Small Molecule Metabolism Research Articles

MicroRNA Expression Profiles in the Subcutaneous Adipose Tissues of Morbidly Obese Chinese Women

Introduction: Obesity is a main global health issue and an outstanding cause of morbidity and mortality. Exploring miRNA profiling may help further studies on obesity. Methods: Three morbidly obese and 5 normal-weight Chinese women were enrolled in the microarray testing group. Abdominal subcutaneous adipose tissue (SAT) samples were excised. Total RNAs including miRNAs were extracted. Affymetrix GeneChip miRNA 4.0 Array was used to compare the expression profiles of miRNAs between the 2 groups. Two algorithms, miRanda and TargetScan, were used to predict target messenger RNAs (mRNAs). Bioinformatics analysis was then done based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The sample sizes were further expanded to 8 morbidly obese and 9 normal-weight subjects, and quantitative real-time PCR (qRT-PCR) was utilized to verify the expression of differential miRNAs and target genes. Results: As per the microarray assay, 58 miRNAs were differentially expressed in the SAT from the morbidly obese and normal-weight groups (Fold >4, p < 0.01, FDR <0.05); 54 of these were downregulated and 4 were upregulated in morbidly obese subjects. A total of 1,333 target genes were jointly predicted by miRanda and TargetScan. Further bioinformatics analysis showed that the differential miRNAs were involved in 269 significant biological functions and 89 significant signaling pathways. The validation experiment by qRT-PCR showed that the expression levels of miRNA-143-5p, miRNA-143-3p, miRNA-145-5p, and let-7a-5p were downregulated in morbidly obese subjects, consistent with the microarray detection. High-mobility group A2 (HMGA2), a target gene of the downregulated miRNA let-7a-5p, was first found to be upregulated 3.19-fold in the SAT of morbidly obese Chinese women when compared to normal-weight controls. Conclusions: MiRNA downregulation is a hallmark of intact SAT in a morbidly obese state. Transcription (DNA-dependent), small-molecule metabolic processes, the MAPK signaling pathway, and cancer-related pathways may play important roles in the occurrence and development of obesity. For the first time, we proved that HMGA2, a target gene of let-7a-5p, is upregulated in the SAT of morbidly obese Chinese women.

Amino Acid and Carbohydrate Metabolism Are Coordinated to Maintain Energetic Balance during Drought in Sugarcane.

The ability to expand crop plantations without irrigation is a major goal to increase agriculture sustainability. To achieve this end, we need to understand the mechanisms that govern plant growth responses under drought conditions. In this study, we combined physiological, transcriptomic, and genomic data to provide a comprehensive picture of drought and recovery responses in the leaves and roots of sugarcane. Transcriptomic profiling using oligoarrays and RNA-seq identified 2898 (out of 21,902) and 46,062 (out of 373,869) transcripts as differentially expressed, respectively. Co-expression analysis revealed modules enriched in photosynthesis, small molecule metabolism, alpha-amino acid metabolism, trehalose biosynthesis, serine family amino acid metabolism, and carbohydrate transport. Together, our findings reveal that carbohydrate metabolism is coordinated with the degradation of amino acids to provide carbon skeletons to the tricarboxylic acid cycle. This coordination may help to maintain energetic balance during drought stress adaptation, facilitating recovery after the stress is alleviated. Our results shed light on candidate regulatory elements and pave the way to biotechnology strategies towards the development of drought-tolerant sugarcane plants.

The gut microbiome drives inter- and intra-individual differences in metabolism of bioactive small molecules

The origin of inter-individual variability in the action of bioactive small molecules from the diet is poorly understood and poses a substantial obstacle to harnessing their potential for attenuating disease risk. Epidemiological studies show that coffee lowers the risk of developing type 2 diabetes, independently of caffeine, but since coffee is a complex matrix, consumption gives rise to different classes of metabolites in vivo which in turn can affect multiple related pathways in disease development. We quantified key urinary coffee phenolic acid metabolites repeated three times in 36 volunteers, and observed the highest inter- and intra-individual variation for metabolites produced by the colonic microbiome. Notably, a urinary phenolic metabolite not requiring the action of the microbiota was positively correlated with fasting plasma insulin. These data highlight the role of the gut microbiota as the main driver of both intra- and inter-individual variation in metabolism of dietary bioactive small molecules.

