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Abstract Background Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved. Results Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 − 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations. Conclusion The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group.

Background: Accurately predicting the survival rate of submandibular gland cancer (SGC) is of significant importance for guiding treatment decision-making and improving patient outcomes. This study was aimed to identify the independent prognostic factors of overall survival (OS) in SGC patients, and develop novel prediction models to aid clinicians in predicting the survival probability. Materials and methods: Patients diagnosed with primary SGC after the year 2010 were extracted from SEER database and then randomly allocated into training and test samples in a 7:3 ratio. Uni- and multi-variable COX analyses were employed using the training sample to ascertain independent prognostic factors for OS. Subsequently, graphic and online dynamic nomograms were established basing on the independent prognostic factors. We utilized C-index, calibration curve, receiver operating characteristic (ROC) curve, and area under ROC curve (AUC) value to evaluate the discrimination capacity and the consistency between predicted and actual survival. Results: A total of 527 SGC patients were included (369 assigned to training group and 158 assigned to test group). The multivariable COX analysis showed that age, sex, marital status, tumor histology, summary stage, metastases to bone, and tumor size were independently associated with OS. Novel graphical and online dynamic (URL: https://yangxg1209.shinyapps.io/overall_survival_submandibular_gland_tumor/) nomograms were established. The C-indices (training: 0.77, 95%CI 0.71–0.84; test: 0.77, 95%CI 0.68–0.85) indicate favorable discrimination ability of the model, and the calibration curves demonstrated favorable consistency between the predicted and actual survival rates. Conclusions: Our study identified the independent prognostic factors influencing OS in patients with SGC, and successfully established and validated novel nomograms, which provide accurate prediction of survival rates and allows for personalized risk assessment.

Abstract Background Stroke attributable to atrial fibrillation (AF related stroke, AFST) accounts for 13 ~ 26% of ischemic stroke. It has been found that AFST patients have a higher risk of disability and mortality than those without AF. Additionally, it’s still a great challenge to treat AFST patients because its exact mechanism at the molecular level remains unclear. Thus, it’s vital to investigate the mechanism of AFST and search for molecular targets of treatment. Long non-coding RNAs (lncRNAs) are related to the pathogenesis of various diseases. However, the role of lncRNAs in AFST remains unclear. In this study, AFST-related lncRNAs are explored using competing endogenous RNA (ceRNA) network analysis and weighted gene co-expression network analysis (WGCNA). Methods GSE66724 and GSE58294 datasets were downloaded from GEO database. After data preprocessing and probe reannotation, differentially expressed lncRNAs (DELs) and differentially expressed mRNAs (DEMs) between AFST and AF samples were explored. Then, functional enrichment analysis and protein-protein interaction (PPI) network analysis of the DEMs were performed. At the meantime, ceRNA network analysis and WGCNA were performed to identify hub lncRNAs. The hub lncRNAs identified both by ceRNA network analysis and WGCNA were further validated by Comparative Toxicogenomics Database (CTD). Results In all, 19 DELs and 317 DEMs were identified between the AFST and AF samples. Functional enrichment analysis suggested that the DEMs associated with AFST were mainly enriched in the activation of the immune response. Two lncRNAs which overlapped between the three lncRNAs identified by the ceRNA network analysis and the 28 lncRNAs identified by the WGCNA were screened as hub lncRNAs for further validation. Finally, lncRNA GAS6-AS1 turned out to be associated with AFST by CTD validation. Conclusion These findings suggested that low expression of GAS6-AS1 might exert an essential role in AFST through downregulating its downstream target mRNAs GOLGA8A and BACH2, and GAS6-AS1 might be a potential target for AFST therapy.

