Unveiling the role of the KLF4/Lnc18q22.2/ULBP3 axis in the tumorigenesis and immune escape of hepatocellular carcinoma under hypoxic condition.

Hepatocellular carcinoma (HCC) represents a significant global health burden, necessitating an in-depth exploration of its molecular underpinnings to facilitate the development of effective therapeutic strategies. This investigation delves into the complex role of long non-coding RNAs (lncRNAs) in the modulation of hypoxia-induced HCC progression, with a specific emphasis on delineating and functionally characterizing the novel KLF4/Lnc18q22.2/ULBP3 axis. To elucidate the effects of hypoxic conditions on HCC cells, we established in vitro models under both normoxic and hypoxic environments, followed by lncRNA microarray analyses. Among the lncRNAs identified, Lnc18q22.2 was found to be significantly upregulated in HCC cells subjected to hypoxia. Subsequent investigations affirmed the oncogenic role of Lnc18q22.2, highlighting its critical function in augmenting HCC cell proliferation and migration. Further examination disclosed that Kruppel-like factor 4 (KLF4) transcriptionally governs Lnc18q22.2 expression in HCC cells, particularly under hypoxic stress. KLF4 subsequently enhances the tumorigenic capabilities of HCC cells through the modulation of Lnc18q22.2 expression. Advancing downstream in the molecular cascade, our study elucidates a novel interaction between Lnc18q22.2 and UL16-binding protein 3 (ULBP3), culminating in the stabilization of ULBP3 protein expression. Notably, ULBP3 was identified as a pivotal element, exerting dual functions by facilitating HCC tumorigenesis and mitigating immune evasion in hypoxia-exposed HCC cells. The comprehensive insights gained from our research delineate a hitherto unidentified KLF4/Lnc18q22.2/ULBP3 axis integral to the understanding of HCC tumorigenesis and immune escape under hypoxic conditions. This newly unveiled molecular pathway not only enriches our understanding of hypoxia-induced HCC progression but also presents novel avenues for therapeutic intervention.

Increasingly amplified stimulation mediated by TaNAC69-B is crucial for the leaf senescence in wheat.

Leaf senescence involves massive multidimensional alterations, such as nutrient redistribution, and is closely related to crop yield and quality. No apical meristem, Arabidopsis transcription activation factor, and Cup-shaped cotyledon (NAC)-type transcription factors integrate various signals and modulate an enormous number of target genes to ensure the appropriate progression of leaf senescence. However, few leaf senescence-related NACs have been functionally characterized in wheat. Based on our previous RNA-sequencing (RNA-seq) data, we focused on a NAC family member, TaNAC69-B, which is increasingly expressed during leaf senescence in wheat. Overexpression of TaNAC69-B led to precocious leaf senescence in wheat and Arabidopsis, and affected several agricultural traits in transgenic wheat. Moreover, impaired expression of TaNAC69-B by virus-induced gene silencing retarded the leaf senescence in wheat. By RNA-seq and quantitative real-time polymerase chain reaction analysis, we confirmed that some abscisic acid (ABA) biosynthesis genes, including AAO3 and its ortholog in wheat, TraesCS2B02G270600 (TaAO3-B), were elevated by the overexpression of TaNAC69-B. Consistently, we observed more severe ABA-induced leaf senescence in TaNAC69-B-OE wheat and Arabidopsis plants. Furthermore, we determined that TaNAC69-B bound to the NAC binding site core (CGT) on the promoter regions of AAO3 and TaAO3-B. Moreover, we confirmed elevated ABA levels in TaNAC69-B-OE wheat lines. Although TaNAC69-B shares 39.83% identity (amino acid) with AtNAP, TaNAC69-B did not completely restore the delayed leaf senescence in the atnap mutant. Collectively, our results revealed a positive feedback loop, consisting of TaNAC69-B, ABA biosynthesis and leaf senescence, that is essential for the regulation of leaf senescence in wheat.

HDA6 modulates Arabidopsis pavement cell morphogenesis through epigenetic suppression of ROP6 GTPase expression and signaling.

