ABSTRACT
Chlamydomonas reinhardtii polysaccharides (CRPs) are bioactive compounds derived from C. reinhardtii, yet their potential in cancer therapy remains largely unexplored. This study optimized the ultrasound-assisted extraction conditions using response surface methodology and proceeded with the isolation and purification of these polysaccharides. The optimal extraction conditions were identified as a sodium hydroxide concentration of 1.5%, ultrasonic power of 200 W, a solid-to-liquid ratio of 1:25 g/mL, an ultrasonic treatment time of 10 min, and a water bath duration of 2.5 h, yielding an actual extraction rate of 5.71 ± 0.001%, which closely aligns with the predicted value of 5.639%. Infrared analysis revealed that CRP-1 and CRP-2 are α-pyranose structures containing furoic acid, while CRP-3 and CRP-4 are ß-pyranose structures containing furoic acid. Experimental results demonstrated that all four purified polysaccharides inhibited the proliferation of cervical (HeLa) hepatoma (HepG-2) and colon (HCT-116) cancer cells, with CRP-4 showing the most significant inhibitory effect on colon cancer and cervical cancer, achieving inhibition rates of 60.58 ± 0.88% and 40.44 ± 1.44%, respectively, and significantly reducing the migration of HeLa cells. DAPI staining confirmed that the four purified polysaccharides inhibit cell proliferation and migration by inducing apoptosis in HeLa cells. CRP-1 has the most significant inhibitory effect on the proliferation of liver cancer cells. This study not only elucidates the potential application of C. reinhardtii polysaccharides in cancer therapy but also provides a scientific basis for their further development and utilization.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Chlamydomonas reinhardtii , Polysaccharides , Polysaccharides/pharmacology , Polysaccharides/isolation & purification , Polysaccharides/chemistry , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , HeLa Cells , Hep G2 Cells , HCT116 Cells , Animals , Cell Line, TumorABSTRACT
The advent of smart grids has facilitated data-driven methods for detecting electricity theft, with a preponderance of research efforts focused on user electricity consumption data. The multi-dimensional power state data captured by Advanced Metering Infrastructure (AMI) encompasses rich information, the exploration of which, in relation to electricity usage behaviors, holds immense potential for enhancing the efficiency of theft detection. In light of this, we propose the Catch22-Conv-Transformer method, a multi-dimensional feature extraction-based approach tailored for the detection of anomalous electricity usage patterns. This methodology leverages both the Catch22 feature set and complementary features to extract sequential features, subsequently employing convolutional networks and the Transformer architecture to discern various types of theft behaviors. Our evaluation, utilizing a three-phase power state and daily electricity usage data provided by the State Grid Corporation of China, demonstrates the efficacy of our approach in accurately identifying theft modalities, including evasion, tampering, and data manipulation.
ABSTRACT
BACKGROUND: Suicidal behaviors have become a serious public health concern globally due to the economic and human cost of suicidal behavior to individuals, families, communities, and society. However, the underlying etiology and biological mechanism of suicidal behavior remains poorly understood. METHODS: We collected different single omic data, including single-cell RNA sequencing (scRNA-seq), bulk mRNA-seq, DNA methylation microarrays from the cortex of Major Depressive Disorder (MDD) in suicide subjects' studies, as well as fluoxetine-treated rats brains. We matched subject IDs that overlapped between the transcriptome dataset and the methylation dataset. The differential expression genes and differentially methylated regions were calculated with a 2-group comparison analysis. Cross-omics analysis was performed to calculate the correlation between the methylated and transcript levels of differentially methylated CpG sites and mapped transcripts. Additionally, we performed a deconvolution analysis for bulk mRNA-seq and DNA methylation profiling with scRNA-seq as the reference profiles. RESULTS: Difference in cell type proportions among 7 cell types. Meanwhile, our analysis of single-cell sequence from the antidepressant-treated rats found that drug-specific differential expression genes were enriched into biological pathways, including ion channels and glutamatergic receptors. CONCLUSIONS: This study identified some important dysregulated genes influenced by DNA methylation in 2 brain regions of depression and suicide patients. Interestingly, we found that oligodendrocyte precursor cells (OPCs) have the most contributors for cell-type proportions related to differential expression genes and methylated sites in suicidal behavior.