Most antiviral and anticancer nucleosides are prodrugs that require stepwise phosphorylation to their triphosphate nucleotide form for biological activity. Monophosphorylation may be rate-limiting, and the nucleotides may be unstable and poorly internalized by target cells. Effective targeting and delivery systems for nucleoside drugs, including oligonucleotides used in molecular therapeutics, could augment their efficacy. The development of a carrier designed to effect selective transmembrane internalization of nucleotides via the asialoglycoprotein receptor (ASGPr) is now reported. In this work, the polycationic, polygalactosyl drug delivery carrier heptakis[6-amino-6-deoxy-2-O-(3-(1-thio-β-D-galactopyranosyl)-propyl)]-β-cyclodextrin hepta-acetate salt (GCyDAc), potentially a bifunctional carrier of (poly)nucleotides, was modeled by molecular docking in silico as an ASGPr-ligand, then synthesized for testing. The antivirals arabinosyl adenine (araA, vidarabine, an early generation antiviral nucleoside), arabinosyl adenine 5′-monophosphate (araAMP), and 12-mer-araAMP (p-araAMP) were selected for individual formulation with GCyDAc to develop this concept. Experimentally, beta cyclodextrin was decorated with seven protonated amino substituents on the primary face, and seven thiogalactose residues on its secondary face. AraA, araAMP, and p-araAMP were individually complexed with GCyDAc and complex formation for each drug was confirmed by differential scanning calorimetry (DSC). Finally, the free drugs and their GCyDAc complexes were evaluated for antiviral activity using ASGPr-expressing HepAD38 cells in cell culture. In this model, araA, araAMP, and p-araAMP showed relative antiviral potencies of 1.0, 1.1, and 1.2, respectively. In comparison, GCyDAc-complexes of araA, araAMP, and p-araAMP were 2.5, 1.3, and 1.2 times more effective than non-complexed araA in suppressing viral DNA production. The antiviral potencies of these complexes were minimally supportive of the hypothesis that ASGPr-targeted, CyD-based charge-association complexation of nucleosides and nucleotides could effectively enhance antiviral efficacy. GCyDAc was non-toxic to mammalian cells in cell culture, as determined using the MTS proliferation assay.

Renal fibrosis is a common feature of all types of chronic kidney disease (CKD) and is tightly regulated by the TGF-β/Smad3 pathway. Let-7i-5p belongs to the let-7 microRNA family with diverse biological functions. It has been reported that let-7i-5p suppresses fibrotic disease in the heart, lungs, and blood vessels, while the role of let-7i-5p in renal fibrosis remains limited. In this study, we aimed to investigate the role of let-7i-5p in renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and TGF-β1–stimulated renal tubular cell line TCMK1. The RNA-targeting CRISPR/Cas13d system was used to knock down let-7i-5p. Renal injury and fibrosis were determined by histological analysis, RT-PCR, Western blot, and immunostaining. Our results have shown that in the kidneys after UUO, the expression of let-7i-5p was significantly increased along with notable tubular injury and interstitial fibrosis. Electroporation of let-7i–targeting Cas13d plasmid efficiently knocked down let-7i-5p in kidneys after UUO with reduced tubular injury, fibrotic area, and expression of fibrotic marker genes α-SMA, fibronectin, and Col1a1. In TGF-β1–stimulated TCMK1 cells, knockdown of let-7i-5p by Cas13d plasmid transfection also blunted the expression of fibrotic marker genes. Most importantly, the genomic locus of let-7i showed enriched binding of Smad3 as revealed by chromatin immunoprecipitation. In TCMK1 cells, the overexpression of Smad3 can directly induce the expression of let-7i-5p. However, the deletion of Smad3 abolished TGF-β1–stimulated let-7i-5p expression. Collectively, these findings suggest that let-7i-5p is a Smad3-dependent microRNA that plays a pathogenic role in renal fibrosis. Let-7i-5p could be a promising target for the treatment of CKD-associated renal fibrosis.

