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In this paper, the problem we investigate is to simultaneously identify the source term and initial value of the time fractional diffusion equation. This problem is ill-posed, i.e., the solution (if exists) does not depend on the measurable data. We give the conditional stability result under the a-priori bound assumption for the exact solution. The modified Tikhonov regularization method is used to solve this problem, and under the a-priori and the a-posteriori selection rule for the regularization parameter, the convergence error estimations for this method are obtained. Finally, numerical example is given to prove the effectiveness of this regularization method.

Various molecular subclasses of hepatocellular carcinoma (HCC) exists, with many novel cooperating oncogenes and tumor suppressor genes involved in its tumorigenesis. The emerging importance of WNT signaling in HCC has been established. However, the intricate genetic mechanisms involved in this complex signaling pathway remains to be elucidated. Importantly, while some cooperating genes have been identified, there are still many unknown genes associated with catenin beta 1 (CTNNB1)-induced HCC. Mutations in both oncogenes and tumor suppressor genes are required for HCC tumorigenesis. The emergence of the CRISPR/Cas9 system has allowed researchers now to target both alleles efficiently. In this novel study, the Sleeping Beauty transposon system was used as a gene delivery system in vivo to stably integrate an expression cassette that carry pools of gRNAs and overexpress a mutant version of CTNNB1 into the hepatocyte genome. We identified 206 candidate genes that drive HCC tumorigenesis in the context of WNT signaling activation and, neurofibromin 2 (NF2) gene, a known tumor suppressor gene with clinical relevance was validated in this proof-of-principle study.

BackgroundThe immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are crucial in maintaining a delicate balance between protective effects and harmful pathological reactions that drive the progression of coronavirus disease 2019 (COVID-19). T cells play a significant role in adaptive antiviral immune responses, making it valuable to investigate the heterogeneity and diversity of SARS-CoV-2-specific T cell responses in COVID-19 patients with varying disease severity.MethodsIn this study, we employed high-throughput T cell receptor (TCR) β repertoire sequencing to analyze TCR profiles in the peripheral blood of 192 patients with COVID-19, including those with moderate, severe, or critical symptoms, and compared them with 81 healthy controls. We specifically focused on SARS-CoV-2-associated TCR clonotypes.ResultsWe observed a decrease in the diversity of TCR clonotypes in COVID-19 patients compared to healthy controls. However, the overall abundance of dominant clones increased with disease severity. Additionally, we identified significant differences in the genomic rearrangement of variable (V), joining (J), and VJ pairings between the patient groups. Furthermore, the SARS-CoV-2-associated TCRs we identified enabled accurate differentiation between COVID-19 patients and healthy controls (AUC > 0.98) and distinguished those with moderate symptoms from those with more severe forms of the disease (AUC > 0.8). These findings suggest that TCR repertoires can serve as informative biomarkers for monitoring COVID-19 progression.ConclusionsOur study provides valuable insights into TCR repertoire signatures that can be utilized to assess host immunity to COVID-19. These findings have important implications for the use of TCR β repertoires in monitoring disease development and indicating disease severity.

Lodging is the most common constraint on grain yield of direct-seeded rice. There is limited information about lodging resistance and its related plant traits in direct-seeded and double-season rice (DDR) in Central China. This study aims to identify the plant traits that achieve high lodging resistance in ultrashort-duration varieties (about 95 days) of DDR. Field experiments were conducted in 2017 and 2018 in Wuxue County, Hubei Province, China, with four ultrashort-duration varieties grown under two nitrogen (N) rates. Lodging-related traits were measured on the 15th day after heading, and yield and yield attributes were measured at maturity. The grain yield of the four varieties ranged from 4.59 to 7.61 t ha–1 across the two N rates, with a total growth duration of 85 to 97 days. Varietal differences in lodging index were mainly explained by the bending moment, which was closely related to plant height. Breaking resistance did not affect the lodging index significantly. Shortening plant height from 95.4 to 80.5 cm decreased the lodging index by 22.4% but did not reduce grain yield. Our results suggested that reducing plant height was effective in improving the lodging resistance of ultrashort-duration varieties of DDR. Lodging resistance should be enhanced by improving breaking resistance rather than reducing plant height to increase DDR grain yield further.

Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines in order to identify potential drug resistant causative genes. Interleukin 7 (IL7) and mal, T cell differentiation protein 2 (MAL2) were identified as candidate genes that promote survival by activating JAK/STAT and PI3K/AKT signaling pathways. Sorafenib-resistant cells exhibited higher clonogenic survival and lower drug sensitivity due to IL7 and MAL2 upregulation. Higher anti-apoptotic effect, clonogenic survival and increased PI3K/AKT/STAT3 activities were observed in IL7 and MAL2 co-overexpressing cells compared with controls or cells overexpressing IL7 or MAL2 individually. Given the critical role of MAL2 in endocytosis, we propose that MAL2 might facilitate the endocytic trafficking of IL7 and its cognate receptors to the plasma membrane, which leads to upregulated JAK/STAT and PI3K/AKT signaling pathways and Sorafenib resistance. Additionally, our previous studies showed that an autophagy-inducing stapled peptide promoted the endolysosomal degradation of c-MET oncogene and overcame adaptive Sorafenib resistance in c-MET+ HCC cells. In this study, we demonstrate that these stapled peptides readily induced autophagy and inhibited the proliferation of both wild-type and Sorafenib-resistant HCC cells co-overexpressing both IL7 and MAL2. Furthermore, these peptides showed synergistic cytotoxicity with Sorafenib in drug-resistant HCC cells co-overexpressing both IL7 and MAL2. Our studies suggest that targeting autophagy may be a novel strategy to overcome IL7/MAL2-mediated Sorafenib resistance in HCC.

