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PubMed2006

Differences in gene expression between the classical and El Tor biotypes of Vibrio cholerae O1.

Differences in whole-genome expression patterns between the classical and El Tor biotypes of Vibrio cholerae O1 were determined under conditions that induce virulence gene expression in the classical biotype. A total of 524 genes (13.5% of the genome) were found to be differentially expressed in the two biotypes. The expression of genes encoding proteins required for biofilm formation, chemotaxis, and transport of amino acids, peptides, and iron was higher in the El Tor biotype. These gene expression differences may contribute to the enhanced survival capacity of the El Tor biotype in environmental reservoirs. The expression of genes encoding virulence factors was higher in the classical than in the El Tor biotype. In addition, the vieSAB genes, which were originally identified as regulators of ctxA transcription, were expressed at a fivefold higher level in the classical biotype. We determined the VieA regulon in both biotypes by transcriptome comparison of wild-type and vieA deletion mutant strains. VieA predominantly regulates gene expression in the classical biotype; 401 genes (10.3% of the genome), including those encoding proteins required for virulence, exopolysaccharide biosynthesis, and flagellum production as well as those regulated by sigmaE, are differentially expressed in the classical vieA deletion mutant. In contrast, only five genes were regulated by VieA in the El Tor biotype. A large fraction (20.8%) of the genes that are differentially expressed in the classical versus the El Tor biotype are controlled by VieA in the classical biotype. Thus, VieA is a major regulator of genes in the classical biotype under virulence gene-inducing conditions.

Amino Acids↗

PubMed2026

Divergent evolutionary strategies in spider venoms: A comparative proteomic profiling of four sympatric species from Yunnan.

Spider venoms comprise complex cocktails of bioactive molecules evolved for predation and defense, representing a valuable resource for biological research and pharmaceutical discovery. In this study, we performed a systematic analysis of venom gland extracts from four common spider species indigenous to Yunnan, China: Agelena limbata, Hippasa lycosina, Lycosa grahami, and Sinopoda pengi. Using an integrated transcriptomic and proteomic targeted profiling approach, we successfully annotated 141 distinct toxins. Comparative analysis revealed significant interspecific heterogeneity, suggesting distinct evolutionary trajectories and "weapon system economics." Both A. limbata and L. grahami exhibited a "peptide-dominant" profile anchored by neurotoxic peptides and isomerases, optimized for rapid chemical paralysis. In contrast, S. pengi displayed a distinct "protein-dominant" signature enriched with high-molecular-weight enzymes and CAP superfamily proteins, likely functioning to facilitate tissue degradation and toxin diffusion. Occupying an intermediate position, H. lycosina demonstrated a hybrid composition. These findings suggest that although these species share the same geographical range, their venom systems have undergone divergent evolutionary adaptations driven by specific ecological niches and hunting strategies. This study represents the first systematic proteomic characterization of these venom components, providing a valuable reservoir of molecular candidates while highlighting the bioinformatic nuances of analyzing whole-gland homogenates.

Animals↗

PubMed2025

Extensive Recombination Suppression and Genetic Degeneration of a Young ZW Sex Chromosome System in Halfbeak Fish.

Sex chromosome systems have evolved independently across the tree of life, at different times in the past, and the evolutionary consequences of lacking recombination in sex-linked regions have been characterized in many old-established systems. However, empirical studies of young sex chromosomes are still scarce, especially in vertebrates. Integrating whole-genome sequencing data of two species of halfbeak fish, Hyporhamphus sajori and Hyporhamphus intermedius, we identified the sex-determining system in H. sajori as female heterogamety, involving a large fully sex-linked ZW region (∼26 Mb) on chromosome 5. The closest relative, H. intermedius, has a small sex-linked region on a different chromosome and shows male heterogamety, suggesting at least one turnover in this fish genus. The H. sajori sex-linked region includes two evolutionary strata, but the estimated Z-W divergence times are small, less than 3 million years for the older stratum, which is less than between the two species. Nevertheless, this evolutionarily young W-linked region is enriched with repetitive sequences, differs from the ancestral state by five inversions, and about one-third of its protein-coding genes have already become nonfunctional. Transcriptomic analysis suggests that some form of dosage compensation may already be evolving for some sex-linked genes.

