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies.

[Association between D-dimer levels and clinical events in patients with mechanical heart valve replacement under oral anticoagulation therapy].

Objective: To investigate the association between D-dimer levels and clinical events in patients with mechanical heart valve replacement under oral anticoagulation therapy. Methods: This prospective study included 640 consecutive patients underwent mechanical heart valve replacement in Wuhan Asia Heart Hospital between January 2013 and June 2014.Patients were assigned to abnormal D-dimer group (D-dimer level>cut off value, n=88) and normal D-dimer group (D-dimer level≤cut off value, n=552) according to D-dimer levels measured at 3 months after the initiation of oral anticoagulation therapy.All patients were followed up for 24 months or until the observation of the end points, which included thrombotic events, bleeding events and all-cause deaths.The anticoagulation therapy was monitored once per 1-2 months by the international normalized ratio (INR), and the target value was 1.8-3.0. Results: During a follow-up period of 24 months, rates of total clinical events (19.30%(17/88) vs. 5.8%(32/552), P<0.01), thrombotic events (11.4%(10/88) vs. 2.3%(13/552), P<0.01), and all-cause deaths (8.0%(7/88) vs. 2.0%(11/552), P<0.01) were all significantly higher in abnormal D-dimer group than in normal D-dimer group.There were no significant difference in bleeding events between the two groups (2.3%(2/88) vs. 3.1%(17/552), P=0.77). Multivariate Cox regression analysis showed that high D-dimer level was an independent risk factor of total clinical events (HR=3.86, 95%CI 1.92-7.76, P<0.01), thrombotic events(HR=5.29, 95%CI 2.12-13.10, P<0.01), and all-cause deaths(HR=5.32, 95%CI 1.71-16.60, P<0.01), but which was not correlated with bleeding events(HR=1.36, 95%CI 0.27-6.84, P=0.71). Conclusion: Elevated D-dimer levels are linked with clinical events in patients with mechanical heart valve replacement under oral anticoagulation therapy.

[Keratectomy combined with intrastromal injection of voriconazole in treating fungal keratitis].

Objective: To investigate the treatment effect of keratectomy combined with intrastromal injection of voriconazole on fungal keratitis. Methods: Retrospective study. Ninety-eight fungal keratitis patients (98 eyes) were treated by keratectomy combined with intrastromal injection of voriconazole in Shandong Eye Hospital from January 2013 to May 2015. The corneal ulcers were mostly located in the paracentral or peripheral cornea, which incompletely blocked the pupil area. Slit lamp and anterior segment optical coherence tomography (AS-OCT) were used for lesion detection. The maximum lesion diameter was ≤5 mm, and the maximum depth was not more than half of the full corneal thickness. Because the anti-fungal drug treatment for 3-7 days was not effective, keratectomy was performed with intrastromal injection of voriconazole. The excision extension was 0.5 mm greater than the ulcer diameter, and keratectomy could be repeated until the infiltrative tissues were completely removed. Anti-fungal drug therapy was carried on after surgery. The wound healing and complications were observed. Results: All the subjects were diagnosed as fungal keratitis by corneal scraping and confocal microscopy. With an average lesion diameter of (3.72±1.23) mm, the corneal ulcers were located in the paracentral cornea in 30 patients (30.6%) and in the peripheral cornea in 68 patients (69.4%). The infiltrative depth of 74.5% of the cases detected by AS-OCT were ≤1/2 corneal thickness. The fungal keratitis in 95 cases was cured successfully. Conjunctival flap covering surgery (2 cases) and penetrating keratoplasty (1 case) were performed when the conditions were poorly controlled. Among the 95 cured cases, the ulcer healing time ranged from 3 to 19 days, and ≤7 days in more than half of the cases (48 cases). The average corneal thickness was (433.2±119.3) µm at 3 months, and the corneal endothelial cell density was (2 344.0±404.6) cells/mm(2). The uncorrected visual acuity was improved in 71(74.7%) eyes, of which 3 cases had a vision of 1.0. Conclusions: For fungal keratitis with a lesion diameter of<6 mm and a depth not more than half of the full corneal thickness, keratectomy combined with intrastromal injection of voriconazole could achieve ideal outcomes. The visual acuity recovered quickly, the therapy course was shortened, and the necessity of keratoplasty and other high risk surgeries was reduced. (Chin J Ophthalmol, 2017, 53: 682-688).

