Improving knockoffs with conditional calibration

The knockoff filter of Barber and Candes (arXiv:1404.5609) is a flexible framework for multiple testing in supervised learning models, based on introducing synthetic predictor variables to control the false discovery rate (FDR). Using the conditional calibration framework of Fithian and Lei (arXiv:2007.10438), we introduce the calibrated knockoff procedure, a method that uniformly improves the power of any knockoff procedure. We implement our method for fixed-X knockoffs and show theoretically and empirically that the improvement is especially notable in two contexts where knockoff methods can be nearly powerless: when the rejection set is small, and when the structure of the design matrix prevents us from constructing good knockoff variables. In these contexts, calibrated knockoffs even outperform competing FDR-controlling methods like the (dependence-adjusted) Benjamini-Hochberg procedure in many scenarios.Comment: 52 pages, 19 figure

Expression and clinical significance of multidrug resistance proteins in brain tumors

<p>Abstract</p> <p>Background</p> <p>To investigate the mechanisms of multidrug resistance of brain tumors, to identify the site of cellular expression of P-gp in human brains in situ and to morphologically determine whether an association may exist between P-gp and caveolin-1.</p> <p>Methods</p> <p>Immunohistochemistry was used to detect the expression and location of P-glycoprotein (P-gp), Multidrug resistance-associated protein (MDR), Lung resistance-related protein (LRP), Topoisomerase II (Topo II) and Glutathione-S-π (GST-π) in 30 patient tumor tissues and 5 normal brain tissues. The sections were subjected to double labeling for P-gp (TRITC labeled) and caveolin-1 (FITC labeled). The location and characteristics of expression of the two proteins in the blood brain barrier(BBB) was observed using a laser scanning microscope.</p> <p>Results</p> <p>High expression of P-gp was detected in vessel walls and the tissue surrounding the vessels. However, expression of P-gp was low in tumor cells. The expression of the other 4 multidrug resistance proteins was not observed in the vessel walls. Laser scanning microscopy showed P-gp and caveolin-1 co-expression: the two proteins co-localized either in the luminal endothelial compartment or at the border of the luminal/abluminal compartments.</p> <p>Conclusion</p> <p>Chemotherapeutics drugs are interrupted in the end-feet of neuroepithelial cells of the BBB by P-gp, which weakens the chemotherapeutic effect. P-gp marks the BBB, and the transporter is localized in the luminal endothelial compartment where it co-localizes with caveolin-1.</p

MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition.

The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOF depletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression

High-fiber-diet-related metabolites improve neurodegenerative symptoms in patients with obesity with diabetes mellitus by modulating the hippocampal–hypothalamic endocrine axis

ObjectiveThrough transcriptomic and metabolomic analyses, this study examined the role of high-fiber diet in obesity complicated by diabetes and neurodegenerative symptoms.MethodThe expression matrix of high-fiber-diet-related metabolites, blood methylation profile associated with pre-symptomatic dementia in elderly patients with type 2 diabetes mellitus (T2DM), and high-throughput single-cell sequencing data of hippocampal samples from patients with Alzheimer's disease (AD) were retrieved from the Gene Expression Omnibus (GEO) database and through a literature search. Data were analyzed using principal component analysis (PCA) after quality control and data filtering to identify different cell clusters and candidate markers. A protein–protein interaction network was mapped using the STRING database. To further investigate the interaction among high-fiber-diet-related metabolites, methylation-related DEGs related to T2DM, and single-cell marker genes related to AD, AutoDock was used for semi-flexible molecular docking.ResultBased on GEO database data and previous studies, 24 marker genes associated with high-fiber diet, T2DM, and AD were identified. Top 10 core genes include SYNE1, ANK2, SPEG, PDZD2, KALRN, PTPRM, PTPRK, BIN1, DOCK9, and NPNT, and their functions are primarily related to autophagy. According to molecular docking analysis, acetamidobenzoic acid, the most substantially altered metabolic marker associated with a high-fiber diet, had the strongest binding affinity for SPEG.ConclusionBy targeting the SPEG protein in the hippocampus, acetamidobenzoic acid, a metabolite associated with high-fiber diet, may improve diabetic and neurodegenerative diseases in obese people

Auxin response factor 6A regulates photosynthesis, sugar accumulation, and fruit development in tomato.