Screening and Functional Prediction of Key Candidate Genes in Hepatitis B Virus-Associated Hepatocellular Carcinoma.

Background The molecular mechanism by which hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) is still unknown. The genomic expression profile and bioinformatics methods were used to investigate the potential pathogenesis and therapeutic targets for HBV-associated HCC (HBV-HCC). Methods The microarray dataset GSE55092 was downloaded from the Gene Expression Omnibus (GEO) database. The data was analyzed by the bioinformatics software to find differentially expressed genes (DEGs). Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, ingenuity pathway analysis (IPA), and protein-protein interaction (PPI) network analysis were then performed on DEGs. The hub genes were identified using Centiscape2.2 and Molecular Complex Detection (MCODE) in the Cytoscape software (Cytoscape_v3.7.2). The survival data of these hub genes was downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA). Results A total of 2264 mRNA transcripts were differentially expressed, including 764 upregulated and 1500 downregulated in tumor tissues. GO analysis revealed that these DEGs were related to the small-molecule metabolic process, xenobiotic metabolic process, and cellular nitrogen compound metabolic process. KEGG pathway analysis revealed that metabolic pathways, complement and coagulation cascades, and chemical carcinogenesis were involved. Diseases and biofunctions showed that DEGs were mainly associated with the following diseases or biological function abnormalities: cancer, organismal injury and abnormalities, gastrointestinal disease, and hepatic system disease. The top 10 upstream regulators were predicted to be activated or inhibited by Z-score and identified 25 networks. The 10 genes with the highest degree of connectivity were defined as the hub genes. Cox regression revealed that all the 10 genes (CDC20, BUB1B, KIF11, TTK, EZH2, ZWINT, NDC80, TPX2, MELK, and KIF20A) were related to the overall survival. Conclusion Our study provided a registry of genes that play important roles in regulating the development of HBV-HCC, assisting us in understanding the molecular mechanisms that underlie the carcinogenesis and progression of HCC.

Metabolic Profiles in Madin-Darby Canine Kidney Cell Lines Infected with H3N2 Canine Influenza Viruses.

Virus replication and host cell growth require host cell metabolic networks to provide energy and precursors for the synthesis of macromolecules. The aim of this study was to investigate the most direct changes in energy metabolism and small-molecule metabolism of Madin-Darby canine kidney (MDCK) cells infected with H3N2 canine influenza virus (CIV) and to determine whether small metabolites contribute to the pathogenesis of CIV. To study the metabolomics of MDCK cells infected with H3N2 CIV, we used liquid chromatography-tandem mass spectrometry combined with multivariate statistical analysis. The results showed that 798 positive ions were detected, among which 33 were upregulated and 11 were downregulated, and 406 negative ions were detected, among which 33 were upregulated and 9 were downregulated. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we found that these differentially expressed molecules were mainly concentrated in the steroid hormone biosynthesis, amino sugar and nucleotide sugar metabolism, sphingolipid metabolism, vitamin B6 metabolism, cysteine and methionine metabolism, vitamin digestion and absorption, arginine and proline metabolism, biosynthesis of amino acids, and folate biosynthesis metabolic pathways. These pathways are involved in energy metabolism and nucleic acid and protein synthesis, which are essential for virus replication. Our experimental data suggest that H3N2 CIV infection reconstitutes/influences cellular metabolic processes, which in turn may contribute to viral replication. These findings are important for the development of enzyme inhibitors or metabolites for the identification of antiviral drugs. In addition, understanding the metabolic interaction between CIV and host cells is also very important for the complex pathogenicity of CIV, providing certain guidance for the treatment of canine influenza.