The transcriptional regulation of Rho-related GTPase from plants (ROPs), which determine cell polarity formation and maintenance during plant development, still remains enigmatic. In this study, we elucidated the epigenetic mechanism of histone deacetylase HDA6 in transcriptional repression of ROP6 and its impact on cell polarity and morphogenesis in Arabidopsis leaf epidermal pavement cells (PCs). We found that the hda6 mutant axe1-4 exhibited impaired jigsaw-shaped PCs and convoluted leaves. This correlated with disruptions in the spatial organizations of cortical microtubules and filamentous actin, which is integral to PC indentation and lobe formation. Further transcriptional analyses and chromatin immunoprecipitation assay revealed that HDA6 specifically represses ROP6 expression through histone H3K9K14 deacetylation. Importantly, overexpression of dominant negative-rop6 in axe1-4 restored interdigitated cell morphology. Our study unveils HDA6 as a key regulator in Arabidopsis PC morphogenesis through epigenetic suppression of ROP6. It reveals the pivotal role of HDA6 in the transcriptional regulation of ROP6 and provides compelling evidence for the functional interplay between histone deacetylation and ROP6-mediated cytoskeletal arrangement in the development of interdigitated PCs.

Localized calcium transients in phragmoplast regulate cytokinesis of tobacco BY-2 cells.

KEY MESSAGE: Plants exhibit a unique pattern of cytosolic Ca2+ dynamics to correlate with microtubules to regulate cytokinesis, which significantly differs from those observed in animal and yeast cells. Calcium (Ca2+) transients mediated signaling is known to be essential in cytokinesis across eukaryotic cells. However, the detailed spatiotemporal dynamics of Ca2+ during plant cytokinesis remain largely unexplored. In this study, we employed GCaMP5, a genetically encoded Ca2+ sensor, to investigate cytokinetic Ca2+ transients during cytokinesis in Nicotiana tabacum Bright Yellow-2 (BY-2) cells. We validated the effectiveness of GCaMP5 to capture fluctuations in intracellular free Ca2+ in transgenic BY-2 cells. Our results reveal that Ca2+ dynamics during BY-2 cell cytokinesis are distinctly different from those observed in embryonic and yeast cells. It is characterized by an initial significant Ca2+ spike within the phragmoplast region. This spike is followed by a decrease in Ca2+ concentration at the onset of cytokinesis in phragmoplast, which then remains elevated in comparison to the cytosolic Ca2+ until the completion of cell plate formation. At the end of cytokinesis, Ca2+ becomes uniformly distributed in the cytosol. This pattern contrasts with the typical dual waves of Ca2+ spikes observed during cytokinesis in animal embryonic cells and fission yeasts. Furthermore, applications of pharmaceutical inhibitors for either Ca2+ or microtubules revealed a close correlation between Ca2+ transients and microtubule organization in the regulation of cytokinesis. Collectively, our findings highlight the unique dynamics and crucial role of Ca2+ transients during plant cell cytokinesis, and provides new insights into plant cell division mechanisms.

Simultaneous determination of five compounds of fried Radix Paeoniae Alba extract in beagle dogs plasma by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry and its application in a pharmacokinetic study.

In this present study, we developed a reliable and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, benzoylpaeoniflorin and isomaltopaeoniflorin in beagle dog plasma. We also analyzed the pharmacokinetics of those components after oral administration of fried Radix Paeoniae Alba (FRPA) in beagle dogs. Plasma samples were processed by protein precipitation with methanol. Chromatographic separation was performed with a Waters HSS-T3 C18 column (100 × 2.1 mm, 1.8 µm, kept at 40°C) using multiple reaction monitoring mode. A gradient elution procedure was used with solvent A (0.02% formic acid-water) and solvent B (0.02% formic acid-acetonitrile) as mobile phases. Method validation was performed as US Food and Drug Administration guidelines, and the results met the acceptance criteria. The method we establish in this experiment was successfully applied to the pharmacokinetic study after oral administration of FRPA extract to beagle dogs.

[Determination of nine components of fried Ziziphi Spinosae Semen extract in beagle dog plasma by UPLC-MS/MS and its application in pharmacokinetic research].