Auxin response factors (ARFs) are involved in auxin-mediated transcriptional regulation in plants. In this study, we performed functional characterization of SlARF6A in tomato. SlARF6A is located in the nucleus and exhibits transcriptional activator activity. Overexpression of SlARF6A increased chlorophyll contents in the fruits and leaves of tomato plants, whereas downregulation of SlARF6A decreased chlorophyll contents compared with those of wild-type (WT) plants. Analysis of chloroplasts using transmission electron microscopy indicated increased sizes of chloroplasts in SlARF6A-overexpressing plants and decreased numbers of chloroplasts in SlARF6A-downregulated plants. Overexpression of SlARF6A increased the photosynthesis rate and accumulation of starch and soluble sugars, whereas knockdown of SlARF6A resulted in opposite phenotypes in tomato leaves and fruits. RNA-sequence analysis showed that regulation of SlARF6A expression altered the expression of genes involved in chlorophyll metabolism, photosynthesis and sugar metabolism. SlARF6A directly bound to the promoters of SlGLK1, CAB, and RbcS genes and positively regulated the expression of these genes. Overexpression of SlARF6A also inhibited fruit ripening and ethylene production, whereas downregulation of SlARF6A increased fruit ripening and ethylene production. SlARF6A directly bound to the SAMS1 promoter and negatively regulated SAMS1 expression. Taken together, these results expand our understanding of ARFs with regard to photosynthesis, sugar accumulation and fruit development and provide a potential target for genetic engineering to improve fruit nutrition in horticulture crops

Evaluation of anti-fatigue property of Porphyridium cruentum in mice

Purpose: To evaluate the potential effects of Porphyridium cruentum (PC) on fatigue induced by forced swimming test in mice. Methods: Mice were randomly divided into normal control group (NC, i.e., untreated non-swimming); model control group (MC, untreated swimming); Spirulina treated group (SP, 800 mg/kg); PC-treated groups (50, 100, and 200 mg/kg), respectively. After intragastric administration for 14 consecutive days, a weight-bearing swimming experiment was conducted for the mice, and the biochemical indicators related to fatigue were examined, including exhaustive swimming time, glucose levels (Glu), hepatic glycogen contents (HG), muscle glycogen contents (MG), glutathione peroxidase activities (GSH-Px), creatine kinase (CK), malondialdehyde (MDA), urea nitrogen levels (SUN), lactate dehydrogenase activities (LDH), lactic acid (LA) as well as superoxide dismutase (SOD). Results: PC significantly prolonged the swimming endurance time compared to MC. After PC treatment, Glu, HG and MG were effectively increased dose-dependently, SUN, LA, LDH and CK levels in serum were significantly reduced. Moreover, PC treatment elevated the bioactivities of two antioxidant enzymes, namely, GSH-Px and SOD, while MDA content decreased when compared to MC group. Conclusion: These results indicate that PC exhibits strong anti-fatigue effect. Thus, PC may be suitable for incorporation in functional food to counter fatigue

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study.Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn’s disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran’s Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction.Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66–0.89, and p = 3.66 × 10−4), SS (OR: 0.75, CI: 0.58–0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68–0.88, and p = 9.85 × 10−5), hypothyroidism (OR: 0.84, 95% CI: 0.78–0.91, and p = 7,08 × 10−6), hyperthyroidism (OR: 0.60, 95% CI: 0.44–0.83, and p = 1.90 × 10−3), sarcoidosis (OR: 0.67, 95% CI: 0.54–0.83, and p = 2.60 × 10−4), and IPF (OR: 0.41, 95% CI: 0.29–0.58, and p = 4.11 × 10−7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18–1.94, and p = 9.66 × 10−4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62–1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37–2.54, and p = 8.01 × 10−5).Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs