Biomarker interaction selection and disease detection based on multivariate gain ratio.

BACKGROUND: Disease detection is an important aspect of biotherapy. With the development of biotechnology and computer technology, there are many methods to detect disease based on single biomarker. However, biomarker does not influence disease alone in some cases. It's the interaction between biomarkers that determines disease status. The existing influence measure I-score is used to evaluate the importance of interaction in determining disease status, but there is a deviation about the number of variables in interaction when applying I-score. To solve the problem, we propose a new influence measure Multivariate Gain Ratio (MGR) based on Gain Ratio (GR) of single-variate, which provides us with multivariate combination called interaction. RESULTS: We propose a preprocessing verification algorithm based on partial predictor variables to select an appropriate preprocessing method. In this paper, an algorithm for selecting key interactions of biomarkers and applying key interactions to construct a disease detection model is provided. MGR is more credible than I-score in the case of interaction containing small number of variables. Our method behaves better with average accuracy [Formula: see text] than I-score of [Formula: see text] in Breast Cancer Wisconsin (Diagnostic) Dataset. Compared to the classification results [Formula: see text] based on all predictor variables, MGR identifies the true main biomarkers and realizes the dimension reduction. In Leukemia Dataset, the experiment results show the effectiveness of MGR with the accuracy of [Formula: see text] compared to I-score with accuracy [Formula: see text]. The results can be explained by the nature of MGR and I-score mentioned above because every key interaction contains a small number of variables in Leukemia Dataset. CONCLUSIONS: MGR is effective for selecting important biomarkers and biomarker interactions even in high-dimension feature space in which the interaction could contain more than two biomarkers. The prediction ability of interactions selected by MGR is better than I-score in the case of interaction containing small number of variables. MGR is generally applicable to various types of biomarker datasets including cell nuclei, gene, SNPs and protein datasets.

C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot-Marie-Tooth disease in a knockout mouse model.

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy and shows clinical and genetic heterogeneity. Mutations in C1orf194 encoding a Ca2+ regulator in neurons and Schwann cells have been reported previously by us to cause CMT disease. In here, we further investigated the function and pathogenic mechanism of C1or194 by generating C1orf194 knockout (KO) mice. Homozygous mutants of C1orf194 mice exhibited incomplete embryonic lethality, characterized by differentiation abnormalities and stillbirth on embryonic days 7.5-15.5. Heterozygous and surviving homozygous C1orf194 KO mice developed motor and sensory defects at the age of 4 months. Electrophysiologic recordings showed decreased compound muscle action potential and motor nerve conduction velocity in the sciatic nerve of C1orf194-deficient mice as a pathologic feature of dominant intermediate-type CMT. Transmission electron microscopy analysis revealed demyelination and axonal atrophy in the sciatic nerve as well as swelling and loss of mitochondrial matrix and other abnormalities in axons and Schwann cells. A histopathologic examination showed a loss of motor neurons in the anterior horn of the spinal cord and muscle atrophy. Shorter internodal length between nodes of Ranvier and Schmidt-Lanterman incisures was detected in the sciatic nerve of affected animals. These results indicate that C1orf194 KO mice can serve as an animal model of CMT with a severe dominant intermediate CMT phenotype that can be used to investigate the molecular mechanisms of the disease and evaluate the efficacy of therapeutic strategies.

Mechanisms of the end-plate potential noise and its implication for the neuromuscular junction anatomy.

We construct a compact model to mimic the membrane voltage response to the concentration of acetylcholine ([ACh]) which is mediated by the stochastic gating of acetylcholine (ACh) receptors. The patterns of the voltage depolarization against [ACh] as well as the accompanying voltage noises are presented. The mechanism of the voltage fluctuation that caused by the stochastic gating of receptors is explained. We consider that our results explain the frequently observed "end-plate (potential) noise" in physiology and electromyographic literature. These results, together with the requirements of evolution pressure on the motor units, explain reasonably the anatomical structure of the neuromuscular junction.

Mild Synthesis of 3,4-Dihydroisoquinolin-1(2H)-ones via Rh(III)-Catalyzed Tandem C-H-Allylation/N-Alkylation Annulation with 2-Methylidenetrimethylene Carbonate.

A tandem rhodium(III)-catalyzed system was established to access 3,4-dihydroisoquinolin-1(2H)-one by coupling of N-methoxy-3-methylbenzamide with 2-methylidenetrimethylene carbonate. This one-pot synthesis protocol processed smoothly under mild reaction conditions. Moreover, a total of 28 examples, broad substrate scope, and high functional-group compatibility were observed. Preliminary mechanism studies were also conducted and demonstrated that the rhodium(III) catalyst played a vital role in the C-H-allylation and N-alkylation cyclization process.