Uptake, recognition and responses to peptidoglycan in the mammalian host

ABSTRACTMicrobiota, and the plethora of signalling molecules that they generate, are a major driving force that underlies a striking range of inter-individual physioanatomic and behavioural consequences for the host organism. Among the bacterial effectors, one finds peptidoglycan, the major constituent of the bacterial cell surface. In the steady-state, fragments of peptidoglycan are constitutively liberated from bacterial members of the gut microbiota, cross the gut epithelial barrier and enter the host system. The fate of these peptidoglycan fragments, and the outcome for the host, depends on the molecular nature of the peptidoglycan, as well the cellular profile of the recipient tissue, mechanism of cell entry, the expression of specific processing and recognition mechanisms by the cell, and the local immune context. At the target level, physiological processes modulated by peptidoglycan are extremely diverse, ranging from immune activation to small molecule metabolism, autophagy and apoptosis. In this review, we bring together a fragmented body of literature on the kinetics and dynamics of peptidoglycan interactions with the mammalian host, explaining how peptidoglycan functions as a signalling molecule in the host under physiological conditions, how it disseminates within the host, and the cellular responses to peptidoglycan.

Toxicity removal and biodegradability enhancement of sludge extract in hydroquinone-rich wastewater via cultivation of Chlorella vulgaris

Excess sludge is rich in organic matter, nitrogen, and phosphorus. However, in the disposal of industrial wastewater with high concentrations of organic matter, the toxic organics accumulate in the sludge will cause sludge toxicity. Microalgae have strong adaptability to toxic environments. Therefore, in the present study, Chlorella vulgaris was cultured in sludge extract and BG11 medium (blank group) with the objectives of reducing both sludge yield and organic toxicity. The results show that the toxic sludge extract could maintain the stable growth of Chlorella vulgaris, and on the 10th day of culture, Chlorella vulgaris obtained higher biomass and photosynthesis efficiency. The BOD/COD (B/C) ratio of the sludge extract increased from 0.12 to 0.37 while the carbon/nitrogen ratio increased by a factor of 4.9, which significantly improved its biodegradability. Excitation emission matrix analysis showed that C. vulgaris removed soluble microbial products and reduced some humic acids. The isobaric tags for relative and absolute quantitation revealed the presence of differential proteins affecting the processes of small molecule metabolism, energy metabolism, and photosynthesis in different media.

Targeted and untargeted metabolomics provide insight into the consequences of glycine-N-methyltransferase deficiency including the novel finding of defective immune function.

Fatty liver disease is increasing along with the prevalence of obesity and type‐2 diabetes. Hepatic fibrosis is a major health complication for which there are no efficacious treatment options available. A better understanding of the fundamental mechanisms that contribute to the accumulation of fibrosis is needed. Glycine‐N‐methyltransferase (GNMT) is a critical enzyme in one‐carbon metabolism that serves to regulate methylation and remethylation reactions. GNMT knockout (GNMT‐/‐) mice display spontaneous hepatic fibrosis and later develop hepatocellular carcinoma. Previous literature supports the idea that hypermethylation as a consequence of GNMT deletion contributes to the hepatic phenotype observed. However, limited metabolomic information is available and the underlying mechanisms that contribute to hepatic fibrogenesis in GNMT‐/‐ mice are still incomplete. Therefore, our goals were to use dietary intervention to determine whether increased lipid load exacerbates steatosis and hepatic fibrosis in this model and to employ both targeted and untargeted metabolomics to further understand the metabolic consequences of GNMT deletion. We find that GNMT mice fed high‐fat diet do not accumulate more lipid or fibrosis in the liver and are in fact resistant to weight gain. Metabolomics analysis confirmed that pan‐hypermethylation occurs in GNMT mice resulting in a depletion of nicotinamide intermediate metabolites. Further, there is a disruption in tryptophan catabolism that prevents adequate immune cell activation in the liver. The chronic cellular damage cannot be appropriately cleared due to a lack of immune checkpoint activation. This mouse model is an excellent example of how a disruption in small molecule metabolism can significantly impact immune function.

