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A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds, 9m emerged as the most effective XO inhibitor with an IC 50 value of 0.70 μM, which was approximately 14-fold more potent than allopurinol. Additionally, compound 9m displayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of 9m in complex with XO by molecular docking and molecular dynamics studies. In vivo hypouricemic studies also suggested that 9m could effectively lower the serum uric acid levels of rat. In summary, compound 9m could be a promising lead for further development of XO inhibitors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gentiana scabra bunge (Adenophora capillaris) is a traditional Chinese medicine crop in the northeast China. In July 2019, the root rot symptoms of A. capillaris were observed in its production field (approximately 1.3 hectares) iningyuan Manchu Autonomous County (41º47'28" N, 124º21'35" E), Fushun City in Liaoning province, China. Typical symptom included wilting, darkening, and rotting of the root collar and vascular bundle, leading to plant defoliation and death. Approximately 25% of the plants in the field showed the symptoms, with 2-year-old plants having more severe symptoms. Root tissue samples were collected from the diseased plants, surface-sterilized with 75% ethanol for 30 s, followed by 2% NaClO for 5 min, rinsed three times in sterile distilled water, and plated onto potato dextrose agar (PDA). After 3 days of incubation at 25 °C, white Fusarium-like colonies grew out from the symptomatic root tissue pieces. Five single-spore isolates were obtained from 10-day-old cultures using single-spore isolating technique. The fungus produced many macroconidia with the typical macroconidia of Fusarium spp. on carnation leaf agar (CLA) after 18 days of incubation at 26°C. They were falculate, slender and slightly curved, and their cells at both ends were sharp. Macroconidia had 3 to 5 septa, measuring 24.8 to 48.6 × 3.5 to 6.4 μm (n=50). Microconidia had 1 to 2 septa, elliptical, rounded tip, measuring 6.7 to 22.5 × 2.4 to 5.5 μm (n=5). Morphologically, the isolates were identified as Fusarium oxysporum (Leslie and Summerell 2006). For molecular identification, the internal transcribed spacer (ITS) region of rDNA and the translation elongation factor-1a (TEF-1α) of Isolate LD528-1 were amplified with the general primer ITS1/ITS4 and TEF-1α primer EF-1/EF-2 (O'Donnell et al. 1998). The resulting sequences were deposited in GenBank (acc. nos. MW418098 and MW423622). BLASTn analysis of the ITS sequence (KU939043) and TEF sequence (MW423622) revealed 99.06% sequence identity with F. oxysporum (KU939043) and 100% with F. oxysporum (MN892354), respectively. For pathogenicity test, a pot experiment was conducted in a greenhouse with 22 to 28°C and 65 to 90% relative humidity. Roots of A. capillaris were dipped in a spore suspension (1×107 conidia/ml) of Isolate LD528-1 for approximately 5 min, and then planted into the pots filled with sterilized field soil. Root dipped in sterilized water served as the controls. There were five pots for the inoculation treatment and three pots for the control treatment. All treated pots were placed and maintained in the greenhouse. After 15 days, 80% of inoculated plants were infected, with the symptoms similar to those observed in the field. The plants in the control treatment did not develop any symptoms. The same fungus was re-isolated from the diseased root tissue and confirmed by morphological and molecular assays as described above. This is the first report of F. oxysporum causing root rot of gentiana scabra bunge in China. This disease can become one of most important diseases in gentiana scabra bunge in China. References: Leslie, J. F., and Summerell, B. A. 2006. The Fusarium Laboratory Manual. Blackwell Publishing Ltd, Iowa, USA. O'Donnell, K., et al. 1998.PNAS, 95:2044. Funding: This work was supported by the Grant of China Agriculture Research System (CARS-21-06).

Objective: To understand the incidence trend of liver cancer in China from 2005 to 2016, and explore the correlation between the incidence trend of liver cancer and the incidence trend of hepatitis B. Methods: The incidence data of liver cancer in China from 2005 to 2016 were collected from the Annual Report of Cancer Registry in China. The incidence data of hepatitis B were collected from China Public Health Science Data Center. World standardized incidence rate (WSR) was calculated according to the World Segi's population. Joinpoint regression model was used to analyze the trend of WSR of liver cancer [measured by average annual percentage change (AAPC)]. The age-period-cohort model was fitted to analyze the age, period and cohort effects in people aged 20- years and above. Pearson correlation coefficient was used to explore the correlation between the incidence of liver cancer and the incidence of hepatitis B. Results: The crude incidence of liver cancer in China showed a trend of first increase before 2009 and then relatively stable. The world standardized morbidity rate of liver cancer in China decreased from 19.11 per 100 000 in 2005 to 17.74 per 100 000 in 2016 (AAPC=-0.5%, 95% CI : -1.3%-0.3%, P =0.240). The incidence of liver cancer in male decreased significantly (AAPC=-1.0%, 95% CI : -1.5%--0.5%, P =0.001). The incidence of liver cancer in women increased from 2005 to 2010 [annual percentage change (APC)=1.7%, 95% CI : -0.1%-3.4%, P =0.059] but showed a significant decrease trend from 2010 to 2016 (APC=-1.6%, 95% CI : -2.3%--1.0%, P =0.001). From 2005 to 2016, the incidence of liver cancer showed a decreasing trend in urban areas (AAPC=-0.3%, 95% CI : -0.8%-0.3%, P =0.316) and rural areas (AAPC=-3.9%, 95% CI : -4.4%--3.3%, P <0.001). Risk for liver cancer increased with age, while the period effect showed a trend of first increase then decrease and cohort effect showed a decrease trend. The morbidity rates of both hepatitis B and liver cancer showed decrease trends from 2009 to 2016, and there was a significant correlation ( r =0.71, 95% CI : 0.01-0.94, P =0.048). Conclusions: From 2005 to 2016, the morbidity rate of liver cancer in China showed a decrease trend, and there were significant gender and urban-rural area specific differences. Age effect had a great impact on the risk for liver cancer. With the progress of population aging in China, liver cancer is still a public health problem, to which close attention needs to be paid.

Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients' blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Huang, Zhao, Zhong, Shi, Guo, Zhao, Xiong, Yin, Chen, Zhang, Zhao, Li, Chen, Niu, Li, Qiu, Wu, Zhang, Tian and Wu.)

Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity with a prevalence of 1%-3%. Genetic factors have been associated with the etiology of AIS. However, previous studies mainly focused on common single nucleotide polymorphisms which confer modest disease risk. Recently, rare variants in FBN1 and other extracellular matrix genes have been implicated in AIS, suggesting a potential overlapping disease etiology between AIS and hereditary connective tissue disorders (HCTD). In this study, we systematically analyzed rare variants in a set of HCTD-related genes in 302 AIS patients who underwent exome sequencing. We firstly focused on pathogenic variants based on a monogenic inheritance and identified nine disease-associated variants in FBN1, COL11A1, COL11A2 and TGFBR2. We then explored the potential interactions between variants in different genes based on the case-control statistics. We identified three ADAMTSL2-LTBP4 variant pairs in three AIS patients and none in controls. Furthermore, we revealed that the variant pairs identified in these genes could affect the interaction between ADAMTSL2 and LTBP4 and upregulate TGF-β signaling pathway in human fibroblasts. Our findings implicate that the aberrant interaction between mutated ADAMTSL2 and LTBP4 was associated with AIS., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Qingjin Huatan Decoction is a classic prescription with the effects of clearing heat, moistening lung, resolving phlegm, and relieving cough. In order to explore the critical quality attributes of Qingjin Huatan Decoction, we identified the blood components of Qingjin Huatan Decoction by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS) under the following conditions, chromatographic column: Acquity UPLC BEH C&#95;(18) column(2.1 mm×100 mm, 1.7 μm); mobile phase: 0.1% formic acid acetonitrile(A)-0.1% formic acid in water(B); gradient elution; flow rate: 0.2 mL·min~(-1); column temperature: 30 ℃; injection volume: 5 μL. The electrospray ionization(ESI) source was used to collect data in both positive and negative ion modes under the following conditions, capillary voltage: 3 kV for the positive ion mode and 2 kV for the negative ion mode; ion source temperature: 110 ℃; cone voltage: 30 V; cone gas flow rate: 50 L·h~(-1); nitrogen degassing temperature: 350 ℃; degassing volume flow rate: 800 L·h~(-1); scanning range: m/z 50-2 000. In this experiment, a total of 66 related components of Qingjin Huatan Decoction were identified, including 22 prototype components and 44 metabolites. The results of this study preliminarily revealed the pharmacodynamic material basis of Qingjin Huatan Decoction in vivo, which has provided an experimental basis for the determination of quality markers of Qingjin Huatan Decoction and the development of new drugs.

In this study, we make an elucidation toward both the therapeutic effect and the mechanism of Shenqi Yanshen Formula (SQYSF) to chronic kidney disease (CKD). CKD mouse model was established and achieved in a way of adenine (200 mg/kg) perfusion. Six weeks later, those mice in the model group were fed with SQYSF (3.60 g/kg/day) every day (the captopril group was given 12.5 mg/kg/day by gavage every day, and control group and the model group were both given the gavage of equal volumes of normal saline); 4 weeks after the administration, we had our detection to physiological indicators of mice, performed ELISA assay to detect inflammatory factor expressions, then assay of 16S sequencing was used to reveal the difference of intestinal flora. Our results showed that after SQYSF treatment, both the expressions of serum creatinine (Scr) and blood urea nitrogen (BUN) came with a significant decline, indicating the outstanding performances of SQYSF in alleviating impairment in renal function and elevating mice's physiological function. SQYSF significantly reduced the degree of renal fibrosis in CKD mice, and remarkably down-regulated the expressions of toll-like receptor 5 (TLR5), nuclear factor-kappaB (NF-κb), p65, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. Additionally, SQYSF has more than ability in significantly changing the composition in mice's intestinal flora, but also in greatly increasing the abundance of Succinivibrionaceae and Aeromonadales in the mouse intestine. This study clarified the therapeutic effect of SQYSF on CKD and regulation of inflammatory factors and intestinal flora, and provided new ideas for treatment on CKD.

Background: Recently, an increasing number of studies have reported that sperm-associated antigen (SPAG) proteins play crucial roles in solid tumorigenesis, and may serve as potentially helpful biomarkers for cancer diagnosis and prognosis. However, very few studies systematically investigated the expression of SPAG family members and their clinical significance in acute myeloid leukemia (AML)., Methods: The expression of SPAGs and their prognostic significance in AML were determined by a systematic analysis on data gathered from public databases, and the results were validated in clinical samples., Results: Using public data, we identified only increased SPAG1 expression negatively associated with survival in AML by Cox regression (P < 0.001) and Kaplan-Meier analysis (P < 0.001). The prognostic value of SPAG1 expression was further confirmed in other independent cohorts. Clinically, higher SPAG1 expression was significantly correlated with white blood cell counts (P = 0.014) and French-American-British (FAB) subtypes (P = 0.024). Moreover, higher SPAG1 expression was more common in + 8 patients (P = 0.034), rarely found with t(8;21) (P = 0.014), and correlated with FLT3 (P < 0.001) and DNMT3A mutations (P = 0.001). Despite these associations, multivariate analysis confirmed the independent prognostic value of SPAG1 expression in AML (P < 0.001). Notably, AML patients with higher SPAG1 expression may benefit from hematopoietic stem cell transplantation (HSCT), whereas patients with lower SPAG1 expression appeared less likely to benefit. Finally, we further validated that SPAG1 expression was significantly increased in newly diagnosed AML patients compared with normal controls (P < 0.001) and with AML patients who achieved complete remission (P < 0.001). Additionally, SPAG1 expression could act as a potentially helpful biomarker for the diagnosis and prognosis of AML (P < 0.001 and = 0.034, respectively)., Conclusions: Our findings demonstrated that SPAG1 overexpression may serve as an independent prognostic biomarker and may guide the choice between HSCT and chemotherapy in patients with AML., (© 2022. The Author(s).)

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM&#95;002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome., (© 2022. The Author(s).)

In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the feasibility of automatic machine learning (autoML) based on native T1 mapping to predict late gadolinium enhancement (LGE) status in hypertrophic cardiomyopathy (HCM)., Methods: Ninety-one HCM patients and 44 healthy controls who underwent cardiovascular MRI were enrolled. The native T1 maps of HCM patients were classified as LGE ( +) or LGE (-) based on location-matched LGE images. An autoML pipeline was implemented using the tree-based pipeline optimization tool (TPOT) for 3 binary classifications: LGE ( +) and LGE (-), LGE (-) and control, and HCM and control. TPOT modeling was repeated 10 times to obtain the optimal model for each classification. The diagnostic performance of the best models by slice and by case was evaluated using sensitivity, specificity, accuracy, and microaveraged area under the curve (AUC)., Results: Ten prediction models were generated by TPOT for each of the 3 binary classifications. The diagnostic accuracy obtained with the best pipeline in detecting LGE status in the testing cohort of HCM patients was 0.80 by slice and 0.79 by case. In addition, the TPOT model also showed discriminability between LGE (-) patients and control (accuracy: 0.77 by slice; 0.78 by case) and for all HCM patients and controls (accuracy: 0.88 for both)., Conclusions: Native T1 map analysis based on autoML correlates with LGE ( +) or (-) status. The TPOT machine learning algorithm could be a promising method for predicting myocardial fibrosis, as reflected by the presence of LGE in HCM patients without the need for late contrast-enhanced MRI sequences., Key Points: • The tree-based pipeline optimization tool (TPOT) is a machine learning algorithm that could help predict late gadolinium enhancement (LGE) status in patients with hypertrophic cardiomyopathy. • The TPOT could serve as an adjuvant method to detect LGE by using information from native T1 maps, thus avoiding the need for contrast agent. • The TPOT also detects native T1 map alterations in LGE-negative patients with hypertrophic cardiomyopathy., (© 2021. European Society of Radiology.)

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6., (© 2021. The Author(s).)

