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PubMed1989

Mouse embryonic stem cells and reporter constructs to detect developmentally regulated genes.

A strategy was devised for identifying regions of the mouse genome that are transcriptionally active in a temporally and spatially restricted manner during development. The approach is based on the introduction into embryonic stem cells of two types of lacZ reporter constructs that can be activated by flanking mouse genomic sequences. Embryonic stem cells containing the lacZ constructs were used to produce chimaeric mice. Developmental regulation of lacZ expression occurred at a high frequency. Molecular cloning of the flanking endogenous genes and introduction of these potential insertional mutations into the mouse germ line should provide an efficient means of identifying and mutating novel genes important for the control of mammalian development.

Animals↗

PubMed2005

Optimization of resolution and sensitivity of 4D NOESY using multi-dimensional decomposition.

Highly resolved multi-dimensional NOE data are essential for rapid and accurate determination of spatial protein structures such as in structural genomics projects. Four-dimensional spectra contain almost no spectral overlap inherently present in lower dimensionality spectra and are highly amenable to application of automated routines for spectral resonance location and assignment. However, a high resolution 4D data set using conventional uniform sampling usually requires unacceptably long measurement time. Recently we have reported that the use of non-uniform sampling and multi-dimensional decomposition (MDD) can remedy this problem. Here we validate accuracy and robustness of the method, and demonstrate its usefulness for fully protonated protein samples. The method was applied to 11 kDa protein PA1123 from structural genomics pipeline. A systematic evaluation of spectral reconstructions obtained using 15-100% subsets of the complete reference 4D 1H-13C-13C-1H NOESY spectrum has been performed. With the experimental time saving of up to six times, the resolution and the sensitivity per unit time is shown to be similar to that of the fully recorded spectrum. For the 30% data subset we demonstrate that the intensities in the reconstructed and reference 4D spectra correspond with a correlation coefficient of 0.997 in the full range of spectral amplitudes. Intensities of the strong, middle and weak cross-peaks correlate with coefficients 0.9997, 0.9965, and 0.83. The method does not produce false peaks. 2% of weak peaks lost in the 30% reconstruction is in line with theoretically expected noise increase for the shorter measurement time. Together with good accuracy in the relative line-widths these translate to reliable distance constrains derived from sparsely sampled, high resolution 4D NOESY data.

Fourier Analysis↗

PubMed2000

High throughput cellular localization of specific plant mRNAs by liquid-phase in situ reverse transcription-polymerase chain reaction of tissue sections.

Advances in high throughput DNA sequencing and bioinformatic gene discovery far outpace our ability to analyze gene function, necessitating development of more efficient means to examine expression at the cellular level. Here we present a polymerase chain reaction-based method to detect mRNA species in situ in which essentially all of the steps are carried out in liquid phase in a 96-well microtiter tray and only the final signal detection is performed on a microscope slide. We demonstrate the sensitivity of the method by the cellular localization of mRNA for the Tkn2 transcription factor in a wide variety of plant tissues, and its selectivity in discriminating a single gene family member by the in situ localization of rbcs3 transcripts. Furthermore, we demonstrate the utility of the in-well in situ method in detecting FDL and IFL1 transcripts in Arabidopsis sections, thus establishing the method as a tool to determine spatial expression pattern of sequences obtained from genomic sequencing projects. Being amenable to robotic processing, in-well in situ reverse transcription-polymerase chain reaction permits a great enhancement in the number of tissue samples that can be processed. Consequently, this method may become a powerful tool for functional genomics studies, permitting the cellular site of transcription of large numbers of sequences obtained from databases to be rapidly established.

Arabidopsis↗

PubMed2006

A rapidly evolving secretome builds and patterns a sea shell.

