ABSTRACT
BACKGROUND: Cervical cancer is a human papillomavirus (HPV)-related disease. HPV type 16 (HPV16), which is the predominant cause of cervical cancer, can encode miRNAs (HPV16-miRNAs). However, the role of HPV16-miRNAs in the pathogenesis of cervical cancer remains unclear. METHODS: Human cervical cancer cell lines SiHa (HPV16-positive) and C33A (HPV-negative), and cervical cancer tissues were collected to investigate the expression levels of two HPV16-miRNAs (HPV16-miR-H1 and HPV16-miR-H6). The overexpression and knockdown of HPV16-miR-H1 and HPV16-miR-H6 were performed using the lentiviral vector system and miRNA inhibitors, respectively. RNA-sequencing (RNA-seq) analysis and H3K27ac chromatin immunoprecipitation and sequencing (CHIP-seq) experiments were utilized to explore the roles of HPV16-miR-H1 and HPV16-miR-H6 facilitated by enhancers. CCK8, EdU, transwell, and wound healing assays were performed to verify the effects of HPV16-miR-H1 and HPV16-miR-H6 on cell proliferation and migration. RESULTS: HPV16-miR-H1 and HPV16-miR-H6 were highly expressed in both SiHa cells and tissue samples from HPV16-positive cervical cancer patients. RNA-seq analysis showed that HPV16-miR-H1 and HPV16-miR-H6 induced the upregulation of numerous tumor progression-associated genes. H3K27ac CHIP-seq experiments further revealed that HPV16-miR-H1 and HPV16-miR-H6 modulated the expression of critical genes by regulating their enhancer activity. The functional study demonstrated that HPV16-miR-H1 and HPV16-miR-H6 increased the migratory capacity of SiHa cells. CONCLUSIONS: Our data shed light on the role of HPV16-encoded miRNAs in cervical cancer, particularly emphasizing their involvement in the miRNA-enhancer-target gene system. This novel regulatory mechanism of HPV16-miRNAs provides new insights and approaches for the development of therapeutic strategies by targeting HPV16-positive cervical cancer.
ABSTRACT
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a clinically validated target on the treatment of cardiovascular disease (CVD). PCSK9 can regulate the hepatocyte surface low density lipoprotein receptor (LDLR) level by binding to LDLR and leading to their degradation in the lysosome. The clinical use of two monoclonal antibodies (alirocumab and evolocumab, approved in 2015) and one small interfering RNA (inclisiran, approved in 2020) which can inhibit PCSK9 function proved that they are very effective in lowering low density lipoprotein cholesterol (LDL-C). However, the high treatment costs and parenteral administration of these drugs prohibited widespread use and reduced their long-term advantage. Comparatively, small molecule drugs have many incomparable advantages of macromolecules, such as lower treatment cost, more drug administration options, superior pharmacokinetic properties, less adverse immunogenic responses and better affordable production. In this paper, we identified a series of benzothiazoles small molecule PCSK9 inhibitors through extensive screening. The structure and activity relationship (SAR) was summarized to facilitate further optimization. Moreover, the primary mechanism of action of the most potent compound was also investigated.
Subject(s)
Anticholesteremic Agents , Benzothiazoles , PCSK9 Inhibitors , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Anticholesteremic Agents/therapeutic use , Cholesterol, LDL , Proprotein Convertase 9/metabolism , Benzothiazoles/chemistry , Benzothiazoles/pharmacologyABSTRACT
In this work, graphene oxide (GO) and epoxy-functionalized graphene oxide (GOSi) are chosen as additives and incorporated into epoxy resin (EP) for nanocomposite photo-coating films (GO/EP and GOSi/EP series). Compared to GO/EP, the GOSi/EP nanocomposite demonstrates strong binding and excellent dispersibility, highlighting covalent bonding between GOSi and the epoxy coating. Furthermore, GOSi/EP-based films demonstrated superior thermal stability and adhesion performance on galvanized steel plates. The corrosion performance of the coated galvanized steel is investigated using electrochemical impedance spectroscopy (EIS) and polarization curve analysis (Tafel). The effectiveness of corrosion protection is evaluated based on a combination of photoreactivity, crosslinking density, dispersity, and adhesion properties. Out of all the treated films, the film based on 0.1GOSi/EP exhibited the highest percentage of inhibition (98.89%) and demonstrated superior long-term anticorrosion stability. In addition, the 0.1GOSi/EP based formulation showed remarkable antibacterial activity against S. aureus, resulting in a 92% reduction. This work demonstrates the development of a facile, environmentally friendly functionalized graphene oxide/epoxy photocured film with superior dual functionalities in both anticorrosion and antibacterial properties. These advancements hold promising potential for impactful practical applications.