Cavernosum smooth muscle relaxation induced by Schisandrol A via the NO-cGMP signaling pathway.

To evaluate the effect of Schisandrol A on rabbit corpus cavernosum smooth muscle and elucidate the potential mechanism. Penises were obtained from healthy male New Zealand White rabbits (2.5-3.0 kg). The pre-contracted penis with phenylephrine (Phe, 10 µM) was treated with accumulative concentrations of Schisandrol A (10-7, 10-6, 10-5 and 10-4 M). The change in intracavernosum pressure (ICP) and tension was recorded, cyclic nucleotides in the cavernosum tissue were measured by radioimmunoassay, mRNA level and expression of endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) were measured by real time PCR and western blot respectively. The corpus cavernosum smooth muscle relaxation induced by Schisandrol A was in a dose-dependent manner. Pre-treatment with NOS inhibitor (Nω nitro-L-arginine-methyl ester, L-NAME) or guanylyl cyclase inhibitor (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, ODQ) significantly diminished the relaxation. The cyclic guanosine monophosphate (cGMP) level was significantly increased in the cavernosum tissue. Real time PCR and western blot showed the mRNA level and expression of eNOS and nNOS was also upregulated. Schisandrol A relaxes the cavernosum smooth muscle by activating NO-cGMP signaling pathway. It may be a new promising treatment for erectile dysfunction and cardiovascular disease.

Additive effects of Artemisia capillaris extract and scopoletin on the relaxation of penile corpus cavernosum smooth muscle.

The objective was to investigate the cellular effect and action mechanism of Artemisia capillaris extract (ACE) and its component, scopoletin, on penile corpus cavernosum smooth muscle (PCCSM). In vitro study with PCCSM, the precontracted PCCSM with phenylephrine was treated with ACE or scopoletin. Cyclic nucleotides in the perfusate were measured by radioimmunoassay and expression of protein and mRNA of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase in the perfused PCCSM were measured by western blot and real-time PCR, respectively. The interaction of ACE or scopoletin with udenafil was also evaluated. ACE and scopoletin exerted a significant and concentration-dependent relaxation in PCCSM. The perfusion with ACE or scopoletin significantly increased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and the perfusion with ACE or scopoletin increased the expression of eNOS mRNA and protein. Furthermore, ACE or scopoletin enhanced udenafil-inducing relaxation in PCCSM. ACE and scopoletin relaxed the PCCSM mainly by activating nitric oxide-cGMP system and cAMP pathway and they may be additive therapeutic candidates for ED patients who do not completely respond to udenafil.

Intracranial aneurysm risk factor genes: relationship with intracranial aneurysm risk in a Chinese Han population.

Few studies have examined the genes related to risk fac-tors that may contribute to intracranial aneurysms (IAs). This study in Chinese patients aimed to explore the relationship between IA and 28 gene loci, proven to be associated with risk factors for IA. We recruited 119 patients with aneurysms and 257 controls. Single factor and logistic regression models were used to analyze the association of IA and IA rup-ture with risk factors. Twenty-eight single nucleotide polymorphisms (SNPs) in 22 genes were genotyped for the patient and control groups. SNP genotypes and allele frequencies were analyzed by the chi-square test. Logistic regression analysis identified hypertension as a factor that increased IA risk (P = 1.0 x 10(-4); OR, 2.500; 95%CI, 1.573-3.972); IA was associated with two SNPs in the TSLC2A9 gene: rs7660895 (P = 0.007; OR, 1.541; 95%CI, 1.126-2.110); and in the TOX gene: rs11777927 (P = 0.013; OR, 1.511; 95%CI, 1.088-2.098). Subsequent removal of the influence of family relationship identified between 12 of 119 patients enhanced the significant association of these SNPs with IA (P = 0.001; OR, 1.691; 95%CI, 1.226-2.332; and P = 0.006; OR, 1.587; 95%CI, 1.137-2.213 for rs7660895 and rs11777927, respectively). Fur-thermore, the minor allele of rs7660895 (A) was also associated with IA rupture (P = 0.007; OR, 2.196; 95%CI, 1.230-3.921). Therefore, hypertension is an independent risk factor for IA. Importantly, the TSL-C2A9 (rs7660895) and TOX (rs11777927) gene polymorphisms may be associated with formation of IAs, and rs7660895 may be associated with IA rupture.

