-
MSystems Jul 2024The erythromycin resistance RNA methyltransferase () confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS...
UNLABELLED
The erythromycin resistance RNA methyltransferase () confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS phenotype). The expression of is often induced by the macrolide-mediated ribosome stalling in the upstream co-transcribed leader sequence, thereby triggering a conformational switch of the intergenic RNA hairpins to allow the translational initiation of . We investigated the evolutionary emergence of the upstream regulatory elements and the impact of allelic variation on erm expression and the MLS phenotype. Through systematic profiling of the upstream regulatory sequences across all known operons, we observed that specific subfamilies, such as and , have independently evolved distinct configurations of small upstream ORFs and palindromic repeats. A population-wide genomic analysis of the upstream regions revealed substantial non-random allelic variation at numerous positions. Utilizing machine learning-based classification coupled with RNA structure modeling, we found that many alleles cooperatively influence the stability of alternative RNA hairpin structures formed by the palindromic repeats, which, in turn, affects the inducibility of expression and MLS phenotypes. Subsequent experimental validation of 11 randomly selected variants demonstrated an impressive 91% accuracy in predicting MLS phenotypes. Furthermore, we uncovered a mixed distribution of MLS-sensitive and MLS-resistant loci within the evolutionary tree, indicating repeated and independent evolution of MLS resistance. Taken together, this study not only elucidates the evolutionary processes driving the emergence and development of MLS resistance but also highlights the potential of using non-coding genomic allele data to predict antibiotic resistance phenotypes.
IMPORTANCE
Antibiotic resistance (AR) poses a global health threat as the efficacy of available antibiotics has rapidly eroded due to the widespread transmission of AR genes. Using Erm-dependent MLS resistance as a model, this study highlights the significance of non-coding genomic allelic variations. Through a comprehensive analysis of upstream regulatory elements within the family, we elucidated the evolutionary emergence and development of AR mechanisms. Leveraging population-wide machine learning (ML)-based genomic analysis, we transformed substantial non-random allelic variations into discernible clusters of elements, enabling precise prediction of MLS phenotypes from non-coding regions. These findings offer deeper insight into AR evolution and demonstrate the potential of harnessing non-coding genomic allele data for accurately predicting AR phenotypes.
PubMed: 38953319
DOI: 10.1128/msystems.00430-24 -
Chronobiology International Jul 2024This study examined the psychometric properties and longitudinal changes of the self-reporting Traditional Chinese version of Biological Rhythms Interview for Assessment...
Chinese self-report version of biological rhythms interview for assessment in neuropsychiatry (C-BRIAN-SR) - psychometric properties and prospective follow-up in patients with non-seasonal depression.
This study examined the psychometric properties and longitudinal changes of the self-reporting Traditional Chinese version of Biological Rhythms Interview for Assessment in Neuropsychiatry (C-BRIAN-SR) among healthy controls (HC) and patients with major depressive episode (MDE). Eighty patients with a current MDE and 80 HC were recruited. Assessments were repeated after two weeks in HC, and upon the discharge of MDE patients to examine the prospective changes upon remission of depression. The C-BRIAN-SR score was significantly higher in the MDE than HC group. The concurrent validity was supported by a positive correlation between scores of C-BRIAN-SR, Insomnia Severity Index and the Hospital Anxiety Depression Scale. C-BRIAN-SR negatively correlated MEQ in the MDE group ( = .30, = 0.009), suggesting higher rhythm disturbances were associated with a tendency toward eveningness. A moderate test-retest reliability was found ( = .61, < 0.001). A cut-off of 38.5 distinguished MDE subjects from HC with 82.9% of sensitivity and 81.0% of specificity. C-BRIAN-SR score normalized in remitted MDE patients but remained higher in the non-remitted. The C-BRIAN-SR is a valid and reliable scale for measuring the biological rhythms and may assist in the screening of patients with MDE.
PubMed: 38953315
DOI: 10.1080/07420528.2024.2373215 -
Analytical Methods : Advancing Methods... Jul 2024Peroxide-mediated oxidation of drug molecules is a known challenge faced throughout the pharmaceutical development pathway-from early-stage stability studies to...