Access to acridones by tandem copper(I)-catalyzed electrophilic amination/Ag(I)-mediated oxidative annulation of anthranils with arylboronic acids.

An efficient and practical approach for the synthesis of medicinally important acridones was developed from anthranils and commercially available arylboronic acids by a tandem copper(I)-catalyzed electrophilic amination/Ag(I)-mediated oxidative annulation strategy. This new and straightforward protocol displayed a broad substrate scope (25 examples) and high functional group tolerance. What's more, a possible mechanistic proposal was also presented.

[4 + 1] annulation reaction of cyclic pyridinium ylides with in situ generated azoalkenes for the construction of spirocyclic skeletons.

Two new types of cyclic pyridinium ylides were designed and further used in reactions with azoalkenes to access structurally diverse spirocyclic compounds. A range of spiropyrazoline oxindoles could be smoothly obtained in up to 99% yield via a [4 + 1] annulation process with oxindole 3-pyridinium ylides as C1 synthons. Similarly, a series of spiropyrazoline indanones could be prepared with indanone 2-pyridinium ylides as C1 synthons. This work represents the first example of cyclic pyridinium ylides as C1 synthons for the efficient construction of spirocyclic compounds.

Characteristics of within-household varicella transmission events associated with school outbreaks in Shanghai, China, 2009-2018.

Transmission of varicella occurs frequently in schools and households. We investigated the characteristics of varicella cases derived from within-household transmission and the modes of varicella transmission between school and household settings in Shanghai, China, from 2009 to 2018. Within-household transmission occurred in 278 households, of which 134 transmission events were between children. Sixty-one household varicella transmission events may be attributed to isolation procedures for infected students during school outbreaks, and 7.6% of school outbreaks were caused by schoolchildren cases derived from within-household transmission. The frequency of 'school-household-school' transmission adds an additional layer of complexity to the control of school varicella outbreaks. Administration of varicella vaccine as post-exposure prophylaxis after exposure is considered to be an effective measure to control varicella spread within households and schools.

Molecular Dynamics Simulations of the Electrocoalescence Behaviors of Two Unequally Sized Conducting Droplets.

The electrocoalescence of droplets plays a crucial role in various fields. However, studies on the effects of droplet radius on the electrocoalescence behaviors of droplets have not been conducted until now. In this work, the electrocoalescence behaviors of two unequally sized conducting droplets are investigated via molecular dynamics (MD) simulations. The influences of electric field strength and droplet radius on the electrocoalescence behaviors of two unequally sized droplets are investigated. When the electric field strength increases, the contact cone angle between the droplets increases, and the two droplets are more likely to partially coalesce and bounce. When the radius of the smaller droplet between the two droplets increases at the same electric field strength, the contact cone angle, daughter droplet size, and ions in the daughter droplet increase, whereas the critical electric field strength ( Ed) for generating the daughter droplet decreases. Furthermore, the daughter droplet is ejected from the smaller droplet when the two droplets have different radii.

Organocatalyzed Asymmetric Dearomative Aza-Michael/Michael Addition Cascade of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes with 2-Aminochalcones.

An organocatalyzed dearomative aza-Michael/Michael addition cascade of 2-nitrobenzofurans and 2-nitrobenzothiophenes with 2-aminochalcones has been developed, opening a new channel to access a series of optically active tetrahydrobenzofuro[3,2- b]quinolines and tetrahydrobenzo[4,5]thieno[3,2- b]quinolines bearing three contiguous stereocenters with excellent diastereo- and enantioselectivities (all cases >20:1 dr, up to 99% ee). This study features the first asymmetric dearomative cascade reaction of 2-nitrobenzofurans and 2-nitrobenzothiophenes beginning with aza-Michael addition. The potential applications of the methodology were demonstrated by the preparative-scale experiment and the versatile transformations of the products.

Ginsenoside Rb1 Prevents Dysfunction of Endothelial Cells by Suppressing Inflammatory Response and Apoptosis in the High-Fat Diet Plus Balloon Catheter-Injured Rabbit Model via the G Protein-Coupled Estrogen Receptor-Mediated Phosphatidylinositol 3-Kinases (PI3K)/Akt Pathway.