ABSTRACT
Pure rotational transitions of the ClSO radical have been observed by Fourier-transform microwave spectroscopy. a-type and b-type transitions, for both 35Cl and 37Cl isotopologues, were detected, and the observed very complicated fine and hyperfine components were assigned well. The intensities of the observed spectra of the two isotopologues correspond to the ratio of the isotope abundances of 35Cl and 37Cl. A total of 21 molecular constants were determined precisely for both 35ClSO and 37ClSO, including the rotational constants, centrifugal distortion constants, electronic spin-rotation constants, nuclear spin-rotation constants, magnetic hyperfine constants, and quadrupole coupling constants of chlorine. The molecular constants show ClSO to have the 2A'' electronic ground state with an out-of-plane unpaired electron. The spin density of the chlorine atom is about 10.6%, which is similar to that of the fluorine atom for FSO, about 8%. Results of the ClSO radical are compared with those of other triatomic radicals with similar structures, the XSS, XSO, and XOO radicals with X = H, F, and Cl, leading to a conclusion that the ClSO radical is more like FSO, but fairly different from the FOO and ClOO radicals.
ABSTRACT
MDM2 is a gene that encodes a protein involved in cell survival, growth, and DNA repair. It has been implicated in the development and progression of glioblastoma (GBM). Inhibition of the MDM2-p53 interaction has emerged as a promising strategy for treating GBM. In this study, we performed comprehensive transcriptomic expression analysis from diverse datasets and observed MDM2 overexpression in a subset of GBM cases. MDM2 negatively regulates the major onco-suppressor p53. The interaction between MDM2 and p53 is a promising target for cancer therapy, as it can trigger p53-mediated cell death in response to different stress conditions, such as oncogene activation or DNA damage. In this study, we have identified a peptide-based inhibition of MDM2 as a therapeutic strategy for GBM. We have further validated the stability of the MDM2-peptide interaction using a molecular structural dynamics approach. The major trajectories, including root mean square of deviation (RMSD), root mean square of fluctuation (RMSF), and radius of gyration (RoG), indicate that the candidate peptides have a more stable binding compared to the native ligand and control drug. The stability of the binding interaction was further estimated by MMGBSA analysis, which also suggests that MDM2 has a stable binding with both peptide molecules. Based on these results, peptides P-1843 and P-3837 could be tested further for experimental validation to confirm their targeted inhibition of MDM-2. This approach could provide a highly selective and efficient inhibitor with potentially fewer side effects and less toxicity compared to small drug-based molecules.
Subject(s)
Glioblastoma , Peptides , Proto-Oncogene Proteins c-mdm2 , Tumor Suppressor Protein p53 , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/metabolism , Humans , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/pathology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , Peptides/chemistry , Peptides/pharmacology , Dose-Response Relationship, Drug , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Structure-Activity Relationship , Transcriptome/drug effects , Molecular Structure , Gene Expression Profiling , Molecular Dynamics SimulationABSTRACT
KEY MESSAGE: The VlLOG11 mediates the cytokinin signaling pathway to regulate grape fruit setting. Fruit set, as an accepted agronomic trait, is inextricably linked with fruit quality and yield. Previous studies have demonstrated that exogenous treatment with the synthetic cytokinin analog, forchlorfenuron (CPPU), significantly enhances fruit set. In this study, a significant reduction in endogenous cytokinins was found by measuring the content of cytokinins in young grape berries after CPPU treatment. LONELY GUYs (VlLOGs), a key cytokinin-activating enzyme working in the biosynthesis pathway of cytokinins, exhibited differential expression. Some differentially expressed VlLOGs genes were presented by RNA seq data and their functions and regulation patterns were further investigated. The results showed that VlLOG11 was differentially expressed in young grape berries after CPPU treatment. Overexpression of VlLOG11 in tomato increases the amount of fruit set, and upregulated the expression of genes associated with cytokinin signaling including SlHK4, SlHK5, SlHP3, SlHP4, SlPHP1, SlPHP2. VlMYB4 and VlCDF3 could regulate the expression of VlLOG11 by directly binding to its promoter in young grape berries during fruit set. These results strongly demonstrated that VlMYB4/VlCDF3-VlLOG11 regulatory module plays a key role in the process of fruit setting in grape. This provided a basis for the molecular mechanism of VlLOG11-mediated cytokinin biosynthesis in young grape fruit set.
Subject(s)
Cytokinins , Fruit , Gene Expression Regulation, Plant , Plant Proteins , Promoter Regions, Genetic , Vitis , Vitis/genetics , Vitis/metabolism , Fruit/genetics , Fruit/metabolism , Fruit/growth & development , Plant Proteins/genetics , Plant Proteins/metabolism , Promoter Regions, Genetic/genetics , Cytokinins/metabolism , Plants, Genetically Modified , Transcription Factors/genetics , Transcription Factors/metabolism , Solanum lycopersicum/genetics , Solanum lycopersicum/metabolism , Solanum lycopersicum/growth & development , Phenylurea Compounds/pharmacology , Signal Transduction/genetics , PyridinesABSTRACT
Angle-of-arrival (AOA) measurements are often used in underwater acoustical localization. Different from the traditional AOA model based on azimuth and elevation measurements, the AOA model studied in this paper uses bearing measurements. It is also often used in the Ultra-Short Baseline system (USBL). However, traditional acoustical localization needs additional range information. If the range information is unavailable, the closed-form solution is difficult to obtain only with bearing measurements. Thus, a localization closed-form solution using only bearing measurements is explored in this article. A pseudo-linear measurement model between the source position and the bearing measurements is derived, and considering the nonlinear relationship of the parameters, a weighted least-squares optimization equation based on multiple constraints is established. Different from the traditional two-step least-squares method, the semidefinite programming (SDP) method is designed to obtain the initial solution, and then a bias compensation method is proposed to further minimize localization errors based on the SDP result. Numerical simulations show that the performance of the proposed method can achieve Cramer-Rao lower bound (CRLB) accuracy. The field test also proves that the proposed method can locate the source position without range measurements and obtain the highest positioning accuracy.
ABSTRACT
BACKGROUND: The aim of this study was to analyse the differences in the phenotypes of missing teeth between a pair of brothers with hypohidrotic ectodermal dysplasia (HED) and to investigate the underlying mechanism by comparing the mutated gene loci between the brothers with whole-exome sequencing. METHODS: The clinical data of the patients and their mother were collected, and genomic DNA was extracted from peripheral blood samples. By Whole-exome sequencing filtered for a minor allele frequency (MAF) ≤0.05 non-synonymous single-nucleotide variations and insertions/deletions variations in genes previously associated with tooth agenesis, and variations considered as potentially pathogenic were assessed by SIFT, Polyphen-2, CADD and ACMG. Sanger sequencing was performed to detect gene variations. The secondary and tertiary structures of the mutated proteins were predicted by PsiPred 4.0 and AlphaFold 2. RESULTS: Both brothers were clinically diagnosed with HED, but the younger brother had more teeth than the elder brother. An EDA variation (c.878 T > G) was identified in both brothers. Additionally, compound heterozygous variations of WNT10A (c.511C > T and c.637G > A) were identified in the elder brother. Digenic variations in EDA (c.878 T > G) and WNT10A (c.511C > T and c.637G > A) in the same patient have not been reported previously. The secondary structure of the variant WNT10A protein showed changes in the number and position of α-helices and ß-folds compared to the wild-type protein. The tertiary structure of the WNT10A variant and molecular simulation docking showed that the site and direction where WNT10A binds to FZD5 was changed. CONCLUSIONS: Compound heterozygous WNT10A missense variations may exacerbate the number of missing teeth in HED caused by EDA variation.