The rice cultivars carrying dep1 (denseanderectpanicle1) have the potential to achieve both high grain yield and high nitrogen use efficiency (NUE). However, few studies have focused on the agronomic and physiological performance of those cultivars associated with high yield and high NUE under field conditions. Therefore, we evaluated the yield performance and NUE of two near-isogenic lines (NILs) carrying DEP1 (NIL-DEP1) and dep1-1 (NIL-dep1) genes under the Nanjing 6 background at 0 and 120 kg N ha−1. Grain yield and NUE for grain production (NUEg) were 25.5 and 21.9% higher in NIL-dep1 compared to NIL-DEP1 averaged across N treatments and planting years, respectively. The yield advantage of NIL-dep1 over NIL-DEP1 was mainly due to larger sink size (i.e., higher total spikelet number), grain-filling percentage, total dry matter production, and harvest index. N utilization rather than N uptake contributed to the high yield of NIL-dep1. Significantly higher NUEg in NIL-dep1 was associated with higher N and dry matter translocation efficiency, lower leaf and stem N concentration at maturity, and higher glutamine synthetase (GS) activity in leaves. In conclusion, dep1 improved grain yield and NUE by increasing N and dry matter transport due to higher leaf GS activity under field conditions during the grain-filling period.

This paper considers the inverse problem of determining an unknown source which depends only one spatial variable on modified Helmholtz equation. This problem is well known to be severely ill-posed, the solution (if it exists) does not depend continuously on the data. Landweber iterative regularization method is used to solve this inverse source problem. The Hölder type error estimates are obtained between the exact solution and regularization solutions under an a priori and an a posteriori regularization parameters choice rules, respectively. Numerical examples are provided to show the effectiveness of the proposed method.

In this paper, we consider the inverse problem for identifying the initial value problem of the time–space fractional nonlinear diffusion equation. The uniqueness of the solution is proved by taking the fixed point theorem of Banach compression, and the ill-posedness of the problem is analyzed through the exact solution. The quasi-boundary regularization method is chosen to solve the ill-posed problem, and the error estimate between the regularization solution and the exact solution is given. Moreover, several numerical examples are chosen to prove the effectiveness of the quasi-boundary regularization method. Finally, our method can be used to solve high dimensional time–space fractional nonlinear diffusion equation, especially in cylindrical and spherical symmetric regions.

Thrombocytopenia can cause substantial morbidity and mortality in critically ill patients. There are multiple etiology factors and various mechanisms associated with thrombocytopenia, of which drug-induced thrombocytopenia (DITP) deserves attention. Herein, we describe a case of severe thrombocytopenia during intensive care unit (ICU) hospitalization that was likely to be associated with vancomycin. By revealing the process of identifying this case of DITP and reviewing relevant clinical studies, a risk alert of vancomycin-related severe hematotoxicity should be considered.

Insoluble dietary fiber (IDF) were isolated from wheat bran (WB) after microbial fermentation with single or mixed strain [Lactobacillus plantarum, Lactobacillus acidophilus, Bacillus subtilis or mixed lactic acid bacteria (L. plantarum and L. acidophilus with ration of 1:1)]. Structure, physicochemical, functional properties, and antioxidant activity of the wheat bran insoluble dietary fiber (W-IDF) modified by fermentation were studied. Fourier transformed infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM) analysis suggested the successful modification of W-IDF. After fermentation with L. plantarum and mixed lactic acid bacteria, the water retention capacity (WRC), oil retention capacity (ORC), and water swelling capacity (WSC) of W-IDF were improved. The sodium cholate adsorption capacity (SCAC), and cation exchange capacity (CEC) of W-IDF modified with L. acidophilus fermentation were significantly increased. Although the cholesterol adsorption capacity (CAC) of W-IDF decreased after modification with probiotic fermentation, nitrite ion adsorption capacity (NIAC), and total phenolic content (TPC) were enhanced. Additionally, W-IDF modified by fermentation with B. subtilis or mixed lactic acid bacteria exhibited superior antioxidant capacity verified by DPPH, ABTS and total reducing power assays. Results manifested that microbial fermentation is a promising methods to modify the W-IDF to provide high-quality functional IDF for food processing and human health management.

ObjectiveWe aimed to evaluate the performance of nanopore amplicon sequencing detection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical samples.MethodWe carried out a single-center, prospective cohort study in a Wuhan hospital and collected a total of 86 clinical samples, including 54 pharyngeal swabs, 31 sputum samples, and 1 fecal sample, from 86 patients with coronavirus disease 2019 (COVID-19) from Feb 20 to May 15, 2020. We performed parallel detection with nanopore-based genome amplification and sequencing (NAS) on the Oxford Nanopore Technologies (ONT) minION platform and routine reverse transcription quantitative polymerase chain reaction (RT-qPCR). In addition, 27 negative control samples were detected using the two methods. The sensitivity and specificity of NAS were evaluated and compared with those of RT-qPCR.ResultsThe viral read number and reference genome coverage were both significantly different between the two groups of samples, and the latter was a better indicator for SARS-CoV-2 detection. Based on the reference genome coverage, NAS revealed both high sensitivity (96.5%) and specificity (100%) compared with RT-qPCR (80.2 and 96.3%, respectively), although the samples had been stored for half a year before the detection. The total time cost was less than 15 h, which was acceptable compared with that of RT-qPCR (∼2.5 h). In addition, the reference genome coverage of the viral reads was in line with the cycle threshold value of RT-qPCR, indicating that this number could also be used as an indicator of the viral load in a sample. The viral load in sputum might be related to the severity of the infection, particularly in patients within 4 weeks after onset of clinical manifestations, which could be used to evaluate the infection.ConclusionOur results showed the high sensitivity and specificity of the NAS method for SARS-CoV-2 detection compared with RT-qPCR. The sequencing results were also used as an indicator of the viral load to display the viral dynamics during infection. This study proved the wide application prospect of nanopore sequencing detection for SARS-CoV-2 and may more knowledge about the clinical characteristics of COVID-19.