ObjectiveThe aim of this study was to evaluate the association between subclinical thyroid dysfunction and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA).MethodsWe examined the association between subclinical thyroid dysfunction and the recurrence of AF at a large university-affiliated cardiac arrhythmia center in China. Data were collected from consecutive patients who underwent RFCA for AF, excluding those with a history of hypothyroidism, hyperthyroidism, or ongoing medical treatment for hypothyroidism or hyperthyroidism, biochemically defined overt thyroid disease, and long-term use of amiodarone before admission. The primary end point was the recurrence of AF in a time-to-event analysis. We compared outcomes in patients who had subclinical hyperthyroidism or hypothyroidism with those who had euthyroid state, using a multivariable Cox model with inverse probability weighting and propensity score matching.ResultsIn all, 93 patients were excluded from 435 consecutive patients who underwent RFCA for AF. Of the remaining 342 patients for the analysis, the prevalence of subclinical hyperthyroidism and subclinical hypothyroidism were 26 (7.6%) and 41 (12.0%), respectively; during a median follow-up of 489 days, 91 patients (26.6%) developed a primary end point event. In the main analysis of the multivariable Cox model, only subclinical hyperthyroidism [hazard ratio: 3.07, 95% confidence interval (CI): 1.54–6.14] was associated with an increased risk of end point event after adjusting for potential confounders. However, the association between subclinical hypothyroidism and the end point event was not significant (hazard ratio: 0.66, 95% CI: 0.31–1.43). Results were consistent either in multiple sensitivity analyses or across all subgroups of analysis. Compared with individuals with free triiodothyronine (fT3) in the lowest quintile, those with fT3 in the highest quintile had an HR of 2.23 (95% CI: 1.16–4.28) for recurrence of AF. With the increase of thyroid-stimulating hormone (TSH), a reduction in the risk of recurrence of AF was detected in the adjusted model, and the hazard ratio (HR) per standard deviation (SD) increase was 0.82 (95% CI: 0.68–0.98).ConclusionIn this retrospective cohort study involving patients who underwent RFCA for AF, patients with subclinical hyperthyroidism were associated with a markedly higher prevalence of recurrence of AF, whereas patients with subclinical hypothyroidism had a similar recurrence rate of AF compared to those with the euthyroid state.

Solid tumours are often poorly oxygenated, which confers resistance to standard treatment modalities. Targeting hypoxic tumours requires compounds, such as nitroimidazoles (NIs), equipped with the ability to reach and become activated within diffusion limited tumour niches. NIs become selectively entrapped in hypoxic cells through bioreductive activation, and have shown promise as hypoxia directed therapeutics. However, little is known about their mechanism of action, hindering the broader clinical usage of NIs. Iodoazomycin arabinofuranoside (IAZA) and fluoroazomycin arabinofuranoside (FAZA) are clinically validated 2-NI hypoxic radiotracers with excellent tumour uptake properties. Hypoxic cancer cells have also shown preferential susceptibility to IAZA and FAZA treatment, making them ideal candidates for an in-depth study in a therapeutic setting. Using a head and neck cancer model, we show that hypoxic cells display higher sensitivity to IAZA and FAZA, where the drugs alter cell morphology, compromise DNA replication, slow down cell cycle progression and induce replication stress, ultimately leading to cytostasis. Effects of IAZA and FAZA on target cellular macromolecules (DNA, proteins and glutathione) were characterized to uncover potential mechanism(s) of action. Covalent binding of these NIs was only observed to cellular proteins, but not to DNA, under hypoxia. While protein levels remained unaffected, catalytic activities of NI target proteins, such as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the detoxification enzyme glutathione S-transferase (GST) were significantly curtailed in response to drug treatment under hypoxia. Intraperitoneal administration of IAZA was well-tolerated in mice and produced early (but transient) growth inhibition of subcutaneous mouse tumours.

Objective To investigate the efficacy and safety of the antithrombotic therapy using the oral anticoagulant rivaroxaban and clopidogrel in Chinese patients with acute coronary syndrome complicated with atrial fibrillation after percutaneous coronary intervention. Methods A total of 100 patients were selected. Patients were randomly divided into two groups: the treatment group (rivaroxaban group) received a therapy of rivaroxaban and clopidogrel. The control group (warfarin group) receivied a combined treatment of warfarin, clopidogrel, and aspirin. The primary outcome endpoint was evaluated based on the adverse cardiac and cerebrovascular events within 12 months. Results A total of 8 (8.00%) main adverse cardiac and cerebrovascular events occurred during the 12 months of follow-up, including 5 (9.80%) in the warfarin group and 3 (6.10%) in the rivaroxaban group. The risk of having main adverse cardiac and cerebrovascular events in the two groups was comparable (P = 0.479). A total of 9 patients (9.00%) were found to have bleeding events, among which 8 patients (15.7%) were in the warfarin group, whereas only 1 patient (2.00%) was in the rivaroxaban group. Therefore, the risk of bleeding in the warfarin group was significantly higher than that in the rivaroxaban group (P = 0.047). Conclusions In Chinese patients with acute coronary syndrome complicated with atrial fibrillation, the efficacy of the dual therapy of oral anticoagulant rivaroxaban plus clopidogrel after percutaneous coronary intervention was similar to that of the traditional triple therapy combined with warfarin, aspirin and clopidogrel, but it has a better safety property, which has potential to widely apply to antithrombotic therapy after PCI