Cell envelope proteases and peptidases of Pseudomonas aeruginosa: multiple roles, multiple mechanisms

Pseudomonas aeruginosa is a Gram-negative bacterium that is commonly isolated from damp environments. It is also a major opportunistic pathogen, causing a wide range of problematic infections. The cell envelope of P. aeruginosa, comprising the cytoplasmic membrane, periplasmic space, peptidoglycan layer and outer membrane, is critical to the bacteria's ability to adapt and thrive in a wide range of environments. Over 40 proteases and peptidases are located in the P. aeruginosa cell envelope. These enzymes play many crucial roles. They are required for protein secretion out of the cytoplasm to the periplasm, outer membrane, cell surface or the environment; for protein quality control and removal of misfolded proteins; for controlling gene expression, allowing adaptation to environmental changes; for modification and remodelling of peptidoglycan; and for metabolism of small molecules. The key roles of cell envelope proteases in ensuring normal cell functioning have prompted the development of inhibitors targeting some of these enzymes as potential new anti-Pseudomonas therapies. In this review, we summarise the current state of knowledge across the breadth of P. aeruginosa cell envelope proteases and peptidases, with an emphasis on recent findings, and highlight likely future directions in their study.

Abstract 19: Examination of HJC0152, a putative modulator of glucose and energy metabolism, for mammary cancer prevention

Abstract Breast cancer (BC) is the most common cancer in women in the US. Approximately 30-40% of BC cases are estrogen-receptor (ER)-negative (ENBC); the majority of these are triple-negative (TNBC). No drugs have been shown to effectively prevent ENBC including TNBC. TNBC incidence is higher in young African American and Hispanic/Latina women, thus the need for preventive agents for TNBC is critical. Developing agents targeting non-ER-based oncogenic pathways will therefore offer alternative and potentially more effective approaches for preventing ENBC/TNBC. Glucose metabolism is an essential energy-producing process for normal cells and is aberrant and reprogrammed in cancer cells including BC cells. We recently developed HJC0152, a novel small-molecule glucose metabolism modulator as a potential cancer preventive agent. HJC0152 has been shown to inhibit glycolysis by differentially regulating glycolytic enzyme expression and the function of mitochondrial respiratory complexes in both EPBC and TNBC cells, leading to reduced production of energy molecule adenosine-triphosphate (ATP), induced apoptosis, and decreased proliferation and tumor progression. In this study, we determined the preventive anti-cancer efficacies of long-term and short-term (inhibition of premalignant lesions) HJC0152 administration in mouse models of ENBC and TNBC. HJC0152 was given orally 6 days/wk for 2-10 months in well-established ENBC model, MMTV-erbB2; and TNBC model, C3(1)/TAgSV40. HJC0152 at 50 and 75 mg/Kg doses delayed and partially prevented mammary tumor development in ENBC (MMTV-erbB2) mice (p=0.0034 for all groups). A maximum 6-week delay was achieved for median time to tumor formation (TTF). In the TNBC (C3(1)/TAgSV40) model, HJC0152 significantly delayed mammary tumor development (p=0.0114 for all groups) and achieved 3.3-week delay for median TTF. Up to 21% less mice developed mammary tumors in both models. In addition, TNBC mice developed less number of tumors per mouse than in ENBC mice, and the tumor volume doubling time increased from 6.9 to 9.2 days. In the short-term premalignant lesion study, the number of mammary intraepithelial neoplasia (MIN) lesion (representing human DCIS) was significantly decreased (p=0.034) in the HJC0152-treated MMTV-erbB2 mice. In the HJC0152-treated C3(1)/TAgSV40 mice, the number of hyperplasia and MIN lesions were significantly decreased (p=0.0014 and 0.0203, respectively). These results demonstrate that HJC0152 suppresses mammary tumor development in ENBC and TNBC models via reducing premalignant lesions, even in the most aggressive TNBC model, C3(1)/TAgSV40. There were no significant side effects or toxicity signs observed in both long- and short-term prevention experiments. We conclude that HJC0152 has promising cancer preventive efficacy by targeting non-ER-based signaling pathways such as STAT3 signaling and glucose metabolism. This study was supported by a NIH/NCI PREVENT Program fund. *Current Affiliation: LSUHSC. Citation Format: Hyejin Kim, Xi Liu, Yefei Wen, Jia Zhou, Romaine Fernando, Shizuko Sei, Powel H. Brown, Qiang Shen. Examination of HJC0152, a putative modulator of glucose and energy metabolism, for mammary cancer prevention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 19.

