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Abstract Polypeptide N-Acetylgalactosaminyltransferase (GALNTs) are critical enzymes that initiate mucin type-O glycosylation, and are closely associated with the occurrence and development of multiple cancers. However, the significance of GALNT2 in clear cell renal cell carcinoma (ccRCC) progression remains largely undetermined. Based on public multi-omics analysis, GALNT2 was strongly elevated in ccRCC versus adjoining nontumor tissues, and it displayed a relationship with poor overall survival (OS) of ccRCC patients. In addition, GALNT2 over-expression accelerated proliferation of renal cancer cell (RCC) lines. In contrast, GALNT2 knockdown using shRNAs suppressed cell proliferation, and this was rescued by LATS2 knockdown. Similarly, GALNT2 deficiency enhanced p-LATS2/LATS2 expression. LATS2 is activated by phosphorylation (p-LATS2) and, in turn, phosphorylate the downstream substrate protein YAP. Phosphorylated YAP (p-YAP) stimulated its degradation and cytoplasmic retention, as it was unable to translocate to the nucleus. This resulted in reduced cell proliferation. Subsequently, we explored the upstream miRNAs of GALNT2. Using dual luciferase reporter assay, we revealed that miR-139-5p interacted with the 3ʹ UTR of GALNT2. Low miR-139-5p expression was associated with worse ccRCC patient outcome. Based on our experiments, miR-139-5p overexpression inhibited RCC proliferation, and this phenotype was rescued by GALNT2 overexpression. Given these evidences, the miR-139-5p-GALNT2-LATS2 axis is critical for RCC proliferation, and it is an excellent candidate for a new therapeutic target in ccRCC.

Gametogenetin binding protein 2 (GGNBP2) was indispensable in normal spermatids for transformation into mature spermatozoa in mice, and when Gametogenetin binding protein 2 is bound to BRCC36 and RAD51, the complex participates in repairing DNA double-strand breaks (DSB) during the meiotic progression of spermatocytes. Ggnbp2 knockout resulted in the up-regulation of H2AK119ubi and down-regulation of H2BK120ubi in GC-2 cells (mouse spermatogonia-derived cell line) and postnatal day 18 testis lysate. Our results also demonstrated that Gametogenetin binding protein 2 inducedASXL1 to activate the deubiquitinating enzyme BAP1 in deubiquitinating H2A, while Gametogenetin binding protein 2 knockout disrupted the interaction between ASXL1 and BAP1, resulting in BAP1 localization change. Furthermore, the Gametogenetin binding protein 2 deletion reduced H2B ubiquitination by affecting E2 enzymes and E3 ligase binding. Gametogenetin binding protein 2 regulated H2A and H2B ubiquitination levels and controlled H3K27 and H3K79 methylation by PRC2 subunits and histone H3K79 methyltransferase. Altogether, our results suggest that Ggnbp2 knockout increased DNA damage response by promoting H2A ubiquitination and H3K27trimethylation (H3K27me3) and reduced nucleosome stability by decreasing H2B ubiquitination and H3K79 dimethylation (H3K79me2), revealing new mechanisms of epigenetic phenomenon during spermatogenesis. Gametogenetin binding protein 2 seems critical in regulating histone modification and chromatin structure in spermatogenesis.

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE–/–LDLR–/–) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

The role of enhancer de-regulation in anti-tumor immunity remains to be explored. Here, the authors suggest that ablation of MLL3 and MLL4, two enhancer-associated H3K4 monomethyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response.