Subject(s)
Depressive Disorder, Major , Suicide , Humans , Animals , Rats , DNA Methylation , Depressive Disorder, Major/genetics , Depressive Disorder, Major/metabolism , Single-Cell Gene Expression Analysis , Brain/metabolism , RNA, Messenger/metabolism , Gene Expression ProfilingABSTRACT
Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) has a significant impact on rice yield and quality worldwide. Traditionally, bactericide application has been commonly used to control this devastating disease. However, the overuse of fungicides has led to a number of problems such as the development of resistance and environmental pollution. Therefore, the development of new methods and approaches for disease control are still urgent. In this paper, a series of cinnamic acid derivatives were designed and synthesized, and three novel T3SS inhibitors A10, A12 and A20 were discovered. Novel T3SS inhibitors A10, A12 and A20 significantly inhibited the hpa1 promoter activity without affecting Xoo growth. Further studies revealed that the title compounds A10, A12 and A20 significantly impaired hypersensitivity in non-host plant tobacco leaves, while applications on rice significantly reduced symptoms of bacterial leaf blight. RT-PCR showed that compound A20 inhibited the expression of T3SS-related genes. In summary, this work exemplifies the potential of the title compound as an inhibitor of T3SS and its efficacy in the control of bacterial leaf blight.
Subject(s)
Oryza , Xanthomonas , Type III Secretion Systems/genetics , Type III Secretion Systems/metabolism , Cinnamates/pharmacology , Cinnamates/metabolism , Xanthomonas/metabolism , Oryza/metabolismABSTRACT
Overhead ground wires typically have strong axial tension and are prone to structural defects caused by corrosion and lightning strikes, which could lead to serious safety hazards. Therefore, it is important to detect defects accurately and quickly to avoid those problems. Existing defect detection methods for overhead ground wires are mainly traditional metal defect detection methods, including eddy current detection, ultrasonic detection, and manual visual inspection. However, those methods have problems of low detection efficiency, high environmental requirements, and insufficient reliability. To solve the above problems, this paper studies a novel type of defect detection technology for overhead ground wire. Firstly, the magnetic leakage characteristics around the defects of overhead ground wires are analyzed, and the defect detection device is designed. Then, the influence of air gap, lift-off distance, defect width, and cross-sectional loss rate on the magnetic flux leakage signal is studied, a novel defect detection method for overhead ground wire is proposed, and experimental verification is carried out. The results show that the proposed method can accurately locate and quantify the defect, which has the advantages of good reliability and high efficiency and lays the foundation for preventing accidents caused by defective overhead ground wires.
ABSTRACT
The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit â¼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (CPNE7, ICAM5, STAT2, and RAF1). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; P = 4.6 × 10-8).
Subject(s)
Adaptation, Physiological/genetics , Inuit/genetics , Arctic Regions , Humans , Intracranial Aneurysm/genetics , Principal Component Analysis , Selection, GeneticABSTRACT
Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.
Subject(s)
Adenosine Triphosphatases/genetics , Intracranial Aneurysm/genetics , Ubiquitin-Protein Ligases/genetics , White People/genetics , Adult , Aged , Alleles , Canada , Case-Control Studies , Cohort Studies , Female , Genome-Wide Association Study , Genotype , Genotyping Techniques , Humans , Intracranial Aneurysm/diagnosis , Male , Middle Aged , Pedigree , Polymorphism, Single Nucleotide , Reproducibility of Results , Sequence Analysis, DNAABSTRACT
Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.
Subject(s)
Schizophrenia, Childhood/genetics , Schizophrenia, Childhood/physiopathology , Adolescent , Adult , Autistic Disorder/genetics , Brain/metabolism , Brain/physiopathology , Child , Comorbidity , Epilepsy/genetics , Exome/genetics , Family/psychology , Female , Genes, X-Linked/genetics , Humans , Intellectual Disability/genetics , Male , Phenotype , Schizophrenia/genetics , Sex Factors , Exome Sequencing/methodsABSTRACT
Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.
Subject(s)
Genetic Predisposition to Disease , Restless Legs Syndrome/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Chromosome Mapping , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 2 , Chromosomes, Human, Pair 6 , Co-Repressor Proteins , Haplotypes , Homeodomain Proteins/genetics , Humans , Introns , MAP Kinase Kinase 5/genetics , Middle Aged , Myeloid Ecotropic Viral Integration Site 1 Protein , Neoplasm Proteins/genetics , Nerve Tissue Proteins , Polymorphism, Single Nucleotide , Repressor Proteins/genetics , Transcription Factors/genetics , White People/geneticsABSTRACT
BACKGROUND: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. METHODS: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. RESULTS: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. CONCLUSION: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.