Our previous work identified a promising isonicotinamide based xanthine oxidase (XO) inhibitor, N-(3-cyano-4-((2-cyanobenzyl)oxy)phenyl)isonicotinamide (1), and concluded that amide is an effective linker in exploring the XO inhibitor chemical space that is completely different from the five-membered ring framework of febuxostat and topiroxostat. Indole, an endogenous bioactive substance and a popular drug construction fragment, was involved in the structural optimization campaign of the present effort. After the installation of some functional groups, N-(1-alkyl-3-cyano-1H-indol-5-yl) was generated and employed to mend the missing H-bond interaction between the 3'-cyano of 1 and Asn768 residue of XO by shortening their distance. In this context, eight kinds of heterocyclic aromatic amide chemotypes were rationally designed and synthesized to investigate the structure-activity relationship (SAR) of amide-based XO inhibitors. The optimized compound a6 (IC 50  = 0.018 μM) exhibits 17.2-fold improved potency than the initial compound 1 (IC 50  = 0.31 μM). Its potency is comparable to that of topiroxostat (IC 50  = 0.013 μM). Molecular docking and molecular dynamics studies proved the existence of the stable H-bond between the cyano group and the Asn768 residue. Moreover, oral administration of a6 (11.8 mg/kg) could effectively reduce serum uric acid levels in an acute hyperuricemia rat model. Liver microsomal stability assay illustrated that compound a6 possesses well metabolic stability in rat liver microsomes. However, the in vivo potency of a6 was much lower than that of topiroxostat, which may be explained by the poor absorption found in the parallel artificial membrane permeability assay (PAMPA). In addition, 6a has non-cytotoxicity against normal cell lines MCF10A and 16HBE. Taken together, this work culminated in the identification of compound 6a as an excellent lead for further exploration of amide-based XO inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There is mounting evidence that demonstrated the association of aberrant NEDD4L expression with diverse human cancers. However, the expression pattern and clinical implication of NEDD4L in acute myeloid leukemia (AML) remains poorly defined., Methods: We systemically determined NEDD4L expression with its clinical significance in AML by both public data and our research cohort. Moreover, biological functions of NEDD4L in leukemogenesis were further tested by in vitro experiments., Results: By the public data, we identified that low NEDD4L expression was correlated with AML among diverse human cancers. Expression of NEDD4L was remarkably decreased in AML compared with controls, and was confirmed by our research cohort. Clinically, low expression of NEDD4L was correlated with greatly lower age, higher white blood cells, and higher bone marrow/peripheral blood blasts. Moreover, NEDD4L underexpression was positively correlated with normal karyotype, FLT3 and NPM1 mutations, but negatively associated with complex karyotype and TP53 mutations. Importantly, the association between NEDD4L expression and survival was also discovered in cytogenetically normal AML patients. Finally, a number of 1024 RNAs and 91 microRNAs were identified to be linked to NEDD4L expression in AML. Among the negatively correlated microRNAs, miR-10a was also discovered as a microRNA that may directly target NEDD4L. Further functional studies revealed that NEDD4L exhibited anti-proliferative and pro-apoptotic effects in leukemic cell line K562., Conclusions: Our findings indicated that NEDD4L underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. Moreover, NEDD4L expression may be involved in leukemogenesis with potential therapeutic target value., (© 2021. The Author(s).)

Impact of globulin addition on the functional and protein structural properties of dough and cooked noodles were investigated. The underlying mechanism was explored through analyzing the interaction between globulin and gluten by using SDS-PAGE, size exclusion chromatography, free sulfhydryl/disulfide bond analysis, laser scanning confocal microscopy and Fourier transform infrared spectroscopy. Results showed that the stiffness/hardness and maximum resistance of dough and cooked noodles were both increased when globulin addition was 1.5% or higher. Besides, extensibility of cooked noodles was also improved when the addition up to 3.0%. The addition of globulin facilitated weakening the S-S bonds in the gluten network and cross-linked with SDS-soluble gluten mainly through non-covalent interactions, especially hydrophobic interactions. Meanwhile, a more rigid protein network structure was observed. Additionally, following cooking, globulin addition accelerated the aggregation of protein molecules. When the addition reached 3%, the protein conformation was transformed from β-sheets and random coils to β-turns., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Depletion of ptk7 is associated with both congenital scoliosis (CS) and adolescent idiopathic scoliosis (AIS) in zebrafish models. However, only one human variant of PTK7 has been reported previously in a patient with AIS. In this study, we systemically investigated the variant landscape of PTK7 in 583 patients with CS and 302 patients with AIS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study. We identified a total of four rare variants in CS and four variants in AIS, including one protein truncating variant (c.464&#95;465delAC) in a patient with CS. We then explored the effects of these variants on protein expression and sub-cellular location. We confirmed that the c.464&#95;465delAC variant causes loss-of-function (LoF) of PTK7 . In addition, the c.353C>T and c.2290G>A variants identified in two patients with AIS led to reduced protein expression of PTK7 as compared to that of the wild type. In conclusion, LoF and hypomorphic variants are associated with CS and AIS, respectively.

Paeoniae Radix Alba is the dried root of Paeonia lactiflora, which was first recorded in the Shennong's Classic of Materia Medica and listed as the top grade. It is a common blood-tonifying herb, and its chemical components are mainly monoterpenes and their glycosides, triterpenes, flavonoids and so on. Modern research has demonstrated that Paeoniae Radix Alba has the activities of anti-inflammation, pain easing, liver protection, and anti-oxidation, and thus it is widely used in clinical practice and has broad development prospects. In this paper, the research progress on the chemical composition, pharmacological effects, and quality control of Paeoniae Radix Alba were summarized. On this basis, the Q-markers of Paeoniae Radix Alba were predicted from the aspects of mass transfer and traceability, chemical composition specificity, and availability and measurability of chemical components, which will provide a scientific basis for the quality evaluation of Paeoniae Radix Alba.

Objective: To compare the effects of different imaging methods on radio-opacity. Digital imaging and traditional film imaging were used to determine the radio-opacity of dental composite resin materials., Methods: Fourteen dental composite resins commonly used in clinic were prepared for disc samples with thickness of 1 mm and diameter of 15 mm respectively. The aluminum step wedge was used as the reference and the disc samples were irradiated with X-rays by the traditional film imaging, phosphor imaging plate and charge-coupled device(CCD) intra-oral X-ray sensor respectively. Exposure was set at 65 kV and 7 mA, with 300 mm focus to film distance and the exposure time was 0.25 s. After developing and fixing the film, the optical density of the image of the sample and that of each step of the aluminum step wedge were measured using the densitometer. The digital image file was exported to grey scale analysis software of Adobe Photoshop ® to measure the average grey value in the sample image and aluminum step wedge image. The curves were drawn corresponding to the optical density/gray value of each step of the aluminum step wedge and its thickness, and the equivalent thickness of the aluminum plate was calculated according to the optical density/gray value of the actual measured thickness of the sample, so as to evaluate the radio-opacity of dental composite resin material., Results: For the same sample, the aluminum equivalent measured by traditional film imaging and two other digital imagings had significant differences among the 14 composite resins ( P < 0.05), and the aluminum equivalent measured by the two digital imagings were greater than that of the traditional film. Moreover the aluminum equivalent measured by the two digital imagings was also different, and the aluminum equivalent measured by the CCD intra-oral X-ray sensor in most composite resins was larger than that measured by phosphor imaging plate. The same sample was photographed with the same imaging method, and the aluminum equivalent was different after three exposures. The standard deviation of aluminum equivalent measured by phosphor imaging plate was the largest, while that measured by CCD intra-oral X-ray sensor was the smallest. Among the 14 dental composite resin materials, the aluminum equivalent of Tetric N-Ceram and Te-Econom Plus measured by traditional film imaging and phosphor imaging plate was significantly higher than other composite resins., Conclusion: Based on clinical significance, three kinds of sensors designed to measure the radio-opacity of dental composite resin, the value of aluminum equivalent will change according to different types of sensors. The aluminum equivalent measured by CCD intra-oral X-ray sensor was higher than that measured by phosphor imaging plate, and the aluminum equivalent measured by phosphor imaging plate was higher than that measured by traditional film imaging. Moreover, even though the same sensor was used, the aluminum equivalent measured by multiple exposures was different. The standard deviation of the aluminum equivalent measured by phosphor imaging plate was greater than that measured by traditional film imaging and CCD intra-oral X-ray sensor. The three sensors in this study could be used for evaluating the radio-opacity of dental composite resin materials. But no matter what kind of sensor was used to measure the radio-opacity of dental composite resin, it complied to ISO 4049: 2019 standard, the materials were suitable for clinical use.

Objective: LncRNA ITGB2-AS1 has been found to play important roles in the occurrence and development of human solid tumors. However, its role in hematological diseases, especially acute myeloid leukemia (AML), remains unclear. The aim of this study was to identify the expression pattern of ITGB2-AS1 in AML patients and to further explore its clinical significance., Methods: ITGB2-AS1 expression was analyzed in public datasets (including TCGA and GSE63270) and further validated in a cohort of 109 AML patients by real-time quantitative PCR (RT-qPCR)., Results: The level of ITGB2-AS1 was up-regulated among two independent cohorts (TCGA, P<0.05; GSE63270, P<0.05), which was confirmed by the data from 109 AML patients enrolled in this study (P<0.05). Clinically, high ITGB2-AS1 expression was associated with older age (P=0.023) and lower complete remission (CR) rate (P=0.005). Multivariate analysis identified that high ITGB2-AS1 expression was an independent prognostic factor not only for CR rate (P=0.027) but also for overall survival (OS) time (P=0.011), and ITGB2-AS1 was positively correlated with ITGB2 expression in both TCGA (r=0.74, P<0.001) and clinical data detected in this study (r=0.881, P<0.001). High ITGB2 expression was also associated with older age (P=0.02) and lower CR rate (P=0.020). Moreover, high ITGB2 expression predicted worse OS (P=0.028)., Conclusion: ITGB2-AS1 is overexpressed in AML and predicts poor prognosis in AML patients.

Background: Glyphosate has been used for weed control in South China in various situations for four decades, and most Eleusine indica populations are suspected to have evolved resistance to glyphosate. This research investigated underling target-site glyphosate resistance mechanisms in six field-collected, putative glyphosate-resistant (R) E. indica populations., Results: The six R E. indica populations were confirmed to be low (1.8 to 2.6-fold) to moderately (5.6- to 8.4-fold) resistant to glyphosate relative to the susceptible (S) population. Sixty-seven glyphosate-surviving plants from the six R populations were used to examine target-site resistance mechanisms. Target-site 5-enolpyruvylshikimate3-phosphate synthase (EPSPS) overexpression (OE) (plus further induction by glyphosate treatment) and gene copy number variation (CNV) occurred in 94% R plants, and among them, 16% had the P106A mutation and 49% had the heterozygous double TIPS (T102I + P106S) mutation (plus P381L). In addition, a low number of R plants (6%) only had the homologous TIPS (plus P381L) mutation. The (CT) 6 insertion mutation in the EPSPS 5†-UTR always associates with EPSPS OE and CNV. Progeny plants possessing EPSPS OE/CNV (and P106A) displayed low level (up to 4.5-fold) glyphosate resistance. In contrast, plants homozygous for the TIPS mutation displayed higher (25-fold) resistance to glyphosate and followed by plants heterozygous for this mutation plus EPSPS OE/CNV (12-fold)., Conclusions: Target-site glyphosate resistance in E. indica populations from South China is common with prevalence of EPSPS OE/induction/CNV conferring low level resistance. Individual plants acquiring both the TIPS mutation and EPSPS OE/CNV are favored due to evolutionary advantages. The role of (CT) 6 insertion mutation in EPSPS CNV is worth further investigation. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Our previous work demonstrated that amide is an efficient linker to explore chemical space of xanthine oxidase (XO) inhibitors that are entirely different from febuxostat and topiroxostat. In this effort, with 3-cyano-1H-indol-5-yl as a key moiety, two series of amide-based XO inhibitors, N-(3-cyano-1H-indol-5-yl)isonicotinamides (2a-w) and N-(3-cyano-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamides (3a-i), were designed and synthesized. The structure-activity relationship investigation identified N-(3-cyano-1-cyclopentyl-1H-indol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (3i, IC 50  = 0.62 μM) as the most promising compound, with 14.4-fold higher in vitro inhibitory potency than allopurinol (IC 50  = 8.91 μM). Molecular simulations provided reasonable interaction modes for the representative compounds. Furthermore, in vivo activity evaluation demonstrated that compound 3i (oral dose of 12.8 mg/kg) has obviously hypouricemic effect on a potassium oxonate induced hyperuricemic rat model. Cytotoxicity assay and ADME prediction also supported that 3i is an excellent lead for further exploration of amide-based XO inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Differences in plant shade tolerance constitute a major mechanism driving the succession of forest communities in subtropical forests. However, the indirect effects of differences in light requirements on the growth of mid- and late-successional tree species are unclear, and this potential growth effect has not been explained at the transcriptome level. Here, a typical mid-successional dominant tree species, Schima superba Gardn. et Champ, and a typical late-successional dominant tree species, Cryptocarya concinna Hance were used as materials and planted under 100% full light (FL) and 30% FL (low light, LL) to explore the responses of tree species in different successional stages of subtropical forests to different light environments. Transcriptome sequencing was used to analyze the expression changes in genes related to growth and photoprotection under different light environments. The young leaves of S. superba accumulated more malondialdehyde (MDA) and superoxide radicals (${\mathrm{O}}&#95;2^{{{}^{\bullet}}^{-}}$) under LL. A lower hormone content (auxin, cytokinin, gibberellin) in the young leaves, a weaker photosynthetic capacity in the mature leaves and significant downregulation of related gene expression were also found under LL, which resulted in the total biomass of S. superba under LL being lower than that under FL. The young leaves of C. concinna had less MDA and ${\mathrm{O}}&#95;2^{{{}^{\bullet}}^{-}}$, and a higher hormone contents under LL than those under FL. There was no significant difference in photosynthetic capacity between mature leaves in contrasting light environments. Although the biomass of C. concinna under LL was less than that under FL, the height of C. concinna under LL was higher than that under FL, indicating that C. concinna could grow well under the two light environments. Our results describing the acclimatization of light at the physiological, molecular and transcriptome levels are important for a complete understanding of successional mechanisms., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: To explore the diagnostic performance of deep learning (DL) model in early detection of the interstitial myocardial fibrosis using native T1 maps of hypertrophic cardiomyopathy (HCM) without late gadolinium enhancement (LGE)., Methods: Sixty HCM patients and 44 healthy volunteers who underwent cardiac magnetic resonance were enrolled in this study. Each native T1 map was labeled according to its LGE status. Then, native T1 maps of LGE (-) and those of the controls were preprocessed and entered in the SE-ResNext-50 model as the matrix for the DL model for training, validation and testing., Results: A total of 241 native T1 maps were entered in the SE-ResNext-50 model. The model achieved a specificity of 0.87, sensitivity of 0.79, and area under curve ( AUC ) of 0.83 ( P <0.05) in distinguishing native T1 maps of LGE (-) from those of the controls in the testing set., Conclusion: The DL model based on SE-ResNext-50 could be used for identifying native T1 maps of LGE (-) with relatively high accuracy. It is a promising approach for early detection of myocardial fibrosis in HCM without the use of contrast agent., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