Animals↗

PubMed2026

Conserved innate immunity components limit transgene expression in adult planarians.

The planarian flatworm Schmidtea mediterranea has become a powerful model for studying whole-body regeneration, tissue patterning, and stem cell regulation. Yet the absence of reliable tools for transgene expression still limits the elucidation of molecular mechanisms in in this system. Here, we establish a proof-of-principle system for plasmid-based expression of NanoLuciferase (NanoLuc) in S. mediterranea, employing commercially available transfection reagents and a panel of endogenous promoter sequences. Despite successful delivery, reporter expression remained low and transient. To identify biological barriers to robust transgene expression, we investigated the role of innate immune pathways. Candidate gene searches and biochemical pull-down of cytoplasmic DNA coupled to mass spectrometry identified several planarian homologs of conserved immune regulators and putative DNA sensors. Through RNA interference screening of conserved innate immune components, we uncover roles for S. mediterranea homologs of Tank-binding kinase 1 (TBK1) and macrophage mannose receptor 1 (MRC1) as potent repressors of transgene expression. Transcriptomic and functional analyses further implicate TBK1 in regulating broad innate immune and stress-response programs, akin to its vertebrate function. Together, our findings demonstrate that innate immune signaling limits transgene expression in S. mediterranea and suggest that modulating these pathways may be key to enabling stable and efficient genetic manipulation in planarians.

Animals↗

PubMed2006

Global analysis of carbohydrate utilization by Lactobacillus acidophilus using cDNA microarrays.

The transport and catabolic machinery involved in carbohydrate utilization by Lactobacillus acidophilus was characterized genetically by using whole-genome cDNA microarrays. Global transcriptional profiles were determined for growth on glucose, fructose, sucrose, lactose, galactose, trehalose, raffinose, and fructooligosaccharides. Hybridizations were carried out by using a round-robin design, and microarray data were analyzed with a two-stage mixed model ANOVA. Differentially expressed genes were visualized by hierarchical clustering, volcano plots, and contour plots. Overall, only 63 genes (3% of the genome) showed a >4-fold induction. Specifically, transporters of the phosphoenolpyruvate:sugar transferase system were identified for uptake of glucose, fructose, sucrose, and trehalose, whereas ATP-binding cassette transporters were identified for uptake of raffinose and fructooligosaccharides. A member of the LacS subfamily of galactoside-pentose hexuronide translocators was identified for uptake of galactose and lactose. Saccharolytic enzymes likely involved in the metabolism of monosaccharides, disaccharides, and polysaccharides into substrates of glycolysis were also found, including enzymatic machinery of the Leloir pathway. The transcriptome appeared to be regulated by carbon catabolite repression. Although substrate-specific carbohydrate transporters and hydrolases were regulated at the transcriptional level, genes encoding regulatory proteins CcpA, Hpr, HprK/P, and EI were consistently highly expressed. Genes central to glycolysis were among the most highly expressed in the genome. Collectively, microarray data revealed that coordinated and regulated transcription of genes involved in sugar uptake and metabolism is based on the specific carbohydrate provided. L. acidophilus's adaptability to environmental conditions likely contributes to its competitive ability for limited carbohydrate sources available in the human gastrointestinal tract.

ATP-Binding Cassette Transporters↗

PubMed2025

DNA methylation controls the expression of tanshinone synthesis genes and the tanshinone accumulation in Salvia miltiorrhiza and Salvia bowleyana.