Anti-ischemia/reperfusion injury effects of notoginsenoside R1 on small molecule metabolism in rat brain after ischemic stroke as visualized by MALDI–MS imaging

Ischemic stroke is a syndrome of severe neurological responses that cause neuronal death, damage to the neurovascular unit and inflammation. Notoginsenoside R1 (NG-R1) is a neuroprotective drug that is commonly used to treat neurodegenerative and cerebrovascular diseases. However, its potential mechanisms on the regulation of small molecule metabolism in ischemic stroke are largely unknown. The aim of this study was to explore the potential mechanisms of NG-R1 on the regulation of small molecule metabolism after ischemic stroke. Here, we found that NG-R1 reduced infarct size and improved neurological deficits by ameliorating neuronal damage and inhibiting glial activation in MCAO/R rats. Furthermore, using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), we clarified that NG-R1 regulated ATP metabolism, the tricarboxylic acid (TCA) cycle, the malate-aspartate shuttle, antioxidant activity, and the homeostasis of iron and phospholipids in the striatum and hippocampus of middle cerebral artery occlusion/reperfusion (MCAO/R) rats. In general, NG-R1 is a promising compound for brain protection from ischemic/reperfusion injury, possibly through the regulation of brain small molecule metabolism.

Knockout of Pi21 by CRISPR/Cas9 and iTRAQ-Based Proteomic Analysis of Mutants Revealed New Insights into M. oryzae Resistance in Elite Rice Line.

Rice blast (Magnaporthe oryzae) is a devastating disease affecting rice production globally. The development of cultivars with host resistance has been proved to be the best strategy for disease management. Several rice-resistance genes (R) have been recognized which induce resistance to blast in rice but R gene-mediated mechanisms resulting in defense response still need to be elucidated. Here, mutant lines generated through CRISPR/Cas9 based targeted mutagenesis to investigate the role of Pi21 against blast resistance and 17 mutant plants were obtained in T0 generation with the mutation rate of 66% including 26% bi-allelic, 22% homozygous, 12% heterozygous, and 3% chimeric and 17 T-DNA-free lines in T1 generation. The homozygous mutant lines revealed enhanced resistance to blast without affecting the major agronomic traits. Furthermore, comparative proteome profiling was adopted to study the succeeding proteomic regulations, using iTRAQ-based proteomic analysis. We identified 372 DEPs, among them 149 up and 223 were down-regulated, respectively. GO analysis revealed that the proteins related to response to stimulus, photosynthesis, carbohydrate metabolic process, and small molecule metabolic process were up-regulated. The most of DEPs were involved in metabolic, ribosomal, secondary metabolites biosynthesis, and carbon metabolism pathways. 40S ribosomal protein S15 (P31674), 50S ribosomal protein L4, L5, L6 (Q10NM5, Q9ZST0, Q10L93), 30S ribosomal protein S5, S9 (Q6YU81, Q850W6, Q9XJ28), and succinate dehydrogenase (Q9S827) were hub-proteins. The expression level of genes related to defense mechanism, involved in signaling pathways of jasmonic acid (JA), salicylic acid (SA), and ethylene metabolisms were up-regulated in mutant line after the inoculation of the physiological races of M. oryzae as compared to WT. Our results revealed the fundamental value of genome editing and expand knowledge about fungal infection avoidance in rice.

Metabolic and OXPHOS Activities Quantified by Temporal ex vivo Analysis Display Patient-Specific Metabolic Vulnerabilities in Human Breast Cancers.