This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, swertisin, N-nornuciferine, 6-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 µm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, 6-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.

ELF1 suppresses autophagy to reduce cisplatin resistance via the miR-152-3p/NCAM1/ERK axis in lung cancer cells.

Resistance to chemotherapeutic drugs limits the efficacy of chemotherapy in non-small cell lung cancer (NSCLC). Autophagy is an essential mechanism which involves in drug resistance. Our previous research has revealed that miR-152-3p represses NSCLC progression. However, the mechanism of miR-152-3p in autophagy-mediated chemoresistance in NSCLC remains unclear. Cisplatin-resistant cell lines (A549/DDP and H446/DDP) were transfected with related vectors and subjected to cisplatin, autophagy inhibitor, activator, or extracellular signal-regulated kinase (ERK) activator. Flow cytometry, CCK8 and colony formation assays were performed for testing apoptosis and cell viability. The related RNAs or proteins were detected by qRT-PCR or Western blot. Chromatin immunoprecipitation, luciferase reporter assay or RNA immunoprecipitation were used for validating the interaction between miR-152-3p and ELF1 or NCAM1. Co-IP verified the binding between NCAM1 and ERK. The role of miR-152-3p in cisplatin resistance of NSCLC was also validated in vivo. The results showed that miR-152-3p and ELF1 were decreased in NSCLC tissues. miR-152-3p reversed cisplatin resistance by inhibiting autophagy through NCAM1. NCAM1 promoted autophagy through the ERK pathway and facilitated cisplatin resistance. ELF1 positively regulated miR-152-3p level by directly interacting with miR-152-3p promoter. miR-152-3p targeted NCAM1 to regulate NCAM1 level and then affected the binding of NCAM1 to ERK1/2. ELF1 inhibited autophagy and reversed cisplatin resistance through miR-152-3p/NCAM1. miR-152-3p inhibited autophagy and cisplatin resistance of xenograft tumor in mice. In conclusion, our study revealed that ELF1 inhibited autophagy to attenuate cisplatin resistance through the miR-152-3p/NCAM1/ERK pathway in H446/DDP and A549/DDP cells, suggesting a potential novel treatment strategy for NSCLC.

Isolation and Identification of Novel Highly Pathogenic Avian Influenza Virus (H5N8) Subclade 2.3.4.4b from Geese in Northeastern China.

H5N8, a highly pathogenic avian influenza, has become a new zoonotic threat in recent years. As of December 28, 2021, at least 3,206 H5N8 cases had been reported in wild birds and poultry worldwide. In January 2021, a novel virus strain named A/goose/China/1/2021 was isolated during an H5N8 goose influenza outbreak in northeastern China. The PB2, PB1, HA, and M genes of A/goose/China/1/2021 were highly identical to those of H5N8 strains emerging in Kazakhstan and Russia in Central Asia from August to September 2020, while the remaining four genes had the closest homology to those of H5N8 viruses isolated in South Korea in East Asia from November to December 2020. We thus speculate that A/goose/China/1/2021 is likely a reassortant virus that formed in the 2020 to 2021 influenza season and that the migratory birds via the two migration routes of Central Asia and East Asia-Australia may have played an essential role in the genetic reassortment of this virus. The phylogenetic analysis indicated that the HA genes of H5N8 viruses belonging to group II of subclade 2.3.4.4b, including A/goose/China/1/2021, may be derived from strains in Central Asia. Given the complex global spread of H5N8 virus, our study highlights the necessity to strengthen the function of the global surveillance network for H5N8 virus and to accelerate the pace of vaccine development to confront the current challenges posed by H5N8 virus of subclade 2.3.4.4. IMPORTANCE H5N8, a highly pathogenic avian influenza, not only has an impact on public health, but also has a huge negative impact on animal health, food safety, safety, and even on the local and international economy. The migratory wild birds play a vital role in the intercontinental transmission of H5N8 virus. It is urgent that we should strengthen the function of the global surveillance network for H5N8 virus and accelerate the pace of vaccine development to confront the current challenges posed by H5N8 virus of subclade 2.3.4.4.