DNA methylation plays pivotal roles in regulating gene expression and the secondary metabolism in plants. Salvia miltiorrhiza and Salvia bowleyana are traditional Chinese medicinal plants with roots enriched with tanshinone components. However, the regulatory mechanism of DNA methylation on tanshinone production remains elusive. Here, we analyzed 30-day-old hairy roots of S. miltiorrhiza and S. bowleyana using targeted high-performance liquid chromatography analysis and found significantly higher tanshinone content in S. miltiorrhiza. Whole-genome bisulfite sequencing revealed elevated DNA methylation levels in S. miltiorrhiza, potentially due to the upregulation of methylation-related genes, including DOMAINS REARRANGED METHYLTRANSFERASE 1 (DRM1), DECREASE IN DNA METHYLATION 1 (DDM1), CHROMOMETHYLASE 2 (CMT1), and CHROMOMETHYLASE 3 (CMT3), alongside the low expression of the demethylase gene REPRESSOR OF SILENCING 1 (ROS1) in S. miltiorrhiza. Additionally, four genes that are involved in tanshinone biosynthesis, including 1-DEOXY-D-XYLULOSE-5-PHOSPHATE REDUCTASE (DXS1), GERANYLGERANYL DIPHOSPHATE SYNTHASE (GGPPS2), 4-HYDROXY-3-METHYLBUT-2-ENYL PYROPHOSPHATE REDUCTASE (HDR2), and COPALYL PYROPHOSPHATE SYNTHASE (CPS3), showed lower methylation levels in the promoters of DXS1, GGPPS2, and CPS3 and a higher DNA methylation level in the gene body of HDR2 in S. miltiorrhiza, which may lead to their high expression and the accumulation of tanshinones. Consistently, overexpression of the SmCMT3 in S. miltiorrhiza significantly reduced the contents of cryptotanshinone, tanshinone I, and tanshinone IIA. Transcriptomic and methylome analyses confirmed that the expression levels of the tanshinone biosynthesis-related genes, including SmMK, SmCPS1, SmDXS2, and SmAACT1, were correlated with their promoter or gene body DNA methylation levels. Our findings reveal that DNA methylation critically regulates tanshinone biosynthesis in S. miltiorrhiza and S. bowleyana, offering valuable insights for breeding.

Abietanes↗

PubMed2005

Genomic analysis of anaerobic respiration in the archaeon Halobacterium sp. strain NRC-1: dimethyl sulfoxide and trimethylamine N-oxide as terminal electron acceptors.

We have investigated anaerobic respiration of the archaeal model organism Halobacterium sp. strain NRC-1 by using phenotypic and genetic analysis, bioinformatics, and transcriptome analysis. NRC-1 was found to grow on either dimethyl sulfoxide (DMSO) or trimethylamine N-oxide (TMAO) as the sole terminal electron acceptor, with a doubling time of 1 day. An operon, dmsREABCD, encoding a putative regulatory protein, DmsR, a molybdopterin oxidoreductase of the DMSO reductase family (DmsEABC), and a molecular chaperone (DmsD) was identified by bioinformatics and confirmed as a transcriptional unit by reverse transcriptase PCR analysis. dmsR, dmsA, and dmsD in-frame deletion mutants were individually constructed. Phenotypic analysis demonstrated that dmsR, dmsA, and dmsD are required for anaerobic respiration on DMSO and TMAO. The requirement for dmsR, whose predicted product contains a DNA-binding domain similar to that of the Bat family of activators (COG3413), indicated that it functions as an activator. A cysteine-rich domain was found in the dmsR gene, which may be involved in oxygen sensing. Microarray analysis using a whole-genome 60-mer oligonucleotide array showed that the dms operon is induced during anaerobic respiration. Comparison of dmsR+ and DeltadmsR strains by use of microarrays showed that the induction of the dmsEABCD operon is dependent on a functional dmsR gene, consistent with its action as a transcriptional activator. Our results clearly establish the genes required for anaerobic respiration using DMSO and TMAO in an archaeon for the first time.

Anaerobiosis↗

PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗

PubMed2004

Toward large-scale modeling of the microbial cell for computer simulation.