Background: The symptoms of coronavirus disease 2019 (COVID-19) range from moderate to critical conditions, leading to death in some patients, and the early warning indicators of the COVID-19 progression and the occurrence of its serious complications such as myocardial injury are limited.Methods: We carried out a multi-center, prospective cohort study in three hospitals in Wuhan. Genome-wide 5-hydroxymethylcytosine (5hmC) profiles in plasma cell-free DNA (cfDNA) was used to identify risk factors for COVID-19 pneumonia and develop a machine learning model using samples from 53 healthy volunteers, 66 patients with moderate COVID-19, 99 patients with severe COVID-19, and 38 patients with critical COVID-19.Results: Our warning model demonstrated that an area under the curve (AUC) for 5hmC warning moderate patients developed into severe status was 0.81 (95% CI 0.77–0.85) and for severe patients developed into critical status was 0.92 (95% CI 0.89–0.96). We further built a warning model on patients with and without myocardial injury with the AUC of 0.89 (95% CI 0.84–0.95).Conclusion: This is the first study showing the utility of 5hmC as an accurate early warning marker for disease progression and myocardial injury in patients with COVID-19. Our results show that phosphodiesterase 4D and ten-eleven translocation 2 may be important markers in the progression of COVID-19 disease.

Abstract Background The efficacy and safety of spinal anesthesia by intrathecal dexmedetomidine (DEX) for parturients undergoing cesarean section are still lack of evidence. This aim of our study was to evaluate the efficacy and safety of intrathecal DEX for parturients undergoing cesarean section to provide more data evidence for intrathecal applications. Methods Three hundred parturients undergoing cesarean section under spinal anesthesia were randomly assigned into three groups: group B: 9.0 mg (1.2 ml) of 0.75% bupivacaine with saline (1 ml); group FB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 20 μg of fentanyl (1 ml); group DB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 5 μg of DEX (1 ml). Intraoperative block characteristics, parturients’ postoperative quality of recovery, maternal and neonatal outcomes and the plasma concentration of DEX were measured. All parturients were followed up for 30 days to determine whether nerve injury occurred. Results Compared with group B, the duration of sensory block in group FB and group DB were significantly prolonged (108.4 min [95% Confidence Interval (CI) = 104.6–112.3] in group B, and 122.0 min [95% CI = 116.8–127.3] in group FB, 148.2 min [95% CI = 145.3–151.1] in group DB). The overall score of quality recovery in group DB (71.6 [95% CI = 71.0–72.2]) was significantly higher than that in group FB (61.5 [95% CI = 60.8–62.2]) and group B (61.7 [95% CI = 61.0–62.4]). There was no statistically significant difference among the three groups for PH, PaO2, and PaCO2 of newborn. The plasma concentration of DEX in umbilical artery and umbilical vein was low and cannot be detected. The 30-days follow-up of parturients did not show any new onset of back, buttock or leg pain or paresthesia. Conclusions DEX is a potential local anesthetic adjuvant that the intrathecal combination of 5 μg DEX can safely exhibit a facilitatory block effect and improve parturients’ recovery quality. Trial registration Chinese Clinical Trial Registry (Registration number # ChiCTR1900022019 ; Date of Registration on March 20th, 2019).

Abstract In this paper, we deal with the inverse problem of identifying the unknown source of time-fractional diffusion equation on a columnar symmetric domain. This problem is ill-posed. Firstly, we establish the conditional stability for this inverse problem. Then the regularization solution is obtained by using the Tikhonov regularization method and the error estimates are derived under the a priori and a posteriori choice rules of the regularization parameter. Three numerical examples are presented to illustrate the validity and effectiveness of our method.

In this manuscript, we study the inverse problem for identifying the initial value of a time-fractional diffusion equation in an axisymmetric region. This is an ill-posed problem, i.e., the solution does not depend continuously on the data. We choose the Landweber iterative regularization method to solve this problem. Under the a priori and the a posteriori regularization parameter choice rules, we present the error estimates between the regularization solutions and the exact solution. We present some examples to show this method’s effectiveness.

In this paper, the inverse problem for identifying the initial value of a time fractional nonhomogeneous diffusion equation in a columnar symmetric region is studied. This is an ill-posed problem, i.e., the solution does not depend continuously on the data. The fractional Tikhonov regularization method is applied to solve this problem and obtain the regularization solution. The error estimations between the regularization solution and the exact solution are also obtained under the priori and the posteriori regularization parameter choice rules, respectively. Some examples are given to show this method’s effectiveness.