Abstract Background As of 2 March, 2020, at least 80 151 coronavirus disease 2019 (COVID-19) cases were reported in China. Most of the patients had a history of visiting Hubei Province or contacting with people who had ever stayed in or passed by Hubei Province or were exposed to symptoms. Some patients got infected through only asymptomatic contact. This study aimed to report the epidemic features and lab identification of a patient confirmed with COVID-19 infection through only asymptomatic contact. Case presentation A 44-year-old man, who lived in Nanchang, Jiangxi Province, China until 6 March 2020, suffered from cough on 27 January 2020. Fever symptoms appeared on 28 January, with a maximum temperature of 38.8 °C, accompanied by cough, sore throat, headache, fatigue, muscle ache, joint ache, and other symptoms. The symptoms continued until he was hospitalized on 30 January. Coronavirus conventional polymerase chain reaction assay was positive for the throat swab sample. The patient, along with his wife and son, drove from Nanchang to back to Honghu City, Hubei Province, on 23 January 2020. After staying with his parents and brother’s family for 3 days, the patient drove back to Nanchang and arrived on 25 January. On the way back home, they stopped by Tongshan service area, Hubei Province, without any close contact with other people. After arriving home in Nanchang City, Jiangxi Province, none of them left their residence. In addition, his parents stayed at home for 20 days with his younger brother’s family before they got back. His younger brother and one of his brother’s children visited Wuhan on 5 January and came home on 6 January 2020. Conclusions This report suggested that, in the early phase of COVID-19 pneumonia, routine screening could miss patients who were virus carriers. Highlighting travel history is of paramount importance for the early detection and isolation of severe acute respiratory syndrome coronavirus 2 cases.

Abstract. Background:. Cervical cancer has the fourth highest incidence and mortality rate of all cancers in women worldwide; it seriously harms their physical and mental health. The aim of this study was to observe the roles and preliminary mechanism of Taurine (Tau)-induced apoptosis in cervical cancer cells. Methods:. Cells from the human cervical cancer cell line SiHa were transfected with the recombinant plasmid pEGFP-N1-MST1 (mammalian sterile 20-like kinase 1); then, the cell proliferation activity was analyzed by the MTT assay, cell apoptosis by flow cytometry, and the related protein levels by Western blotting. Results:. Tau inhibited the proliferation of SiHa cells and induced apoptosis in these cells (the apoptotic rate was 21.95% in the Tau 160 mmol/L group and 30% in the Tau 320 mmol/L group), upregulated the expression of the MST1 (control, 0.53; Tau 40–320 mmol/L groups, 0.84–1.45) and Bax (control, 0.45; Tau 40–320 mmol/L groups, 0.64–1.51) proteins (P

Abstract Background & Aims Ticagrelor has been acknowledged as a new oral antagonist of P2Y12-adenosine diphosphate receptor, as a strategy with more rapid onset as well as more significant platelet inhibition function in acute coronary syndrome (ACS) patients. The clinical benefit of ticagrelor compared with clopidogrel remains controversial. The current meta-analysis was conducted to better evaluate the role of ticagrelor in comparison of clopidogrel in treating ACS patients. Methods The publications involving the safety as well as the efficacy of clopidogrel versus ticagrelor were screened and identified updated to June 2018. After rigorous review, eligible randomized controlled trials (RCTs) were extracted and propensity score matching (PSM) analysis was conducted. To analyze the summary odds ratios (ORs) of the endpoints of interest, we applied Meta-analysis Revman 5.3 software. Results There were a total of 10 studies that met our inclusion criteria, of which the risk of bleeding rate (P = 0.43), MI (P = 0.14), and stroke (P = 0.70) had no association with significant differences between patients receiving ticagrelor or clopidogrel. Nonetheless, higher rate of dyspnea was observed in ticagrelor group (OR = 1.87, 95% CI: 1.70–2.05, P

