Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

A pair of readers of bivalent chromatin mediate formation of Polycomb-based "memory of cold" in plants.

The Polycomb-group chromatin modifiers play important roles to repress or switch off gene expression in plants and animals. How the active chromatin state is switched to a Polycomb-repressed state is unclear. In Arabidopsis, prolonged cold induces the switching of the highly active chromatin state at the potent floral repressor FLC to a Polycomb-repressed state, which is epigenetically maintained when temperature rises to confer "cold memory," enabling plants to flower in spring. We report that the cis-acting cold memory element (CME) region at FLC bears bivalent marks of active histone H3K4me3 and repressive H3K27me3 that are read and interpreted by an assembly of bivalent chromatin readers to drive cold-induced switching of the FLC chromatin state. In response to cold, the 47-bp CME and its associated bivalent chromatin feature drive the switching of active chromatin state at a recombinant gene to a Polycomb-repressed domain, conferring cold memory. We reveal a paradigm for environment-induced chromatin-state switching at bivalent loci in plants.

Flowering repressor CmSVP recruits the TOPLESS corepressor to control flowering in chrysanthemum.

Plant flowering time is induced by environmental and endogenous signals perceived by the plant. The MCM1-AGAMOUSDEFICIENS-Serum Response Factor-box (MADS-box) protein SHORT VEGETATIVE PHASE (SVP) is a pivotal repressor that negatively regulates the floral transition during the vegetative phase; however, the transcriptional regulatory mechanism remains poorly understood. Here, we report that CmSVP, a chrysanthemum (Chrysanthemum morifolium Ramat.) homolog of SVP, can repress the expression of a key flowering gene, a chrysanthemum FLOWERING LOCUS T-like gene (CmFTL3), by binding its promoter CArG element to delay flowering in the ambient temperature pathway in chrysanthemum. Protein-protein interaction assays identified an interaction between CmSVP and CmTPL1-2, a chrysanthemum homologue of TOPLESS (TPL) that plays critical roles as transcriptional corepressor in many aspects of plant life. Genetic analyses revealed the CmSVP-CmTPL1-2 transcriptional complex is a prerequisite for CmSVP to act as a floral repressor. Furthermore, overexpression of CmSVP rescued the phenotype of the svp-31 mutant in Arabidopsis (Arabidopsis thaliana), overexpression of AtSVP or CmSVP in the Arabidopsis dominant-negative mutation tpl-1 led to ineffective late flowering, and AtSVP interacted with AtTPL, confirming the conserved function of SVP in chrysanthemum and Arabidopsis. We have validated a conserved machinery wherein SVP partially relies on TPL to inhibit flowering via a thermosensory pathway.

Multimodal contrastive representation learning for drug-target binding affinity prediction.

In the biomedical field, the efficacy of most drugs is demonstrated by their interactions with targets, meanwhile, accurate prediction of the strength of drug-target binding is extremely important for drug development efforts. Traditional bioassay-based drug-target binding affinity (DTA) prediction methods cannot meet the needs of drug R&D in the era of big data. Recent years we have witnessed significant success on deep learning-based models for drug-target binding affinity prediction task. However, these models only considered a single modality of drug and target information, and some valuable information was not fully utilized. In fact, the information of different modalities of drug and target can complement each other, and more valuable information can be obtained by fusing the information of different modalities. In this paper, we introduce a multimodal information fusion model for DTA prediction that is called FMDTA, which fully considers drug/target information in both string and graph modalities and balances the feature representations of different modalities by a contrastive learning approach. In addition, we exploited the alignment information of drug atoms and target residues to capture the positional information of string patterns, which can extract more useful feature information in SMILES and target sequences. Experimental results on two benchmark datasets show that FMDTA outperforms the state-of-the-art model, demonstrating the feasibility and excellent feature capture capability of FMDTA. The code of FMDTA and the data are available at: https://github.com/bestdoubleLin/FMDTA.

Object phase-valid region segmentation method for FPP-based three-dimensional measurement.

