Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy.

Alzheimer's disease (AD) is a sporadic or familial neurodegenerative disease of insidious onset with progressive cognitive decline. Although numerous studies have been conducted or are underway on AD, there are still no effective drugs to reverse the pathological features and clinical manifestations of AD. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. As a classical mechanistic target of rapamycin (mTOR) inhibitor, rapamycin has been shown to be beneficial in a variety of AD mouse and cells models, both before the onset of disease symptoms and the early stage of disease. Although many basic studies have demonstrated the therapeutic effects of rapamycin in AD, many questions and controversies remain. This may be due to the variability of experimental models, different modes of administration, dose, timing, frequency, and the availability of drug-targeting vehicles. Rapamycin may delay the development of AD by reducing ß-amyloid (Aß) deposition, inhibiting tau protein hyperphosphorylation, maintaining brain function in APOE ε4 gene carriers, clearing chronic inflammation, and improving cognitive dysfunction. It is thus expected to be one of the candidates for the treatment of Alzheimer's disease.

Genome-Wide Identification and Analysis of the WRKY Gene Family in Asparagus officinalis.

In recent years, the related research of the WRKY gene family has been gradually promoted, which is mainly reflected in the aspects of environmental stress and hormone response. However, to make the study of the WRKY gene family more complete, we also need to focus on the whole-genome analysis and identification of the family. In previous studies, the whole WRKY gene family of Arabidopsis, legumes and other plants has been thoroughly studied. However, since the publication of Asparagus officinalis genome-wide data, there has never been an analysis of the whole WRKY gene family. To understand more broadly the function of the WRKY gene family, the whole genome and salt stress transcriptome data of asparagus were used for comprehensive analysis in this study, including WRKY gene family identification, phylogenetic tree construction, analysis of conserved mods and gene domains, extraction of cis-acting elements, intron/exon analysis, species collinearity analysis, and WRKY expression analysis under salt stress. The results showed that a total of 70 genes were selected and randomly distributed on 10 chromosomes and one undefined chromosome. According to the functional classification of Arabidopsis thaliana, the WRKY family of asparagus was divided into 11 subgroups (C1-C9, U1, U2). It is worth considering that the distribution rules of gene-conserved motifs, gene domains and introns/exons in the same subfamily are similar, which suggests that genes in the same subfamily may regulate similar physiological processes. In this study, 11 cis-acting elements of WRKY family were selected, among which auxin, gibberellin, abscisic acid, salicylic acid and other hormone-regulated induction elements were involved. In addition, environmental stress (such as drought stress and low-temperature response) also accounted for a large proportion. Interestingly, we analyzed a total of two tandem duplicate genes and 13 segmental duplication genes, suggesting that this is related to the amplification of the WRKY gene family. Transcriptome data analysis showed that WRKY family genes could regulate plant growth and development by up-regulating and down-regulating gene expression under salt stress. Volcanic maps showed that 3 and 15 AoWRKY genes were significantly up-regulated or down-regulated in NI&NI+S and AMF&AMF+S, respectively. These results provide a new way to analyze the evolution and function of the WRKY gene family, and can provide a reference for the production and research of asparagus.

An interventional study of baicalin on neuronal pentraxin-1, neuronal pentraxin-2, and C-reactive protein in Alzheimer's disease rat model.

Background: Baicalin has been shown to promote spatial learning and neural regeneration, which might increase the differentiation of neural stem cells in Alzheimer's disease (AD) rat models. We aimed to study the role of baicalin on neuronal pentraxin-1 (NPTX-1), neuronal pentraxin-2 (NPTX-2), and C-reactive protein (CRP) in AD model rats. Methods: The 30 male Sprague Dawley rats were divided into three groups: the control group, the AD model group, and the AD + baicalin group. Then, the Morris water maze was used to verify the effect of baicalin on the memory and spatial learning of rats. Immunohistochemistry and immunofluorescence were used to observe the expression of NPTX-1, NPTX-2, and CRP in brain tissue. Results: Compared with the AD model group, the AD rats treated with baicalin spent significantly less time finding escape latencies (P = 0.008) and had longer cross-platform times in the target quadrant (P = 0.015). In addition, the AD + baicalin group had significantly higher numbers of hippocampal neurons compared with the AD model group (P < 0.05). Baicalin also obviously decreased the apoptosis of neurons. Moreover, compared with the AD model group, the NPTX-1 and CRP expression in the AD + baicalin group was significantly reduced (P = 0.000) while the expression of NPTX-2 in the brain tissue of AD rats was significantly increased (P = 0.000). Conclusions: Baicalin can play a therapeutic role by downregulating NPTX-1, upregulating NPTX-2, and downregulating CPR in AD model rats.

Genetic evidence supporting a causal role of Janus kinase 2 in prostate cancer: a Mendelian randomization study.