We report a measurement of the observed cross sections of e^{+}e^{-}→J/ψX based on 3.21  fb^{-1} of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686)→J/ψX)=(64.4±0.6±1.6)% and B(ψ(3770)→J/ψX)=(0.5±0.2±0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ(3686)→J/ψX and ψ(3770)→J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→J/ψX. Under this assumption, we extracted the R(3760) mass M&#95;{R(3760)}=3766.2±3.8±0.4  MeV/c^{2} , total width Γ&#95;{R(3760)}^{tot}=22.2±5.9±1.4  MeV, and product of leptonic width and decay branching fraction Γ&#95;{R(3760)}^{ee}B[R(3760)→J/ψX]=(79.4±85.5±11.7)  eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.

It was previously reported that PRR34-AS1 was overexpressed in some solid tumors. PRR34-AS1 promoter was shown to have a differential methylation region (DMR), and was hypomethylated in acute myeloid leukemia (AML). Therefore, the present study used real-time quantitative PCR (RQ-PCR) to explore the expression characteristics of PRR34-AS1 in AML. In addition, the correlation between the expression of PRR34-AS1 and clinical prognosis of AML was determined. The findings of this study indicated that high PRR34-AS1 expression was bound up with shorter overall survival (OS) in AML patients (p = 0.002). Moreover, patients with high expression of PRR34-AS1 had significantly lower complete remission (CR) rate compared with those with low expression of PRR34-AS1 after induction chemotherapy. Furthermore, multivariate analysis confirmed that PRR34-AS1 expression was an independent factor affecting CR in whole-AML, non-APL-AML, and CN-AML patients (p = 0.032, 0.039, and 0.036, respectively). Methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to explore the methylation status of PRR34-AS1. PRR34-AS1 promoter showed a pattern of hypomethylation in AML patients compared with normal controls (p = 0.122). Notably, of whole-AML and non-APL-AML patients, PRR34-AS1 hypomethylated patients presented a significantly shorter OS than those with a hypermethylated PRR34-AS1 (p = 0.010 and 0.037, respectively). Multivariate analysis confirmed that the hypomethylation of PRR34-AS1 served as an independent prognostic indicator in both whole-cohort AML and non-APL-AML categories (p = 0.057 and 0.018, respectively). In summary, the findings of this study showed that abnormalities in PRR34-AS1 are associated with poor prognosis in AML. Therefore, monitoring this index may be important in the prognosis of AML and can provide information on effective chemotherapy against the disease., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring FGFR1 variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) FGFR1 . As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, FGFR1 variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously.

Background: Patients undergoing lumbar spine surgery usually suffer severe pain in the postoperative period. The erector spinae plane block (ESPB), first published in 2016, can anesthetize the ventral and dorsal rami of thoracic nerves and produce an extensive multi-dermatomal sensory block., Aim: To assess whether bilateral ultrasound-guided ESPB at a lower thoracic level could improve pain control and quality of recovery in patients undergoing lumbar spine surgery., Methods: A total of 60 patients aged 18-80 years scheduled to undergo lumbar spine surgery with general anesthesia were randomly assigned to two groups: ESPB group (preoperative bilateral ultrasound-guided ESPB at T10 vertebral level) and control group (no preoperative ESPB). Both groups received standard general anesthesia. The main indicator was the duration to the first patient controlled intravenous analgesia (PCIA) bolus., Results: In the ESPB group, the duration to the first PCIA bolus was significantly longer than that in the control group (h) [8.0 (4.5, 17.0) vs 1.0 (0.5, 6), P < 0.01], and resting and coughing numerical rating scale (NRS) scores at 48 h post operation were significantly lower than those in the control group ( P < 0.05). There was no significant difference between the two groups regarding resting and coughing NRS scores at 24 h post operation. Sufentanil consumption during the operation was significantly lower in the ESPB group than in the control group ( P < 0.01), while there was no significant difference between the two groups regarding morphine consumption at 24 or 48 h post operation. In the ESPB group, Modified Observer's Assessment of Alertness/Sedation score within 20 min after extubation was higher and duration in the post-anesthesia care unit was shorter than those in the control group ( P < 0.01)., Conclusion: In patients undergoing lumbar spine surgery, ultrasound-guided ESPB at a lower thoracic level improves the analgesic effect, reduces opioid consumption, and improves postoperative recovery., Competing Interests: Conflict-of-interest statement: None declared., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

To further explore the research of novel PARP-1 inhibitors, we designed and synthesized a series of novel amide PARP-1 inhibitors based on our previous research. Most compounds displayed certain antitumor activities against four tumor cell lines (A549, HepG2, HCT-116, and MCF-7). Specifically, the candidate compound R8e possessed strong anti-proliferative potency toward A549 cells with the IC 50 value of 2.01 μM. Compound R8e had low toxicity to lung cancer cell line. And the in vitro enzyme inhibitory activity of compound R8e was better than rucaparib. Molecular docking studies provided a rational binding model of compound R8e in complex with rucaparib. The following cell cycle and apoptosis assays revealed that compound R8e could arrest cell cycle in the S phase and induce cell apoptosis. Western blot analysis further showed that compound R8e could effectively inhibit the PAR's biosynthesis and was more effective than rucaparib. Overall, based on the biological activity evaluation, compound R8e could be a potential lead compound for further developing novel amide PARP-1 inhibitors., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Adult non-degenerative scoliosis accounts for 90% of spinal deformities in young adults. However, perioperative complications and related risk factors of long posterior instrumentation and fusion for the treatment of adult non-degenerative scoliosis have not been adequately studied., Methods: We evaluated clinical and radiographical results from 146 patients with adult non-degenerative scoliosis who underwent long posterior instrumentation and fusion. Preoperative clinical data, intraoperative variables, and perioperative radiographic parameters were collected to analyze the risk factors for perioperative complications. Potential and independent risk factors for perioperative complications were evaluated by univariate analysis and logistic regression analysis., Results: One hundred forty-six adult non-degenerative scoliosis patients were included in our study. There were 23 perioperative complications for 21 (14.4%) patients, eight of which were cardiopulmonary complications, two of which were infection, six of which were neurological complications, three of which were gastrointestinal complications, and four of which were incision-related complication. The independent risk factors for development of total perioperative complications included change in Cobb angle (odds ratio [OR] = 1.085, 95% CI = 1.035 ~ 1.137, P = 0.001) and spinal osteotomy (OR = 3.565, 95% CI = 1.039 ~ 12.236, P = 0.043). The independent risk factor for minor perioperative complications is change in Cobb angle (OR = 1.092, 95% CI = 1.023 ~ 1.165, P = 0.008). The independent risk factors for major perioperative complications are spinal osteotomy (OR = 4.475, 95% CI = 1.960 ~ 20.861, P = 0.036) and change in Cobb angle (OR = 1.106, 95% CI = 1.035 ~ 1.182, P = 0.003)., Conclusions: Our study indicate that change in Cobb angle and spinal osteotomy are independent risk factors for total perioperative complications after long-segment posterior instrumentation and fusion in adult non-degenerative scoliosis patients. Change in Cobb angle is an independent risk factor for minor perioperative complications. Change in Cobb angle and spinal osteotomy are independent risk factors for major perioperative complications.

Aims: The blood-brain barrier (BBB) is a specialized and indispensable structure in brain blood vessels that is damaged during Alzheimer's disease (AD). CD147 is expressed on the BBB and deeply engaged in the AD pathological process. In this study, we aimed to provide a better understanding of the roles of CD147 in BBB function in health and neurodegenerative disease., Methods and Results: We measured CD147 expression in mouse brains and demonstrated that CD147 is exclusively expressed in brain endothelial cells (BECs), and its expression decreases with age. After constructing endothelial-specific CD147 knockout mice, we performed RNA-sequencing on BECs isolated from mice of different ages as well as a range of database analyses. We found that endothelial CD147 is essential for the dual functions of the BBB, including barrier maintenance and transporter regulation. This study also shows that CD147 plays a pivotal role in neurodegenerative diseases, particularly in AD., Conclusions: Our findings suggested that targeting CD147 in BECs may represent a novel therapeutic strategy, which promoted the design of future experimental investigations and the mechanistic understanding of neurodegenerative diseases., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Phenotypic plasticity affords invasive plant species the ability to colonize a wide range of habitats, but physiological plasticity of their stems is seldom recognized. Investigation of the stem plasticity of invasive plant species could lead to a better understanding of their invasiveness. We performed pot experiments involving defoliation treatments and isolated culture experiments to determine whether the invasive species Mikania micrantha exhibits greater plasticity in the stems than do three non-invasive species that co-occur in southern China and then explored the mechanism underlying the modification of its stem photosynthesis. Our results showed that the stems of M. micrantha exhibited higher plasticity in terms of either net or gross photosynthetic rate in response to the defoliation treatment. These effects were positively related to an increased stem elongation rate. The enhancement of stem photosynthesis in M. micrantha resulted from the comprehensive action involving increases in the Chl a / b ratio, D1 protein and stomatal aperture, changes in chloroplast morphology and a decrease in anthocyanins. Increased plasticity of stem photosynthesis may improve the survival of M. micrantha under harsh conditions and allow it to rapidly recover from defoliation injuries. Our results highlight that phenotypic plasticity promotes the invasion success of alien plant invaders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zheng, Zhang, Li, Liang, Zhang, Cai and Peng.)

Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Purpose: ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of ROR2 in children with short stature and to identify the underlying molecular mechanisms., Methods: We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2 . We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined., Results: We identified 12 mutations in ROR2 in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments in vitro . The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2., Conclusion: We expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gui, Yu, Li, Zhao, Zhao, Yan, Cheng, Lin, Zheng, Shao, Zhao, Zhao, Niu, Zhao, Wang, Xie, Wei, Gui, Li, Chen, Wang, Song, Gong, Zhang, Fan, Wu, Chen and Wu.)

CSF1R encodes the colony-stimulating factor 1 receptor which regulates the proliferation, differentiation, and biological activity of monocyte/macrophage lineages. Pathogenic variants in CSF1R could lead to autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia or autosomal recessive skeletal dysplasia. In this study, we identified three heterozygous deleterious rare variants in CSF1R from a congenital vertebral malformation (CVM) cohort. All of the three variants are located within the carboxy-terminal region of CSF1R protein and could lead to an increased stability of the protein. Therefore, we established a zebrafish model overexpressing CSF1R . The zebrafish model exhibits CVM phenotypes such as hemivertebral and vertebral fusion. Furthermore, overexpression of the mutated CSF1R mRNA depleted of the carboxy-terminus led to a higher proportion of zebrafish with vertebral malformations than wild-type CSF1R mRNA did ( p = 0.03452), implicating a gain-of-function effect of the C-terminal variant. In conclusion, variants affecting the C-terminal of CSF1R could cause CVM though a potential gain-of-function mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Zhao, Yan, Zhao, Lin, Wang, Niu, Li, Qiu, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Zhang, Wu and Wu.)

We present an analysis of the process ψ(3686)→Ω^{-}Ω[over ¯]^{+} (Ω^{-}→K^{-}Λ, Ω[over ¯]^{+}→K^{+}Λ[over ¯], Λ→pπ^{-}, Λ[over ¯]→p[over ¯]π^{+}) based on a dataset of 448×10^{6}  ψ(3686) decays collected with the BESIII detector at the BEPCII electron-positron collider. The helicity amplitudes for the process ψ(3686)→Ω^{-}Ω[over ¯]^{+} and the decay parameters of the subsequent decay Ω^{-}→K^{-}Λ (Ω[over ¯]^{+}→K^{+}Λ[over ¯]) are measured for the first time by a fit to the angular distribution of the complete decay chain, and the spin of the Ω^{-} is determined to be 3/2 for the first time since its discovery more than 50 years ago.