Peroxide-mediated oxidation of drug molecules is a known challenge faced throughout the pharmaceutical development pathway-from early-stage stability studies to manufacturing processes. During the initial development stage, the major source of peroxide is the formulation excipients, whether they are pre-loaded or generated due to slow degradation, and in the late phase, peroxides can be introduced during sanitization processes or generated cavitation. In essence, a control strategy for peroxide mitigation often becomes a critical quality attribute for successful drug development. To this end, quantitation of peroxide is essential to monitor the peroxide level to ensure product quality and proposed shelf-life. However, methods for reliable and robust quantitation to detect trace levels of peroxide in a complex drug product matrix become increasingly challenging. This article discusses three high-throughput assays based on absorbance, fluorescence and chemiluminescence measurements to detect peroxide at a low level and compares the methods through validation studies in water. Selected methods have also been tested to understand the forced degradation of model peptide drug products with spiked hydrogen peroxide. Peptide degradation profiles and residual peroxide levels are presented to provide an understanding of the suitability of the quantitation methods and their performance.
PubMed: 38953302
DOI: 10.1039/d4ay00652f -
Cancer Medicine Jul 2024Recent studies provide compelling evidence linking the gut microbiota to most cancers. Nevertheless, further research is required to establish a definitive causal...
BACKGROUND
Recent studies provide compelling evidence linking the gut microbiota to most cancers. Nevertheless, further research is required to establish a definitive causal relationship between the gut microbiota and malignant cardiac tumors.
METHODS
The genome-wide association studies (GWAS) data on the human gut Microbiota, included in the IEU Open GWAS project, was initially collected by the MiBioGen consortium. It encompasses 14,306 individuals and comprises a total of 5,665,279 SNPs. Similarly, the GWAS data on malignant cardiac tumors, also sourced from the IEU Open GWAS project, was initially stored in the finnGen database, including 16,380,303 SNPs observed within a cohort of 174,108 individuals within the European population. Utilizing a two-sample Mendelian randomization (MR) methodology, we examined whether there exists a causal association between the gut microbiota and cardiac tumors. Additionally, to bolster the credibility and robustness of the identified causal relationships, we conducted an extensive array of sensitivity analyses, encompassing Cochran's Q test, MR-PRESSO tests, MR-Egger interpret test, directionality test and leave-one-out analysis.
RESULTS
Our analysis unveiled seven distinct causal associations between genetic susceptibility in the gut microbiota and the incidence of malignant cardiac tumors. Among these, the Family Rikenellaceae, genus Eubacterium brachy group, and genus Ruminococcaceae UCG009 exhibited an elevated risk of cardiac tumors, while the phylum Verrucomicrobia, genus Lactobacillus, genus Ruminiclostridium5, and an unknown genus id.1868 were genetically linked to a reduced risk of cardiac tumors. The causal relationship between these two bacteria, belonging to the phylum Verrucomicrobia (OR = 0.178, 95% CI: 0.052-0.614, p = 0.006) and the genus Ruminococcaceae UCG009 (OR = 3.071, 95% CI: 1.236-7.627, p = 0.016), and cardiac tumors was further validated through sensitivity analyses, reinforcing the robustness and reliability of the observed associations.
CONCLUSION
Our MR analysis confirms that the phylum Verrucomicrobia displays significant protection against cardiac tumor, and the genus Ruminococcaceae UCG009 leads to an increasing risk of cardiac tumor.
Topics: Humans; Mendelian Randomization Analysis; Gastrointestinal Microbiome; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Heart Neoplasms; Risk Factors
PubMed: 38953300
DOI: 10.1002/cam4.7455 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To construct a risk prediction model by integrating the molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and immune-related genes.Methods With...