Background & Aims: Zinc finger and BTB domain containing 20 (ZBTB20) has been implicated as a potential oncogene in liver cancer. However, knockout studies have shown it to be a transcriptional repressor of the alpha-foetoprotein (Afp) gene in adult liver, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumour severity in certain cases of hepatocellular carcinoma (HCC). As there are many discrepancies in the literature regarding its role in liver tumourigenesis, the aim of this study was to elucidate the role of ZBTB20 in HCC tumourigenesis. Methods: A reverse genetic study using the Sleeping Beauty (SB) transposon system in mice was performed to elucidate the role of ZBTB20 in HCC tumourigenesis. In vitro ZBTB20 gain- and loss-of-function experiments were used to assess the relationship amongst ZBTB20, peroxisome proliferator activated receptor gamma (PPARG) and catenin beta 1 (CTNNB1). Results: Transgenic overexpression of ZBTB20 in hepatocytes and in the context of transformation related protein (Trp53) inactivation induced hepatic hypertrophy, activation of WNT/CTNNB1 signalling, and development of liver tumours. In vitro overexpression and knockout experiments using CRISPR/Cas9 demonstrated the important role for ZBTB20 in downregulating PPARG, resulting in activation of the WNT/CTNNB1 signalling pathway and its downstream effectors in HCC tumourigenesis. Conclusions: These findings demonstrate a novel interaction between ZBTB20 and PPARG, which leads to activation of the WNT/CTNNB1 signalling pathway in HCC tumourigenesis. Lay summary: ZBTB20 has been implicated as a potential oncogene in liver cancer. Herein, we uncover its important role in liver cancer development. We show that it interacts with PPARG to upregulate the WNT/CTNNB1 signalling pathway, leading to tumourigenesis.

Intravitreal injection is one of the most commonly used treatment methods in ophthalmology at present. It is easy to operate and has a shorter operation time. However, there is no consensus on whether it is necessary to dilate pupils before intravitreal injection. For this reason, we conducted an online questionnaire survey. On the basis of relevant research, we discussed the above issues and put forward our proposals. It is not necessary to dilate pupils before intravitreal injection.

Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic disease in adults and children worldwide. Importantly, there are currently no approved treatments available for NAFLD. This study aims to investigate the potential applications of sodium tanshinone IIA sulfonate (STS) on improving the NAFLD condition using both in vitro and in vivo approaches. The results showed that STS markedly inhibited lipid accumulation in oleic acid (OA) and palmitic acid (PA) treated HepG2 and primary immortalized human hepatic (PIH) cells. STS suppressed lipogenesis by inhibiting expression of sterol regulatory element binding transcription factor 1 (SREBF1), fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD). In addition, STS reduced inflammation in cells treated with OA-PA, shown by decreased transcriptional levels of tumor necrosis factor (TNF), transforming growth factor beta 1 (TGFB1) and interleukin 1 beta (IL1B). Consistently, protective effects on hepatic steatosis in db/db mice were observed after STS administration, demonstrated by decreased lipid accumulation in mouse hepatocytes. This protective effect might be associated with STS induced activation of sirtuin 1 (SIRT1)/protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1) pathways. Our findings suggest a potential therapeutic role for STS in the treatment of NAFLD.

The neuromuscular junction (NMJ) consists of three components, namely presynaptic motor neurons, postsynaptic muscle fibers and perisynaptic Schwann cells (PSCs). The role of Schwann cells (SCs) in regulating NMJ structural and functional development remains unclear. In this study, mice with conditional inactivation of neurofibromin 1 (Nf1) and phosphatase and tensin homolog (Pten), specifically in SCs, resulted in delayed NMJ maturation that led to delayed muscle growth, recapitulating the muscular dystrophy condition observed in human neurofibromatosis type I syndrome (NF1) patients. Expression levels of NMJ development related molecules such as cholinergic receptor, nicotinic, alpha polypeptide 1 (Chrna1), agrin (Agrn), dystrophin, muscular dystrophy (Dmd), laminin, beta 2 (Lamb2) and dystroglycan 1 (Dag1) were also downregulated. To further explore the molecular alterations in these SCs, NF1- and PTEN-related pathways were analyzed in mutant sciatic nerves. As expected, hyperactive RAS/PI3K/AKT/mTOR signaling pathways were identified, suggesting the importance of these pathways for NMJ development, and subsequent muscle maturation.

Abstract Background Benign breast papilloma is currently managed with conservative management with close observation. In contrast, papilloma with high-risk or malignant lesions warrants surgical excision. The purpose of our study was to investigate magnetic resonance imaging (MRI) features of breast papilloma and to identify imaging diagnostic indicators for papilloma with high-risk or malignant lesions. Methods MRI features of 175 surgically confirmed papillomas on 158 patients were retrospectively reviewed. The 175 cases included 132 cases of benign papilloma and 43 cases of papilloma with high-risk or malignant lesions. The MRI features of these lesions were classified into three types: mass, non-mass enhancement (NME), and occult lesion. The occult lesion was defined as the presence of only ductal dilation without any enhanced lesions on MRI. For a mass lesion, the mixed mass-NME lesion was considered if linear, segmental or regional enhanced lesion was found adjacent to the mass. Clinical and MRI features were compared by univariate and multivariate analysis between the benign papilloma and the papilloma with high-risk or malignant lesions. Results Multivariate logistic regression analysis demonstrated that clinical characteristics including being or older than 50 years (odds ratio [OR] = 4.506), having bloody nipple discharge (OR = 4.499), and concurrent breast cancer (OR = 5.083) were significant indicators for papilloma with high-risk or malignant lesions. On MRI, most papillomas presented as mass (n = 135, 77.1%), and fewer as NME (n = 37, 21.1%) and occult lesion (n = 3, 1.7%). For the mass lesion, the logistic regression analysis demonstrated that a mass size exceeding 10 mm (OR = 2.956) and mixed mass-NME lesion (OR = 4.143) were independent risk indicators for a papilloma with high-risk or malignant lesions. For the NME lesion, the segmental or regional distribution was more commonly observed in the papilloma with high-risk or malignant lesions (61.5%) than the benign papilloma (12.5%) (P = 0.006). All the cases of occult lesions were benign papillomas. Conclusions MRI features including a mass size exceeding 10 mm, mixed mass-NME lesion, and NMEs with segmental or regional distribution indicate a papilloma with high-risk or malignant lesions.