Research on mitochondrial metabolism and respiration are rapidly developing areas, however, efficient and widely accepted methods for studying these in solid tumors are still missing. Here, we developed a new method without isotope tracing to quantitate time dependent mitochondrial citrate efflux in cell lines and human breast cancer samples. In addition, we studied ADP-activated respiration in both of the sample types using selective permeabilization and showed that metabolic activity and respiration are not equally linked. Three times lower amount of mitochondria in scarcely respiring MDA-MB-231 cells convert pyruvate and glutamate into citrate efflux at 20% higher rate than highly respiring MCF-7 mitochondria do. Surprisingly, analysis of 59 human breast cancers revealed the opposite in clinical samples as aggressive breast cancer subtypes, in comparison to less aggressive subtypes, presented with both higher mitochondrial citrate efflux and higher respiration rate. Additionally, comparison of substrate preference (pyruvate or glutamate) for both mitochondrial citrate efflux and respiration in triple negative breast cancers revealed probable causes for high glutamine dependence in this subtype and reasons why some of these tumors are able to overcome glutaminase inhibition. Our research concludes that the two widely used breast cancer cell lines fail to replicate mitochondrial function as seen in respective human samples. And finally, the easy method described here, where time dependent small molecule metabolism and ADP-activated respiration in solid human cancers are analyzed together, can increase success of translational research and ultimately benefit patients with cancer.

Targeted Metabolomics Revealed the Regulatory Role of Manganese on Small-Molecule Metabolism of Biofilm Formation in Escherichia coli

Biofilms are special microbial communities produced by many microorganisms, such as bacteria, viruses, and fungi. Biofilms enable the microorganisms to possess the capacity against a diversity of stressful environments. Yet, biofilm formation often causes tough challenges in clinical infections, food quality, and environmental issues, however, the formation mechanism of biofilms are still incompletely understood which seriously impedes the development of new strategies to eradicate biofilms in different niches. In this study, we sought to explore the regulatory role of manganese (Mn2+) on small-molecule metabolism of biofilm formation in Escherichia coli (E. coli). Using structural imaging assay combined with precision-targeted metabolomics method, to investigate how biofilm formation responded to various concentrations of Mn2+, we found that Mn2+ could inhibit biofilm formation through the regulation of phenotypic morphology and metabolic reprogramming. Collectively, our work discovered 16 differential functional metabolites and associated three metabolic pathways involving glycolysis, TCA cycle, and tryptophan metabolism that were changed mostly by Mn2+ during biofilm formation, which can differentiate biofilms from the relevant planktonic cells. Altogether, this study demonstrated that Mn2+ can inhibit biofilm formation to regulate metabolic reprogramming and micro-structure, such effort provides novel insight into the regulation of metabolic features of biofilm formation, which enables the development of new strategies to eradicate biofilm formation for addressing the challenging problems in different areas by targeting the regulation of Mn2+ to the biosynthesis and expressions of functional metabolites produced by different microorganisms.

Identification of long noncoding RNAs involved in adaptability to chronic hypoxic by whole transcriptome sequencing.

Hypoxia affects the physiology of cells and organisms; however, the mechanisms associated with hypoxia adaptation remain unknown in Tibetan chickens. In this study, we aimed to identify long noncoding RNAs (lncRNAs) involved in hypoxia adaptation in Tibetan chickens and Daheng broilers, to provide insights into the mechanisms underlying hypoxia induction. RNA sequencing results revealed that a total of 5504 lncRNAs and 16,779 microRNAs were differentially expressed in four Tibetan chickens and four Daheng broilers; 70 lncRNAs were up-regulated and 113 lncRNAs were down-regulated in the Tibetan chickens compared to the expression levels in the Daheng broilers. The differentially expressed lncRNAs (DElncRNAs) were enriched in the following Gene ontology terms: protein complex localization, small-molecule metabolic process, and RNA splicing. Kyoto Encyclopedia of Genes and Genomes analyses revealed that the DElncRNAs were mainly enriched in pathways that regulate cell junctions and intercellular spaces and oxygen or energy metabolism, mainly involved in hypoxic adaption. Moreover, a predicted ceRNA network with five DElncRNAs interacted with three miRNAs that acted on 42 pathways through 19 target genes. Quantitative real-time polymerase chain reaction was used to verify that the expression levels of ENSGALG00000008047, ENSGALG00000050044, and ENSGALG00000053982 were significantly lower in Tibetan chickens than in the Daheng broilers, consistent with the RNA sequencing results. We obtained lncRNA expression profiles for the heart tissue of Tibetan chickens for the first time and have provided novel data that may aid research on biological adaptation to hypoxic stress.