In most existing studies based on fringe projector profilometry (FPP), the whole scenario is reconstructed, or the ideal experimental settings are established to segment the object easily. However, in real industrial scenarios, automated object detection and segmentation are essential to perform object-level measurement. To address the problem, a dual-wavelet feature interaction network (DWFI-Net) is developed in this paper to perform object phase-valid region segmentation, where both the background and shadow are removed. In our work, the modulation and wrapped phase maps are considered as inputs innovatively. The modulation maps provide abundant structures and textures, while the wrapped phase maps complement and enhance shadows and edges. An adaptive wavelet feature interaction (AWFI) module is presented to learn and fuse the features, where discrete wavelet transformation (DWT) is applied to decompose the features. An edge-aware discrete cosine transformation (EDCT) module is developed as a decoder, where the discrete cosine transformation (DCT) is applied to interpret the fused features. Qualitative and quantitative experiments are performed to verify the superiority of our DWFI-Net and its effectiveness on object-level three-dimensional measurement based on FPP.

Comparison of Easydo Activator, ultrasonic and needle irrigation techniques on sealer penetration and smear layer removal in vitro.

The effects of Easydo Activator (EA), a new sonic irrigation system, on sealer penetration at the root apex were compared to needle irrigation (NI) and passive ultrasonic irrigation (PUI) in this study. Forty-two single-rooted teeth were prepared and randomly divided into three groups (n = 14): group 1: NI; group 2: PUI; and group 3: EA. A solution of 3% sodium hypochlorite (NaOCl) was used for irrigation. Nine teeth in each group were filled with AH Plus sealer mixed with CY5 fluorescent dye and a single gutta-percha cone. The sealer penetration area, maximum penetration depth and percentage of sealer penetration at 5 mm and 1 mm from the apex were analyzed by confocal laser scanning microscopy (CLSM). The remaining 5 teeth in each group were subjected to test smear layer scores by scanning electron microscopy (SEM). The CLSM evaluation showed that increases in the area, depth and percentage of sealer penetration were detected at 1 and 5 mm from the root apex in the PUI group compared with the NI group, and greater increases were observed in the EA group (P < 0.05). The SEM experiment showed that the lowest scores for the smear layer and debris removal were achieved by the EA group when compared with the PUI and NI groups (P < 0.05). In conclusion, EA was superior to PUI and NI regarding sealer penetration at the root apex during endodontic treatment, and it could provide a new technical idea for clinical root canal therapy.

The Cm14-3-3µ protein and CCT transcription factor CmNRRa delay flowering in chrysanthemum.

The floral transition from vegetative to reproductive growth is pivotal in the plant life cycle. NUTRITION RESPONSE AND ROOT GROWTH (OsNRRa), as a CONSTANS, CONSTANS-LIKE, TOC1 (CCT) domain protein, delays flowering in rice, and an orthologous protein, CmNRRa, inhibits flowering in chrysanthemum; however, the underlying mechanism remains unknown. In this study, using yeast two-hybrid screening, we identified the 14-3-3 protein family member Cm14-3-3µ as a CmNRRa-interacting protein. A combination of bimolecular fluorescence complementation, pull-down, and co-immunoprecipitation assays was performed to confirm the physical interaction between CmNRRa and Cm14-3-3µ. In addition, expression analysis showed that CmNRRa but not Cm14-3-3µ responded to the diurnal rhythm, whereas both genes were highly expressed in leaves. Moreover, the function of Cm14-3-3µ in flowering time regulation was similar to that of CmNRRa. Furthermore, CmNRRa repressed chrysanthemum FLOWERING LOCUS T-like 3 (CmFTL3) and an APETALA 1 (AP1)/FRUITFULL (FUL)-like gene (CmAFL1) but induced TERMINAL FLOWER1 (CmTFL1) directly by binding to their promoters. Cm14-3-3µ enhanced the ability of CmNRRa to regulate the expression of these genes. These findings suggest that there is a synergistic relationship between CmNRRa and Cm14-3-3µ in flowering repression in chrysanthemum.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Transcriptomic and physiological analysis of the effect of octanoic acid on Meloidogyne incognita.