Background: Low educational attainment has been reported as a risk factor for many diseases. However, conclusion on the association between educational attainment and endometrial cancer (EC) are inconsistent in previous observational studies. This study aims to explore the potential causal association between educational attainment and EC.Methods: A Mendelian Randomization analysis was performed using publicly summary-level data sets of genome-wide association studies (GWAS). A total of 306 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of educational attainment from the Social Science Genetic Association Consortium GWAS summary data of 1,131,881 participants of European ancestry. SNPs of EC were obtained from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium and the UK Biobank involving 121,885 people. We conducted inverse variance weighted (IVW) to estimate the causal effect as our primary outcome. And we perform several sensitivity analyses, including MR-Egger regression, weighted median method, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier) global test, and leave-one-out sensitivity analysis, to evaluate the effect of pleiotropism on the causal estimates.Results: Genetic predisposition towards 4.2 years of additional educational attainment was associated with 38% lower risk of EC. (odds ratio 0.72, 95% confidence interval 0.62 to 0.83; p = 1.65*10−5). The consistent results of sensitivity analyses indicated our causal estimates were reliable. Genetic predisposition towards longer educational attainment was associated with lower risk of obesity, high waist-to-hip ratio (WHR), and diabetes.Conclusion: This study indicated that low educational attainment was a causal risk factor for EC, especially for EC with endometrioid histology. Low educational attainment might lead to EC through the mediator of obesity, high WHR, and diabetes.

Diabetic retinopathy (DR) is increasingly becoming a main complication of diabetes, and is difficult to cure. In our research, network pharmacology analysis suggested that both compound Danshen dripping pills (CDDP) and bezafibrate (BZF) have potential protective effects against DR and the two drugs may act synergistically. The pharmacological effects of the coadministration of CDDP and BZF were elucidated in db/db mice, which simulate DR. Fluorescein fundus angiography showed that coadministration attenuated vascular leakage. Optical coherence tomography and hematoxylin and eosin staining showed that coadministration improved retinal thickness better than CDDP monotherapy. In addition, cell fluorescence images of reactive oxygen species revealed that coadministration of CDDP and BZF had more potent effects against oxidative stress than CDDP monotherapy. Metabolomics analysis showed that coadministration reduced the ratio of oxidized glutathione to reduced glutathione further than CDDP monotherapy. Coadministration of CDDP and BZF may provide additional protective effects by resisting vascular leakage, increasing retinal thickness, and inhibiting inflammation and oxidative stress in DR.

Background: The etiology of preeclampsia (PE) remains unclear. With the utilization of metabolomics, dysregulated production of several metabolic components in human plasma, such as lipids, amino acids, androgens and estrogens, was found to be important in the pathogenesis of PE. Transcriptomics adds more in-depth information, and the integration of transcriptomics and metabolomics may yield further insight into PE pathogenesis than either one alone.Objectives: We investigated the placental metabolomics and transcriptomics of PE patients to identify affected metabolic pathways and potential biological targets for exploring the disease pathogenesis.Methods: Integrated transcriptomics and metabolomics were used to analyze five paired human placentas from patients with severe PE and normal pregnancies. This was followed by further validation of our findings in a publicly available dataset of 173 PE vs. 157 control placentas. In addition, weighted gene coexpression network construction was performed to assess the correlation between genetic alterations and diseases.Results: We identified 66 and 41 differentially altered metabolites in negative and positive ion modes, respectively, in the PE group compared to the control group, and found 2,560 differentially expressed genes. Several pathways were aberrantly altered in the PE placenta at both the metabolic and transcriptional levels, including steroid hormone biosynthesis, the cAMP signaling pathway, neuroactive ligand–receptor interactions, taste transduction and prion diseases. Additionally, we found 11 differential metabolites and 11 differentially expressed genes involved in the steroid hormone biosynthesis pathway, indicating impaired metabolism of steroid hormones in the PE placenta. Furthermore, we found that CYP11A1, HSD3B2, and HSD17B6 are highly correlated with diseases.Conclusion: Our findings provide a profile of the dysregulated steroid hormone biosynthesis in PE placenta, we observed a dysregulated cortisol-to-cortisone ratio, testosterone accumulation, decreased testosterone downstream metabolites, impaired production of estrone and estriol, and aberrant hydroxylation and methylation of estradiol. Disorders of placental steroid hormone metabolism might be a consequence or a compensatory change in pathological placentation in PE, which underscores the need to investigate the physiology of steroid hormone metabolites in the etiology of PE.

KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and its downstream targets in gonadal steroidogenic cells for the development and homeostasis of reproductive functions remain to be determined. To understand the functions of KRAS signaling in gonadal theca and interstitial cells, we generated a Kras mutant (tKrasMT) mouse line that selectively expressed a constitutively active KrasG12D in these cells. KrasG12D expression in ovarian theca cells did not block follicle development to the preovulatory stage. However, tKrasMT females failed to ovulate and thus were infertile. The phosphorylated ERK1/2 and forkhead box O1 (FOXO1) and total FOXO1 protein levels were markedly reduced in tKrasMT theca cells. KrasG12D expression in theca cells also curtailed the phosphorylation of ERK1/2 and altered the expression of several ovulation-related genes in gonadotropin-primed granulosa cells. To uncover downstream targets of KRAS/FOXO1 signaling in theca cells, we found that the expression of bone morphogenic protein 7 (Bmp7), a theca-specific factor involved in ovulation, was significantly elevated in tKrasMT theca cells. Chromosome immunoprecipitation assays demonstrated that FOXO1 interacted with the Bmp7 promoter containing forkhead response elements and that the binding activity was attenuated in tKrasMT theca cells. Moreover, Foxo1 knockdown caused an elevation, whereas Foxo1 overexpression resulted in an inhibition of Bmp7 expression, suggesting that KRAS signaling regulates FOXO1 protein levels to control Bmp7 expression in theca cells. Thus, the anovulation phenotype observed in tKrasMT mice may be attributed to aberrant KRAS/FOXO1/BMP7 signaling in theca cells. Our work provides the first in vivo evidence that maintaining normal KRAS activity in ovarian theca cells is crucial for ovulation and female fertility.

It is clinical reported that YangXue QingNao Wan (YXQNW) combined with donepezil can significantly improve the cognitive function of AD patients. However, the mechanism is not clear. A network pharmacology approach was employed to predict the protein targets and affected pathways of YXQNW in the treatment of AD. Based on random walk evaluation, the correlation between YXQNW and AD was calculated; while a variety of AD clinical approved Western drugs were compared. The targets of YXQNW were enriched and analyzed by using the TSEA platform and MetaCore. We proved that the overall correlation between YXQNW and AD is equivalent to clinical Western drugs, but the mechanism of action is very different. Firstly, YXQNW may promote cerebral blood flow velocity by regulating platelet aggregation and the vasoconstriction/relaxation signal pathway, which has been verified by clinical meta-analysis. Secondly, YXQNW may promote Aβ degradation in the liver by modulating the abnormal glucose and lipid metabolisms via the adiponectin-dependent pathway, RXR/PPAR-dependent lipid metabolism signal pathway, and fatty acid synthase activity signal pathway. We also verified whether YXQNW indeed promoted Aβ degradation in hepatic stellate cells. This work provides a novel scientific basis for the mechanism of YXQNW in the treatment of AD.

Ischemic stroke (IS) is an acute neurological injury that occurs when a vessel supplying blood to the brain is obstructed, which is a leading cause of death and disability. Salvia miltiorrhiza has been used in the treatment of cardiovascular and cerebrovascular diseases for over thousands of years due to its effect activating blood circulation and dissipating blood stasis. However, the herbal preparation is chemically complex and the diversity of potential targets makes difficult to determine its mechanism of action. To gain insight into its mechanism of action, we analyzed “Salvianolic acid for injection” (SAFI), a traditional Chinese herbal medicine with anti-IS effects, using computational systems pharmacology. The potential targets of SAFI, obtained from literature mining and database searches, were compared with IS-associated genes, giving 38 common genes that were related with pathways involved in inflammatory response. This suggests that SAFI might function as an anti-inflammatory agent. Two genes associated with inflammation (PTGS1 and PTGS2), which were inhibited by SAFI, were preliminarily validated in vitro. The results showed that SAFI inhibited PTGS1 and PTGS2 activity in a dose-dependent manner and inhibited the production of prostaglandin E2 induced by lipopolysaccharide in RAW264.7 macrophages and BV-2 microglia. This approach reveals the possible pharmacological mechanism of SAFI acting on IS, and also provides a feasible way to elucidate the mechanism of traditional Chinese medicine (TCM).