Subject(s)
Anodontia , Ectodermal Dysplasia 1, Anhidrotic , Ectodermal Dysplasia , Tooth , Male , Humans , Ectodermal Dysplasia 1, Anhidrotic/complications , Ectodermal Dysplasia 1, Anhidrotic/genetics , Ectodermal Dysplasia/genetics , Phenotype , Anodontia/genetics , Mutation , Wnt Proteins/geneticsABSTRACT
The prevention and control requirements for HIV/AIDS vary significantly among different populations, posing substantial challenges to the formulation and implementation of intervention strategies. Dynamically assessing the heterogeneity and disease progression trajectories of various groups is crucial. Latent class growth model (LCGM) serves as a statistical approach that fits a longitudinal data into N subgroups of individual development trajectories, identifying and analyzing the progression paths of different subgroups, thereby offering a novel perspective for disease control strategies. LCGM has shown significant advantages in the application of HIV/AIDS prevention and control, especially in gaining a deeper understanding and analysis of epidemiological characteristics, risk behaviors, psychological research, heterogeneity in testing, and dynamic changes. Summarizing the advantages and limitations of applying LCGM can provide a reliable basis for precise prevention and control of HIV/AIDS.
Subject(s)
Acquired Immunodeficiency Syndrome , Humans , Acquired Immunodeficiency Syndrome/prevention & control , HIV Infections/prevention & control , Disease Progression , Latent Class Analysis , Models, StatisticalABSTRACT
Plant architecture and stress tolerance play important roles in rice breeding. Specific leaf morphologies and ideal plant architecture can effectively improve both abiotic stress resistance and rice grain yield. However, the mechanism by which plants simultaneously regulate leaf morphogenesis and stress resistance remains elusive. Here, we report that SRL10, which encodes a double-stranded RNA-binding protein, regulates leaf morphology and thermotolerance in rice through alteration of microRNA biogenesis. The srl10 mutant had a semi-rolled leaf phenotype and elevated sensitivity to high temperature. SRL10 directly interacted with catalase isozyme B (CATB), and the two proteins mutually increased one other's stability to enhance hydrogen peroxide (H2 O2 ) scavenging, thereby contributing to thermotolerance. The natural Hap3 (AGC) type of SRL10 allele was found to be present in the majority of aus rice accessions, and was identified as a thermotolerant allele under high temperature stress in both the field and the growth chamber. Moreover, the seed-setting rate was 3.19 times higher and grain yield per plant was 1.68 times higher in near-isogenic line (NIL) carrying Hap3 allele compared to plants carrying Hap1 allele under heat stress. Collectively, these results reveal a new locus of interest and define a novel SRL10-CATB based regulatory mechanism for developing cultivars with high temperature tolerance and stable yield. Furthermore, our findings provide a theoretical basis for simultaneous breeding for plant architecture and stress resistance.
Subject(s)
Oryza , Thermotolerance , Thermotolerance/genetics , Oryza/metabolism , Catalase/genetics , Catalase/metabolism , Isoenzymes/metabolism , Plant Breeding , Edible Grain , Plant Proteins/genetics , Plant Proteins/metabolism , Plant Leaves/genetics , Plant Leaves/metabolismABSTRACT
A green method to construct C-S bonds using sulfonyl chlorides and alcohols/acids via a PIII/PVâO catalytic system is reported. The organophosphorus-catalyzed umpolung reaction promotes us to propose the "dual-substrate deoxygenation" strategy. Herein, we adopt the "dual-substrate deoxygenation" strategy, which achieves the deoxygenation of sulfonyl chlorides and alcohols/acids to synthesize thioethers/thioesters driven by PIII/PVâO redox cycling. The catalytic method represents an operationally simple approach using stable phosphine oxide as a precatalyst and shows broad functional group tolerance. The potential application of this protocol is demonstrated by the late-stage diversification of drug analogues.