Analysis of testicular-internal spermatic vein variation and the recreation of varicocoele in a Sprague-Dawley rat model.

Many laboratories tried to recreate the varicocoele model have met with varied success. To recreate a consistent varicocoele model by exploring the anatomic variability of the testicular-spermatic venous system in Sprague-Dawley (SD) rats. Seventy-two sexually mature SD male rats were randomly divided into three groups containing 24 rats per group. Partial ligation of the left renal vein and internal spermatic vein (ISV) communicating branches to common iliac vein and ISV communicating branches ligation (RVISVCBCIV) or partial ligation of the left renal vein and ISV communicating branches ligation (RVISVCB). The results showed that the mean diameter of the left ISV was significantly increased in the RVISVCBCIV group compared with the control and RVISVCB groups (p < 0.001). Using ISV as the reference, the sensitivity of varicocoele was 71.43%, and the specificity was 80%. In addition, the positive predictive value was 83.33%, and the negative predictive value was 66.67%. Sperm count, motility, Johnsen score and the spermatogenic cell density were lower in the RVISVCBCIV group compared with the control (p < 0.01). The apoptotic index was higher in the RVISVCBCIV group compared with control groups (p < 0.01). The RVISVCBCIV provides a more effective method for establishing a varicocoele-induced model.

Simultaneous Quantification of Six Major Flavonoids From Fructus sophorae by LC-ESI-MS/MS and Statistical Analysis.

A new, sensitive and selective high-performance liquid chromatography-tandem mass spectrometric method has been developed for the determination of six major flavonoids including sophoricoside, genistin, genistein, rutin, quercetin, kaempferol in Fructus sophorae. Principal component analysis and hierarchical clustering analysis were used to classify and differentiate these samples. Chromatographic separation was performed on a C18 column with linear gradient elution of methanol and 0.05% acetic acid (v/v) at a flow rate of 0.8 ml/min. The detection was accomplished in the negative mode using multiple-reaction monitoring. The total run time was 8.0 min. Full validation of the assay was carried out including linearity, precision, accuracy, recovery, limit of detection and limit of quantification. The validated method was successfully applied to the simultaneous determination of these active components in Fructus sophorae. The results demonstrated that the quantitative difference in content of six active compounds was useful for chemotaxonomy of many samples from different sources and the standardization and differentiation of many similar samples. Simultaneous quantification of bioactive components by high-performance liquid chromatography-tandem mass spectrometric method coupled with chemometric techniques would be a well-acceptable strategy to comprehensively control the quality of Fructus sophorae.

Chromosome microarray analysis in a clinical environment: new perspective and new challenge.

The analysis of the human genome has largely been undertaken in a research environment, but recent developments in technology and associated workflow have allowed diagnostic laboratories to interrogate DNA at significantly improved levels of resolution. Principally, whole genome-based analysis of copy number changes using microarrays has led to this method replacing conventional karyotyping as a routine diagnostic workhorse. The resolution offered by microarrays is an improvement of at least an order of magnitude compared to karyotyping, but it comes at a cost in terms of the time spent in data interpretation. Overall, however, the die has been cast and cytogeneticists need to become familiar with the tools use by molecular geneticists and bioinformaticists. The following review provides a brief background to array technology, but uses a series of case studies to illustrate the usefulness and challenges of interpreting array data.