In the post-genomic era, the large-scale, systematic, and functional analysis of all cellular components using transcriptomics, proteomics, and metabolomics, together with bioinformatics for the analysis of the massive amount of data generated by these "omics" methods are the focus of intensive research activities. As a consequence of these developments, systems biology, whose goal is to comprehend the organism as a complex system arising from interactions between its multiple elements, becomes a more tangible objective. Mathematical modeling of microorganisms and subsequent computer simulations are effective tools for systems biology, which will lead to a better understanding of the microbial cell and will have immense ramifications for biological, medical, environmental sciences, and the pharmaceutical industry. In this review, we describe various types of mathematical models (structured, unstructured, static, dynamic, etc.), of microorganisms that have been in use for a while, and others that are emerging. Several biochemical/cellular simulation platforms to manipulate such models are summarized and the E-Cell system developed in our laboratory is introduced. Finally, our strategy for building a "whole cell metabolism model", including the experimental approach, is presented.

Biotechnology↗

PubMed2005

Changes of anti-oxidative enzymes and membrane peroxidation for soil water deficits among 10 wheat genotypes at seedling stage.

Drought is one of the major factors limiting crop production globally, with increasing global climate change making the situation more serious. Wheat is the staple food for more than 35% of world population, so wheat anti-drought physiology study is of importance to wheat production and biological breeding for the sake of coping with abiotic and biotic conditions. Much research is involved in this hot topic, but the pace of progress is not so large because of drought resistance being a multiple-gene-control quantitative character and wheat genome being larger (16,000 Mb). On the other hand, stress adaptive mechanisms are quite different, with stress degree, time course, materials, and experimental plots, thus increasing the complexity of the issue in question. Additionally, a little study is related to the whole life circle of wheat, which cannot provide a comprehensive understanding of its anti-drought machinery. We selected 10 kinds of wheat genotypes as materials, which have potential to be applied in practice, and measured relative change of anti-oxidative enzymes and membrane peroxidation through wheat whole growth-developmental circle (i.e. seedling, tillering and maturing). Here, we firstly reported the results of seedling stage as follows: (1) 10 wheat genotypes can be grouped into three kinds (A-C, respectively) according to their changing trend of the measured indices; (2) A performed better resistance drought under the condition of treatment level 1 (appropriate level), whose activities of anti-oxidative enzymes (POD, SOD, CAT) were higher and MDA lower and chlorophyll a+b higher; (3) B exhibited stronger anti-drought under treatment level 2 (light stress level), whose activities of anti-oxidative enzymes were higher, MDA lower and chlorophyll higher; (4) C expressed anti-drought to some extent under treatment level 3 (serious stress), whose activities of anti-oxidative enzymes were stronger, MDA lower and chlorophyll higher; (5) these results demonstrated that different wheat genotypes have different physiological mechanisms to adapt themselves to changing drought stress, whose molecular basis is discrete gene expression profiling (transcriptom); (6) our results also showed that the concept accepted by most researchers, 70-75% QF is a proper supply for plants, was doubted, because this level could not reflect the true suitable level of wheat. The study in this respect is the key to wheat anti-drought and biological saving-water; (7) our research can provide insights into physiological mechanisms of crop anti-drought and direct practical materials for wheat anti-drought breeding.

Antioxidants↗

PubMed2004

Identification of changes in the transcriptome profile of human hepatoma HepG2 cells stimulated with interleukin-1 beta.

Interleukin-1 (IL-1) is the principal pro-inflammatory cytokine participating in the initiation of acute phase response. Human hepatoma HepG2 cells were exposed to 15 ng/ml of IL-1beta for times ranging from 1 to 24 h and the total RNA was isolated. Then cDNA was obtained and used for differential display with 10 arbitrary primers and 9 oligo(dT) primers designed by Clontech. Validation of observed changes of differentially expressed known genes was carried out by RT-PCR or Northern blot analysis. Out of 90 cDNA strands modulated by IL-1, 46 have been successfully reamplified and their sequencing indicates that they represent 36 different cDNA templates. By GenBank search, 26 cDNA clones were identified as already known genes while 10 showed no homology to any known gene. The identified transcripts modulated by IL-1 in HepG2 cells code for intracellular proteins of various function: trafficking/motor proteins (3 genes), proteins participating in the translation machinery or posttranscriptional/posttranslational modifications (7 genes), proteases (1 gene), proteins involved in metabolism (6 genes), activity modulators (3 genes), proteins of the cell cycle machinery (2 genes) and those functionally unclassified (4 genes). Majority of genes responded to IL-1 within 1 to 6 h (early genes), while two were late response genes (12-24 h) and four showed prolonged response over the whole 24-h period. Most of the observed changes of expression were in the range of two- to threefold increase in comparison to control untreated cells. Among identified genes, no typical secretory acute phase protein was found. The obtained results suggest that IL-1 affects the expression of several genes in HepG2 cells, especially those engaged in the synthesis and modifications of proteins.