Subject(s)
Abnormalities, Multiple/genetics , Autistic Disorder/pathology , Fingers/abnormalities , Intellectual Disability/genetics , Intellectual Disability/pathology , Microcephaly/genetics , Microcephaly/pathology , Muscle Hypotonia/genetics , Muscle Hypotonia/pathology , Myopia/genetics , Myopia/pathology , Obesity/genetics , Obesity/pathology , Phenotype , Sequence Deletion/genetics , Vesicular Transport Proteins/genetics , Autistic Disorder/genetics , Base Sequence , Developmental Disabilities/classification , Developmental Disabilities/ethnology , Developmental Disabilities/genetics , Developmental Disabilities/pathology , Female , Fingers/pathology , Genes, Recessive , Genotype , Haplotypes/genetics , Homozygote , Humans , Intellectual Disability/classification , Intellectual Disability/ethnology , Male , Microcephaly/classification , Microcephaly/ethnology , Molecular Sequence Data , Muscle Hypotonia/classification , Muscle Hypotonia/ethnology , Myopia/classification , Myopia/ethnology , Obesity/classification , Obesity/ethnology , Pakistan , Pedigree , Retinal Degeneration , Sequence Analysis, DNAABSTRACT
Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, Pâ=â9.03 × 10(-11), ORâ=â1.23) and a locus on 16q12.1 (rs3104767, Pâ=â9.4 × 10(-19), ORâ=â1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.
Subject(s)
Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 2/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Restless Legs Syndrome/genetics , Humans , Polymorphism, Single Nucleotide/genetics , Reproducibility of Results , Risk FactorsABSTRACT
Metabolic dysregulation of catecholamines (CAs) is implicated in various human diseases. Simultaneously analyzing these acidic and alkaline CAs and their metabolites poses a significant challenge for clinical detection. This study introduces an efficient method employing automated online solid-phase extraction coupled with tandem mass spectrometry (aoSPE-MS/MS). The method employs weak cation exchange (WCX) and mixed-mode anion exchange (MAX) adsorbents to fabricate an on-line solid-phase extraction (SPE) column, along with an automated injection and multi-valve switching capabilities. The setup allows for automated extraction and analysis of urine samples in 15â¯minutes while retaining a wide range of acidic and basic CAs and their metabolites. The applicability of this method was demonstrated by optimising the adsorbent dosage volume, extraction solvent, and extraction rate. The limits of detection (LODs) and limits of quantitation (LOQs) for the 8 CAs and their metabolites were determined using the aoSPE-MS/MS approach, with ranges of 0.0625 â¼ 62.5â¯ng/mL and 0.125 â¼ 125â¯ng/mL, respectively. Additionally, assessments were made on the linearity, accuracy, and precision within and between batches, as well as matrix and ionic effects, and spiked recoveries. The study discovered that the aoSPE-MS/MS technique simplifies operation, increases efficiency, saves time, and has low detection and quantification limits when detecting a wide range of acid and alkaline CAs and their metabolites in urine. The study successfully demonstrated the high-throughput and automated detection of the 8 CAs and their metabolites with varying acidity and alkalinity in human urine samples. This method is expected to be a potential powerful tool for clinical detection.
Subject(s)
Catecholamines , Limit of Detection , Solid Phase Extraction , Tandem Mass Spectrometry , Humans , Solid Phase Extraction/methods , Tandem Mass Spectrometry/methods , Catecholamines/urine , Catecholamines/metabolism , Reproducibility of Results , Hydrogen-Ion Concentration , AutomationABSTRACT
Microorganisms are the most common cause of food spoilage. Pseudomonas aeruginosa is a common foodborne pathogen that causes food spoilage and poses a serious threat to food safety. As a crucial target in antitoxicity strategies, the quorum sensing (QS) system shows promising potential for further development. The garlic extract diallyl disulfide exhibits inhibitory activity against the QS system of P. aeruginosa, with disulfide bonds serving as the active component. However, the biological activity of other symmetric disulfides has not been investigated in this capacity. The study synthesized 39 disulfide bond-containing analogs and evaluated their activity as quorum sensing inhibitors (QSIs). The results showed that p-hydroxyphenyl substitution can replace the allyl groups while maintaining strong biological activity. The virulence factors production was reduced by compound 2i, with the strongest inhibitory effect being observed on elastase production. Synergistic inhibition was observed in the presence of antibiotics like ciprofloxacin and tobramycin. 2i successfully inhibited P. aeruginosa infection in the Galleria mellonella larvae model. Primary mechanism studies using transcriptome, surface plasmon resonance and molecular docking suggested that 2i inhibits the QS system by targeting the LasR protein. Thus, compound 2i could be used in developing QSIs for the control of P. aeruginosa infections.