Small peptide LINC00511-133aa encoded by LINC00511 regulates breast cancer cell invasion and stemness through the Wnt/ß-catenin pathway.

LINC00511 is an long non-coding RNA (lncRNA) of ncRNAs,This study aimed to investigate whether the lncRNA LINC00511 could encode a small peptide, LINC00511-133aa, and whether this peptide could promote breast cancer cell metastasis and stemness by activating the wnt/ß-catenin pathway. The LINC00511-133aa coding sequence vector and control vector were transfected into MCF-7 and MDA-MB-231 breast cancer cells, with subsequent assessment of peptide expression using PCR, western blotting, and immunofluorescence assays. Cell proliferation, invasion, and apoptosis were evaluated using CCK8, apoptotic, wound healing, and transwell invasion assays, while the characteristic changes of tumor stem cells were detected through sphere-forming assay and western blot analyses of the stemness markers Oct4, Nanog, and SOX2. Results showed that LINC00511-133aa was indeed encoded by LINC00511 and promoted the invasiveness and stemness of breast cancer cells while limiting apoptosis by modulating the expression levels of wnt/ß-catenin pathway-related proteins Bax, c-myc, and CyclinD1, as well as facilitating ß-catenin protein entry into the nucleus. This study provides evidence for the potential involvement of lncRNA LINC00511 and its peptide product in breast cancer progression via the regulation of the wnt/ß-catenin pathway.

Reversible cardiac function and left ventricular hypertrophy in a Chinese man with mitochondrial myopathy: a case report.

BACKGROUND: Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy. CASE PRESENTATION: A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up. CONCLUSIONS: This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.

Computed tomography radiomic features and clinical factors predicting the response to first transarterial chemoembolization in intermediate-stage hepatocellular carcinoma.

BACKGROUND: According to clinical practice guidelines, transarterial chemoembolization (TACE) is the standard treatment modality for patients with intermediate-stage hepatocellular carcinoma (HCC). Early prediction of treatment response can help patients choose a reasonable treatment plan. This study aimed to investigate the value of the radiomic-clinical model in predicting the efficacy of the first TACE treatment for HCC to prolong patient survival. METHODS: A total of 164 patients with HCC who underwent the first TACE from January 2017 to September 2021 were analyzed. The tumor response was assessed by modified response evaluation criteria in solid tumors (mRECIST), and the response of the first TACE to each session and its correlation with overall survival were evaluated. The radiomic signatures associated with the treatment response were identified by the least absolute shrinkage and selection operator (LASSO), and four machine learning models were built with different types of regions of interest (ROIs) (tumor and corresponding tissues) and the model with the best performance was selected. The predictive performance was assessed with receiver operating characteristic (ROC) curves and calibration curves. RESULTS: Of all the models, the random forest (RF) model with peritumor (+10 mm) radiomic signatures had the best performance [area under ROC curve (AUC) = 0.964 in the training cohort, AUC = 0.949 in the validation cohort]. The RF model was used to calculate the radiomic score (Rad-score), and the optimal cutoff value (0.34) was calculated according to the Youden's index. Patients were then divided into a high-risk group (Rad-score > 0.34) and a low-risk group (Rad-score ≤ 0.34), and a nomogram model was successfully established to predict treatment response. The predicted treatment response also allowed for significant discrimination of Kaplan-Meier curves. Multivariate Cox regression identified six independent prognostic factors for overall survival, including male [hazard ratio (HR) = 0.500, 95% confidence interval (CI): 0.260-0.962, P = 0.038], alpha-fetoprotein (HR = 1.003, 95% CI: 1.002-1.004, P < 0.001), alanine aminotransferase (HR = 1.003, 95% CI: 1.001-1.005, P = 0.025), performance status (HR = 2.400, 95% CI: 1.200-4.800, P = 0.013), the number of TACE sessions (HR = 0.870, 95% CI: 0.780-0.970, P = 0.012) and Rad-score (HR = 3.480, 95% CI: 1.416-8.552, P = 0.007). CONCLUSIONS: The radiomic signatures and clinical factors can be well-used to predict the response of HCC patients to the first TACE and may help identify the patients most likely to benefit from TACE.

