Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression

ObjectsThe incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis.DesignTwo HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models.ResultsA global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis.ConclusionsThe liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

Network-Based Approach and IVI Methodologies, a Combined Data Investigation Identified Probable Key Genes in Cardiovascular Disease and Chronic Kidney Disease

In fact, the risk of dying from CVD is significant when compared to the risk of developing end-stage renal disease (ESRD). Moreover, patients with severe CKD are often excluded from randomized controlled trials, making evidence-based therapy of comorbidities like CVD complicated. Thus, the goal of this study was to use an integrated bioinformatics approach to not only uncover Differentially Expressed Genes (DEGs), their associated functions, and pathways but also give a glimpse of how these two conditions are related at the molecular level. We started with GEO2R/R program (version 3.6.3, 64 bit) to get DEGs by comparing gene expression microarray data from CVD and CKD. Thereafter, the online STRING version 11.1 program was used to look for any correlations between all these common and/or overlapping DEGs, and the results were visualized using Cytoscape (version 3.8.0). Further, we used MCODE, a cytoscape plugin, and identified a total of 15 modules/clusters of the primary network. Interestingly, 10 of these modules contained our genes of interest (key genes). Out of these 10 modules that consist of 19 key genes (11 downregulated and 8 up-regulated), Module 1 (RPL13, RPLP0, RPS24, and RPS2) and module 5 (MYC, COX7B, and SOCS3) had the highest number of these genes. Then we used ClueGO to add a layer of GO terms with pathways to get a functionally ordered network. Finally, to identify the most influential nodes, we employed a novel technique called Integrated Value of Influence (IVI) by combining the network's most critical topological attributes. This method suggests that the nodes with many connections (calculated by hubness score) and high spreading potential (the spreader nodes are intended to have the most impact on the information flow in the network) are the most influential or essential nodes in a network. Thus, based on IVI values, hubness score, and spreading score, top 20 nodes were extracted, in which RPS27A non-seed gene and RPS2, a seed gene, came out to be the important node in the network.

Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules

Factor quinolinone inhibitors are promising anti-cancer compounds, initially characterized as specific inhibitors of the oncogenic transcription factor LSF (TFCP2). These compounds exert anti-proliferative activity at least in part by disrupting mitotic spindles. Herein, we report additional interphase consequences of the initial lead compound, FQI1, in two telomerase immortalized cell lines. Within minutes of FQI1 addition, the microtubule network is disrupted, resulting in a substantial, although not complete, depletion of microtubules as evidenced both by microtubule sedimentation assays and microscopy. Surprisingly, this microtubule breakdown is quickly followed by an increase in tubulin acetylation in the remaining microtubules. The sudden breakdown and partial depolymerization of the microtubule network precedes FQI1-induced morphological changes. These involve rapid reduction of cell spreading of interphase fetal hepatocytes and increase in circularity of retinal pigment epithelial cells. Microtubule depolymerization gives rise to FH-B cell compaction, as pretreatment with taxol prevents this morphological change. Finally, FQI1 decreases the rate and range of locomotion of interphase cells, supporting an impact of FQI1-induced microtubule breakdown on cell motility. Taken together, our results show that FQI1 interferes with microtubule-associated functions in interphase, specifically cell morphology and motility.

An Analytical and Numerical Detour for the Riemann Hypothesis

From the functional equation of Riemann’s zeta function, this article gives new insight into Hadamard’s product formula. The function and its family of associated functions, expressed as a sum of rational fractions, are interpreted as meromorphic functions whose poles are the poles and zeros of the function. This family is a mathematical and numerical tool which makes it possible to estimate the value of the function at a point in the critical strip from a point on the critical line .Generating estimates of at a given point requires a large number of adjacent zeros, due to the slow convergence of the series. The process allows a numerical approach of the Riemann hypothesis (RH). The method can be extended to other meromorphic functions, in the neighborhood of isolated zeros, inspired by the Weierstraß canonical form. A final and brief comparison is made with the and functions over finite fields.

Protein expression of prognostic genes in primary melanoma and benign nevi

Purpose To evaluate the protein expression characteristics of genes employed in a recently introduced prognostic gene expression assay for patients with cutaneous melanoma (CM). Methods We studied 37 patients with CM and 10 with benign (melanocytic) nevi (BN). Immunohistochemistry of primary tumor tissue was performed for eight proteins: COL6A6, DCD, GBP4, KLHL41, KRT9, PIP, SCGB1D2, SCGB2A2. Results The protein expression of most markers investigated was relatively low (e.g., DCD, KRT9, SCGB1D2) and predominantly cytoplasmatic in melanocytes and keratinocytes. COL6A6, GBP4, and KLHL41 expression was significantly enhanced in CM when compared to BN. DCD protein expression was significantly correlated with COL6A6, GBP4, and KLHL41. GBP4 was positively correlated with KLHL41 and inversely correlated with SCGB2B2. The latter was also inversely correlated with serum S100B levels at time of initial diagnosis. The presence of SCGB1D2 expression was significantly associated with ulceration of the primary tumor. KRT9 protein expression was significantly more likely found in acral lentiginous melanoma. The presence of DCD expression was less likely associated with superficial spreading melanoma subtype but significantly associated with non-progressive disease. The absence of SCGB2A2 expression was significantly more often observed in patients who did not progress to stage III or IV. Conclusions The expression levels observed were relatively low but differed in part with those found in BN. Even though we detected some significant correlations between the protein expression levels and clinical parameters (e.g., CM subtype, course of disease), there was no major concordance with the protective or risk-associated functions of the corresponding genes included in a recently introduced prognostic gene expression assay.

