LUX ARRHYTHMO links CBF pathway and jasmonic acid metabolism to regulate cold tolerance of tea plants.

Cold stress declines the quality and yield of tea, yet the molecular basis underlying cold tolerance of tea plants (Camellia sinensis) remains largely unknown. Here, we identified a circadian rhythm component LUX ARRHYTHMO (LUX) that potentially regulates cold tolerance of tea plants through a genome-wide association study and transcriptomic analysis. The expression of CsLUX phased with sunrise and sunset and was strongly induced by cold stress. Genetic assays indicated that CsLUX is a positive regulator of freezing tolerance in tea plants. CsLUX was directly activated by CsCBF1 and repressed the expression level of CsLOX2, which regulates the cold tolerance of tea plants through dynamically modulating jasmonic acid content. Furthermore, we showed that the CsLUX-CsJAZ1 complex attenuated the physical interaction of CsJAZ1 with CsICE1, liberating CsICE1 with transcriptional activities to withstand cold stress. Notably, a single-nucleotide variation of C-to-A in the coding region of CsLUX was functionally validated as the potential elite haplotype for cold response, which provided valuable molecular markers for future cold resistance breeding in tea plants.

Artificial intelligence-driven prediction of multiple drug interactions.

When a drug is administered to exert its efficacy, it will encounter multiple barriers and go through multiple interactions. Predicting the drug-related multiple interactions is critical for drug development and safety monitoring because it provides foundations for practical, safe compatibility and rational use of multiple drugs. With the progress of artificial intelligence (AI) technology, a variety of novel prediction methods for single interaction have emerged and shown great advantages compared to the traditional, expensive and time-consuming laboratory research. To promote the comprehensive and simultaneous predictions of multiple interactions, we systematically reviewed the application of AI in drug-drug, drug-food (excipients) and drug-microbiome interactions. We began by outlining the model methods, evaluation indicators, algorithms and databases commonly used to build models for three types of drug interactions. The models based on the metabolic enzyme P450, drug similarity and drug targets have empathized among the machine learning models of drug-drug interactions. In particular, we discussed the limitations of current approaches and identified potential areas for future research. It is anticipated the in-depth review will be helpful for the development of the next-generation of systematic prediction models for simultaneous multiple interactions.

DrugSK: A Stacked Ensemble Learning Framework for Predicting Drug Combinations of Multiple Diseases.

Combination therapy is an important direction of continuous exploration in the field of medicine, with the core goals of improving treatment efficacy, reducing adverse reactions, and optimizing clinical outcomes. Machine learning technology holds great promise in improving the prediction of drug synergy combinations. However, most studies focus on single disease-oriented collaborative predictive models or involve excessive feature categories, making it challenging to predict the majority of new drugs. To address these challenges, the DrugSK comprehensive model was developed, which utilizes SMILES-BERT to extract structural information from 3492 drugs and trains on reactions from 48,756 drug combinations. DrugSK is an integrated learning model capable of predicting interactions among various drug categories. First, the primary learner is trained from the initial data set. Random forest, support vector machine, and XGboost model are selected as primary learners and logistic regression as secondary learners. A new data set is then "generated" to train level 2 learners, which can be thought of as a prediction for each model. Finally, the results are filtered using logistic regression. Furthermore, the combination of the new antibacterial drug Drafloxacin with other antibacterial agents was tested. The synergistic effect of Drafloxacin and Isavuconazonium in the fight against Candida albicans has been confirmed, providing enlightenment for the clinical treatment of skin infection. DrugSK's prediction is accurate in practical application and can also predict the probability of the outcome. In addition, the tendency of Drafloxacin and antifungal drugs to be synergistic was found. The development of DrugSK will provide a new blueprint for predicting drug combination synergies.

Single-cell profiling identifies T cell subsets associated with control of tuberculosis dissemination.