Carcinoma, Hepatocellular↗

PubMed2026

The genome of Thesium ramosoides (Santalales) reveals evolutionary dynamics associated with parasitism and alpine adaptation.

Plant species adapting to complex environments experience contrasting selection pressures that drive the expansion and contraction of different gene families. However, few studies have investigated simultaneous genomic responses to such diverse selective forces. Here, we generate a high-quality genome assembly for the hemiparasitic plant Thesium ramosoides, the first for the largest genus in the Santalales, and explore the genomic basis underlying the evolution of parasitism and alpine adaptation. Unlike many other parasitic plants, the Thesium genome has not undergone additional rounds of whole-genome duplication, making it particularly tractable for studying gene family evolution. Our analyses reveal substantial loss of photosynthesis-related genes and contraction of biotic defense gene families, likely reflecting adaptation to a hemiparasitic lifestyle and reduced pathogen pressure at high altitudes. The absence of key root hair development genes correlates with the degenerate root hair phenotype observed in this species. Furthermore, hallmarks of high-altitude adaptation include the expansion of gene families involved in responses to hypoxia. Notably, expansion of gene families associated with meristem development is consistent with the presence of below-ground crown buds that enable rapid regeneration after mountain fires. Unexpectedly, we detected tandem duplication and diversification of the strigolactone receptor gene D14, which regulates secondary shoot formation, but not of its ancestral paralog KAI2, which mediates seed germination in response to the smoke-derived compound karrikin. This finding suggests divergent signaling mechanisms underlying fire adaptation across different parasitic plant lineages. By integrating time-series transcriptomic data, we propose a post-fire "defense first, repair later, recovery last" model, in which resources are reallocated from immediate defense to rapid repair and ultimately to long-term recovery, to explain the adaptation of T. ramosoides to fire-prone habitats. Our study provides critical insights into the complex and contrasting genomic dynamics that drive adaptation to multiple co-occurring selection pressures.

Genome, Plant↗

PubMed2002

Marked increase in CC chemokine gene expression in both human and mouse mast cell transcriptomes following Fcepsilon receptor I cross-linking: an interspecies comparison.

Rodent mast cells (MCs) are common experimental tools but are somewhat different from their human counterparts in their responses to certain cytokines and drugs. We examined the expression of more than 10 000 distinct genes in human and mouse cultured MCs using high-density oligonucleotide probe arrays to find molecules similarly regulated and expressed by the 2 MC types. After stimulation via high-affinity Fcepsilon receptor I (FcepsilonRI), the transcriptional levels of several CC chemokines were markedly increased, and I-309 (CCL1), macrophage inflammatory protein-1alpha (MIP-1alpha) (CCL3) and MIP-1beta (CCL4) were found among the 10 most increased human and mouse transcripts from approximately 12 000 genes (including some expressed sequence tags). In addition, a costimulatory molecule that was originally found on the membrane of activated T cells, 4-1BB (CD137), was found among the 10 most increased transcripts. The FcepsilonRI-induced expression of CC chemokines and 4-1BB was also detected at the protein level in both MC types. The conservation of these responses suggests that MCs play a crucial role in recruitment of various CCR-expressing cells into the tissue in a manner dependent on immunoglobin E, and that FcepsilonRI-mediated induction of several CC chemokines and 4-1BB is highly conserved between human and mouse. Interspecies comparison studies at the whole genome expression level should be useful for the interpretation of experimental data obtained in animal models of human pathobiology.

Animals↗

PubMed2004

Role for glyoxalase I in Alzheimer's disease.