BACKGROUND: Janus kinase-2 (JAK2) inhibitors are now being tried in basic research and clinical practice in prostate cancer (PCa). However, the causal relationship between JAK2 and PCa has not been uniformly described. Here, we examined the cause-effect relation between JAK2 and PCa. METHODS: Two-sample Mendelian randomization (MR) analysis of genetic variation data of JAK2, PCa from IEU OpenGWAS Project was performed by inverse variance weighted, MR-Egger, and weighted median. Cochran's Q heterogeneity test and MR-Egger multiplicity analysis were performed to normalize the MR analysis results to reduce the effect of bias on the results. RESULTS: Five instrumental variables were identified for further MR analysis. Specifically, combining the inverse variance-weighted (OR: 1.0009, 95% CI: 1.0001-1.0015, p = 0.02) and weighted median (OR: 1.0009, 95% CI: 1.0000-1.0017, p = 0.03). Sensitivity analysis showed that there was no heterogeneity (p = 0.448) and horizontal multiplicity (p = 0.770) among the instrumental variables. CONCLUSIONS: We found JAK2 was associated with the development of PCa and was a risk factor for PCa, which might be instructive for the use of JAK2 inhibitors in PCa patients.

Causal Association Between mTOR-Dependent Protein Levels and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. OBJECTIVE: This study aims to investigate the causal effects of the mTOR signaling targets on AD. METHODS: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. RESULTS: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). CONCLUSION: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.

Non-pharmacological and nonsurgical interventions in male urinary incontinence: A scoping review.

AIMS: To describe and synthesize non-pharmacological and nonsurgical interventions for male urinary incontinence from the existing literature. METHODS: A scoping review was conducted following the methodology suggested by Arksey and O'Malley: (1) identification of the research questions; (2) identification of relevant studies using a three-step search recommended by JBI: an initial search within PubMed and CINAHL, a comprehensive literature search within PubMed, CINAHL, EMBASE, PsycINFO, Cochrane Library, and literature search of references lists; (3) study selection; (4) data extraction and charting; (5) collation, summarization, and reporting of the results. The PRISMA-ScR Checklist was used to report. RESULTS: A total of 4602 studies were identified, of which 87 studies were included. Approximately 78% were randomized controlled trials. More than 88% of the participants were men with prostate cancer. Exercising pelvic floor muscles 30 times per day for 12 weeks was the most frequently reported. Parameters of electrical stimulation were typically set up to 50 Hz and 300 µs for frequency and width of pulse, respectively, and lasted for 15 min. Pure pelvic floor muscle training, Pilates, Yoga, whole body vibration, diaphragm/abdominal muscle training, micturition interruption exercise, acupuncture, and auriculotherapy showed positive effects on reducing urinary incontinence. CONCLUSION: The findings suggested implementing pelvic floor muscle training alone before or after surgery can both prompt the recovery of continence in men after prostate cancer surgery. The decision to use biofeedback or electrical stimulation to enhance the therapeutic effect of pelvic floor muscle training should be approached with caution. More rigorous designed studies are needed to validate the effectiveness of Traditional Chinese Medicine techniques and diverse novel methods. RELEVANCE TO CLINICAL PRACTICE: Physicians and nurses need to be up to date on the latest evidence-based non-pharmacological and nonsurgical interventions in male urinary incontinence and select appropriate interventions based on available medical resources and patient preferences.

Genome-Wide Identification and Analysis of the R2R3-MYB Gene Family in Theobroma cacao.

The MYB gene family is involved in the regulation of plant growth, development and stress responses. In this paper, to identify Theobroma cacao R2R3-MYB (TcMYB) genes involved in environmental stress and phytohormones, we conducted a genome-wide analysis of the R2R3-MYB gene family in Theobroma cacao (cacao). A total of 116 TcMYB genes were identified, and they were divided into 23 subgroups according to the phylogenetic analysis. Meanwhile, the conserved motifs, gene structures and cis-acting elements of promoters were analyzed. Moreover, these TcMYB genes were distributed on 10 chromosomes. We conducted a synteny analysis to understand the evolution of the cacao R2R3-MYB gene family. A total of 37 gene pairs of TcMYB genes were identified through tandem or segmental duplication events. Additionally, we also predicted the subcellular localization and physicochemical properties. All the studies showed that TcMYB genes have multiple functions, including responding to environmental stresses. The results provide an understanding of R2R3-MYB in Theobroma cacao and lay the foundation for a further functional analysis of TcMYB genes in the growth of cacao.

Genome-Wide Identification and Analysis of the GRAS Transcription Factor Gene Family in Theobroma cacao.