To identify T cell subsets associated with control of tuberculosis, single-cell transcriptome and T cell receptor sequencing were performed on total T cells from patients with tuberculosis and healthy controls. Fourteen distinct subsets of T cells were identified by unbiased UMAP clustering. A GZMK-expressing CD8+ cytotoxic T cell cluster and a SOX4-expressing CD4+ central memory T cell cluster were depleted, while a MKI67-expressing proliferating CD3+ T cell cluster was expanded in patients with tuberculosis compared with healthy controls. The ratio of Granzyme K-expressing CD8+CD161-Ki-67- and CD8+Ki-67+ T cell subsets was significantly reduced and inversely correlated with the extent of TB lesions in patients with TB. In contrast, ratio of Granzyme B-expressing CD8+Ki-67+ and CD4+CD161+Ki-67- T cells and Granzyme A-expressing CD4+CD161+Ki-67- T cells were correlated with the extent of TB lesions. It is concluded that granzyme K-expressing CD8+ T cell subsets might contribute to protection against tuberculosis dissemination.

Ensemble learning-based gene signature and risk model for predicting prognosis of triple-negative breast cancer.

Although medical science has been fully developed, due to the high heterogeneity of triple-negative breast cancer (TNBC), it is still difficult to use reasonable and precise treatment. In this study, based on local optimization-feature screening and genomics screening strategy, we screened 25 feature genes. In multiple machine learning algorithms, feature genes have excellent discriminative diagnostic performance among samples composed of multiple large datasets. After screening at the single-cell level, we identified genes expressed substantially in myeloid cells (MCGs) that have a potential association with TNBC. Based on MCGs, we distinguished two types of TNBC patients who showed considerable differences in survival status and immune-related characteristics. Immune-related gene risk scores (IRGRS) were established, and their validity was verified using validation cohorts. A total of 25 feature genes were obtained, among which CXCL9, CXCL10, CCL7, SPHK1, and TREM1 were identified as the result after single-cell level analysis and screening. According to these entries, the cohort was divided into MCA and MCB subtypes, and the two subtypes had significant differences in survival status and tumor-immune microenvironment. After Lasso-Cox screening, IDO1, GNLY, IRF1, CTLA4, and CXCR6 were selected for constructing IRGRS. There were significant differences in drug sensitivity and immunotherapy sensitivity among high-IRGRS and low-IRGRS groups. We revealed the dynamic relationship between TNBC and TIME, identified a potential biomarker called Granulysin (GNLY) related to immunity, and developed a multi-process machine learning package called "MPMLearning 1.0" in Python.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population.

BACKGROUND AND PURPOSE: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. METHODS: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. RESULTS: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004-4.270) and CMB presence (OR = 1.542; 95% CI, 1.012-2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069-3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064-2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346-0.915). CONCLUSIONS: COW configuration was significantly related to various covert vascular brain injuries.

A bibliometric and visualized analysis of liver fibrosis from 2002 to 2022.

Fibrosis of the liver is a degenerative alteration that occurs in the majority of chronic liver disorders. Further progression can lead to cirrhosis, liver failure, and hepatocellular carcinoma, which can seriously affect the health and lives of patients. The field of liver fibrosis research has flourished in the last 20 years, with approximately 9000 articles retrieved from the Web of Science Core Collection database alone. In order to identify future research hotspots and potential paths in a thorough and scientifically reliable manner, it is important to organize and visualize the research on this topic from a holistic and very general perspective. This study used bibliometric analysis with CiteSpace and VOSviewer software to provide a quantitative analysis, hotspot mining, and commentary of articles published in the field of liver fibrosis over the last 20 years. This bibliometric analysis contains a total of 8994 articles with 45667 authors from 6872 institutions in 97 countries, published in 1371 journals and citing 156 309 references. The literature volume has steadily increased over the last 20 years. Research has focused on gastroenterology and hepatology, pharmacology and pharmacy, and medicine, research, and experimental areas. We found that the pathological mechanisms, diagnostic and quantitative methods, etiology, and antifibrotic strategies constitute the knowledge structure of liver fibrosis. Finding mechanisms for liver fibrosis regression, identifying precise noninvasive diagnostic and prognostic biomarkers, and creating efficient liver fibrosis patient treatments are the main goals of current research.

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin.

Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE<2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8 mg/kg/day from 0.5 to 2 years old, 9.2 mg/kg/day from 3 to 6 years old, 9.4 mg/kg/day from 7 to 12 years old, and 8.2 mg/kg/day from 13 to 18 years old, taken in half for 2-5 days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic-pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.