Integrated Bioinformatics Analysis of DNA Methylation Biomarkers in Thyroid Cancer Based on TCGA Database.

Previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes in thyroid cancer (TC), but these results of individual genes are far from enough. In this work, we aimed to investigate the onset and pattern of methylation changes during the progression of TC by informatics analysis. We downloaded the DNA methylation and RNA sequencing datasets from The Cancer Genome Atlas focusing on TC. Abnormally methylated differentially expressed genes (DEGs) were sorted and pathways were analyzed. The KEGG and GO were then used to perform enrichment and functional analysis of identified pathways and genes. Gene-drug interaction network and human protein atlas were applied to obtain feature DNA methylation biomarkers. In total, we identified 2170 methylation-driven DEGs, including 1054 hypermethylatedlow-expression DEGs and 1116 hypomethylated-high-expression DEGs at the screening step. Further analysis screened total of eight feature DNA methylation biomarkers (RXRG, MET, PDGFRA, FCGR3A, VEGFA, CSF1R, FCGR1A and C1QA). Pathway analysis showed that aberrantly methylated DEGs mainly associated with transcriptional misregulation in cancer, MAPK signaling, and intrinsic apoptotic signaling in TC. Taken together, we have identified novel aberrantly methylated genes and pathways linked to TC, which might serve as novel biomarkers for precision diagnosis and disease treatment.

Prevalence and genotype distribution of group A rotavirus circulating in Shanxi Province, China during 2015-2019.

BACKGROUND: Group A rotavirus (RVA), despite being a leading cause of gastroenteritis in infants and young children, is less studied in Shanxi Province, China. The current study was conducted to determine the prevalence and genetic characterization of RVA in hospitalized children younger than 10 years of age with the diagnosis of acute gastroenteritis in Shanxi Province, China. METHODS: A hospital-based active surveillance of rotavirus gastroenteritis was conducted at Children's Hospital of Shanxi from Jan 1, 2015, through Dec 31, 2019. Rotavirus was detected in stool samples by real-time quantitative reverse transcription PCR (qRT-PCR). G- and P-genotypes were determined by reverse transcription PCR (RT-PCR) and nucleotide sequencing. RESULTS: A total of 961 children younger than 10 years of age was enrolled over the study period, of whom 183 (19.0%) were positive for RVA. The highest RVA-infection frequency (23.7%) was found among children aged 12-23 months, and the seasonal peak was in December. G9P[8] was most prevalent (76.0%), followed by G3P[8] (7.1%), G2P[4] (3.3%), G1P[8] (0.5%) and G9P[4] (0.5%). CONCLUSIONS: These results report for the first time that RVA was one of the main causes of severe infectious gastroenteritis in children, and a high proportion of G9P[8] strains circulating in most areas of Shanxi Province. While the protective efficacy of the rotavirus vaccines has been demonstrated against G9P[8] strains, our results highlight that the dominant strains have not been effectively controlled in China.

Identification and functional prediction of circRNAs in Populus Euphratica Oliv. heteromorphic leaves.

Populus euphratica Oliv. has typical heterophylly. Linear, lanceolate, ovate and broad-ovate leaves appeared in turn from sprouting to development, to maturity. The environmental adaptabilities of P. euphraticas with different leaves were also different. To explore the role of circRNAs on the morphogenesis of P. euphratica heteromorphic leaves (P.hl) and their stress response, the expression profile of circRNAs was analyzed by strand-specific RNA sequencing for the above four kinds of heteromorphic leaves. According to ceRNA hypothesis, 18 differentially expressed cirRNAs (DECs) could influence the expression of 84 mRNAs by antagonizing 23 miRNAs in five sample-pairs. Based on the function of 84 mRNAs, these DECs participate in development process, response to stimulus, response to hormonal et al. Therefore, these circRNAs were involved in the P.hl morphogenesis and stress response by interacting with miRNAs and mRNAs. Our study complemented the genebank of P. euphratica and provided a new strategy for studying leaf development.

Synthesis and characterization of a photoresponsive doxorubicin/combretastatin A4 hybrid prodrug.