BACKGROUND The initiation of atherosclerosis (AS) is attributed to the dysfunction of endothelial cells (ECs) via the inhibition of g protein-coupled estrogen receptor (GPER). In the current study, we assessed the potential of Ginsenoside Rb1 (Rb1) to attenuate the dysfunction of ECs via GPER-mediated PI3K/Akt pathway. MATERIAL AND METHODS AS was induced in rabbits and then the AS rabbits were treated with Rb1. Thereafter, the ECs were isolated from AS and healthy rabbits, and treated with Rb1. The effect of Rb1 on blood lipid levels in AS rabbits and on apoptosis, inflammatory response, and GPER/PI3K/Akt axis activity in ECs was detected. Furthermore, the activities of GPER and PI3K were modulated to verify the key role of the axis in the anti-AS effect of Rb1. RESULTS The levels of total cholesterol, low-density lipoprotein (LDL), and triglyceride in AS rabbits were suppressed by Rb1 while the high-density lipoprotein (HDL) level was increased. In in vitro assays, Rb1 administration inhibited apoptosis process and the production of pro-inflammation cytokines in AS ECs. The expression levels of GPER, p-PI3K, and p-Akt were upregulated by Rb1, associated with the increased level of Bcl-2 and reduced level of Bax. When the activity of GPER was inhibited by GP-15 in AS ECs, the treatment effect of Rb1 was blocked. However, the activation of PI3K could restore the protective effect of Rb1 after the inhibition of GPER. CONCLUSIONS The anti-AS potential of Rb1 was exerted by restoring the regular function of ECs via the activation of GPER-mediated PI3K/Akt signaling.

Establishment and application of a flow cytometry-based method for detecting histone acetylation levels.

Histone deacetylase inhibitors, which have also received attention in AIDS and other diseases, are a new class of anticancer drugs developed in recent years. However, there is still a lack of a unified and reliable method for detecting histone acetylation levels in basic and clinical research. In this study, we developed a flow cytometry-based method to detect histone acetylation levels by comparing different sample processing temperature (on ice vs. room temperature), permeabilization method (intracellular vs. nuclear), antibody dose (antibody titration) and antibody incubation time (time gradient) using whole blood and peripheral blood mononuclear cells. In addition, we applied this optimized method in in vitro experiment and clinical trial of Chidamide (the only China FDA approved HDACi), the result of which confirmed that the flow cytometry-based method for detecting histone acetylation levels is a reliable, fast and convenient method which can be used in basic and clinical research.

Antidepressant-like and anxiolytic-like effects of hydrogen sulfide in streptozotocin-induced diabetic rats through inhibition of hippocampal oxidative stress.

Depression is highly prevalent in individuals with diabetes, and depressive symptoms are less responsive to current antidepressant therapies. Oxidative stress plays a major role both in the pathogenesis of diabetes and in major depression and anxiety disorders. Hydrogen sulfide (H2S), the third gaseous mediator, is a novel signaling molecule in the brain that has both antioxidative activity and antidepressant-like and anxiolytic-like effects. We hypothesized that H2S could produce antidepressant-like and anxiolytic-like effects in diabetic patients through its antioxidative effect. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic rats. We found that H2S alleviated depressive-like behaviors of STZ-induced diabetic rats in the forced swimming and tail suspension tests and reduced their anxiety-like behaviors in the elevated plus maze test. We also found that H2S significantly reduced levels of malondialdehyde and 4-hydroxynonenal and elevated levels of superoxide dismutase and reduced glutathione in the hippocampus of STZ-induced diabetic rats. The results provide evidence for antidepressant-like and anxiolytic-like effects of H2S in STZ-induced diabetic rats and suggest that the therapeutic effects may result from inhibition of hippocampal oxidative stress. These findings suggest that elevating H2S signaling is a potential target for treatment of depressive and anxiety disorders related to diabetes.

[Inhibition of MCF-7/ADR cells by DOX-loaded pluronic-attached PAMAM dendrimer conjugate].

Pluronic modified polyamidoamine (PAMAM) conjugate (PF127-PAMAM) was prepared and the inhibiting effect of MDR against MCF-7/ADR was investigated with doxorubicin (DOX) as model drug. 1H NMR and FTIR spectra showed that the conjugate was synthesized successfully. Element analysis accurately measured that 27.63% amino of per PAMAM was modified by pluronic (PAMAM : PF127, 1 : 35.37 mole ratio). PF127-PAMAM showed an increased size and a reduced zeta potential compared to PAMAM. PF127-PAMAM had lower hemolytic toxicity and cytotoxicity due to the reduced zeta potential and the protection of PF127. Each PF127-PAMAM molecular could load 19.58 DOX molecules, and the complex exhibited sustained and pH-sensitive release behavior. PF127-PAMAM/DOX exhibited weaker cytotoxicity than free DOX in MCF-7 cells; while the complex showed much stronger reverse effect of drug resistance in MCF-7/ADR cells, and resistance reversion index (RRI) was as high as 33.15.