Objective To construct a risk prediction model by integrating the molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and immune-related genes.Methods With GSE71729 data set (=145) as the training set,the differentially expressed genes and differential immune-related genes between the squamous and non-squamous subtypes of PDAC were integrated to construct a regulatory network,on the basis of which five immune marker genes regulating the squamous subtype were screened out.An integrated immune score (IIS) model was constructed based on patient survival information and immune marker genes to predict the clinical prognosis of PDAC patients,and its predictive performance was tested with 5 validation sets (=758).Results PDAC patients were assigned into high risk and low risk groups according to the IIS.In both training and validation sets,the overall survival of patients in the high risk group was shorter than that in the low risk group (both <0.001).The multivariable Cox regression showed that IIS was an independent prognostic factor for PDAC (=2.16,95%=1.50-3.10,<0.001).Conclusion IIS can be used for risk stratification of PDAC patients and may become a potential prognostic marker for PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Prognosis; Pancreatic Neoplasms; Female; Male; Middle Aged; Biomarkers, Tumor; Risk Assessment
PubMed: 38953259
DOI: 10.3881/j.issn.1000-503X.15736 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To demonstrate the feasibility of oblique lumbar interbody fusion (OLIF) combined with 4-screw fixation for treating two-level lumbar degenerative...
Objective To demonstrate the feasibility of oblique lumbar interbody fusion (OLIF) combined with 4-screw fixation for treating two-level lumbar degenerative diseases.Methods An intact finite element model of L3-S1 (M0) was constructed and validated.Then,we constructed the M1 model by simulating OLIF surgery at L3/4 and L4/5 segments on the M0 model.By attachment of posterior 4-screw or 6-screw fixation to the M1 model,three 4-screw fixation models (M2-M4) and one 6-screw fixation model (M5) were established.The segmental and overall range of motion (ROM) and the peak von Mises stresses of superior endplate,cage,and posterior screw-rod were investigated under each implanted condition.Results Under the motion modes of forward flexion,backward extension,bilateral (left and right) flexion,and left and right rotation,the L3/4 ROM of M2 model and L4/5 ROM of M3 model increased,while the L3/4 and L4/5 ROM of M4 and M5 models significantly decreased compared with those of M1 model.Under all motion modes,the L4 superior endplate in M2 model and the L5 superior endplate in M3 model showed the maximum peak von Mises stress,and the peak von Mises stresses of L4 and L5 superior endplates in M4 and M5 models were close.The L3/4 cage in M2 model and the L4/5 cage in M3 model showcased the largest peak von Mises stress,and the peak von Mises stresses of cages in M4 and M5 models were close.The peak stresses of internal fixation in M2-M5 models were close.Conclusion Four-screw fixation can replace 6-screw fixation in the OLIF surgery for treating two-level degenerative lumbar diseases.
Topics: Spinal Fusion; Humans; Finite Element Analysis; Lumbar Vertebrae; Bone Screws
PubMed: 38953258
DOI: 10.3881/j.issn.1000-503X.15878 -
Journal of Chemical Information and... Jul 2024Deep learning holds great potential for expediting the discovery of new polymers from the vast chemical space. However, accurately predicting polymer properties for...
Deep learning holds great potential for expediting the discovery of new polymers from the vast chemical space. However, accurately predicting polymer properties for practical applications based on their monomer composition has long been a challenge. The main obstacles include insufficient data, ineffective representation encoding, and lack of explainability. To address these issues, we propose an interpretable model called the Polymer Graph Convolutional Neural Network (PGCNN) that can accurately predict various polymer properties. This model is trained using the RadonPy data set and validated using experimental data samples. By integrating evidential deep learning with the model, we can quantify the uncertainty of predictions and enable sample-efficient training through uncertainty-guided active learning. Additionally, we demonstrate that the global attention of the graph embedding can aid in discovering underlying physical principles by identifying important functional groups within polymers and associating them with specific material attributes. Lastly, we explore the high-throughput screening capability of our model by rapidly identifying thousands of promising candidates with low and high thermal conductivity from a pool of one million hypothetical polymers. In summary, our research not only advances our mechanistic understanding of polymers using explainable AI but also paves the way for data-driven trustworthy discovery of polymer materials.
PubMed: 38953249
DOI: 10.1021/acs.jcim.4c00555 -
Angewandte Chemie (International Ed. in... Jul 2024To explore the mechanisms and therapeutic strategies for G-quadruplex (G4) mediated diseases, it is crucial to manipulate and intervene in intracellular G4 structures...