Predicting drug properties with parameter-free machine learning: pareto-optimal embedded modeling (POEM)

The prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of small molecules from their molecular structure is a central problem in medicinal chemistry with great practical importance in drug discovery. Creating predictive models conventionally requires substantial trial-and-error for the selection of molecular representations, machine learning (ML) algorithms, and hyperparameter tuning. A generally applicable method that performs well on all datasets without tuning would be of great value but is currently lacking. Here, we describe pareto-optimal embedded modeling (POEM), a similarity-based method for predicting molecular properties. POEM is a non-parametric, supervised ML algorithm developed to generate reliable predictive models without need for optimization. POEM’s predictive strength is obtained by combining multiple different representations of molecular structures in a context-specific manner, while maintaining low dimensionality. We benchmark POEM relative to industry-standard ML algorithms and published results across 17 classifications tasks. POEM performs well in all cases and reduces the risk of overfitting.

MicroRNA-9 might be a novel protective factor for osteoarthritis patients

BackgroundThe study aimed to identify the targeting genes and miRNAs using the microarray expression profile dataset for Osteoarthritis (OA) patients. Differentially expressed genes (DEGs) between OA and control samples were identified using Bayes method of limma package. Subsequently, a protein-protein interaction (PPI) network was constructed. miRNAs and transcription factor (TFs) based on DEGs in PPI network were identified using Webgestalt and ENCODE, respectively. Finally, MCODE, Gene Ontology (GO) function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed. The expressions of several DEGs and predicted miRNAs in OA rats were detected by RT-PCR.ResultsA total of 594 DEGs were identified. In PPI network, there were 313 upregulated DEGs and 22 downregulated DEGs. Besides, the regulatory relationships included 467 upregulated interactions and 85 downregulated interactions (miR-124A → QKI and MAP 1B) between miRNA and DEGs in PPI network. The module from downregulated DEGs-TFs-miRNA networks was mainly enriched to low-density lipoprotein particle clearance, response to linoleic acid, and small molecule metabolic process BP terms. Moreover, QKI, MAP 1B mRNA and miR-9 expressions were significantly reduced in OA rats.ConclusionmiR-9 might be a protective factor for OA patients via inhibiting proliferation and differentiation of cartilage progenitor cells. miR-124A might play an important role in progression of OA through targeting QKI and MAP 1B.

Proteomic dissection of the similar and different responses of wheat to drought, salinity and submergence during seed germination