Subject(s)
Organophosphorus Compounds , Catalysis , Oxygen/chemistry , Alcohols/chemistry , Acids/chemistry , Organophosphorus Compounds/chemistryABSTRACT
Although previous studies on the genotypic diversity and antifungal susceptibility of the Cryptococcus neoformans species complex (CNSC) isolates from China revealed ST5 genotype isolates being dominant, the information about the CNSC isolates from Chinese HIV-infected patients is limited. In this study, 171 CNSC isolates from HIV-infected patients in the Chongqing region of Southwest China were genotyped using the International Society for Human and Animal Mycology-multilocus sequence typing consensus scheme, and their antifungal drug susceptibilities were determined following CLSI M27-A3 guidelines. Among 171 isolates, six sequence types (STs) were identified, including the dominant ST5 isolates, the newly reported ST15, and four diploid VNIII isolates (ST632/ST636). Moreover, a total of 1019 CNSC isolates with STs and HIV-status information were collected and analyzed from Mainland China in the present study. A minimum spanning analysis grouped these 1019 isolates into three main subgroups, which were dominated by the ST5 clonal complex (CC5), followed by the ST31 clonal complex (CC31) and ST93 clonal complex (CC93). The trend of resistance or decreasing susceptibility of clinical CNSC isolates to azole agents within HIV-infected patients from the Chongqing region is increasing, especially resistance to fluconazole.
In this paper, novel ST15 and four diploid VNIII isolates (ST632/ST636) were found in 171 CNSC isolates in Southwest China, including evidence for resistance to fluconazole. Moreover, we clustered the 1019 clinical CNSC isolates reported so far from Mainland China into three major subgroups.
Subject(s)
Cryptococcosis , Cryptococcus neoformans , HIV Infections , Humans , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Cryptococcosis/microbiology , Cryptococcosis/veterinary , Diploidy , Microbial Sensitivity Tests/veterinary , Genotype , China/epidemiology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/veterinaryABSTRACT
Although people living with HIV/AIDS (PLWHA) are known to be vulnerable to psychological distress (PD), little is known about the prevalence of PD among PLWHA. A systematic literature search of several databases was conducted from inception to August 2021 focusing on studies reporting on PD symptoms among PLWHA. The overall prevalence estimates were pooled using a random-effects meta-analysis. Differences according to study-level characteristics were examined using stratified meta-analysis. We pooled and analyzed data from 15 studies comprising 5593 PLWHA. The prevalence rate of PD among PLWHA was 43.7% (95% Confidence Interval: 29.9-57.5%). Subgroup analyses by gender, country, CD4 count, employment status and ever attended school found no statistically significant differences in the prevalence of PD. Heterogeneity in the prevalence of PD among PLWHA was partially explained by the assessment tool. Further large-scale studies of high quality are warranted to identify risk factors of PD in PLWHA in their respective socio-cultural contexts.
Subject(s)
Acquired Immunodeficiency Syndrome , HIV Infections , Humans , HIV Infections/epidemiology , HIV Infections/psychology , Acquired Immunodeficiency Syndrome/epidemiology , Prevalence , Risk Factors , CD4 Lymphocyte CountABSTRACT
Pure rotational transitions of two conformers of the CH2CHCO radical have been observed by Fourier-transform microwave spectroscopy, where one conformer is called the s-trans-3-propenalyl radical and the other the 3-propenolyl radical. The observed two conformers have different electronic states. The former, the s-trans-3-propenalyl radical, has the 2A' electronic state and can be written as CH2CHCO, where the unpaired electron resides mainly on the terminal CO carbon. On the other hand, the latter, 3-propenolyl radical has the 2A'' electronic state and can be written as CH2CHCO. We were able to observe pure rotational transitions of the two conformers. Since both of the species have an unpaired electron, there exist spin-rotation interactions due to the unpaired electron and the magnetic hyperfine interactions due to the three coupling protons. The observed very complicated spectra, caused by these interactions, were assigned, leading to detailed molecular constants including the fine and hyperfine coupling constants for both of the species. The determined molecular constants support the electronic structures of the two conformers. There exists a controversy as to which of the two conformers is the lowest energy one. Our present observation led to the conclusion that s-trans-3-propenalyl is the lowest energy conformer.