To explore the mechanisms and therapeutic strategies for G-quadruplex (G4) mediated diseases, it is crucial to manipulate and intervene in intracellular G4 structures using small molecular tools. While hundreds of G4 stabilizers have been developed, there is a significant gap in the availability of G4 unwinding agents. Here, we propose a strategy to disrupt G-quadruplexes by forming G-C hydrogen bonds with chemically modified cytidine trimers. We validated a good G4 unwinder, the 2'-F cytidine trimer (2'-F C3). 2'-F C3 does not inhibit cell growth nor cause severe DNA damage at a concentration below 10 μM. Moreover, 2'-F C3 does not affect gene transcription nor RNA splicing, while it significantly enhances the translation of G4-containing mRNA and upregulates RNA splicing, RNA processing and cell cycle pathways. The discovery of this G4 unwinder provides a functional tool for the chemical modulation of G4s in living cells.
PubMed: 38953247
DOI: 10.1002/anie.202407353 -
Journal of the American Society For... Jul 2024Extracts prepared from the seeds of the medicinal plant milk thistle [ (L.) Gaertn. ()] are widely used as dietary supplements due to anti-inflammatory, antitumor, and...
Extracts prepared from the seeds of the medicinal plant milk thistle [ (L.) Gaertn. ()] are widely used as dietary supplements due to anti-inflammatory, antitumor, and hepatoprotective effects. Called silymarin, the main components of lipophilic extracts of milk thistle seeds are flavonoids and flavonolignans including silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, taxifolin, and 2,3-dehydrosilybins. The aim of this study was to develop a method based on UHPLC-MS/MS for the chemical authentication and standardization of milk thistle silymarin. Validation included the method of standard addition to account for the lack of a blank matrix. Potential matrix effects were investigated by analyzing silymarin standards dissolved only in the initial UHPLC mobile phase. Measurements of six flavonolignans and taxifolin in the milk thistle extract using UHPLC-MS/MS with standard addition or external standard calibration produced similar results for all analytes except silydianin and 2,3-dehydrosilybin B, which showed significant peak enhancement during negative ion electrospray due to botanical matrix effects. The UHPLC-MS/MS-based method of standard addition requires <10 min per injection and is suitable for the standardization of silymarin from milk thistle in support of preclinical and clinical studies of safety and efficacy.
PubMed: 38953246
DOI: 10.1021/jasms.4c00125 -
Skin Research and Technology : Official... Jul 2024Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of...
OBJECTIVE
Observational studies have identified a dual effect of circulating inflammatory proteins and immune cells on cancer progression. However, the specific mechanisms of action have not been clarified in the exacerbation of cutaneous-origin tumors. Therefore, this study aims to investigate whether the causal relationship between circulating inflammatory factors and basal cell carcinoma (BCC), cutaneous malignant melanoma (SKCM), and cutaneous squamous cell carcinoma (cSCC) is regulated by immune cells.
METHODS
This study employed the Two-Sample Mendelian Randomization (TSMR) approach to investigate the causal relationships between 91 circulating inflammatory factors and three prevalent types of skin cancer from a genetic perspective. Bayesian Weighted Mendelian Randomization (BWMR) was also used to validate correlation and reverse MR to assess inverse relationships. Subsequent sensitivity analyses were conducted to limit the impact of heterogeneity and pleiotropy. Finally, the two-step Mendelian Randomization (two-step MR) method was utilized to ascertain the mediating effects of specific immune cell traits in the causal pathways linking circulating inflammatory factors with BCC, SKCM, and cSCC.
RESULTS
The Inverse Variance Weighted (IVW) method and the Bayesian Weighted Algorithm collectively identified nine inflammatory factors causally associated with BCC, SKCM, and cSCC. The results from Cochran's Q test, mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger intercept were not statistically significant (p < 0.05). Additionally, the proportions mediated by CD4+ CD8dim T cell %leukocyte, CD4-CD8-Natural Killer T %T cell, and CD20 on IgD-CD38-B cell for FIt3L, CCL4, and OSM were 9.26%, 8.96%, and 10.16%, respectively.
CONCLUSION
Immune cell levels potentially play a role in the modulation process between circulating inflammatory proteins and cutaneous-origin exacerbated tumors. This finding offers a new perspective for the in-depth exploration of cutaneous malignancies.
Topics: Humans; Skin Neoplasms; Melanoma; Carcinoma, Basal Cell; Mendelian Randomization Analysis; Carcinoma, Squamous Cell; Bayes Theorem; Melanoma, Cutaneous Malignant
PubMed: 38953214
DOI: 10.1111/srt.13774