Root knot nematodes are the most devastating root pathogens, causing severe damage and serious economic losses to agriculture worldwide. Octanoic acid has been reported as one of the nematicides, and its mode of action is not fully understood. The main objective of this study was to elucidate the effect of octanoic acid on Meloidogyne incognita by transcriptomic analysis combined with physiological and biochemical assays. In the toxicity assays with octanoic acid, the threshold concentration with nematicidal activity and the maximum concentration to which nematodes could respond were 0.03 µL/mL and 0.08 µL/mL respectively. Microscopic observation combined with protein and carbohydrates assays confirmed that the structure of the second-stage juveniles (J2s) was severely disrupted after 72 h of immersion in octanoic acid. Transcriptome analysis has shown that octanoic acid can interfere with the nematode energy metabolism, lifespan and signaling. Although the effects are multifaceted, the findings strongly point to the cuticle, lysosomes, and extracellular regions and spaces as the primary targets for octanoic acid. In addition, nematodes can withstand the negative effects of low concentration of octanoic acid to some extent by up-regulating the defense enzyme system and heterologous metabolic pathways. These findings will help us to explore the nematicidal mechanism of octanoic acid and provide important target genes for the development of new nematicides in the future.

A Cadaveric Limb Analysis of the Posterior Tibial Musculotendinous Junction to determine the feasibility of Interosseous Membrane Tendon Transfer.

The transfer of the posterior tibial tendon through the interosseous membrane is potentially an effective treatment to correct the deformity of the foot and ankle. Our study aimed to evaluate the anatomical feasibility of anterior transfer of the posterior tibial tendon through the interosseous membrane route using the musculotendinous junction (MTJ). Eighteen adult cadavers were used. The width and thickness of the tibial posterior MTJ, width of the interosseous membrane at the corresponding level, and the window size of the interosseous membrane were measured. Additionally, the distance between the distal end of the MTJ and the tip of the medial malleolus were recorded. The mean length of the posterior tibial tendon was 83.60 mm, the mean distance of the posterior tibial MTJ to medial malleolus tip was 45.48 mm and the mean length of MTJ was 31.74 mm. The mean width of distal end of MTJ was 7.76 mm, thickness of distal end of MTJ was 4.07 mm and the mean width of the interosseous membrane at the distal end of MTJ was 4.76 mm. We found the mean width of the proximal end of MTJ was 20.68 mm, the mean thickness of proximal end of MTJ was 5.52 mm, and mean width of interosseous membrane at the proximal end of MTJ was 8.76 mm. Our study has demonstrated that a 31 mm length incision made at approximately 45 mm from the proximal end of the medial malleolus can safely reach the MTJ. We recommend an opening length of the interosseous membrane of at least 20 mm.

The subcortical maternal complex protein Nlrp4f is involved in cytoplasmic lattice formation and organelle distribution.

In mammalian oocytes and embryos, the subcortical maternal complex (SCMC) and cytoplasmic lattices (CPLs) are two closely related structures. Their detailed compositions and functions remain largely unclear. Here, we characterize Nlrp4f as a novel component associated with the SCMC and CPLs. Disruption of maternal Nlrp4f leads to decreased fecundity and delayed preimplantation development in the mouse. Lack of Nlrp4f affects organelle distribution in mouse oocytes and early embryos. Depletion of Nlrp4f disrupts CPL formation but does not affect the interactions of other SCMC proteins. Interestingly, the loss of Khdc3 or Tle6, two other SCMC proteins, also disrupts CPL formation in mouse oocytes. Thus, the absence of CPLs and aberrant distribution of organelles in the oocytes caused by disruption of the examined SCMC genes, including previously reported Zbed3, Nlrp5, Ooep and Padi6, indicate that the SCMC is required for CPL formation and organelle distribution. Consistent with the role of the SCMC in CPL formation, the SCMC forms before CPLs during mouse oogenesis. Together, our results suggest that the SCMC protein Nlrp4f is involved in CPL formation and organelle distribution in mouse oocytes.

KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma.