Aims: To determine the risk of liver injury associated with the use of different intravenous lipid emulsions (LEs) in large populations in a real-world setting in China.Methods: A prescription sequence symmetry analysis was performed using data from 2015 Chinese Basic Health Insurance for Urban Employees. Patients newly prescribed both intravenous LEs and hepatic protectors within time windows of 7, 14, 28, 42, and 60 days of each other were included. The washout period was set to one month according to the waiting-time distribution. After adjusting prescribing time trends, we quantify the deviation from symmetry of patients initiating LEs first and those initiating hepatic protectors first, by calculating adjusted sequence ratios (ASRs) and relevant 95% confidence intervals. Analyses were further stratified by age, gender, and different generations of LEs developed.Results: In total, 416, 997, 1,697, 2,072, and 2,342 patients filled their first prescriptions with both drugs within 7, 14, 28, 42, and 60 days, respectively. Significantly increased risks of liver injury were found across all time windows, and the strongest effect was observed in the first 2 weeks [ASR 6.97 (5.77–8.42) ∼ 7.87 (6.04–10.61)] in overall patients. In subgroup analyses, female gender, age more than 60 years, and soybean oil-based and alternative-LEs showed higher ASRs in almost all time windows. Specially, a lower risk for liver injury was observed in the first 14 days following FO-LEs administration (ASR, 3.42; 95% CI, 0.81–14.47), but the risk started to rise in longer time windows.Conclusion: A strong association was found between LEs use and liver injury through prescription sequence symmetry analysis in a real-world setting, which aligns with trial evidence and clinical experience. Differences revealed in the risks of liver injury among various LEs need further evaluation.

The conversion of cellular prion protein (PrPC) to disease-provoking conformer (PrPSc) is crucial in the pathogenesis of prion diseases. Heparin has been shown to enhance mammalian prion protein misfolding. As spontaneous prion disease has not been reported in non-mammalian species, such as chicken, it is interesting to explore the influence of heparin on the conversion of chicken prion protein (ChPrP). Herein, we investigated the influences of heparin on biochemical properties of full-length recombinant ChPrP, with murine prion protein (MoPrP) as control. The results showed that at low heparin concentration (10 μg/mL), a great loss of solubility was observed for both MoPrP and ChPrP using solubility assays. In contrast, when the concentration of heparin was high (30 μg/mL), the solubility of MoPrP and ChPrP both decreased slightly. Using circular dichroism, PK digestion and transmission electron microscopy, significantly increased β-sheet content, PK resistance and size of aggregates were observed for MoPrP interacted with 30 μg/mL heparin, whereas 30 μg/mL heparin-treated ChPrP showed less PK resistance and slight increase of β-sheet structure. Therefore, heparin can induce conformational changes in both MoPrP and ChPrP and the biochemical properties of the aggregates induced by heparin could be modified by heparin concentration. These results highlight the importance of concentration of cofactors affecting PrP misfolding.

AimTo identify common drug-related problems (DRPs) during pharmacy intervention and consultation in an intensive care unit (ICU); to explore the gap between physicians and pharmacists on their understanding of each other’s capabilities and needs.MethodWe conducted a single-center prospective study in the ICU of a tertiary academic hospital for 21 months. A pharmaceutical care (PC) model was implemented by a pharmacy team, and data were collected during pharmacy intervention and consultation. Data analysis was performed on identified DRPs, causes and their relationships. DRPs’ frequency during intervention and consultation was compared. Problem-level descriptive analysis and network analysis were conducted using R 3.6.3.ResultImplementation of PC model greatly improved the efficacy of pharmacists in both interventions proposed to solve DRPs (from 13.6 to 20.1 cases per month) and number of patients being closely monitored (from 7.7 to 16.9 per month). Pharmacists identified 427 DRPs during pharmacy intervention with primarily adverse drug events (ADEs, 34.7%) and effect of treatment not optimal (25.5%), and 245 DRPs during consultation (mainly ADEs, 58.4%). About three-fifths DRPs were caused by antibiotics. Comparing DRPs identified during pharmacy intervention and consultation, physicians consulted pharmacists more on questions related to medication safety, while pharmacists also paid attention to treatment effectiveness, which was consulted less commonly.ConclusionImplementation of PC model is beneficial in guiding pharmacy practice and improving efficacy especially under limited human resources. Physicians and pharmacists shall continue ensuring drug safety and be familiar with the scope of PC and clinical need for a better cooperation.

In vivo cell fate reprogramming has emerged as a new method for understanding cell plasticity and as potential treatment for tissue regeneration. Highly efficient and precise reprogramming requires fully understanding of the transcriptomes which function within different cell types. Here, we adopt weighted gene co-expression network analysis (WGCNA) to explore the molecular mechanisms of self-renewal in several well-known stem cell types, including embryonic stem cells (ESC), primordial germ cells (PGC), spermatogonia stem cells (SSC), neural stem cells (NSC), mesenchymal stem cells (MSC), and hematopoietic stem cells (HSC). We identified 37 core genes that were up-regulated in all of the stem cell types examined, as well as stem cell correlated gene co-expression networks. The validation of the co-expression genes revealed a continued protein-protein interaction network that included 823 nodes and 3113 edges. Based on the topology, we identified six densely connected regions within the continued protein-protein interaction network. The SSC specific genes Itgam, Cxcr6, and Agtr2 bridged four densely connected regions that consisted primarily of HSC-, NSC-, and MSC-correlated genes. The expression levels of identified stem cell related transcription factors were confirmed consistent with bioinformatics prediction in ESCs and NSCs by qPCR. Exploring the mechanisms underlying adult stem cell self-renewal will aid in the understanding of stem cell pool maintenance and will promote more accurate and efficient strategies for tissue regeneration and repair.