P301L mutant tau transgenic mice develop neurofibrillary tangles, a histopathologic hallmark of Alzheimer's disease and frontotemporal dementia (FTDP-17). To identify differentially expressed genes and to gain insight into pathogenic mechanisms, we performed a stringent analysis of the microarray dataset obtained with RNA from whole brains of P301L mutant mice and identified a single up-regulated gene, glyoxalase I. This enzyme plays a critical role in the detoxification of dicarbonyl compounds and thereby reduces the formation of advanced glycation end products. In situ hybridization analysis revealed expression of glyoxalase I in all brain areas analyzed, both in transgenic and control mice. However, levels of glyoxalase I protein were significantly elevated in P301L brains, as shown by Western blot analysis and immunohistochemistry. Moreover, a glyoxalase I-specific antiserum revealed many intensely stained flame-shaped neurons in Alzheimer's disease brain compared with brains from nondemented controls. In addition, we examined a single nucleotide polymorphism predicting a nonconservative amino acid substitution at position 111 (E111A) in ethnically independent populations. We identified significant and consistent deviations from Hardy-Weinberg equilibrium, which points to the presence of selection forces. The E111A single nucleotide polymorphism was not associated with the risk for Alzheimer's disease in the overall population. Together, our data demonstrate the potential of transcriptomics applied to animal models of human diseases. They suggest a previously unidentified role for glyoxalase I in neurodegenerative disease.

Alzheimer Disease↗

PubMed2005

A microarray data-based semi-kinetic method for predicting quantitative dynamics of genetic networks.

BACKGROUND: Elucidating the dynamic behaviour of genetic regulatory networks is one of the most significant challenges in systems biology. However, conventional quantitative predictions have been limited to small networks because publicly available transcriptome data has not been extensively applied to dynamic simulation. RESULTS: We present a microarray data-based semi-kinetic (MASK) method which facilitates the prediction of regulatory dynamics of genetic networks composed of recurrently appearing network motifs with reasonable accuracy. The MASK method allows the determination of model parameters representing the contribution of regulators to transcription rate from time-series microarray data. Using a virtual regulatory network and a Saccharomyces cerevisiae ribosomal protein gene module, we confirmed that a MASK model can predict expression profiles for various conditions as accurately as a conventional kinetic model. CONCLUSION: We have demonstrated the MASK method for the construction of dynamic simulation models of genetic networks from time-series microarray data, initial mRNA copy number and first-order degradation constants of mRNA. The quantitative accuracy of the MASK models has been confirmed, and the results indicated that this method enables the prediction of quantitative dynamics in genetic networks composed of commonly used network motifs, which cover considerable fraction of the whole network.

Amino Acid Motifs↗

PubMed2006

Computational models with thermodynamic and composition features improve siRNA design.

BACKGROUND: Small interfering RNAs (siRNAs) have become an important tool in cell and molecular biology. Reliable design of siRNA molecules is essential for the needs of large functional genomics projects. RESULTS: To improve the design of efficient siRNA molecules, we performed a comparative, thermodynamic and correlation analysis on a heterogeneous set of 653 siRNAs collected from the literature. We used this training set to select siRNA features and optimize computational models. We identified 18 parameters that correlate significantly with silencing efficiency. Some of these parameters characterize only the siRNA sequence, while others involve the whole mRNA. Most importantly, we derived an siRNA position-dependent consensus, and optimized the free-energy difference of the 5' and 3' terminal dinucleotides of the siRNA antisense strand. The position-dependent consensus is based on correlation and t-test analyses of the training set, and accounts for both significantly preferred and avoided nucleotides in all sequence positions. On the training set, the two parameters' correlation with silencing efficiency was 0.5 and 0.36, respectively. Among other features, a dinucleotide content index and the frequency of potential targets for siRNA in the mRNA added predictive power to our model (R = 0.55). We showed that our model is effective for predicting the efficiency of siRNAs at different concentrations. We optimized a neural network model on our training set using three parameters characterizing the siRNA sequence, and predicted efficiencies for the test siRNA dataset recently published by Novartis. On this validation set, the correlation coefficient between predicted and observed efficiency was 0.75. Using the same model, we performed a transcriptome-wide analysis of optimal siRNA targets for 22,600 human mRNAs. CONCLUSION: We demonstrated that the properties of the siRNAs themselves are essential for efficient RNA interference. The 5' ends of antisense strands of efficient siRNAs are U-rich and possess a content similarity to the pyrimidine-rich oligonucleotides interacting with the polypurine RNA tracks that are recognized by RNase H. The advantage of our method over similar methods is the small number of parameters. As a result, our method requires a much smaller training set to produce consistent results. Other mRNA features, though expensive to compute, can slightly improve our model.