Objective: To investigate the role of oxidative stress in human renal tubular epithelial cells (HK-2) induced by high glucose and the underlying signal pathway in vitro. Methods: MYPT1, pro-caspase-3, PGC-1α, and Drp1 protein expressions were measured by Western blot. MnSOD2, Drp1 and PGC-1α mRNA expressions were detected by real time PCR. Results: Results showed that high glucose significantly up-regulated the protein expressions of MYPT1, pro-caspase-3 and the mRNA expression of MnSOD2 in HK-2 cells; while Rho kinase inhibitor fasudil and ROCK1 siRNA inhibited protein expressions of pro-caspase-3 and the mRNA expression of MnSOD2 in HK-2 cells induced by high glucose. Importantly, fasudil and ROCK1 siRNA markedly inhibited the expressions of mitochondrial motor proteins Drp1 and mitochondrial gene PGC-1α in HK-2 cells induced by high glucose. Conclusions: Our findings suggest that Rho kinase signal pathway is involved in mitochondrial oxidative damage and apoptosis in high glucose-induced renal tubular epithelial cells by regulating mitochondrial motor proteins Drp1 and mitochondrial gene PGC-1α. Targeting Rho kinase signal pathway might be a potential strategy for the treatment of diabetic nephropathy.

The effect of high pressure on the microstructure of hypo-peritectic Al–38wt.%Ni alloy was studied. The results show that Al3Ni and Al3Ni2 phases coexist at ambient pressure. However, it becomes a typical hyper-eutectic microstructure when synthesized at 2 GPa and 4 GPa. Meanwhile, the interface temperature of Al3Ni and Al3Ni2 phases was calculated with the combination of the BCT dendrite growth model, which is suitable for the Al3Ni2 phase. According to the highest interface temperature principle, the result shows that the Al3Ni phase dominates over 1–5 GPa. Finally, the Debye temperature and potential energy of the hypo-peritectic Al–38wt.%Ni alloy under different pressures were researched. Based on the low temperature specific heat-capacity curve. The Debye temperatures at ambient pressure, 2 GPa, and 4 GPa are 504.4 K, 508.71 K and 515.36 K, respectively, and the potential energy in the lowest point decreases with the increase of pressure.

Both the additive and multiplicative models of crop yield and water supply are polynomial equations, and the number of parameters increases linearly when the growing period is specified. However, interactions among multiple parameters occasionally lead to unreasonable estimations of certain parameters, which were water sensitivity coefficients but with negative value. Additionally, evapotranspiration must be measured as a model input. To facilitate the application of these models and overcome the aforementioned shortcomings, a simple model with only three parameters was derived in this paper based on certain general quantitative relations of crop yield (Y) and water supply (W). The new model, Y/Ym–Wk/(Wk+whk), fits an S or a saturated curve of crop yield with the cumulative amount of water. Three parameters are related to biological factors: the yield potential (Ym), the water requirement to achieve half of the yield potential (half-yield water requirement, wh), and the water sensitivity coefficient (k). The model was validated with data from 24 maize lines obtained in the present study and 17 maize hybrids published by other authors. The results showed that the model was well fit to the data, and the normal root of the mean square error (NRMSE) values were 2.8 to 17.8% (average 7.2%) for the 24 maize lines and 2.7 to 12.7% (average 7.4%) for the 17 maize varieties. According to the present model, the maize water-sensitive stages in descending order were pollen shedding and silking, tasselling, jointing, initial grain filling, germination, middle grain filling, late grain filling, and end of grain filling. This sequence was consistent with actual observations in the maize field. The present model may be easily used to analyse the water use efficiency and drought tolerance of maize at specific stages.

Abstract: During meiosis in flowering plants, degradation of the callose wall in tetrads releases newly produced microspores, which develop into mature pollen grains. In this study, we identified zbs1, a male-sterile mutant of naked oat (Avena nuda L.) that displayed complete spikelet sterility due to inviable mature pollen. The abnormal pollen grains originated from microspores with a defective callose wall and cell plate during meiosis. The defective callose wall and cell plate of the zbs1 mutant were detected by the labeling of cell wall epitopes (β-1,3-glucan) with immunogold during meiosis, and an abnormal chromosome configuration was observed by propidium iodide staining. The mature pollen grains of the zbs1 mutant were irregular in shape, and abnormal germination was observed by scanning electron microscopy. Together, our results indicate that the cause of male sterility in zbs1 is abnormal meiosis.