Background: Tanreqing injection (TRQ) is a traditional Chinese medicine commonly used in China to treat pulmonary diseases presenting as phlegm-heat syndrome. Robust data on the safety of TRQ from real-world observational cohorts are currently lacking.Objective: To evaluate as the incidence, type, and predictors of adverse events (AEs) and adverse drug reactions (ADRs) of TRQ in clinical practice in China.Methods: We conducted a population-based cohort, multicenter study to evaluate the incidence, manifestation, outcomes, and risk factors of AEs and ADRs following TRQ use in China. Between April 2014 and May 2015 a total of 30,322 consecutive inpatients/emergency attendance patients from 90 hospitals across China administrated TRQ were followed-up for 7 days. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression to identify predictors of ADRs.Results: The incidence of AEs and ADRs was 1.4 and 0.3%, respectively. Skin and subcutaneous tissue disorders were the most common ADRs. All ADRs were mild or moderate in severity, except for one serious case of anaphylactic reaction. The majority of ADRs (72.8%) occurred in the first 2 h after TRQ administration. Two-thirds of patients (66.1%) in the study were prescribed TRQ off-label, including infants aged ≤24 months. A history of food allergy (OR 4.50, 95% CI: 1.35–15.00), drug allergy (OR 2.77, 95% CI: 1.56–4.94), and fast infusion speed (off-label use) (OR 2.10, 95% CI: 1.27–3.50) were associated with an increased risk of ADRs.Conclusion: TRQ is well tolerated in the general population, yet off-label use is prevalent. Efforts are required to educate prescribers to adhere to the drug label in order to minimize potential patient harm.

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of soft tissue neoplasm with extremely poor prognosis and no effective medical options currently available. MPNSTs can occur either sporadically or in association with the neurofibromatosis type 1 (NF1) syndrome. Importantly, activation of RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and WNT/CTNNB1 signaling pathways has been reported in both NF1‐related and late‐stage sporadic MPNSTs. In this study, we found that DAW22, a natural sesquiterpene coumarin compound isolated from Ferula ferulaeoides (Steud.) Korov., could inhibit cell proliferation and colony formation in five established human MPNST cancer cell lines. Further molecular mechanism exploration indicated that DAW22 could target the main components in the MPNST tumorigenic pathways: namely suppress phosphorylation of AKT and ERK, and reduce levels of non‐phospho (active) CTNNB1. Using the xenograft mouse model transplanted with human MPNST cancer cell line, daily treatment with DAW22 for 25 days was effective in reducing tumor growth. These results support DAW22 as an alternative therapeutic compound for MPNST treatment by affecting multiple signaling transduction pathways in its disease progression.

Abstract In this paper, we study an inverse initial value problem for the fractional diffusion equation with discrete noise. This problem is ill-posed in the sense of Hadamard. We apply the trigonometric method in a nonparametric regression associated with the quasi-boundary value regularization method to deal with this ill-posed problem. The corresponding convergence estimate for this method is obtained. The numerical results show that this regularization method is flexible and stable.

Abstract In this paper, identifying the initial value for high dimension heat equation with inhomogeneous source on a spherical symmetric domain is investigated. The truncation regularization method is a powerful technique for solving this inverse problem. We prove the convergence estimates between the regularization solution and the exact solution under the prior and the posterior regularization parameter choice rulers. A numerical example is presented to validate the effectiveness of this method.

In this paper, we study an inverse problem to identify the initial value problem of the homogeneous Rayleigh–Stokes equation for a generalized second-grade fluid with the Riemann–Liouville fractional derivative model. This problem is ill posed; that is, the solution (if it exists) does not depend continuously on the data. We use the Landweber iterative regularization method to solve the inverse problem. Based on a conditional stability result, the convergent error estimates between the exact solution and the regularization solution by using an a priori regularization parameter choice rule and an a posteriori regularization parameter choice rule are given. Some numerical experiments are performed to illustrate the effectiveness and stability of this method.

Abstract In this paper, we investigate an inverse problem to determine an unknown source term that has a separable-variable form in the time-fractional diffusion equation, whereby the data is obtained at a certain time. This problem is ill-posed, and we use the Landweber iterative regularization method to solve this inverse source problem. Two kinds of convergence rates are obtained by using an a priori and an a posteriori regularization parameters choice rules, respectively. Numerical examples are provided to show the effectiveness of the proposed method.

Abstract This paper is devoted to identifying an unknown source for a time-fractional diffusion equation with variable coefficients in a general bounded domain. This is an ill-posed problem. Firstly, we obtain a regularization solution by the Landweber iterative regularization method. The convergence estimates between regularization solution and exact solution are given under a priori and a posteriori regularization parameter choice rules, respectively. The convergence estimates we obtain are optimal order for any p in two parameter choice rules, i.e., it does not appear to be a saturating phenomenon. Finally, the numerical examples in the one-dimensional and two-dimensional cases show our method is feasible and effective.

Abstract In this paper, we mainly consider the inverse problem for identifying the unknown heat source in spherical symmetric domain. We propose a truncation regularization method combined with an a posteriori regularization parameter choice rule to deal with this problem. The Hölder type convergence estimate is obtained. Numerical results are presented to illustrate the accuracy and efficiency of this method.

Abstract In this paper, we consider the inverse problem of identifying the unknown source for the modified Helmholtz equation. We propose the Landweber iterative regularization method to solve this problem and obtain the regularization solution. Under the a priori and a posteriori regularization parameters choice rules, we all obtain the Hölder type error estimates between the exact solution and the regularization solutions. Several numerical examples are also provided to show that the Landweber iterative method works well for solving this problem.