Land-use classification based on high-resolution remote sensing imagery and deep learning models.

High-resolution imagery and deep learning models have gained increasing importance in land-use mapping. In recent years, several new deep learning network modeling methods have surfaced. However, there has been a lack of a clear understanding of the performance of these models. In this study, we applied four well-established and robust deep learning models (FCN-8s, SegNet, U-Net, and Swin-UNet) to an open benchmark high-resolution remote sensing dataset to compare their performance in land-use mapping. The results indicate that FCN-8s, SegNet, U-Net, and Swin-UNet achieved overall accuracies of 80.73%, 89.86%, 91.90%, and 96.01%, respectively, on the test set. Furthermore, we assessed the generalization ability of these models using two measures: intersection of union and F1 score, which highlight Swin-UNet's superior robustness compared to the other three models. In summary, our study provides a systematic analysis of the classification differences among these four deep learning models through experiments. It serves as a valuable reference for selecting models in future research, particularly in scenarios such as land-use mapping, urban functional area recognition, and natural resource management.

Thiol-Triggered Tandem Dearomative Michael Addition/Intramolecular Henry Reaction of 2-Nitrobenzofurans: Access to Sulfur-Containing Polyheterocyclic Compounds.

An efficient dearomative cyclization of 2-nitrobenzofurans via a thiol-triggered tandem Michael addition/intramolecular Henry reaction has been developed. A range of thiochromeno[3,2-b]benzofuran-11-ols and tetrahydrothieno[3,2-b]benzofuran-3-ols could be obtained in up to 99% yield and up to >20:1 dr. The valuable thiochromone fused benzofurans could be prepared with the reaction of 2-nitrobenzofurans and 2-mercaptobenzaldehyde via the tandem dearomative Michael addition/intramolecular Henry reaction/rearomatization/oxidative dehydrogenation process in a one-pot two-step operation. A mechanism for the reaction was tentatively proposed.

Production of γ-aminobutyric acid-enriched sourdough bread using an isolated Pediococcus pentosaceus strain JC30.

A γ-aminobutyric acid (GABA)-producing strain JC30 was isolated from traditional kimchi, which was identified as Pediococcus pentosaceus by 16S rDNA sequencing. P. pentosaceus JC30 was highly tolerant to acid, bile salt, and high temperatures. The survival rate of JC30 in MRS medium (pH 2.5) for 3 h was 60.96 %. Furthermore, the survival rate of JC30 in MRS medium with 3 mg/mL bile salt for 24 h was 86.62 %. The survival rate of JC30 in MRS medium at 56 °C and 58 °C for 10 min was 97.17 % and 78.20 %, respectively. When 2 % v/v JC30 (8.0 log10 CFU/mL) was added to prepare sourdough and the sourdough was then used to make bread, the bread had a higher specific volume (5.13 ± 0.12 mL/g) and GABA content (3.32 ± 0.04 mg/g DW) than the control.

Identification of P21 (CDKN1A) Activated Kinase 4 as a Susceptibility Gene for Familial Non-Medullary Thyroid Carcinoma.

Background: Familial non-medullary thyroid carcinoma (FNMTC) is a genetically predisposed disease with unclear genetic mechanisms. This makes research on susceptibility genes important for the diagnosis and treatment options. Methods: This study included a five-member family affected by papillary thyroid carcinoma. The candidate genes were identified through whole-exome sequencing and Sanger sequencing in family members, other FNMTC patients, and sporadic non-medullary thyroid carcinoma patients. The pathogenicity of the mutation was predicted using in silico tools. Cell phenotype experiments in vitro and models of lung distant metastasis in vivo were conducted to confirm the characteristics of the mutation. Transcriptome sequencing and mechanistic validation were employed to compare the disparities between PAK4 wild-type (WT) and PAK4 mutant (MUT) cell lines. Results: This mutation alters the protein structure, potentially increasing instability by affecting hydrophobicity, intra-molecular hydrogen bonding, and phosphorylation sites. It specifically promotes phosphorylated PAK4 nuclear translocation and expression in thyroid tissue and cell lines. Compared with the WT cells line, PAK4 I417T demonstrates enhanced proliferation, invasiveness, accelerated cell division, and inhibition of cell apoptosis in vitro. In addition, it exhibits a significant propensity for metastasis in vivo. It activates tumor necrosis factor signaling through increased phosphorylation of PAK4, JNK, NFκB, and c-Jun, unlike the WT that activates it via the PAK4-NFκ-MMP9 axis. In addition, PAK4 MUT protein interacts with matrix metalloproteinase (MMP)3 and regulates MMP3 promoter activity, which is not observed in the WT. Conclusions: Our study identified PAK4: c.T1250C: p.I417T as a potential susceptibility gene for FNMTC. The study concludes that the mutant form of PAK4 exhibits oncogenic function, suggesting its potential as a novel diagnostic molecular marker for FNMTC.