BACKGROUND: While the correlation between PD-L1 expression and KRAS mutation has been previously reported in other solid tumors such as non-small cell lung cancer (NSCLC), whether PD-L1 can be modulated by ERK signaling downstream of KRAS in intrahepatic cholangiocarcinoma (iCCA) and the underlying molecular regulatory mechanism remain unclear. METHODS: The expression of ERK, p-ERK, PD-L1 and autophagy markers following KRAS knockdown or Ras/Raf/MEK/ERK signaling inhibitors treatment was examined in two human iCCA cell lines (HuCCT1 and RBE) using western blotting and immunofluorescence. Both pharmacological autophagy inhibitors and short-interfering RNA against ATG7 were applied to inhibit autophagy. The apoptosis rates of iCCA cell lines were detected by flow cytometry and CCK-8 after co-culturing with CD3/CD28-activated human CD8+ T lymphocytes. Immunohistochemistry was applied to detect the correlation of ERK, p-ERK and PD-L1 in 92 iCCA tissues. RESULTS: The present study demonstrated that the PD-L1 expression level was distinctly reduced in KRAS-mutated iCCA cell lines when ERK signaling was inhibited and ERK phosphorylation levels were lowered. The positive association between p-ERK and PD-L1 was also verified in 92 iCCA tissue samples. Moreover, ERK inhibition induced autophagy activation. Both inhibiting autophagy via autophagy inhibitors and genetically silencing the ATG7 expression partially reversed the reduced PD-L1 expression caused by ERK inhibition. In addition, ERK-mediated down-regulation of PD-L1 via autophagy pathways induced the apoptosis of iCCA cells when co-cultured with CD3/CD28-activated human CD8+ T lymphocytes in vitro. CONCLUSIONS: Our results suggest that ERK signaling inhibition contributes to the reduction of PD-L1 expression through the autophagy pathway in iCCA. As a supplement to anti-PD-1/PD-L1 immunotherapy, ERK-targeted therapy may serve as a potentially novel treatment strategy for human KRAS-mutated iCCA.

Aestuarium zhoushanense is a later heterotypic synonym of Marivivens donghaensis, and transfer of Paradonghicola geojensis to the genus Marivivens as Marivivens geojensis comb. nov.

The 16S rRNA genes of Aestuarium zhoushanense G7T and Paradonghicola geojensis FJ12T shared 100 % sequence identity with Marivivens donghaensis AM-4T. Phylogeny of 16S rRNA gene sequences showed that the three type strains formed a monophyletic clade within the genus Marivivens. Whole genome sequence comparisons showed that three type strains shared 46.7-69.7 % digital DNA-DNA hybridization, 92.1-96.4 % average nucleotide identity and 96.2-98.1 % average amino acid identity. The high 16S rRNA gene similarity values show that three type strains should belong to the same genus. The pan-genome of the five strains contained 5754 genes including 1877 core genes. Based on the principle of priority, we propose that A. zhoushanense Yu et al. 2019 is a later heterotypic synonym of M. donghaensis Park et al. 2016, and P. geojensis should be reclassified as Marivivens geojensis comb. nov., respectively.

Optimization of endometrial cancer organoids establishment by cancer-associated fibroblasts.

Most endometrial cancers (EC) are diagnosed at an early stage with a favorable prognosis. However, for patients with advanced or recurrent disease, the chemotherapy response rate and overall survival remain poor. A novel in vitro model, tumor organoids, has important value in providing a more individualized treatment plan for tumor patients. However, the slow growth of the established EC organoid seriously hinders the application of EC organoids. Cancer-associated fibroblasts (CAFs), the main component of tumor stroma, have been reported to promote the proliferation of endometrial cancer cell lines and primary endometrial cancer cells in vivo and in vitro. Therefore, we optimized the current endometrial cancer organoid by introducing CAFs isolated from EC lesions. Here we developed long-term expandable organoids from endometrial cancer lesions, which show disease-associated traits and cancer-linked mutations. Based on the co-culture of CAFs and endometrial cancer organoids, we found that CAFs could promote the growth of endometrial cancer organoids, might by secreting factors according to the result that CAFs could also promote the growth. Our research provided a more promising model for the basic and preclinical study of endometrial cancer.

Design and fabrication of reusable core-shell composite microspheres based on nanodiamond for selective enrichment of phosphopeptides.