Topological states of matter are particularly interesting for both fundamental research and practical applications. Simulating topological phases in a quantum system is of great interest due to the ability to explore a plethora of topologically nontrivial phenomena in a controllable fashion. We propose and analyze an efficient scheme for simulating topological Zak phase in two-dimensional spin-phononic crystal networks. We show that through a specially designed periodic driving, one can selectively control and enhance the bipartite silicon-vacancy center arrays, so as to obtain chiral-symmetry-protected spin-spin couplings. More importantly, the Floquet engineering spin-spin interactions support rich quantum phases associated with topological invariants. In momentum space, we analyze and simulate the topological nontrivial properties of the one- and two-dimensional systems. As an application in quantum information processing, we study the robust quantum state transfer via topologically protected edge states. This work opens up new prospects for studying quantum acoustics and offers an experimentally feasible platform for the study of topological phases of matter.

Tricin, a flavone isolated from rice bran, has been shown to be chemopreventive in a colorectal cancer (CRC) mouse model. This study aimed to illustrate the inhibitory activities of tricin in colon cancer cells and in a metastatic CRC mouse model. BALB/c mice injected with mouse Colon26-Luc cells into the rectum wall were treated with tricin (37.5 mg/kg) daily for 18 days. Orthotopic colon tumor growth and metastasis to lungs were assessed by in vivo bioluminescence imaging. Results showed that tricin suppressed Colon-Luc cells motility and downregulated phosphorylated Akt, Erk1/2 and NF-κB expressions of human colon cancer HT-29 cells. While tricin treatment suppressed tumor growth and lung metastasis as well as altered the populations of myeloid-derived suppressor cells and regulatory T cells in spleens. In summary, the tumor microenvironment modulatory and anti-metastatic effects of tricin in colon cancer mouse model were shown for the first time, suggesting the potential development of tricin-containing food supplements for CRC patients.

We propose an efficient scheme for simulating the topological phases of matter based on silicon-vacancy (SiV) center arrays in phononic crystals. This phononic band-gap structure allows for long-range spin-spin interactions with a tunable profile. Under a particular periodic microwave driving, the band-gap-mediated spin-spin interaction can be further designed with the form of the Su-Schrieffer-Heeger (SSH) Hamiltonian. In momentum space, we investigate the topological characters of the SSH model and show that the topological nontrivial phase can be obtained through modulating the periodic driving fields. Furthermore, we explore the zero-energy topological edge states at the boundary of the color center arrays and study the robust quantum information transfer via the topological edge states. This setup provides a scalable and promising platform for studying topological quantum physics and quantum information processing with color centers and phononic crystals.

In the essay, we consider an initial value question for a mixed initial-boundary value of time-fractional diffusion-wave equations. This matter is an ill-posed problem; the solution relies discontinuously on the measured information. The truncation regularization technique is used for restoring the initial value functions. The convergence estimations are given in a priori regularization parameter choice regulations and a posteriori regularization parameter choice regulations. Numerical examples are given to demonstrate this is effective and practicable.

Oil reservoir production systems are usually associated with a temperature gradient and oil production facilities frequently suffer from pipeline corrosion failures. Both bacteria and archaea potentially contribute to biocorrosion of the oil production equipment. Here the response of microbial populations from the petroleum reservoir to temperature gradient and corrosion of carbon steel coupons were investigated under laboratory condition. Carbon steel coupons were exposed to production water from a depth of 1809 m of Jiangsu petroleum reservoir (China) and incubated for periods of 160 and 300 days. The incubation temperatures were set at 37, 55, and 65°C to monitoring mesophilic, thermophilic and hyperthermophilic microorganisms associated with anaerobic carbon steel corrosion. The results showed that corrosion rate at 55°C (0.162 ± 0.013 mm year-1) and 37°C (0.138 ± 0.008 mm year-1) were higher than that at 65°C (0.105 ± 0.007 mm year-1), and a dense biofilm was observed on the surface of coupons under all biotic incubations. The microbial community analysis suggests a high frequency of bacterial taxa associated with families Porphyromonadaceae, Enterobacteriaceae, and Spirochaetaceae at all three temperatures. While the majority of known sulfate-reducing bacteria, in particular Desulfotignum, Desulfobulbus and Desulfovibrio spp., were predominantly observed at 37°C; Desulfotomaculum spp., Thermotoga spp. and Thermanaeromonas spp. as well as archaeal members closely related to Thermococcus and Archaeoglobus spp. were substantially enriched at 65°C. Hydrogenotrophic methanogens of the family Methanobacteriaceae were dominant at both 37 and 55°C; acetoclastic Methanosaeta spp. and methyltrophic Methanolobus spp. were enriched at 37°C. These observations show that temperature changes significantly alter the microbial community structure in production fluids and also affected the biocorrosion of carbon steel under anaerobic conditions.

Camellia assamica var. kucha is a local tea in the Yunnan province of China and people there believe its intake can relieve fatigue and their tiredness. Theacrine, a lesser-known purine alkaloid, was first discovered in this kind of tea. Here, we found that theacrine (15 mg/kg) could be absorbed into the blood and pass across the blood–brain barrier after oral administration. The effect and mechanism of theacrine on central fatigue were examined by employing a restraint stress model in mice. Results of behavioral tests suggested that oral administration of theacrine (5, 10, 15 mg/kg) significantly reversed learning and memory impairment caused by central fatigue. In addition, levels of fatigue-related neurotransmitters in the brains of restraint mice, including 5-hydroxytryptamine and dopamine as well as their metabolites, were restored by theacrine. Further, we found that the anti-fatigue effect of theacrine was associated with the regulation of brain glucose metabolism and the inhibition of phosphodiesterases.