Wheat (Triticum aestivum L.) is one of the major crops worldwide and its production is inevitably subjected to various biotic/abiotic stresses during the life cycle. Drought, salinity and flooding are among the most severe abiotic stresses restricting wheat yields and could occur at very early stages such as seed germination. How wheat seed germination responds to these different stresses remains incomplete. To fill the information gap, a label-free proteomic analysis was applied to decipher the proteomic profiling of the germinating wheat seeds subjected to PEG, NaCl and submergence treatments. In total, 4295 proteins were detected, of which 465, 397 and 732 showed significant alterations in abundance under those stresses when compared with control. A common denominator found in the response observed to all three stresses are changes related to small molecule metabolic processes, and particularly in pathways associated with phenylpropanoid biosynthesis and fatty acid degradation. It was also noticeable that pathways like cysteine and methionine metabolism in the PEG or submergence treatment and starch and sucrose metabolism in the submergence treatment are specifically pronounced. Functional analysis of putative proteins participating in these pathways revealed distinct responsive patterns across different stresses. SignificanceWheat (Triticum aestivum L.) is one of the most important staple crops in the world, but its growth and productivity are frequently restrained by stresses such as drought, salinity and flooding. To date, many resources have been documented to investigate how wheat responds and adapts to these individual stresses during plant development and yield formation, but little attention was paid to the understandings of the internal link between different conditions, especially during the germination process, a critical stage that determines the optimal growth of wheat. In this study, we carried out the proteome profiling of the germinating seeds of a common wheat cultivar, Chinese Spring, subjected to PEG, NaCl and submergence stresses. We found that the phenylpropanoid biosynthesis and fatty acid degradation pathways were enriched as the ubiquitous stress responses, while some pathways were stress-specific, for instance, starch and sucrose metabolism against submergence. The changes in some of the altered processes were further validated by physiological and molecular approaches. Our results suggest that the overall pathway profiles concerned with the three stresses were similar, but the specific procedures and components in each process varied greatly. The altered proteins and processes can be taken as effective candidates in future breeding and agronomic modification researches.

Epilepsy and developmental disorders: Next generation sequencing in the clinic.

The advent of Next Generation Sequencing (NGS) has led to a redefining of the genetic landscape of the epilepsies. Hundreds of single gene epilepsies have been described. Genes associated with epilepsy involve diverse processes. Now a substantial proportion of individuals with epilepsy can receive a high definition molecular genetic diagnosis. In this review we update the current genetic landscape of the epilepsies and categorise the major functional groupings of epilepsy-associated genes. We describe currently available genetic testing approaches. We perform a literature review of NGS studies and review the factors which determine yield in cohorts undergoing testing. We identify factors associated with positive genetic diagnosis and consider the utility of genetic testing in terms of treatment selection as well as more qualitative aspects of care. Epilepsy-associated genes can be grouped into five broad functional categories: ion transport; cell growth and differentiation; regulation of synaptic processes; transport and metabolism of small molecules within and between cells; and regulation of gene transcription and translation. Early onset of seizures, drug-resistance, and developmental comorbidity are associated with higher diagnostic yield. The most commonly implicated genes in NGS studies to date, in order, are SCN1A, KCNQ2, CDKL5, SCN2A, and STXBP1. In unselected infantile cohorts PRRT2, a gene associated with self-limited epilepsy, is frequently implicated. Genetic diagnosis provides utility in terms of treatment choice closing the diagnostic odyssey, avoiding unnecessary further testing, and informing future reproductive decisions. Genetic testing has become a first line test in epilepsy. As techniques improve and understanding advances, its utility is set to increase. Genetic diagnosis, particularly in early onset developmental and epileptic encephalopathies, influences treatment choice in a significant proportion of patients. The realistic prospect of gene therapy is a cause for optimism.

De novo transcriptome and proteome analysis of Dictyophora indusiata fruiting bodies provides insights into the changes during morphological development

De novo transcriptome assembly and shotgun proteome analysis of Dictyophora indusiata fruiting bodies were performed. A total of 19,704 unigenes were sequenced, and 4380 proteins were identified. Annotation and functional analysis of the identified proteins were significantly enriched in small molecule synthetic and metabolic processes, protein modification regulation (phosphorylation and ubiquitination), and vesicle transport. Furthermore, quantitative developmental transcriptome analysis was performed between the peach-shaped and mature fruiting bodies, and the results revealed that the metabolism and transport activities were upregulated in the mature stage, while protein translation was downregulated; this regulation is likely the main reason for the significant changes in the nutrients of fruiting bodies. Furthermore, the cell wall stress-dependent MAPK sub-pathway was activated in the mature stage, and fungal cell wall degradation-related genes were upregulated, which could promote reconstruction of the cell wall and might play a key role in the morphological development of D. indusiata fruiting bodies.