A kind of core-shell composite microsphere (CM) with nano-on-micro structure was synthesized via grafting amine-modified nanodiamonds onto the surface of monodisperse nonporous polymeric microsphere. In this way, the agglomeration of nanodiamond particles in the solution was avoided. After modification with pyrogallol groups, CM could chelate titanium ions (Ti4+) and thus be utilized as immobilized metal affinity chromatography (IMAC) sorbent to enrich phosphopeptides from biological samples. The resulting Ti4+-CM exhibited high enrichment efficiency and specificity to phosphopeptides. A total of 106 of unique phosphopeptides mapped to 29 phosphoproteins were clearly identified from 5 µL of a milk digest after enrichment. Owing to the strong chelation between Ti4+ and pyrogallol ligands, the Ti4+ is not released from the sorbent after completion of the enrichment process. As a result, the Ti4+-CM sorbent could be reused, and no significant loss of enrichment efficiency occurred even on the fourth run employing a ß-casein digest as the sample. The strategy adopted presents a new way to prepare a high-performance reusable IMAC sorbent.

Role of NOD2 and hepcidin in inflammatory periapical periodontitis.

The immunological response occurring during periapical inflammation includes expression of nucleotide binding oligomerization domain containing 2 and hepcidin. Nucleotide binding oligomerization domain containing 2 deficiency increases infiltration of inflammatory cells close to alveolar bone. Hepcidin has an important role in iron metabolism affecting bone metabolism.We investigated the role of nucleotide binding oligomerization domain containing 2 and hepcidin in inflammatory periapical periodontitis. Periapical periodontitis was induced in rats and confirmed by micro-computed tomography. Nucleotide binding oligomerization domain 2 and hepcidin were evaluated through immunohistochemistry. Bioinformatics analysis was undertaken usingthe Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases. Micro-computer tomography revealed alveolar bone resorption in the periapical region and furcation area of mandibular molars in rats of the periapical periodontitis group. Immunohistochemistry showed increased expressionof nucleotide binding oligomerization domain containing 2 and hepcidin around root apices in rats of the periapical periodontitis group. Bioinformatics analysis of differentially expressed genes in inflamed and non-inflamed tissues revealed enrichment in the NOD-like receptor signaling pathway. Our data suggest that nucleotide binding oligomization domain contain2 and hepcidin have important roles in periapical periodontitis severity because they can reduce alveolar bone loss.They could elicit new perspectives for development of novel strategies for periapical periodontitis treatment.

The Chinese version of the Oral Health Impact Profile-14 (OHIP-14) questionnaire among college students: factor structure and measurement invariance across genders.

BACKGROUND: The Oral Health-related Quality of Life (OHRQoL) is a multi-dimensional concept commonly used to examine the impact of health status on quality of life, and the Oral Health Impact Profile-14 (OHIP-14) questionnaire is a good self-assessment tool. This study was designed to investigate the factor structure of the OHIP-14 scale Chinese version, measurement invariance and latent mean differences across genders among college students. METHODS: The online survey was completed by 919 college students. This study used confirmatory factor analysis (CFA) to check the structural models of the OHIP-14 scale, The correlation of each item with the scale total score could test homogeneity, and Cronbach's alpha (Cronbach's α) could evaluate internal consistency. Multi-group CFA was used to explore whether the Chinese version of the OHIP-14 scale was used in male and female populations for measurement consistency. T-test compared scores between men and women. Regression analyses were used to evaluate the relationship between age, gender, education, subject, and the score on the OHIP-14 scale. RESULTS: We found that the 7-factor structure had the best fit index in the sample. According to Cronbach's α, the overall score of OHIP was 0.958, and Cronbach's α for 7 factors was: functional limitation was 0.800, physical pain was 0.854, psychological discomfort was 0.902, physical disability was 0.850, psychological disability was 0.768, social disability was 0.862, social handicap was 0.819 and the test-retest reliability interval was 0.723. Multi-group confirmatory factor analysis supported residual measurement invariance across gender. T-test for scores showed that females scored higher significantly than men as did the overall score, in terms of physical pain (p<0.001), physical disability (p<0.001), and psychological disability (p<0.001). CONCLUSIONS: This study found the OHIP-14 Chinese version to be a good tool for assessing the college students' OHRQoL in China, allowing people to conduct self-assessments.

Detection of Exogenous γ-Hydroxybutyric Acid in Rat Blood Exosomes.