Deep subsurface petroleum reservoir ecosystems harbor a high diversity of microorganisms, and microbial influenced corrosion is a major problem for the petroleum industry. Here, we used high-throughput sequencing to explore the microbial communities based on genomic 16S rDNA and metabolically active 16S rRNA analyses of production water samples with different extents of corrosion from a high-temperature oil reservoir. Results showed that Desulfotignum and Roseovarius were the most abundant genera in both genomic and active bacterial communities of all the samples. Both genomic and active archaeal communities were mainly composed of Archaeoglobus and Methanolobus. Within both bacteria and archaea, the active and genomic communities were compositionally distinct from one another across the different oil wells (bacteria p = 0.002; archaea p = 0.01). In addition, the sulfate-reducing microorganisms (SRMs) were specifically assessed by Sanger sequencing of functional genes aprA and dsrA encoding the enzymes adenosine-5′-phosphosulfate reductase and dissimilatory sulfite reductase, respectively. Functional gene analysis indicated that potentially active Archaeoglobus, Desulfotignum, Desulfovibrio, and Thermodesulforhabdus were frequently detected, with Archaeoglobus as the most abundant and active sulfate-reducing group. Canonical correspondence analysis revealed that the SRM communities in petroleum reservoir system were closely related to pH of the production water and sulfate concentration. This study highlights the importance of distinguishing the metabolically active microorganisms from the genomic community and extends our knowledge on the active SRM communities in corrosive petroleum reservoirs.

In present paper, we deal with a backward diffusion problem for a time-fractional diffusion problem with a nonlinear source in a strip domain. We all know this nonlinear problem is severely ill-posed, i.e., the solution does not depend continuously on the measurable data. Therefore, we use the Fourier truncation regularization method to solve this problem. Under an a priori hypothesis and an a priori regularization parameter selection rule, we obtain the convergence error estimates between the regular solution and the exact solution at 0 ≤ x < 1 .

In this paper, the Cauchy problem of the modified Helmholtz equation (CPMHE) with perturbed wave number is considered. In the sense of Hadamard, this problem is severely ill-posed. The Fourier truncation regularization method is used to solve this Cauchy problem. Meanwhile, the corresponding error estimate between the exact solution and the regularized solution is obtained. A numerical example is presented to illustrate the validity and effectiveness of our methods.

Bioactive metabolites in Codonopsis pilosula are of particular interest as an immunostimulant. Methyl jasmonate (MeJA) plays an important role in the elicitation of metabolite biosynthesis. Here, we explored the response of metabolites to MeJA elicitation in C. pilosula adventitious roots and multiple shoots. The results showed that the biomass, polysaccharide, and lobetyolin content of adventitious roots exhibited the highest increases with 100 µmol·L−1 MeJA at the 16th day of subculture, whereas the atractylenolide III (a terpenoid) content increased extremely with 50 µmol·L−1 MeJA treatment at the 7th day of subculture. In addition, the biomass and lobetyolin content significantly increased at the 4th day after treatment. Similarly, the polysaccharide and lobetyolin content increased in multiple shoots. Further identification of different metabolites responding to MeJA by 1H-NMR showed an extremely significant increase of the lobetyolinin level, which coincided with lobetyolin. Accordingly, the precursor, fatty acids, showed a highly significant decrease in their levels. Furthermore, a significant increase in β-d-fructose-butanol glycoside was detected, which was accompanied by a decrease in the sucrose level. Accordingly, the enzyme genes responsible for terpenoid and carbohydrate biosynthesis, CpUGPase, and CpPMK, were up regulated. In conclusion, MeJA promoted culture growth and accelerated bioactive metabolite accumulation by regulating the expression of the metabolite biosynthesis related genes, CpUGPase and CpPMK in C. pilosula.

The objective of this study was to evaluate the association between dietary antioxidant intake (carotenoid, vitamin C, E and selenium) intake and metabolic syndrome (MS).This cross-sectional study included 2069 subjects undergoing a regular health checkup. Biochemical test results and data on dietary intakes were collected for analysis. Adjustment for energy intake and multi-variable logistic regression were performed to determine adjusted odds ratios (ORs) and corresponding 95% confidence intervals (95%CI) for the relationship between dietary antioxidants intake and MS. The lowest quartile of antioxidant intake was regarded as the reference category.Dietary vitamin C intake (P values for trend were 0.02 in energy adjusted analysis and 0.08 in multivariable adjusted analysis) had a negative association with MS, as did selenium intake in the second quartile (energy adjusted OR: 0.60, 95%CI: 0.43 to 0.85; multivariable adjusted OR: 0.60, 95%CI: 0.43 to 0.86). However, there was no significant relationship between dietary carotenoid and vitamin E intake and MS.Subjects with low intake of vitamin C might be predisposed to development of MS, while dietary selenium intake had a moderate negative association with MS. Dietary carotenoid and vitamin E intake was not associated with MS.

This paper discusses the problem of determining an unknown source which depends only on one variable for the modified Helmholtz equation. This problem is ill-posed in the sense that the solution (if it exists) does not depend continuously on the data. The regularization solution is obtained by the quasireversibility regularization method. Convergence estimate is presented between the exact solution and the regularization solution. Moreover, numerical results are presented to illustrate the accuracy and efficiency of this method.

This paper deals with an inverse problem for identifying an unknown source which depends only on one variable in two-dimensional Poisson equation, with the aid of an extra measurement at an internal point. Since this problem is illposed, we obtain the regularization solution by the modified regularization method. Furthermore, we obtain the Hölder-type error estimate between the regularization solution and the exact solution. The numerical results show that the proposed method is stable and the unknown source is recovered very well.