AIM: To conduct a comparative study of effectiveness of silicone hydrogel contact lens and hydrogel contact lens, which are used in patients after laser-assisted subepithelial keratomileusis (LASEK). METHODS: Sixty-three patients (121 eyes) with a spherical equivalent ≤-5.0 D were chosen after undergoing LASEK in 2012 at Guangdong General Hospital. They were randomly divided into 2 groups. The silicone hydrogel group included 32 cases (61 eyes) that wore silicone hydrogel contact lenses for 4-6d after the operation, while the hydrogel group included 31 cases (60 eyes) who wore hydrogel contact lenses for 4-6d after the operation. Patients’ self-reported postoperative symptoms (including pain, photophobia, tears, and foreign body sensation) were evaluated. The healing time of the corneal epithelium, the visual acuity of patients without contact lens after epithelial healing, and the incidence of delayed corneal epithelial shedding were also assessed. The follow-up time was 1mo. RESULTS: Postoperative symptoms were milder in the silicone hydrogel group than in the hydrogel group. There were significant differences in pain, foreign body sensation, and photophobia between the 2 groups (P0.05). The healing time of the corneal epithelium in the silicone hydrogel lens group was markedly shorter than that in the hydrogel group (4.07±0.25 vs 4.33±0.82d, t=2.43, P=0.02). Visual acuity without contact lenses after healing of the corneal epithelium was better in the silicone hydrogel group compared with the hydrogel group (χ2=7.76, P=0.02). There was no significant difference in the occurrence of delayed corneal epithelial shedding between the 2 groups (P>0.05). CONCLUSION: Patients with LASEK using silicon hydrogel contact lenses had less discomfort and shorter corneal epithelial healing time compared with those using hydrogel contact lenses, suggesting that silicon hydrogel contact lenses may be considered to be a better choice of bandage contact lens after LASEK.

Purpose: Pharmacokinetic (PK) data are generally derived from blood samples withdrawn serially over a defined period after dosing. In small animals, blood sampling after dosing presents technical difficulties, particularly when short time intervals and frequent sampling are required. Positron emission tomography (PET) is a non-invasive functional imaging technique that can provide semi-quantitative temporal data for defined volume regions of interest (vROI), to support kinetic analyses in blood and other tissues. The application of preclinical small-animal PET to determine and compare PK parameters for [18F]FDG and [18F]FAZA, radiopharmaceuticals used clinically for assessing glucose metabolism and hypoxic fractions, respectively, in the same mammary EMT6 tumor-bearing mouse model, is reported here. Methods: Two study groups were used: normal BALB/c mice under isoflurane anesthesia were intravenously injected with either [18F]FDG or [18F]FAZA. For the first group, blood-sampling by tail artery puncture was used to collect blood samples which were then analyzed with Radio-microTLC. Dynamic PET experiments were performed with the second group of mice and analyzed for blood input function and tumor uptake utilizing a modified two compartment kinetic model. Heart and inferior vena cava vROIs were sampled to obtain image-derived data. PK parameters were calculated from blood samples and image-derived data. Time-activity curves (TACs) were also generated over regions of liver, kidney and urinary bladder to depict clearance profiles for each radiotracer. Results: PK values generated by classical blood sampling and PET image-derived analysis were comparable to each other for both radiotracers. Heart vROI data were suitable for analysis of [18F]FAZA kinetics, but metabolic uptake of radioactivity mandated the use of inferior vena cava vROIs for [18F]FDG analysis. While clearance (CL) and blood half-life (t½) were similar for both [18F]FDG and [18F]FAZA for both sampling methods, volume of distribution yielded larger differences, indicative of limitations such as partial volume effects within quantitative image-derived data. [18F]FDG underwent faster blood clearance and had a shorter blood half-life than [18F]FAZA. Kinetic analysis of tumor uptake from PET image data showed higher uptake and longer tumor tissue retention of [18F]FDG, indicative of the tumor’s glucose metabolism rate, versus lower tumor uptake and retention of [18F]FAZA. While [18F]FAZA possesses a somewhat greater hepatobiliary clearance , [18F]FDG clears faster through the renal system which results in faster radioactivity accumulation in the urinary bladder. Conclusions: The present study provides a working example of the applicability of functional PET imaging as a suitable tool to determine PK parameters in small animals. The comparative analysis in the current study demonstrates that it is feasible to use [18F]FDG PET and [18F]FAZA PET in the same model to analyze their blood PK parameters, and to estimate kinetic parameters for these tracers in tumor. This non-invasive imaging-based determination of tissue kinetic parameters facilitates translation from pre-clinical to clinical phases of drug development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Selection of quantitative characteristics, division of their expression ranges, and selection of example varieties are key issues on developing DUS Test Guidelines, which are more crucial for quantitative characteristics since their expressions vary in different degrees. Taking the development of DUS Test Guideline of Ranunculus asiaticus L. as an example, this paper applied statistic-based approaches for the analyses of quantitative characteristics. We selected 9 quantitative characteristics from 18 pre-selected characteristics, based on within-variety uniformity, stability between different growing cycles, and correlation among characteristics, by the analyses of coefficient of variation, paired-samples t-test and partial correlation. The expression ranges of the 9 selected quantitative characteristics were divided into different states using descriptive statistics and distribution frequency of varieties. Eight of the 9 selected quantitative characteristics were categorized as standard characteristics as they showed one peak in distribution frequency of 120 varieties in various expressions of the characteristics, whereas, plant height can be categorized as grouping characteristic since it gave two peaks, and can group the varieties into pot and cut varieties. Finally, box-plot was applied to visually select the example varieties, and varieties 7, 12, and 28 were determined as the example varieties for plant height. The methods described in this paper are effective for the selection of quantitative characteristics, division of expression ranges, and selection of example varieties in Ranunculus asiaticus L. for DUS test, and may also be interest for other plant genera.

Rotundic acid (RA, 1), a natural compound, exhibits potent tumor cell growth inhibiting properties. To date there are no reports on derivatives of RA. Furthermore, the 28-COOH position of RA might make it unstable and induced serious gastrointestinal side effects when it was applied in vivo. Therefore, in order to explore and make use of this compound, eight new amino acid derivatives of RA at the 28-COOH position were synthesized and evaluated for their cytotoxicities in vitro on three tumor cell lines including A375, HepG2 and NCI-H446. As a result, a few of these new amino acid derivatives showed stronger cytotoxicity. Compound 5a was found to have the best inhibition activity on the three tested human tumor cell lines with IC50 values of less than 10 μM compared with RA treatment. Meanwhile, the cytotoxicity of compound 6b was significantly higher than that of RA on the A375 cell line and almost the same as RA on the HepG2 and NCI-H446 cell lines. Hence, compounds 5a and 6b may serve as potential lead compounds for the development of new anti-tumor drugs.

PURPOSE. Iododeoxyuridine (IUdR) has a very short in vivo half-life and consequently achieves low target-tissue concentrations with concomitant lower efficacy than would be predicted from in vitro studies. This work reports the preparation of IUdR:?-cyclodextrin (?-CyD) inclusion complexes designed to reduce in vivo inactivation of IUdR. METHODS. IUdR was derivatized with either 1-adamantanecarbonyl chloride or 4-(1-adamantyl-carbamoyl)butanoic acid, to prepare 5’-O-(1-adamantoyl)-5-iodo-2’-deoxyuridine 1 and 5’-O-(4-(1-adamantylcarbamoyl)butoyl)-5-iodo-2’-deoxy-uridine 4, respectively. ?-CyD complexes 5 and 6 were formed by vigorous stirring of 1:1 solutions of ?-CyD and 1 or 4, respectively, in D2O under argon. Complexation was inferred from DSC, powder x-ray diffractometry and NMR spectrometry. The dissociation of 5 in water and under cholesterol challenge, and the effect of complexation on the stability of 1 was determined by incubation in plasma. RESULTS. IUdR coupling with adamantanecarbonyl chloride proceeded smoothly to afford 1 (69 %) and the di-substituted derivative, 3’,5’-di-O-(1-adamantoyl)-5-iodo-2’-deoxyuridine 2 (8 %); 4 was obtained in 42 % yield. The formation of 1:1 complexes 5 and 6 was inferred from NMR chemical shift data. In serum, 1 was 90 % hydrolyzed to IUdR in 30 min, compared to 10 % hydrolysis of 1 to IUdR when from complex 5. CONCLUSIONS. Inclusion complexes were formed between ?-CyD and adamantamine-IUdR conjugates at 1:1 molar ratios. The complex 5 was resistant to dissociation by cholesterol challenge, and 5 was more slowly converted to IUdR than non-complexed 1. In vivo studies are required to further exploit the ?-CyD inclusion complex approach for improved delivery of nucleoside derivatives.