BACKGROUND: Instructions to fabricate mineralized structures with distinct nanoscale architectures, such as seashells and coral and vertebrate skeletons, are encoded in the genomes of a wide variety of animals. In mollusks, the mantle is responsible for the extracellular production of the shell, directing the ordered biomineralization of CaCO3 and the deposition of architectural and color patterns. The evolutionary origins of the ability to synthesize calcified structures across various metazoan taxa remain obscure, with only a small number of protein families identified from molluskan shells. The recent sequencing of a wide range of metazoan genomes coupled with the analysis of gene expression in non-model animals has allowed us to investigate the evolution and process of biomineralization in gastropod mollusks. RESULTS: Here we show that over 25% of the genes expressed in the mantle of the vetigastropod Haliotis asinina encode secreted proteins, indicating that hundreds of proteins are likely to be contributing to shell fabrication and patterning. Almost 85% of the secretome encodes novel proteins; remarkably, only 19% of these have identifiable homologues in the full genome of the patellogastropod Lottia scutum. The spatial expression profiles of mantle genes that belong to the secretome is restricted to discrete mantle zones, with each zone responsible for the fabrication of one of the structural layers of the shell. Patterned expression of a subset of genes along the length of the mantle is indicative of roles in shell ornamentation. For example, Has-sometsuke maps precisely to pigmentation patterns in the shell, providing the first case of a gene product to be involved in molluskan shell pigmentation. We also describe the expression of two novel genes involved in nacre (mother of pearl) deposition. CONCLUSION: The unexpected complexity and evolvability of this secretome and the modular design of the molluskan mantle enables diversification of shell strength and design, and as such must contribute to the variety of adaptive architectures and colors found in mollusk shells. The composition of this novel mantle-specific secretome suggests that there are significant molecular differences in the ways in which gastropods synthesize their shells.

Animal Structures↗

PubMedDate not supplied

[The regulatory mechanisms of early embryogenesis in the mouse].

The mechanisms involved in the regulation of preimplantation mammalian development have been considered using the example of mouse embryos. The role of four factors affecting the program of early embryogenesis is discussed: nucleocytoplasmic interactions, "maternal" control of development, cell-to-cell interactions, and genomic imprinting. The current concepts of the spatial and temporal regulation of developmental processes have been reviewed, as well as the perspectives of some trends in the experimental embryology of mammals.

Animals↗

PubMed1998

Prolonged and increasing expression of Fos related antigens in the hippocampus of adjuvant arthritic rats.

OBJECTIVE: To study the influence of chronic arthritis on induction of Fos related antigens in the brain. METHODS: We studied 3 different experimental rat groups: rats with adjuvant induced arthritis (AR), paraffin oil (vehicle) injected rats (VR), and normal control rats (NCR). At 2, 4, and 6 days after and 2.4, 8, 12, and 18 weeks after inoculation, sections from the hippocampus were immunostained with antibodies against c-Fos and other Fos related antigens (FRA). Immunostained neurons in CA1, CA2, CA3, and dentate gyrus were counted and their expression pattern was studied. To relate the expression of FRA to the upregulation of an opioid peptide, leucine-enkephalin (Leu-enk), double immunohistochemistry for FRA and Leu-enk was performed. RESULTS: Brain samples of the NCR group exhibited very few FRA immunoreactive cells. All the 4 regions of AR and VR hippocampus had upregulated FRA expression in very early stages of arthritis induction. Hippocampus of the VR rats showed generally diminished FRA expression in later stages of arthritis. Hippocampus of the AR rats, in contrast, showed increased FRA expression in the later stages. This increased expression of FRA topographically and chronologically coincided with upregulation of Leu-enk. CONCLUSION: Longterm arthritis presumably caused prolonged and increased expression of FRA. Increased expression of Leu-enk, which temporally and spatially colocalized with FRA, may represent longterm genomic changes that occur in patients with rheumatoid arthritis.

Animals↗

PubMed2005

Vestige: maximum likelihood phylogenetic footprinting.