COMMUTATIVE NEUTRIX CONVOLUTION PRODUCT OF GENERALIZED FRESNEL COSINE INTEGRALS AND APPLICATIONS

The generalized Fresnel cosine integral $C_k(x)$ and its associated functions $C_{k+}(x)$ and $C_{k-}(x)$ are defined as locally summable functions on the real line. The generalized Fresnel cosine integrals have huge applications in physics, specially in optics and electromaghetics. In many diffraction problems the generalized Fresnel integrals plays an important role. In this paper are calculated the commutative neutrix convolutions of the generalized Fresnel cosine integral and its associated functions with $x^r, r=0,1,2,\dots$.

The Function of Flavonoids in the Diurnal Rhythm under Rapidly Changing UV Conditions—A Model Study on Okra

Flavonoids are favored compounds in plant responses to UV exposure and act in UV absorption and antioxidant activity. Here, it was investigated, with okra as a model species, how fast plants can react to changing UV conditions and to what extent these reactions take place. Okra (Abelmoschus esculentus) plants were exposed to either full or nearly no UV radiation. The diurnal rhythm of the plants was driven by the UV radiation and showed up to a 50% increase of the flavonoid content (measured optically in the +UV plants). This was reflected only in the trends in UV-absorption and antioxidant activity of the extracts but not in the soluble flavonoid glycosides and hydroxycinnamic acid derivatives. In a second experiment, a transfer from a −UV to a +UV condition at 9:00 CDT showed the immediate start of the diurnal rhythm, while this did not occur if the transfer occurred later in the day; these plants only started a diurnal rhythm the following day. After an adaptation period of seven days, clear differences between the +UV and -UV plants could be found in all parameters, whereas plants transferred to the opposite UV condition settle between the +UV and -UV plants in all parameters. Broadly, it can be seen that the flavonoid contents and associated functions in the plant are subject to considerable changes within one day and within several days due to the UV conditions and that this can have a considerable impact on the quality of plant foods.

Rapid Detection of Small Faults and Oscillations in Synchronous Generator Systems Using GMDH Neural Networks and High-Gain Observers

This paper presents a robust and efficient fault detection and diagnosis framework for handling small faults and oscillations in synchronous generator (SG) systems. The proposed framework utilizes the Brunovsky form representation of nonlinear systems to mathematically formulate the fault detection problem. A differential-flatness model of SG systems is provided to meet the conditions of the Brunovsky form representation. A combination of high-gain observer and group method of data handling neural network is employed to estimate the trajectory of the system and to learn/ approximate the fault and uncertainties associated functions. The fault detection mechanism is developed based on output residual generation and monitoring so that any unfavourable oscillation and/or fault occurrence can be detected rapidly. Accordingly, an average L1-norm criterion is proposed for rapid decision making of faulty situations. The performance of the proposed framework is investigated for two benchmark scenarios which are actuation fault and fault impact on system dynamics. The simulation results demonstrate the capacity and effectiveness of the proposed solution for rapid fault detection and diagnosis in SG systems in practice, and thus enhancing service maintenance, protection, and life cycle of SGs.

A Multi Omics Approach Unravels Metagenomic and Metabolic Alterations of a Probiotic and Synbiotic Additive in Rainbow Trout (Oncorhynchus Mykiss)

BackgroundAnimal protein production is increasingly looking towards microbiome associated services such as the design of new and better probiotic solutions to further improve gut health and production sustainability. Here, we investigate the functional effects of bacteria based pro- and synbiotic feed additives on microbiome associated functions in relation to growth performance in the commercially important rainbow trout (Oncorhynchus mykiss). We combine complementary insights from multiple omics datasets from gut content samples, including 16S bacterial profiling, whole metagenomes, and untargeted metabolomics, to investigate bacterial metagenomic assembled genomes (MAGs) and their molecular interactions with host metabolism.ResultsOur findings reveal, that (I) feed additives changed the microbiome and that rainbow trout reared with feed additives had a significantly reduced relative abundance of the salmonid related Candidatus Mycoplasma salmoninae in both the mid and distal gut content, (II) genome resolved metagenomics revealed that alterations of microbial arginine biosynthesis and terpenoid backbone synthesis pathways were directly associated with presence of Candidatus Mycoplasma salmoninae, (III) differences in the composition of intestinal microbiota among feed types were directly associated with significant changes of the metabolomic landscape, including lipids and lipid-like metabolites, amino acids, bile acids, and steroid-related metabolites.ConclusionOur results demonstrate how use of multi-omics to investigate complex host-microbiome interactions enable us to better evaluate the functional potential of probiotics compared to studies that only measure overall growth performance or that only characterise the microbial composition in intestinal environments.