TiZrTaNb-based high-entropy alloys (HEAs) are research frontier of biomedical materials due to their high hardness, good yield strength, excellent wear resistance and corrosion resistance. Sn, as an essential trace element in the human body that plays a significant role in physiological process. It has stable chemical properties and a low elastic modulus. In this study, a new material, TiZrTaNbSn HEAs, was proposed as a potential biomedical alloy. The Ti35Zr25Ta15Nb15Sn10 biomedical high-entropy alloys (BHEAs) were successfully prepared through an arc melting furnace and then remelted using a German high-temperature and high-pressure apparatus under GPa-level (4 GPa and 7 GPa). The precipitation behavior of the needle-like HCP-Zr5Sn3 phase that precipitates discontinuously at the grain boundary was successfully controlled. The phase constitution, microstructure, and corrosion resistance of the alloy were studied. The results show that the needle-like HCP-Zr5Sn3 phase is eliminated and the (Zr, Sn)-rich nanoprecipitated phase is precipitated in the microstructure under high pressure, which leads to the narrowing of grain boundaries and consequently improves the corrosion resistance of the alloy. In addition, the formation mechanisms of (Zr, Sn)-rich nanoprecipitates in BHEAs were discussed. More Zr and Sn dissolve in the matrix due to the effect of high pressure, during the cooling process, they precipitate to form a (Zr, Sn)-rich nano-precipitated phase. [ABSTRACT FROM AUTHOR]

According to the standard thin disc theory, it is predicted that the radiation-pressure-dominated inner region of a thin disc is thermally unstable, while observations suggest that it is common for a thin disc of more than 0.01 Eddington luminosity to be in a thermally stable state. Previous studies have suggested that magnetically driven winds have the potential to suppress instability. In this work, we implement one-dimensional global simulations of the thin accretion disc to study the effects of magnetically driven winds on thermal instability. The winds play a role in transferring the angular momentum of the disc and cooling the disc. When the mass outflow rate of winds is low, the important role of winds is to transfer the angular momentum and then shorten the outburst period. When the winds have a high mass outflow rate, they can calm down the thermal instability. We also explore the parameter space of the magnetic field strength and the mass loading parameter. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a common feature of all types of chronic kidney disease (CKD) and is tightly regulated by the TGF-ß/Smad3 pathway. Let-7i-5p belongs to the let-7 microRNA family with diverse biological functions. It has been reported that let-7i-5p suppresses fibrotic disease in the heart, lungs, and blood vessels, while the role of let-7i-5p in renal fibrosis remains limited. In this study, we aimed to investigate the role of let-7i-5p in renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and TGF-ß1-stimulated renal tubular cell line TCMK1. The RNA-targeting CRISPR/Cas13d system was used to knock down let-7i-5p. Renal injury and fibrosis were determined by histological analysis, RT-PCR, Western blot, and immunostaining. Our results have shown that in the kidneys after UUO, the expression of let-7i-5p was significantly increased along with notable tubular injury and interstitial fibrosis. Electroporation of let-7i-targeting Cas13d plasmid efficiently knocked down let-7i-5p in kidneys after UUO with reduced tubular injury, fibrotic area, and expression of fibrotic marker genes a-SMA, fibronectin, and Col1a1. In TGF-ß1-stimulated TCMK1 cells, knockdown of let-7i-5p by Cas13d plasmid transfection also blunted the expression of fibrotic marker genes. Most importantly, the genomic locus of let-7i showed enriched binding of Smad3 as revealed by chromatin immunoprecipitation. In TCMK1 cells, the overexpression of Smad3 can directly induce the expression of let-7i-5p. However, the deletion of Smad3 abolished TGF-ß1-stimulated let-7i-5p expression. Collectively, these findings suggest that let-7i-5p is a Smad3-dependent microRNA that plays a pathogenic role in renal fibrosis. Let-7i-5p could be a promising target for the treatment of CKD-associated renal fibrosis. [ABSTRACT FROM AUTHOR]