OBJECTIVES: To find a method to distinguish exogenous gamma-hydroxybutyrate (GHB) from endogenous GHB by establishing ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) based on exosome for quantitative detection of GHB in the rat blood. METHODS: Adult male SD rats were divided into 1 h, 5 h, 10 h administration group and control group. After 1 h, 5 h and 10 h of single precursor of GHB gamma-butyrolactone (GBL) intraperitoneal injection in administration groups, 5 mL blood was collected from the abdominal aorta. Meanwhile, the control group was given a same dose of normal saline, and 5 mL blood was collected at 1 h. Among the 5 mL blood, 0.5 mL was directly detected by HPLC-MS after pretreatment, and exosomes were extracted from the remaining blood by differential centrifugation and detected. RESULTS: The concentration of GHB in the control group was (87.36±33.48) ng/mL, and the concentration with administration at 1 h, 5 h and 10 h was (110 400.00±1 766.35) ng/mL, (1 479.00±687.01) ng/mL and (133.60±12.17) ng/mL, respectively. The results of exosome detection showed that no peak GHB signal was detected in the control group and the 10 h administration group, and the concentrations of GHB at 1 h and 5 h administration groups were (91.47±33.44) ng/mL and (49.43±7.05) ng/mL, respectively. CONCLUSIONS: GHB was detected in blood exosome by UPLC-MS, which indicated that exogenous GHB could be detected in plasma exosomes, while endogenous GHB could not be detected, suggesting that this method may be used as a basis to determine whether there is exogenous drug intake.

The let-7f-5p-Nme4 pathway mediates tumor necrosis factor α-induced impairment in osteogenesis of bone marrow-derived mesenchymal stem cells.

Although tumor necrosis factor α (TNF-α)-mediated inflammation significantly impacts osteoporosis, the mechanisms underlying the osteogenic differentiation defects of bone marrow-derived mesenchymal stem cells (BM-MSCs) caused by TNF-α remain poorly understood. We found that TNF-α stimulation of murine BM-MSCs significantly upregulated the expression levels of several microRNAs (miRNAs), including let-7f-5p, but this increase was significantly reversed by treatment with the kinase inhibitor BAY 11-7082. To study gain- or loss of function, we transfected cells with an miRNA inhibitor or miRNA mimic. We then demonstrated that let-7f-5p impaired osteogenic differentiation of BM-MSCs in the absence and presence of TNF-α, as evidenced by alkaline phosphatase and alizarin red staining as well as quantitative assays of the mRNA levels of bone formation marker genes in differentiated BM-MSCs. Moreover, let-7f-5p targets the 3' untranslated region of Nucleoside diphosphate kinase 4 (Nme4) mRNA and negatively regulates Nme4 expression in mouse BM-MSCs. Ectopic expression of Nme4 completely reversed the inhibitory effects of the let-7f-5p mimic on osteogenic differentiation of mouse BM-MSCs. Furthermore, inhibition of let-7f-5p or overexpression of Nme4 in BM-MSCs restored in-vivo bone formation in an ovariectomized animal model. Collectively, our work indicates that let-7f-5p is involved in TNF-α-mediated reduction of BM-MSC osteogenesis via targeting Nme4.

U-PASS: unified power analysis and forensics for qualitative traits in genetic association studies.

SUMMARY: Despite the availability of existing calculators for statistical power analysis in genetic association studies, there has not been a model-invariant and test-independent tool that allows for both planning of prospective studies and systematic review of reported findings. In this work, we develop a web-based application U-PASS (Unified Power analysis of ASsociation Studies), implementing a unified framework for the analysis of common association tests for binary qualitative traits. The application quantifies the shared asymptotic power limits of the common association tests, and visualizes the fundamental statistical trade-off between risk allele frequency and odds ratio. The application also addresses the applicability of asymptotics-based power calculations in finite samples, and provides guidelines for single-SNP-based association tests. In addition to designing prospective studies, U-PASS enables researchers to retrospectively assess the statistical validity of previously reported associations. AVAILABILITY AND IMPLEMENTATION: U-PASS is an open-source R Shiny application. A live instance is hosted at https://power.stat.lsa.umich.edu. Source is available on https://github.com/Pill-GZ/U-PASS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.