Background: Coronary artery disease (CAD) exerts a global challenge to public health. Genetic heritability is one of the most vital contributing factors in the pathophysiology of CAD. Co-expression network analysis is an applicable and robust method for the interpretation of biological interaction from microarray data. Previous CAD studies have focused on peripheral blood samples since the processes of CAD may vary from tissue to blood. It is therefore necessary to find biomarkers for CAD in heart tissues; their association also requires further illustration.Materials and Methods: To filter for causal genes, an analysis of microarray expression profiles, GSE12504 and GSE22253, was performed with weighted gene co-expression network analysis (WGCNA). Co-expression modules were constructed after batch effect removal and data normalization. The results showed that 7 co-expression modules with 8,525 genes and 1,210 differentially expressed genes (DEGs) were identified. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Four major pathways in CAD tissue and hub genes were addressed in the Hybrid Mouse Diversity Panel (HMDP) and Human Protein Atlas (HPA), and isoproterenol (ISO)/doxycycline (DOX)-induced heart toxicity models were used to validate the hub genes. Lastly, the hub genes and risk variants were verified in the CAD cohort and in genome-wide association studies (GWAS).Results: The results showed that RNF181 and eight other hub genes are perturbed during CAD in heart tissues. Additionally, the expression of RNF181 was validated using RT-PCR and immunohistochemistry (IHC) staining in two cardiotoxicity mouse models. The association was further verified in the CAD patient cohort and in GWAS.Conclusion: Our findings illustrated for the first time that the E3 ubiquitination ligase protein RNF181 may serve as a potential biomarker in CAD, but further in vivo validation is warranted.

Self-insertion of needles into the urethra is rare among children, especially in adolescents with no evident history of mental illness. It is usually an urological emergency condition and needs surgery as soon as possible. The case we report here is a 14 year-old boy with urethral self-insertion of a sewing needle which was lodged in urethra for 9 years. The needle was successfully removed by urethrocystoscope with a surgical grasper. Our objective of this case report is to remind urologists and pediatrician of the possibility of urethral foreign bodies and recommend scrotal ultrasonography as the first examination modality.

Changes in decidual macrophage polarization affect local inflammatory microenvironment and lead to adverse pregnancy outcomes. However, the regulatory mechanism of macrophage polarization in preeclampsia (PE) remains unclear. In this study, we found that α7nAChR expression was significantly down-regulated in decidual macrophages in PE patients compared to normal pregnant women, accompanied by a reduced proportion of M2 phenotype and an increased proportion of M1 phenotype; these results suggested that the reduced α7nAChR activity might contribute to changes in the polarization of decidual macrophages. Then, we further investigated the regulatory role of α7nAChR activation by nicotine on decidual macrophage polarization and placental remodeling in the PE-like mouse model. The PE mice were obtained by i.p. injection of 10 µg/kg lipopolysaccharide (LPS) gestational day (GD) 13, and 40 µg/kg LPS daily until GD16. Subcutaneous injection of 1.0 mg/kg nicotine was administrated from GD14 to GD18. Nicotine treatment increased the decreased M2 phenotype and inhibited the increased M1 phenotype in decidua of pregnant mice induced by LPS. The levels of pro-inflammatory cytokines in decidua were higher but the levels of anti-inflammatory cytokines were lower in PE mice compared to the controls, nicotine reversed these changes. The level of choline acetyltransferase (CHAT) was reduced in the LPS-treated group, it was increased following nicotine treatment. Damage of spiral artery remodeling and down-regulation of markers related to trophoblast invasion in placentas were found in PE mice; nicotine improved these pathological structures of placentas. α-bungarotoxin (α-BGT) which is specific antagonist for α7nAChR could abolish the effects of nicotine on decidual macrophage polarization, trophoblast arrangement and vascular structure in placental tissue in PE mice. These results suggest that α7nAChR plays an important regulatory role in maternal-fetal inflammation and placental remodeling in preeclampsia and may provide a theoretical basis for the discovery of new strategies for preeclampsia.

Missing tag incidents are common in RFID-enabled supply-chain and warehousing scenarios due to cargo theft and employee error operations, which may lead to serious economic losses or potential safety hazards. On the premise of ensuring the accuracy of missing tag detection, this paper aims to improve the time efficiency in an integrated RFID system. Unlike prior work focusing on detecting missing items from a large number of homogeneous tags that are monitored by a single reader, one integrated RFID system possesses multiple readers to communicate with the heterogeneous tags, which have different categorical attributes. In addition, the prior work required repeating the execution several times to capture the missing tags in assorted categories, which is of low time efficiency. Thus, a protocol called Multi-reader Missing Tag Detection (MMTD) is proposed to capture the missing tag quickly and reliably, which can detect missing tags from different categories in a parallel manner and is much more time-efficient than previous work. MMTD has two major advantages compared to prior work: (i) It leverages the knowledge of the spatial distribution of tags to divide up a difficult detection task into several lightweight tasks, which are shared by multiple readers. (ii) It personalizes the time frame of the reader based on the tag population to optimize the utilization of the communication channel. The final simulation results reveal that MMTD is the best in time-efficiency among the comparison protocols, and MMTD outperforms the other missing tag detection protocols by at least 1.5× in the Integrated RFID scenarios.

A 65-year-old man presented with a giant ulcerative and malodorous genital mass rapidly growing for 5 months. On first presentation, he noticed a 3 cm × 2 cm cauliflower-like mass located in the penile dorsal shaft. But, he rejected any operation. Unfortunately, the lesion became aggressive and eventually destroyed the entire penile shaft and urethra within a five-month period. He underwent a radical penectomy, scrotal extended resection, formation of a perineal urethrostomy and left inguinal lymph node biopsy. Pathology revealed poor-differentiated invasive squamous cell carcinoma. The patient had an uneventful recovery.

We report on the observation of dual-pulses laser-produced plasmas (DP-LPPs), following a femtosecond Ti: sapphire pulse laser ablate soil generated a substantial number of soil aerosol particle clusters of soil target and then a nanosecond Nd:YAG pulse laser re-ablated the soil aerosol particles clusters. The temporal evolution of the fs laser-produced plasmas (fs-LPPs) highlight a different in plasma plume expansion dynamics and particles clusters distributions where, the initial position and velocity of plasma plume expansion are 0.79 mm and 4.8 km/s, the terminal position is 2.2 mm and the velocity gradually become slower and slower, in the delay time range of 150 ns to 2.1 μs. There are three distribution states contains a columnar particle fluid flow region, “Mushroom cloud” fluid flow region, and arbitrary shape fluid flow region of the particles scattering images of different inter-pulse time at 1, 5, 9, 10, 30, 50, 200, 400 and 800 μs. Based on the Boltzmann plot method and Stark broadening, the plasma temperature and electron density is also investigated, the results shows that DP-LPPs optical emission spectrum (OES) has a narrow linear broadening and enhanced spectral intensity, associates with the higher plasma temperature and lower electron density compare with the single fs-LPPs.

Basal cell carcinoma (BCC) is the most commonly occurring carcinoma among humans. Reports of this lesion on nonexposed areas, such as the scrotum, soles, vulva, groin, pubic region, and axilla, are relatively uncommon. We present the case of a male patient with BCC located in the scrotum with a duration of 12 years who was successfully treated by local excision. Histopathology revealed infiltration by BCC. Our objective of this report is to remind specialists like urologists of the possibility of scrotal BCC when encountering scrotal lesions of unknown origin or not responding to topical treatments in a reasonable time frame.

Increasing sample temperature is an effective method for improving emission intensity of laser-induced breakdown spectroscopy (LIBS). An increase in the sample temperature requires only simple modification to LIBS system, and does not require sample pretreatment. In addition, the formation and decay of laser-induced plasma (LIP) are a dynamic physical process. Time-resolved spectroscopy can enrich the dynamic information of LIBS and increase data dimension. The further analysis of the time-resolved LIBS data has the potential to understand the physical process. In this study, a beam of nanosecond laser was used to excite brass sample to produce plasma. The time-resolved spectroscopy of the LIP was measured at different sample temperatures. The results indicated that increasing sample temperature improved optical emission intensity in LIBS, and increased the plasma persistence. We also obtained plasma temperature and electron density at different sample temperatures. The time-resolved plasma temperature and electron density in the case with higher sample temperature were higher than those in the case with lower sample temperature. Moreover, the decay of electron density at higher sample temperature was faster than that at lower sample temperature.

Apart from sharing common ancestry with chordates, sea cucumbers exhibit a unique morphology and exceptional regenerative capacity. Here we present the complete genome sequence of an economically important sea cucumber, A. japonicus, generated using Illumina and PacBio platforms, to achieve an assembly of approximately 805 Mb (contig N50 of 190 Kb and scaffold N50 of 486 Kb), with 30,350 protein-coding genes and high continuity. We used this resource to explore key genetic mechanisms behind the unique biological characters of sea cucumbers. Phylogenetic and comparative genomic analyses revealed the presence of marker genes associated with notochord and gill slits, suggesting that these chordate features were present in ancestral echinoderms. The unique shape and weak mineralization of the sea cucumber adult body were also preliminarily explained by the contraction of biomineralization genes. Genome, transcriptome, and proteome analyses of organ regrowth after induced evisceration provided insight into the molecular underpinnings of visceral regeneration, including a specific tandem-duplicated prostatic secretory protein of 94 amino acids (PSP94)-like gene family and a significantly expanded fibrinogen-related protein (FREP) gene family. This high-quality genome resource will provide a useful framework for future research into biological processes and evolution in deuterostomes, including remarkable regenerative abilities that could have medical applications. Moreover, the multiomics data will be of prime value for commercial sea cucumber breeding programs.

Adenomatoid tumors (AT) are the most common paratesticular neoplasms and account for approximately 30% of all paratesticular masses. Most of them occur in the third or fourth decade and present as well-defined firm and painless masses. We report here a case of adenomatoid tumor from tunica albuginea. This patient is a 12-year-old boy with left testicular pain for 6 months. Scrotal ultrasonography revealed a solid mass of paratesticular origin. The histology and immunohistochemistry confirmed the final diagnosis. A right tumor resection was performed. Because of its rarity, the clinical and histopathologic appearance is seldom illustrated. Here we present a case report and a comprehensive literature review with the objective of providing useful information on this entity.

Calculation of the stress intensity factor K is a crucial and difficult task in linear elastic fracture mechanics. With the capacity to solve complex input-output problems of an underlying system, machine learning is especially useful in the calculation of K. However, when faced with complex systems, such as the firtree groove structure of a turbine disk, the data--consuming issue has always been a thorny problem in K-solutions combined with machine learning studies for a long time. In this paper, a novel K-solution method called PA-GPR (Pool-based Active learning with Gaussian Process Regression) for the calculation of the stress intensity factor for surface cracks in the firtree groove structure of a turbine disk is proposed. Using the pool-based active learning strategy, the proposed K-solution method could make the GPR model have a great regression performance with a few samples required. In the pool-based active learning strategy analysis, the learning function based on greedy sampling is proposed to select samples with a high contribution to the training of the GPR model. The calculation of K for a semi-elliptical surface crack in the firtree groove structure is evaluated to verify the accuracy and effectiveness of the proposed method. The results show that this novel method is accurate, time-saving and effective. [ABSTRACT FROM AUTHOR]