As a crucial transcription factor for spermatogenesis, GATA-binding protein 4 (GATA4) plays important roles in the functioning of Sertoli and Leydig cells. Conditional knockout of GATA4 in mice results in age-dependent testicular atrophy and loss of fertility. However, whether GATA4 is associated with human azoospermia has not been reported. Herein, we analyzed the GATA4 gene by direct sequencing of samples obtained from 184 Chinese men with idiopathic nonobstructive azoospermia (NOA). We identified a missense mutation (c.191G>A, p.G64E), nine single-nucleotide polymorphisms (SNPs), and one rare variant (c. * 84C>T) in the 3´ untranslated region (UTR). Functional studies demonstrated that the p.G64E mutation did not affect transactivation ability of GATA4 for spermatogenesis-related genes (claudin-11 and steroidogenic acute regulatory protein, Star), and the 3´ UTR rare variant c. * 84C>T did not generate microRNA-binding sites to repress GATA4 expression. To our knowledge, this is the first report to investigate the association between GATA4 and azoospermia; our results indicate that mutations in GATA4 may not be pathogenic for NOA in Chinese men., Competing Interests: None

Congenital scoliosis (CS) is a congenital disease caused by malformations of vertebrae. Recent studies demonstrated that DNA modification could contribute to the pathogenesis of disease. This study aims to identify epigenetic perturbations that may contribute to the pathogenesis of CS. Four CS patients with hemivertebra were enrolled and underwent spine correction operations. DNA was extracted from the hemivertebrae and spinal process collected from the specimen during the hemivertebra resection. Genome-wide DNA methylation profiling was examined at base-pair resolution using whole-genome bisulfite sequencing (WGBS). We identified 343 genes with hyper-differentially methylated regions (DMRs) and 222 genes with hypo-DMRs, respectively. These genes were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, calcium signaling pathway, and axon guidance in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and were enriched in positive regulation of cell morphogenesis involved in differentiation, regulation of cell morphogenesis involved in differentiation, and regulation of neuron projection development in Biological Process of Gene Ontology (GO-BP) terms. Hyper-DMR-related genes, including IGHG1 , IGHM , IGHG3 , RNF213 , and GSE1, and hypo DMR-related genes, including SORCS2 , COL5A1 , GRID1 , RGS3 , and ROBO2 , may contribute to the pathogenesis of hemivertebra. The aberrant DNA methylation may be associated with the formation of hemivertebra and congenital scoliosis., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Background: Klippel-Feil syndrome (KFS) represents the rare and complex deformity characterized by congenital defects in the formation or segmentation of the cervical vertebrae. There is a wide gap in understanding the detailed mechanisms of KFS because of its rarity, heterogeneity, small pedigrees, and the broad spectrum of anomalies., Methods: We recruited eight patients of Chinese Han ethnicity with KFS, five patients with congenital scoliosis (CS) who presented with congenital fusion of the thoracic or lumbar spine and without known syndrome or cervical deformity, and seven healthy controls. Proteomic analysis by data-independent acquisition (DIA) was performed to identify the differential proteome among the three matched groups and the data were analyzed by bioinformatics tools including Gene Ontology (GO) categories and Ingenuity Pathway Analysis (IPA) database, to explore differentially abundant proteins (DAPs) and canonical pathways involved in the pathogenesis of KFS., Results: A total of 49 DAPs were detected between KFS patients and the controls, and moreover, 192 DAPs were identified between patients with KFS and patients with CS. Fifteen DAPs that were common in both comparisons were considered as candidate biomarkers for KFS, including membrane primary amine oxidase, noelin, galectin-3-binding protein, cadherin-5, glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin-1, CD109 antigen, and eight immunoglobulins. Furthermore, the same significant canonical pathways of LXR/RXR activation and FXR/RXR activation were observed in both comparisons. Seven of DAPs were apolipoproteins related to these pathways that are involved in lipid metabolism., Conclusions: This study provides the first proteomic profile for understanding the pathogenesis and identifying predictive biomarkers of KFS. We detected 15 DAPs that were common in both comparisons as candidate predictive biomarkers of KFS. The lipid metabolism-related canonical pathways of LXR/RXR and FXR/RXR activation together with seven differentially abundant apolipoproteins may play significant roles in the etiology of KFS and provide possible pathogenesis correlation between KFS and CS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5155). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Myocardial fiber deformation measurements have been reported to be associated with adverse outcomes in patients with acute heart failure and those with myocardial infarction. However, few studies have addressed the prognostic value of global circumferential strain (GCS) in dilated cardiomyopathy (DCM) patients with severely impaired systolic function. This study aimed to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived GCS in DCM patients with severely reduced ejection. Consecutive DCM patients with severely reduced ejection fraction (EF <35%) who underwent CMR were included. GCS was calculated from CMR cine images. The clinical endpoint was a composite of all-cause mortality, heart transplantation, implantable cardioverter defibrillator (ICD) implantation and aborted sudden cardiac death (SCD). A total of 129 patients with a mean EF of 15.33% (11.36%-22.27%) were included. During a median follow-up of 518 days, endpoint events occurred in 50 patients. Patients with GCS ≥ the median (-5.17%) had significantly reduced event-free survival as compared with those with GCS < the median (P<0.01). GCS was independently associated with adverse events after adjusting for clinical and imaging risk factors including extent of late gadolinium enhancement (LGE) (P<0.05). Adding GCS into the model including the extent of LGE resulted in significant improvements in the C-statistic (from 0.706 to 0.742; P<0.05) with a continuous net reclassification improvement (NRI) of 29.71%. It was concluded that GCS derived from CMR could be useful for risk stratification in DCM patients with severely reduced EF, which may increase common imaging risk factors including LGE.

Choriocarcinoma is a highly malignant gynaecological tumour. This disease becomes life-threatening once brain haemorrhage or brain herniation occurs. Timely and accurate brain surgery can gain treatment time for patients that have a large number of cerebral haemorrhages and/or brain herniation. This current report describes a case of choriocarcinoma secondary to a hydatidiform mole in a 55-year-old woman that presented with neurological symptoms. Following admission to hospital, computed tomography examination found that lung and brain metastases were accompanied by cerebral haemorrhage. Cerebral hernia occurred during induction chemotherapy treatment and emergency surgery was performed. The patient recovered after individual chemotherapy and rehabilitation treatment. Patients with a very high risk of choriocarcinoma with brain metastasis should be referred to a comprehensive medical centre. Necessary surgical treatment and individualized chemotherapy can reduce the mortality of patients with choriocarcinoma brain metastasis.

Background: Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated., Results: In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML., Conclusions: Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC 50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC 50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The persistence of macrophage-derived foam cells in the artery wall fuels atherosclerosis development. However, the mechanism of foam cell formation regulation remains elusive. We are committed to determining the role that CD147 might play in macrophage foam cell formation during atherosclerosis. In this study, we found that CD147 expression was primarily increased in mouse and human atherosclerotic lesions that were rich in macrophages and could be upregulated by ox-LDL. High-throughput compound screening indicated that ox-LDL-induced CD147 upregulation in macrophages was achieved through PI3K/Akt/mTOR signaling. Genetic deletion of macrophage CD147 protected against foam cell formation by impeding cholesterol uptake, probably through the scavenger receptor CD36. The opposite effect was observed in primary macrophages isolated from macrophage-specific CD147 -overexpressing mice. Moreover, bioinformatics results indicated that CD147 suppression might exert an atheroprotective effect via various processes, such as cholesterol biosynthetic and metabolic processes, LDL and plasma lipoprotein clearance, and decreased platelet aggregation and collagen degradation. Our findings identify CD147 as a potential target for prevention and treatment of atherosclerosis in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lv, Wang, Cui, Liu, Zhang, Lu, Li, Yong, Liu, Zhang, Zhang, Zhang, Li, Nan, Zhang, Guo, Wang, Chen and Bian.)