To explore the application of photoremovable protecting groups (PPGs) in the field of combination chemotherapy, we designed and synthesized a photoresponsive hybrid prodrug 4 that bearing both doxorubicin (DOX) and combretastatin A4 (CA4). Light triggered drug release investigation found that DOX release was mainly accomplished by 405 nm light while CA4 release was mainly triggered by 365 nm light, i.e., prodrug 4 exhibited a quasi-sequential release behavior when a sequential light irradiation strategy was applied. Cell viability evaluation confirmed the increased cytotoxicity of prodrug 4 compared with individual drugs towards MDA-MB-231cells, indicating that a synergistic effect was achieved.

Ferret badger rabies in Zhejiang, Jiangxi and Taiwan, China.

Ferret badger (FB, Melogale moschata) rabies is an increasing public health threat to humans, with FBs being a major reservoir and vector of rabies in China. Based on 152 published nucleotide sequences of the FB rabies virus (RABV) nucleoprotein, phylogenetic analysis revealed them to be clustered into six FB-related lineages, FB-I to FB-VI. The genetic features of members of lineage FB-VI suggest that cross-species transmission occurs between FBs and dogs. Here, we describe the phylogenetic relationships between FB-RABVs, their geographic segregation, and their evolutionary dynamics in epizootic regions.

Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties.

Vismodegib is an oral and high selective hedgehog (Hh) inhibitor used for the treatment of basal cell carcinoma (BCC). In this work, analogs of Vismodegib with deuterium-for-hydrogen replacement at certain metabolically active sites were prepared and found to have a better pharmacokinetic properties in mice. In particular, deuterated compound SKLB-C2211 obviously altered the blood circulation behavior compared to its prototype, which was demonstrated by significantly prolonged blood circulation half-life time (t1/2) and increased AUC0→∞. These results suggested SKLB-C2211 had the potential to be a long-acting inhibitor against Hh signaling pathway, and laid the foundation for the further research of its druggability.

Identification and function analyses of senescence-associated WRKYs in wheat.

Leaf senescence is a positive, highly regulated, complex process, and transcription factors play important roles in the regulation of this process. We identified and characterized 116 WRKYs from the wheat genome database. Thirteen TaWRKYs were confirmed as senescence-associated genes. We focused on TaWRKY7, which is up-regulated in the natural leaf senescence process. TaWRKY7 is expressed in different tissues of wheat and is localized in the nucleus. It shows transcriptional activation activity in yeast cells. The ectopic over-expression of TaWRKY7 in Arabidopsis (Arabidopsis thaliana) significantly promoted early leaf senescence under darkness treatment and prevented leaf moisture losses. TaWRKY7 played important roles in the senescence process and was involved in abiotic stress responses. Our transcriptomic and genetic studies on WRKYs suggest that WRKY transcription factors are a type of vital regulator in leaf senescence in wheat (Triticum aestivum L.).

Will China's Cooperative Medical System fail again? Insight from farmer satisfaction survey.

This paper studied the sustainability of China's New Rural Cooperative Medical System (NCMS) by evaluating the satisfaction rate of its participants-the farmers. The study related the overall satisfaction of the farmers to their satisfaction with the four different aspects of the program. It also identified which personal and program attributes affect the farmers' satisfaction rate. Survey data of 1278 households from 66 counties in Shandong Province of China were collected in 2011 using a multi-stage stratified cluster-sampling method. To overcome the nepotistic barriers in rural China, field surveys in each township were conducted by university students from the same place. Data were analyzed using multiple regressions and structural equation modeling method. The results showed that 86% of the farmers were either satisfied or very satisfied with the NCMS and 82% indicated their intention to continue participating in the program. Aside from its financial benefits, both the publicity and reimbursement procedure of the program were found to be significant factors in influencing the satisfaction of the farmers. Majority of the participants held positive opinions toward the NCMS, contradicting the negative assessments made by many previous studies. Given the high proportion of farmers willing to continue with the program, it is likely to be sustainable in the near future. Greater publicity and education efforts should be made to make the farmers better informed about the program, and measures should be taken to improve its reimbursement procedure and the setting of the premium level.

Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties.

Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202.