Artificial Intelligence↗

PubMed2026

Deciphering the Role of LNX2 as a Potential Contributor to Neurodevelopmental Disorders.

BACKGROUND/OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by a complex and multifactorial genetic architecture. In this study, we report a male patient, born to non-consanguineous healthy parents, presenting with ADHD and oppositional defiant disorder (ODD). METHODS: Trio-based whole-exome sequencing (WES) was performed in the proband and both parents. Variant classification was performed according to American College of Medical Genetics and Genomics (ACMG) guidelines, and the potential pathogenicity of the identified variant was further assessed through multiple in silico prediction algorithms and protein structural analyses. RESULTS: WES identified a homozygous variant in the LNX2 gene (NM_153371.4: c.1165G>A, p.Ala389Thr), classified as a variant of uncertain significance (VUS) and supported by multiple in silico predictions. LNX2 is expressed during brain development and encodes an E3 ubiquitin ligase involved in neuronal differentiation and synaptic function. The identified variant is located within the PDZ2 domain, a functionally relevant region involved in protein-protein interactions. Although the variant is reported in population databases (gnomAD ID: rs148429804), it has not been associated with any clinical phenotype, and its presence in the homozygous state has been reported only once, remaining extremely rare and lacking clinical annotation. Structural modelling predicted localized rearrangement of the hydrogen-bonding network within the PDZ2 domain without major conformational changes. Integrative transcriptomic, and single-cell analyses further supported the biological relevance of LNX2 in neurodevelopment, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs. CONCLUSION: Although the identified LNX2 variant cannot be considered causative for the patient's phenotype and a definitive disease-gene relationship cannot be established based on a single individual, the complementary genetic, structural, and transcriptomic findings support the biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders. Additional independent patients and functional studies will be required to clarify its contribution to human disease.

Child↗

PubMed2006

Microarray and genetic analysis of electron transfer to electrodes in Geobacter sulfurreducens.

Whole-genome analysis of gene expression in Geobacter sulfurreducens revealed 474 genes with transcript levels that were significantly different during growth with an electrode as the sole electron acceptor versus growth on Fe(III) citrate. The greatest response was a more than 19-fold increase in transcript levels for omcS, which encodes an outer-membrane cytochrome previously shown to be required for Fe(III) oxide reduction. Quantitative reverse transcription polymerase chain reaction and Northern analyses confirmed the higher levels of omcS transcripts, which increased as power production increased. Deletion of omcS inhibited current production that was restored when omcS was expressed in trans. Transcript expression and genetic analysis suggested that OmcE, another outer-membrane cytochrome, is also involved in electron transfer to electrodes. Surprisingly, genes for other proteins known to be important in Fe(III) reduction such as the outer-membrane c-type cytochrome, OmcB, and the electrically conductive pilin "nanowires" did not have higher transcript levels on electrodes, and deletion of the relevant genes did not inhibit power production. Changes in the transcriptome suggested that cells growing on electrodes were subjected to less oxidative stress than cells growing on Fe(III) citrate and that a number of genes annotated as encoding metal efflux proteins or proteins of unknown function may be important for growth on electrodes. These results demonstrate for the first time that it is possible to evaluate gene expression, and hence the metabolic state, of microorganisms growing on electrodes on a genome-wide basis and suggest that OmcS, and to a lesser extent OmcE, are important in electron transfer to electrodes. This has important implications for the design of electrode materials and the genetic engineering of microorganisms to improve the function of microbial fuel cells.

Bacterial Outer Membrane Proteins↗