Objectives: Fibromyalgia (FM) is the most common chronic pain disease in middle-aged women. Patients may also complain of migraine, irritable bowel syndrome and depression, which seriously affect their work and life, causing huge economic losses to society. However, the pathogenesis of FM is still controversial and the effect of the current treatment is far from satisfactory., Methods: Differentially expressed genes (DEGs) and miRNAs (DEMs) were found between FM and normal blood samples. The pathway and process enrichment analysis of the genes were performed. Protein-protein interaction network were constructed. Hub genes were found and analysed in The Comparative Toxicogenomics Database., Results: A total of 102 genes were up-regulated and 46 down-regulated, 206 miRNAs down-regulated, and 15 up-regulated in FM. CD38, GATM, HDC, FOS were found as canditate genes. These genes were significantly associated with musculoskeletal disease, mental disorder, immune system disease. There was partial overlap between metformin therapy-related genes and FM-related genes., Conclusions: We found DEGs and DEMs in FM patients through bioinformatics analysis, which may be involved in the occurrence and development of FM and serve as potential targets for diagnosis and treatment.

Objective: Insufcient exercise blood pressure response(blunted ABPR) and lower blood pressure during the recovery period (LBP)after exercise are common abnormalities in patients with hypertrophic cardiomyopathy (HCM). The purpose of this study was to analyze the related factors of these two types of abnormal blood pressure response in HCM patients and their relationship with cardiopulmonary function. Methods: A total of 219 consecutive HCM patients who underwent CPET in Fuwai hospital were recruited from April 1, 2018 to Jan 31, 2020 with a complete clinical assessment, including electrocardiography, HOLTER, rest echocardiography and cardiac MRI. One hundred and eleven healthy age- and gender-matched volunteers enrolled as control group. Results: The incidences of blunted ABPR and LBP in HCM patients were much higher than normal control group (8.7% vs 1.8%, P=0.016; 6.8% vs 0.0%, P=0.003, respectively). In HCM group, patients with blunted ABPR combined more coronary artery disease (CAD) (P=0.029), pulmonary hypertension (PH) (P=0.002) and atrial fibrillation/flutter (P=0.036) compared with patients without blunted ABPR. Compared with HCM patients without LBP, the patients with LBP had higher rest left ventricular outflow tract (LVOT) gradient (P=0.017) and left ventricular ejection fraction (P=0.043), more incidence of LVOT obstructive (P=0.015) and systolic anterior motion (P=0.022). After Logistic regression analysis, CAD and PH were independent factor of blunted ABPR, while LBP was only independently associated with rest LVOT gradient. Blunted ABPR was associated with lower Peak VO 2 , peak heart rate and hear rate reserve, and higher NT-proBNP (P=0.019), VE/VO 2 (P=0.000). LBP was not associated with any index of cardiopulmonary function. Conclusion: The incidences of blunted ABPR and LBP in HCM patients were much higher than normal control group. In HCM patients, CAD and PH were independent determinants of blunted ABPR, while LBP was only independently associated with rest LVOT gradient. Patients with blunted ABPR had lower cardiopulmonary function, but LBP was not associated cardiopulmonary function.

Three inorganic-organic hybrid gallo-/alumino-borates [Ga 2 B 7 O 14 (OH)]·H 2 dah ( 1 , dah = 1,6-diaminohexane), K 2 [Ga 2 B 7 O 14 (OH)(en) 0.5 ] ( 2 , en = ethylenediamine), and K 2 [Al 2 B 7 O 14 (OH)(en) 0.5 ]·H 2 O ( 3 ) were synthesized under solvothermal conditions. Compound 1 features a 3D porous-layered structure built by the alternation of [GaB 4 O 10 (OH)] 6- , [B 3 O 6 ] 3- clusters and GaO 4 tetrahedra, in which the novel [GaB 4 O 10 (OH)] 6- cluster is first observed. Compounds 2 and 3 are isostructural and made by [MB 4 O 10 (OH)] 6- , [B 3 O 6 (en) 0.5 ] 3- clusters and MO 4 tetrahedra (M = Ga/Al); their 3D porous layers are similar to those of 1 and further bridged by en linkers through the rare B-N-C covalent bonds, resulting in the 3D inorganic-organic hybrid framework. This is the first main-group metal borate with organic molecules participating in the oxoboron frameworks through B-N bonds. Optical diffuse-reflectance spectra reveal that 1 , 2 , and 3 are potential wide-band-gap semiconductors.

Background: Lung squamous cell carcinoma (LUSC) accounts up for approximately 30% of all lung cancers with a high mortality. The study was aimed at finding genes critical in the diagnosis and prognosis of LUSC., Materials and Methods: The differentially expressed (DE) genes (DEGs) and DE lncRNAs (DELs) from 501 LUSC and 49 normal lung tissues, and DE miRNAs (DEMs) from 478 LUSC and 45 normal lung tissues were respectively obtained via the TCGA database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and co-expression network analyses were performed. Survival analysis and receiver operating characteristic curve of hub mRNAs were also analyzed. Competitive endogenous RNA networks of lncRNAs, miRNAs and mRNAs were constructed., Results: A total of 5747 DEGs, 378 DEMs and 3141 DELs in LUSC were identified in LUSC. The DEGs including AUARK, CDK1, KIF11 and EXO1 were proven to be significant metastatic indicators in LUSC, and 2 DEGs were significantly associated with the survival in LUSC patients. Some genes might have connections with many other gene nodes through a co-expression network. Four lncRNAs, 2 mRNAs and 2 miRNAs were identified as the candidates for the competitive miRNA-mRNA-lncRNA network and might serve as prognostic markers in LUSC., Conclusions: We identified the differentially expressed lncRNAs, miRNAs and mRNAs in LUSC, providing further insights into the molecular mechanism of LUSC tumorigenesis and the potential prognostic biomarkers or therapeutic targets for LUSC., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression.

Using 2.93  fb^{-1} of e^{+}e^{-} collision data collected at a center-of-mass energy of 3.773 GeV with the BESIII detector, the first observation of the doubly Cabibbo-suppressed decay D^{+}→K^{+}π^{+}π^{-}π^{0} is reported. After removing decays that contain narrow intermediate resonances, including D^{+}→K^{+}η, D^{+}→K^{+}ω, and D^{+}→K^{+}ϕ, the branching fraction of the decay D^{+}→K^{+}π^{+}π^{-}π^{0} is measured to be (1.13±0.08&#95;{stat}±0.03&#95;{syst})×10^{-3}. The ratio of branching fractions of D^{+}→K^{+}π^{+}π^{-}π^{0} over D^{+}→K^{-}π^{+}π^{+}π^{0} is found to be (1.81±0.15)%, which corresponds to (6.28±0.52)tan^{4}θ&#95;{C}, where θ&#95;{C} is the Cabibbo mixing angle. This ratio is significantly larger than the corresponding ratios for other doubly Cabibbo-suppressed decays. The asymmetry of the branching fractions of charge-conjugated decays D^{±}→K^{±}π^{±}π^{∓}π^{0} is also determined, and no evidence for CP violation is found. In addition, the first evidence for the D^{+}→K^{+}ω decay, with a statistical significance of 3.3σ, is presented and the branching fraction is measured to be B(D^{+}→K^{+}ω)=(5.7&#95;{-2.1}^{+2.5}&#95;{stat}±0.2&#95;{syst})×10^{-5}.