Different Types of Circulatory Inflammatory Biomarkers Associated with Cerebral Arterial Atherosclerosis and Dolichoectasia.

BACKGROUND: Although inflammation is found to be related to arteriopathy pathogenesis, it is yet to be determined the distinct correlations of specific inflammatory biomarker types contributing to different cerebral large vessel diseases. We aimed to investigate the association between multiple inflammatory biomarkers and cerebral atherosclerosis and dolichoectasia in a community-based sample. METHODS: A total of 960 participants of the Shunyi study were included. A panel of 14 circulatory inflammatory biomarkers was assessed and then grouped in three sets as systemic, endothelial-related, and media-related inflammation, based on underlying different inflammatory cascades. Intracranial atherosclerotic stenosis (ICAS), dolichoectasia estimated by magnetic resonance angiography, and carotid plaques estimated by ultrasound were also performed. RESULTS: Endothelial-related inflammatory group was related to the presence of ICAS (R2 = 0.215, p = 0.024) and carotid plaques (R2 = 0.342, p = 0.013). Backward stepwise elimination showed that E-selectin was prominent (ß = 0.67, 95% CI: 0.54-0.85, p = 0.001; ß = 0.79, 95% CI: 0.68-0.93, p = 0.005). Systemic inflammatory group was associated with an increased basilar artery diameter (R2 = 0.051, p < 0.001), and backward stepwise elimination showed that IL-6 was prominent (ß = 0.07, 95% CI: 0.03-0.11, p < 0.001). CONCLUSION: Different types of inflammatory biomarkers were associated with atherosclerosis and dolichoectasia, respectively, implying dissimilar inflammatory processes. Further confirming of their distinct anti-inflammatory roles as potential therapeutic targets is warrant.

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. RESULTS: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

Rapid Multi-Residue Detection Methods for Pesticides and Veterinary Drugs.

The excessive use or abuse of pesticides and veterinary drugs leads to residues in food, which can threaten human health. Therefore, there is an extremely urgent need for multi-analyte analysis techniques for the detection of pesticide and veterinary drug residues, which can be applied as screening techniques for food safety monitoring and detection. Recent developments related to rapid multi-residue detection methods for pesticide and veterinary drug residues are reviewed herein. Methods based on different recognition elements or the inherent characteristics of pesticides and veterinary drugs are described in detail. The preparation and application of three broadly specific recognition elements-antibodies, aptamers, and molecular imprinted polymers-are summarized. Furthermore, enzymatic inhibition-based sensors, near-infrared spectroscopy, and SERS spectroscopy based on the inherent characteristics are also discussed. The aim of this review is to provide a useful reference for the further development of rapid multi-analyte analysis of pesticide and veterinary drug residues.

Host Prdx6 contributing to the intracellular survival of Brucella suis S2 strain.

BACKGROUND: Brucellosis is a worldwide zoonotic infectious disease that is transmitted in various ways and causes great harm to humans and animals. The brucellosis pathogen is Brucella, which mainly resides in macrophage cells and survives and replicates in host cells. However, the mechanisms underlying Brucella survival in macrophage cells have not been thoroughly elucidated to date. Peroxiredoxin 6 (Prdx6) is a bifunctional protein that shows not only GSH peroxidase activity but also phospholipase A2 activity and plays important roles in combating oxidative damage and regulating apoptosis. RESULTS: Recombinant mouse (Mus musculus) Prdx6 (MmPrdx6) was expressed and purified, and monoclonal antibodies against MmPrdx6 were prepared. Using the Brucella suis S2 strain to infect RAW264.7 murine macrophages, the level of intracellular Prdx6 expression first decreased and later increased following infection. Overexpressing Prdx6 in macrophages resulted in an increase in B. suis S2 strain levels in RAW264.7 cells, while knocking down Prdx6 reduced the S2 levels in cells. CONCLUSIONS: Host Prdx6 can increase the intracellular survival of B. suis S2 strain and plays a role in Brucella infection.

Intracranial Arterial Dolichoectasia and Stenosis: Risk Factors and Relation to Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Intracranial arterial dolichoectasia (IADE) is a poorly understood arteriopathy compared with intracranial atherosclerotic stenosis (ICAS). We aimed to investigate the risk factors of IADE and ICAS and their relationship with neuroimaging markers of cerebral small vessel disease in a population-based study. METHODS: This study comprised 1237 participants (aged 57.2±9.4 years, 37.6% men) who underwent brain magnetic resonance imaging and magnetic resonance angiography. IADE was assessed based on basilar artery dolichoectasia (diameter, height of bifurcation, and laterality of basilar artery) and dilation of basilar artery and internal carotid artery (intracranial volume-adjusted diameter ≥2 SD). ICAS was defined as any degree of stenosis in at least 1 intracranial artery. The neuroimaging markers of cerebral small vessel disease, including lacunes, white matter hyperintensities, microbleeds, dilated perivascular spaces, and brain atrophy, were evaluated. RESULTS: Basilar arterial dolichoectasia was observed in 3.6% (45/1237); intracranial arterial dilation in 5.9% (67/1142); and ICAS in 15.7% (194/1237). Older age, higher systolic blood pressure, diabetes mellitus, higher LDL-C (low-density lipoprotein cholesterol) and lower HDL-C (high-density lipoprotein cholesterol) were associated with the presence of ICAS (all P<0.001), whereas only older age was associated with IADE. ICAS was associated with lacunes (odds ratio, 2.91; 95% confidence interval, 1.96-4.34; P<0.001), increased white matter hyperintensities volume (ß±SE, 0.54±0.13; P<0.001), and brain atrophy (ß±SE, -1.16±0.21; P<0.001), whereas basilar arterial dolichoectasia was mainly associated with dilated perivascular spaces in basal ganglia (odds ratio, 2.20; 95% confidence interval, 1.20-4.02; P=0.01) and, to a lesser extent, associated with lacunes and microbleeds. CONCLUSIONS: IADE and ICAS had different risk factor profiles and associated with different imaging phenotypes of cerebral small vessel disease, suggesting different underlying mechanisms.

The consequence of cerebral small vessel disease: Linking brain atrophy to motor impairment in the elderly.

In the elderly, brain structural deficits and gait disturbances due to cerebral small vessel disease (CSVD) have been well demonstrated. The relationships among CSVD, brain atrophy, and motor impairment, however, are far from conclusive. Particularly, the effect of CSVD on subcortical nuclear atrophy, motor performance of upper extremities, and associating patterns between brain atrophy and motor impairment remains largely unknown. To address these gaps, this study recruited 770 community-dwelling subjects (35-82 years of age), including both CSVD and non-CSVD individuals. For each subject, four motor tests involving upper and lower extremities were completed. High-resolution structural MRI was applied to extract gray matter (GM) volume, white matter volume, cortical thickness, surface area, and subcortical nuclear (caudate, putamen, pallidum, and thalamus) volumes. The results showed worse motor performance of lower extremities but relatively preserved performance of upper extremities in the CSVD group. Intriguingly, there was a significant association between the worse performance of upper extremities and atrophy of whole-brain GM and pallidum in the CSVD group but not in the non-CSVD group. In addition, mediation analysis confirmed a functional CSVD-to-"brain atrophy"-to-"motor impairment" pathway, that is, a mediating role of thalamic atrophy in the CSVD effect on walking speed in the elderly, indicating that CSVD impairs walking performance through damaging the integrity of the thalamus in aging populations. These findings provide important insight into the functional consequences of CSVD and highlight the importance of evaluating upper extremities functions and exploring their brain mechanisms in CSVD populations during aging.

Molecular characterization and differential expression analysis of interleukin 1ß from Ovis aries.