Subject(s)
Anti-Bacterial Agents , Disulfides , Garlic , Plant Extracts , Pseudomonas aeruginosa , Quorum Sensing , Quorum Sensing/drug effects , Pseudomonas aeruginosa/drug effects , Garlic/chemistry , Disulfides/chemistry , Disulfides/pharmacology , Plant Extracts/pharmacology , Plant Extracts/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Animals , Moths/drug effects , Moths/microbiology , Molecular Docking Simulation , Structure-Activity Relationship , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Bacterial Proteins/chemistry , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiologyABSTRACT
To identify potent inhibitors of the type III secretion system (T3SS) in the foodborne pathogen Pseudomonas aeruginosa, we synthesized 35 thiazole-containing aryl amides by merging salicylic acid with various heterocycles through active splicing. Screening for exoS promoter activity led to the discovery of a highly effective T3SS inhibitor from these 35 compounds. Through subsequent experiments, it was confirmed that compound II-22 specifically targeted the T3SS of P. aeruginosa. Additionally, compound II-22 inhibited the secretion of the effector protein ExoS by modulating the CyaB-cAMP/Vfr-ExsA and ExsCED-ExsA regulatory pathways. Furthermore, compound II-22 suppressed the transcription of genes involved in the needle complex assembly, leading to reduced bacterial virulence. Further validation through inoculation tests using Galleria mellonella larvae demonstrated the strong in vivo efficacy of compound II-22. The study also revealed that compound II-22 enhanced the bactericidal activity of antibiotics, such as CIP (ciprofloxacin) and TOB (tobramycin). These results could help develop novel antimicrobial drugs to reduce bacterial resistance.
Subject(s)
Amides , Anti-Bacterial Agents , Bacterial Proteins , Drug Design , Pseudomonas aeruginosa , Thiazoles , Type III Secretion Systems , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Type III Secretion Systems/genetics , Type III Secretion Systems/antagonists & inhibitors , Type III Secretion Systems/metabolism , Thiazoles/pharmacology , Thiazoles/chemistry , Thiazoles/chemical synthesis , Amides/pharmacology , Amides/chemistry , Amides/chemical synthesis , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Animals , Microbial Sensitivity Tests , Moths/microbiology , HumansABSTRACT
Apple fruit skin color fading is not well understood although the molecular mechanism of skin color formation is well known. The red-fleshed apple cultivar 'Daihong' (DH) exhibited fading skin color during fruit development despite having a heterozygous R6 allele but lacking Red-TE for red fruit skin. In this study, transcriptomic analysis revealed the expression level of MdMYB10 increased with fruit development whereas reduced expression levels of MdMYBPA1, MdCHS, MdANS, MdUFGT, MdLAR, and MdANR were observed, consistent with decreased levels of chalcone, anthocyanin, catechin, epicatechin, and procyanidin B2. Whole-genome bisulfite sequencing (WGBS) indicated a global gain in cytosine methylation levels and increased methylation in 5' and 3' flanking regions of genes and transposable elements (TEs), and in TE bodies in all CG, CHG and CHH contexts, especially the mCHH context, during fruit development. The increased DNA methylation was attributed to reduced expression levels of DNA demethylase genes, including MdDME1, MdROS1, and MdROS2. Association analysis revealed a significant negative correlation between promoter methylation levels of MdCHS, MdCHI, MdMYBPA1, and their respective transcript levels, as well as a negative correlation between promoter methylation levels of MdCHS, MdCHI, MdANR, and MdFLS, and the content of chalcones, naringenin-7-glucoside, epicatechin, and quercetin. Treatment with the DNA demethylation agent 5-aza-2'-deoxycytidine verified the negative correlation between DNA methylation and gene expression within the flavonoid pathway. These findings suggest that hypermethylation in promoter regions of genes of the flavonoid biosynthesis pathway is associated with the reduction of gene expression and flavonoid content, and fruit skin color fading during DH apple development.