ABSTRACT
BACKGROUND: Colorectal cancer (CRC) screening is the most efficient strategy to reduce disease-related mortality. In this study, we aimed to investigate the association of a methylation-based stool DNA test with serum protein biomarker panel (CEA, CA125, CA199, and AFP) in CSC patients and their relationship with pathological features to improve the diagnostic efficacy and applicability in CSC in the Chinese population. METHODS: In this double-blinded case-control study, we enrolled 150 participants from our hospital, including 50 CRC patients, 50 adenomas, and 50 healthy controls. We compared the cycling threshold (Ct) values of stool DNA-based SDC2 measured by quantitative methylation-specific PCR (MSP) in the three groups. We also evaluated the differences and correlation between serum concentrations of tumor biomarker and pathological features in patients with CSC, including TNM stage (I, II, III), tumor size, and lymph node metastasis. The discrimination performance of indexes was assessed using sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC). RESULTS: CSC was more common in middle-aged people and men. The methylation-based stool DNA test was not significantly correlated with other tumor indicators except CEA, and the difference was statistically significant. Compared with the normal control group, the combined diagnostic value of the methylation-based stool DNA test and tumor indicators was significantly higher than individual biomarkers alone, especially the methylation-based stool DNA test combined with CEA and AFP, which improved the AUC to 0.96. This combination can increase the positive rate of pathological stage diagnosis. CONCLUSIONS: Combining a methylation-based stool DNA test with CEA and AFP can significantly improve the diagnostic value of CRC and can be used to confirm the diagnosis of colorectal cancer. This combination can also be used as a reliable indicator identifying early-stage CRC patients and pathology. A large-scale study is underway to further define the clinical application of this method for the diagnosis of CRC among Chinese populations.
Subject(s)
Biomarkers, Tumor , Colorectal Neoplasms , Male , Middle Aged , Humans , Biomarkers, Tumor/genetics , DNA Methylation , Case-Control Studies , alpha-Fetoproteins , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA , Syndecan-2/geneticsABSTRACT
OBJECTIVE: The purpose of this study was to investigate the associations between mobile phone dependency, bedtime procrastination, FoMO, and sleep quality among college students during the COVID-19 outbreak. Specifically, we examined whether bedtime procrastination and FoMO mediate the relationship between mobile phone dependency and sleep quality. METHODS: A total of 881 college students completed an online survey in May 2022 in Shanghai, China. Mobile Phone Involvement Questionnaire, Bedtime Procrastination Scale, Fear of Missing Out Scale and Pittsburgh Sleep Quality Index were used to assess mobile phone dependency, bedtime procrastination, fear of missing out, and sleep quality, respectively. Multiple linear regression and mediation analysis were conducted. RESULTS: The correlation analyses indicated mobile phone dependency was positively associated with fear of missing out, bedtime procrastination, and poor sleep quality among college students. The structural equation modeling analyses revealed that mobile phone dependency had significant indirect effects on sleep quality through bedtime procrastination (indirect effect: 0.030, 95%CI: 0.022-0.041) and fear of missing out (indirect effect: 0.013, 95%CI: 0.003-0.023). CONCLUSION: The findings indicated that bedtime procrastination and fear of missing out are mediators mediating the relationship between mobile phone dependency with sleep quality. Bedtime procrastination and fear of missing out should be considered as potential intervention targets for reducing mobile phone dependency and improving sleep quality in college students.
Subject(s)
COVID-19 , Cell Phone , Procrastination , Humans , Sleep Quality , China/epidemiology , COVID-19/epidemiology , Students , FearABSTRACT
Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.
Subject(s)
Antineoplastic Agents , Pancreatic Neoplasms , Protein Kinase Inhibitors , Protein Serine-Threonine Kinases , Humans , Cell Line, Tumor , Gemcitabine/chemistry , Gemcitabine/pharmacology , Intracellular Signaling Peptides and Proteins , Pancreatic Neoplasms/enzymology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Computer Simulation , Pancreatic NeoplasmsABSTRACT
The Autonomous Underwater Vehicle (AUV) is usually equipped with multiple sensors, such as an inertial navigation system (INS), ultra-short baseline system (USBL), and Doppler velocity log (DVL), to achieve autonomous navigation. Multi-source information fusion is the key to realizing high-precision underwater navigation and positioning. To solve the problem, a fusion scheme based on factor graph optimization (FGO) is proposed. Due to multiple iterations and joint optimization of historical data, FGO could usually show a better performance than the traditional Kalman filter. In addition, considering that USBL and DVL are usually heavily influenced by the environment, outliers are often present. A robust integrated navigation algorithm based on a maximum correntropy criterion and FGO scheme is proposed. The proposed algorithm solves the problem of multi-sensor fusion and non-Gaussian noise. Numerical simulations and field tests demonstrate that the proposed FGO scheme shows a better performance and robustness than the traditional Kalman filter. Compared with the traditional Kalman filtering, the positioning accuracy is improved by 5.3%, 9.1%, and 5.1% in the east, north, and height directions. It can realize a more accurate navigation and positioning of underwater multi-sensors.