GRAS genes exist widely and play vital roles in various physiological processes in plants. In this study, to identify Theobroma cacao (T. cacao) GRAS genes involved in environmental stress and phytohormones, we conducted a genome-wide analysis of the GRAS gene family in T. cacao. A total of 46 GRAS genes of T. cacao were identified. Chromosomal distribution analysis showed that all the TcGRAS genes were evenly distributed on ten chromosomes. Phylogenetic relationships revealed that GRAS proteins could be divided into twelve subfamilies (HAM: 6, LISCL: 10, LAS: 1, SCL4/7: 1, SCR: 4, DLT: 1, SCL3: 3, DELLA: 4, SHR: 5, PAT1: 6, UN1: 1, UN2: 4). Of the T. cacao GRAS genes, all contained the GRAS domain or GRAS superfamily domain. Subcellular localization analysis predicted that TcGRAS proteins were located in the nucleus, chloroplast, and endomembrane system. Gene duplication analysis showed that there were two pairs of tandem repeats and six pairs of fragment duplications, which may account for the rapid expansion in T. cacao. In addition, we also predicted the physicochemical properties and cis-acting elements. The analysis of GO annotation predicted that the TcGRAS genes were involved in many biological processes. This study highlights the evolution, diversity, and characterization of the GRAS genes in T. cacao and provides the first comprehensive analysis of this gene family in the cacao genome.

Genome-Wide Identification and Analysis of the MADS-Box Gene Family in Theobroma cacao.

The MADS-box family gene is a class of transcription factors that have been extensively studied and involved in several plant growth and development processes, especially in floral organ specificity, flowering time and initiation and fruit development. In this study, we identified 69 candidate MADS-box genes and clustered these genes into five subgroups (Mα: 11; Mß: 2; Mγ: 14; Mδ: 9; MIKC: 32) based on their phylogenetical relationships with Arabidopsis. Most TcMADS genes within the same subgroup showed a similar gene structure and highly conserved motifs. Chromosomal distribution analysis revealed that all the TcMADS genes were evenly distributed in 10 chromosomes. Additionally, the cis-acting elements of promoter, physicochemical properties and subcellular localization were also analyzed. This study provides a comprehensive analysis of MADS-box genes in Theobroma cacao and lays the foundation for further functional research.

Genome-Wide Analysis of the NAC Domain Transcription Factor Gene Family in Theobroma cacao.

As a plant-specific transcription factor, the NAC (NAM, ATAF1/2 and CUC2) domain protein plays an important role in plant growth and development, as well as stress resistance. Based on the genomic data of the cacao tree, this study identified 102 cacao NAC genes and named them according to their location within the genome. The phylogeny of the protein sequence of the cacao tree NAC family was analyzed using various bioinformatic methods, and then divided into 12 subfamilies. Then, the amino-acid composition, physicochemical properties, genomic location, gene structure, conserved domains, and promoter cis-acting elements were analyzed. This study provides information on the evolution of the TcNAC gene and its possible functions, laying the foundation for further research on the NAC family.

How long should the fully hillside-closed forest protection be implemented on the Loess Plateau, Shaanxi, China?

BACKGROUND: Restoration of degraded forest ecosystem is crucial for regional sustainable development. To protect the country's fragile and fragmented environment, the Chinese government initiated an ecological engineering project, the Natural Forest Protection Program, in seventeen provinces in China beginning in 1998. Fully hillside-closed forest protection (vegetation restoration naturally without any artificial disturbance) was one of vital measures of the Natural Forest Protection Program applied nation wide. Whether plant diversity, biomass and age structure of dominant tree species and soil nutrients in protected stands may become better with increase of protected period are still open problems. METHODS: We investigated community diversity, biomass of dominant tree species, age structures, and analyzed soil chemical properties of a Pinus tabulaeformis population at protected sites representing different protected ages at Huanglongshan Forest Bureau on the Loess Plateau, Shaanxi, China. RESULTS: Plant species richness of Pinus tabulaeformis community was significantly affected (p < 0.05) by forest protection and the effect attenuated with protection age. Shannon evenness index of plant species generally increased with protection age. Stands protected for 45 years had the highest tree biomass and considerable natural regeneration capacity. Contents of organic carbon, available phosphorus and available potassium in top soil increased in protected stands less than 45 years, however decreased significantly thereafter. Long-term forest protection also decreased the content of mineral nitrogen in top soil. DISCUSSION: We found that the richness of shrubs and herbs was significantly affected by forest protection, and evenness indices of tree, shrub and herb increased inconsistently with protected ages. Forest protection created more complex age structures and tree densities with increasing age of protection. Content of soil mineral nitrogen at 0-20 cm soil depth showed a decreasing trend in stands of up to 30 years. Soil available phosphorus and potassium contents were higher in stands with greater proportions of big and medium trees. Long-term protection (>45 years) of Pinus tabulaeformis stands in southeast Loess Plateau, China, may be associated with decreasing plant species richness, proportion of medium to large trees, dominant biomass of Pinus tabulaeformis and soil nutrients.