ABSTRACT
With the increasing reports of antibiotic resistance in this species, Pseudomonas aeruginosa is a common human pathogen with important implications for public health. Bacterial quorum sensing (QS) systems are potentially broad and versatile targets for developing new antimicrobial compounds. While previous reports have demonstrated that certain amide compounds can inhibit bacterial growth, there are few reports on the specific inhibitory effects of these compounds on bacterial quorum sensing systems. In this study, thirty-one amide derivatives were synthesized. The results of the biological activity assessment indicated that A9 and B6 could significantly inhibit the expression of lasB, rhlA, and pqsA, effectively reducing several virulence factors regulated by the QS systems of PAO1. Additionally, compound A9 attenuated the pathogenicity of PAO1 to Galleria mellonella larvae. Meanwhile, RT-qPCR, SPR, and molecular docking studies were conducted to explore the mechanism of these compounds, which suggests that compound A9 inhibited the QS systems by binding with LasR and PqsR, especially PqsR. In conclusion, amide derivatives A9 and B6 exhibit promising potential for further development as novel QS inhibitors in P. aeruginosa.
Subject(s)
Amides , Anti-Bacterial Agents , Drug Discovery , Molecular Docking Simulation , Pseudomonas aeruginosa , Quorum Sensing , Pseudomonas aeruginosa/drug effects , Quorum Sensing/drug effects , Amides/pharmacology , Amides/chemistry , Amides/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Microbial Sensitivity Tests , Dose-Response Relationship, Drug , AnimalsABSTRACT
Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Restless Legs Syndrome , Restless Legs Syndrome/genetics , Humans , Risk Factors , Female , Male , Polymorphism, Single Nucleotide , Mendelian Randomization Analysis , Machine LearningABSTRACT
The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (µ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of â¼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.
Subject(s)
Autistic Disorder/genetics , DNA Mutational Analysis/methods , Mutagenesis/genetics , Mutation/genetics , Schizophrenia/genetics , Base Pairing/genetics , Cell Line , Chromosome Segregation/genetics , Cohort Studies , Family , Female , Gene Expression Regulation , Humans , MaleABSTRACT
Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.
Subject(s)
Carrier Proteins/genetics , Mutation, Missense/genetics , Nerve Tissue Proteins/genetics , Neurons/cytology , Schizophrenia/genetics , Amino Acid Sequence , Animals , Base Sequence , Computational Biology , DNA Primers/genetics , Female , Humans , Male , Microsatellite Repeats/genetics , Molecular Sequence Data , Pedigree , Rats , Sequence Analysis, DNA , ZebrafishABSTRACT
Objective: To analyze the clinical effect of visual electrophysiological examination combined with targeted health education nursing in children. Methods: A total of 100 children who underwent visual electrophysiological examinations in the Ophthalmology Department of our hospital from March 2019 to March 2021 were selected as the study subjects. The children were randomly divided into two groups, the control group and the observation group, with 50 children in each group. Children in the control group received routine nursing, while those in the observation group received a combination of routine nursing and targeted health education nursing. The nursing satisfaction, degree of cooperation with examination, examination time, changes in the psychological state, and the stress response of the children and their families were then compared and analyzed. Results: The nursing satisfaction of the observation group was higher than that of the control group (94.0% vs. 80.0%) (P < 0.05). The degree to which children in the observation group cooperated with examination was higher than that of children in the control group (96.0% vs. 78.0%) (P < 0.05). The average time spent on VEP and ERG examinations by children in the observation group was 6.33 ± 1.37 hours and 55.25 ± 4.92 hours, respectively, significantly lower than that of 12.45 ± 1.02 hours and 70.36 ± 5.31 hours, respectively, spent by children in the control group (P < 0.05). After intervention, the depression, hostility, anxiety, and obsession scores of children in the observation group were all significantly lower than those of children in the control group (P < 0.05). There was an increase in the heart rate, respiratory rate, and mean arterial pressure in children from both groups, but the magnitude of increase in the observation group was much smaller than that in the control group (P < 0.05). Conclusion: The combination of visual electrophysiological examination and targeted health education nursing in children has a remarkable clinical effect. It improves the children's degree of comfort as well as the parents' degree of satisfaction. It also reduces the time spent on examinations, facilitates the smooth completion of examinations, and improves the efficiency of examinations. This nursing method is one that merits more widespread promotion and clinical application.