Subject(s)
Algorithms , Autonomous Vehicles , Ultrasonography, DopplerABSTRACT
Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia/myopathy, respectively. The mechanism by which they disrupt mitochondrial cristae, however, has been uncertain. Using the first C2/C10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/C10 are intimately linked. Similar to patients with C10 mutations, we found that C2/C10 DKO mice have disrupted mitochondrial cristae, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (L-OPA1) by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 knock-in (KI) mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities because of both C10 mutation and C2/C10 loss. Using OMA1 activation as a functional assay, we found that C2 and C10 are partially functionally redundant, and some but not all disease-causing mutations have retained activity. Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , DNA-Binding Proteins/genetics , Frontotemporal Dementia/genetics , Metalloproteases/genetics , Mitochondrial Proteins/genetics , Parkinson Disease/genetics , Transcription Factors/genetics , Amyotrophic Lateral Sclerosis/pathology , Animals , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/genetics , Cardiomyopathies/pathology , Disease Models, Animal , Frontotemporal Dementia/pathology , Genetic Predisposition to Disease , HeLa Cells , Humans , Mice , Mice, Knockout , Mitochondria/genetics , Mitochondria/pathology , Mutation/genetics , Parkinson Disease/pathologyABSTRACT
BACKGROUND: E2 ubiquitin-conjugating (UBC) enzymes are an integral component of the ubiquitin proteasome system that play an important role in plant development, growth, and external stress responses. Several UBC genes have been identified in various plants. However, no studies exploring the functions of UBC genes in regulating fruit of strawberry have been reported. In the present study, a systematic analysis of the entire UBC family members were conducted in the genome of strawberry (Fragaria ×ananassa) based on bioinformatics method, and the gene functioning in strawberry ripening was explored. RESULTS: A total of 191 UBC genes were identified in the genome of cultivated strawberry. These genes were unevenly distributed across the 28 chromosomes from the 4 subgenomes of cultivated strawberry, ranging from 3 to 11 genes per chromosome. Moreover, the expansion of FaUBC genes in strawberry was mainly driven by WGD. All the FaUBC genes were clarified into 13 groups and most of them were included in the group VI. The gene structure analysis showed that the number of exons varied from 1 to 23, and the structure of genes had few differences within the same groups but a distinction in different groups. Identification of the cis-acting elements of the promoter revealed multiple regulatory elements that responded to plant growth and development, phytohormone responsive, and abiotic and biotic stress. Data from functional annotation indicated that FaUBC genes play a role in a variety of biological processes. The RNA-seq data showed that FaUBC genes displayed different expression pattern during the fruit ripening process and clarified into 6 clusters. In particular, cluster 3 exhibiting a sudden expression increase in the turning red stage were speculated to be involved in fruit ripening. Hence, two FaUBC genes (FaUBC76 and FaUBC78) were selected for gene function analysis by transient over-expression method. The results indicated that FaUBC76 has a positive effect on the fruit development and ripening in strawberry by up-regulating accumulation of anthocyanins. Moreover, expression of some maturity-related genes were also significantly increased, further supporting a role for FaUBC76 in the regulation of fruit ripening or softening. On the contrary, the overexpression of FaUBC78 significantly increased the firmness of strawberry fruit, indicating that FaUBC78 had a positive role in inhibiting the decrease of strawberry fruit firmness. CONCLUSION: Our study not only provide comprehensive information on system evolution and function on UBC genes, but also give a new insight into explore the roles of FaUBC genes in the regulation of strawberry ripening.