The interleukin-1 family is an important component of the innate immune system and plays an important role in regulating immune responses on the invasion of intracellular parasites in the acquired immune system. Interleukin 1ß (IL-1ß) is one of the members of the IL-1 family that predominantly activates downstream signaling pathways to play immunological functions of stimulating T and B lymphocyte activation and promoting the various syntheses of inflammatory substances in conjunction with other cytokines. Here, a full-length IL-1ß cDNA (OaIL-1ß) of sheep (Ovis aries) was cloned using rapid amplification of cDNA ends (RACE), which consists of 1494 bp and contains a 5'-UTR region with a length of 83 bp, a complete ORF of 801 bp in length, and a 3'-UTR region with a length of 642 bp. Recombinant protein OaIL-1ß was expressed and purified, and the monoclonal antibody against IL-1ß of sheep is prepared. Western blotting results showed that the sheep IL-1ß protein was detected in the heart, liver, lung, kidney, stomach, intestine, muscle, lymph nodes and leukocytes with the highest expression in the muscle and the lowest expression in the lung. Different bacteria treating sheep white blood cells induced differential expression of OaIL-1ß. Compared with the normal sheep, OaIL-1ß in the buffy coat was differentially expressed in the Brucella melitensis-challenged group and the B. suis S2 strain-inoculated group. However, whether IL-1ß may be considered as a molecular biomarker for differing Brucella-infected animals from brucellosis-vaccinated animals or not need to be further studied.

Protein nutritional value, polyphenols and antioxidant properties of corn fermented with Agaricus brasiliensis and Agaricus bisporus.

Solid-state fermentation (SSF) with Agaricus brasiliensis and Agaricus bisporus on corn was carried out. The results showed that SSF with the two fungi made up the deficiency of tryptophan in corn and improved the protein nutritional value of corn. The conjugated polyphenols contents in fermented corn decreased and free polyphenols (FPP) contents increased. FPP contents in corn fermented with the two fungi reached respectively 25 and 88 times of control, total polyohenols contents reached respectively 1.4 and 3.3 times of control. The antioxidant properties (i.e. 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, reducing power, ferrous ion chelating ability and superoxide anion radical scavenging ability) of fermented corn were improved significantly. SSF with A. bisporus was more favorable to the enhancement in protein nutritional value and antioxidant properties of corn than that of A. brasiliensis. The results indicated that SSF with the two fungi could upgrade the protein nutritional value, FPP content and antioxidant properties of corn.

The effects of fat layer on temperature distribution during microwave atrial fibrillation catheter ablation.

To investigate the effects of fat layer on the temperature distribution during microwave atrial fibrillation catheter ablation in the conditions of different ablation time; 3D finite element models (fat layer and no fat layer) were built, and temperature distribution was obtained based on coupled electromagnetic-thermal analysis at 2.45 GHz and 30 W of microwave power. Results shown: in the endocardial ablation, the existence of the fat layer did not affect the shape of the 50 °C contour before 30 s. The increase speed of depth became quite slowly in the model with fat layer after 30 s. When ablation depth needed fixed, there are no significant effect on effectively ablation depth whether fat layer over or not. However, the existence of fat layer makes the temperature lower in the myocardium, and maximum temperature point closer to the myocardium surface. What is more, in the model with fat layer, effective ablation reach lower maximum temperature and the shallower depth of 50 °C contour. But there are larger ablation axial length and transverse width. In this case, doctor should ensure safety of normal cardiac tissue around the target tissue. In the epicardial ablation, the existence of fat layer seriously affects result of the microwave ablation. The epicardial ablation needs more heating time to create lesion. But epicardial ablation can be better controlled in the shape of effective ablation area because of the slowly increase of target variables after the appearing of 50 °C contour. Doctor can choose endocardial or epicardial ablation in different case of clinic requirement.

[Digital Identification Based on Image Processing for Mountain Cultivated Ginseng].

Objective: To identify mountain cultivated ginseng using a digital method. Methods: Image information of mountain cultivated ginseng was processed using the Matlab 2014 a software box. Based on the shape, color and texture features,18 image information from ginseng rhizome, body, grain, peel, fibrous root, were extracted and a digital mountain cultivated ginseng database model was established. Results: Digital identification based on image processing could be met by the features obtained from mountain cultivated ginseng. The recognition rate of ginseng was 96%. Conclusion: A lot of information from ginseng were extracted based on image processing. A fast and accurate digital identification of mountain cultivated ginseng is achieved successfully undamaged.