Chromosomal localization of mutated genes in non-syndromic familial thyroid cancer.

Familial non-medullary thyroid carcinoma (FNMTC) is a type of thyroid cancer characterized by genetic susceptibility, representing approximately 5% of all non-medullary thyroid carcinomas. While some cases of FNMTC are associated with familial multi-organ tumor predisposition syndromes, the majority occur independently. The genetic mechanisms underlying non-syndromic FNMTC remain unclear. Initial studies utilized SNP linkage analysis to identify susceptibility loci, including the 1q21 locus, 2q21 locus, and 4q32 locus, among others. Subsequent research employed more advanced techniques such as Genome-wide Association Study and Whole Exome Sequencing, leading to the discovery of genes such as IMMP2L, GALNTL4, WDR11-AS1, DUOX2, NOP53, MAP2K5, and others. But FNMTC exhibits strong genetic heterogeneity, with each family having its own pathogenic genes. This is the first article to provide a chromosomal landscape map of susceptibility genes associated with non-syndromic FNMTC and analyze their potential associations. It also presents a detailed summary of variant loci, characteristics, research methodologies, and validation results from different countries.

The implications for potential marginal land resources of cassava across worldwide under climate change challenges.

The demand for energy plants is foreseen to grow as worldwide energy and climate policies promote the use of bioenergy for climate change mitigation. To avoid competing with food production, it's critical to assess future changes in marginal land availability for energy plant development. Using a machine learning method, boosted regression tree, this study modeled potential marginal land resources suitable for cassava under current and different climate change scenarios, based on cassava occurrence records and environmental covariates. The findings revealed that, currently, over 80% of the 1357.24 Mha of available marginal land for cassava cultivation is distributed in Africa and South America. Under three climate change scenarios, by 2030, worldwide suitable marginal land resources were predicted to grow by 39.71Mha, 66.21 Mha, and 39.31Mha for the RCP4.5, RCP6.0, and RCP8.5 scenarios, respectively; by 2050, the potential marginal land suitable for cassava will increase by 38.98Mha, 83.02 Mha, and 55.43Mha, respectively; by 2080, the global marginal land resources were estimated to rise by 40.82 Mha, 99.74 Mha, and 21.87 Mha from now, respectively. Our results highlight the impacts of climate change on potential marginal land resources of cassava across worldwide, which provide the basis for assessing bioenergy potential in the future.

Family history of malignant or benign thyroid tumors: implications for surgical procedure management and disease-free survival.

Background: Current guidelines lack a standardized management for patients with family history of thyroid carcinoma (fTC),particularly benign thyroid neoplasm (fBTN). Our objective was to investigate the influence of various family histories on the selection of surgical approaches and disease-free survival (DFS). Methods: A cohort study was conducted involving 2261 patients diagnosed with differentiated thyroid carcinoma including those with fTC (n=224), fBTN (n=122), and individuals without a family history of thyroid carcinoma (nfTC; n=1915). Clinicopathological characteristics were collected. DFS was estimated using Kaplan-Meier analysis and factors affecting DFS were identified using Cox proportional hazard model. Results: Compared to nfTC, small tumor size, clinically lymph node-positive, extrathyroidal extension, vascular invasion, Hashimoto's disease and nodular goiter were more common in fTC and fBTN groups. They had lower T stage and a lower rate of good response to TSH suppression therapy but received more radioiodine therapy. It is worth noting that fTC is associated with male, bilateral and multifocal tumors, as well as central lymph node metastasis and distant metastasis. Both fTC (aHR = 2.45, 95% CI=1.11-5.38; P = 0.03) and fBTN (aHR = 3.43, 95% CI=1.27-9.29; P = 0.02) were independent predictors of DFS in patients who underwent lobectomy, but not total thyroidectomy. For 1-4 cm thyroid carcinomas with clinically node-negative, fTC was identified as an independent predictor, whereas fBTN was not. Conclusion: Our findings indicate that a family history, particularly of malignancy, is associated with a more aggressive disease. Family history does not affect the prognosis of patients who undergo total thyroidectomy, but it may increase the risk of postoperative malignant events in those who have a lobectomy. Additionally, it may be necessary to monitor individuals with a family history of benign thyroid neoplasms.