BACKGROUND: Phylogenetic footprinting is the identification of functional regions of DNA by their evolutionary conservation. This is achieved by comparing orthologous regions from multiple species and identifying the DNA regions that have diverged less than neutral DNA. Vestige is a phylogenetic footprinting package built on the PyEvolve toolkit that uses probabilistic molecular evolutionary modelling to represent aspects of sequence evolution, including the conventional divergence measure employed by other footprinting approaches. In addition to measuring the divergence, Vestige allows the expansion of the definition of a phylogenetic footprint to include variation in the distribution of any molecular evolutionary processes. This is achieved by displaying the distribution of model parameters that represent partitions of molecular evolutionary substitutions. Examination of the spatial incidence of these effects across regions of the genome can identify DNA segments that differ in the nature of the evolutionary process. RESULTS: Vestige was applied to a reference dataset of the SCL locus from four species and provided clear identification of the known conserved regions in this dataset. To demonstrate the flexibility to use diverse models of molecular evolution and dissect the nature of the evolutionary process Vestige was used to footprint the Ka/Ks ratio in primate BRCA1 with a codon model of evolution. Two regions of putative adaptive evolution were identified illustrating the ability of Vestige to represent the spatial distribution of distinct molecular evolutionary processes. CONCLUSION: Vestige provides a flexible, open platform for phylogenetic footprinting. Underpinned by the PyEvolve toolkit, Vestige provides a framework for visualising the signatures of evolutionary processes across the genome of numerous organisms simultaneously. By exploiting the maximum-likelihood statistical framework, the complex interplay between mutational processes, DNA repair and selection can be evaluated both spatially (along a sequence alignment) and temporally (for each branch of the tree) providing visual indicators to the attributes and functions of DNA sequences.

Algorithms↗

PubMed2005

MAPPER: a search engine for the computational identification of putative transcription factor binding sites in multiple genomes.

BACKGROUND: Cis-regulatory modules are combinations of regulatory elements occurring in close proximity to each other that control the spatial and temporal expression of genes. The ability to identify them in a genome-wide manner depends on the availability of accurate models and of search methods able to detect putative regulatory elements with enhanced sensitivity and specificity. RESULTS: We describe the implementation of a search method for putative transcription factor binding sites (TFBSs) based on hidden Markov models built from alignments of known sites. We built 1,079 models of TFBSs using experimentally determined sequence alignments of sites provided by the TRANSFAC and JASPAR databases and used them to scan sequences of the human, mouse, fly, worm and yeast genomes. In several cases tested the method identified correctly experimentally characterized sites, with better specificity and sensitivity than other similar computational methods. Moreover, a large-scale comparison using synthetic data showed that in the majority of cases our method performed significantly better than a nucleotide weight matrix-based method. CONCLUSION: The search engine, available at http://mapper.chip.org, allows the identification, visualization and selection of putative TFBSs occurring in the promoter or other regions of a gene from the human, mouse, fly, worm and yeast genomes. In addition it allows the user to upload a sequence to query and to build a model by supplying a multiple sequence alignment of binding sites for a transcription factor of interest. Due to its extensive database of models, powerful search engine and flexible interface, MAPPER represents an effective resource for the large-scale computational analysis of transcriptional regulation.

Algorithms↗

PubMed2001

Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes.

BACKGROUND: The availability of complete genome sequences enables all the members of a gene family to be identified without limitations imposed by temporal, spatial or quantitative aspects of mRNA expression. Using the nearly completed human genome sequence, we combined in silico and experimental approaches to define the complete human nuclear receptor (NR) set. This information was used to carry out a comparative genomic study of the NR superfamily. RESULTS: Our analysis of the human genome identified two novel NR sequences. Both these contained stop codons within the coding regions, indicating that both are pseudogenes. One (HNF4 gamma-related) contained no introns and expressed no detectable mRNA, whereas the other (FXR-related) produced mRNA at relatively high levels in testis. If translated, the latter is predicted to encode a short, non-functional protein. Our analysis indicates that there are fewer than 50 functional human NRs, dramatically fewer than in Caenorhabditis elegans and about twice as many as in Drosophila. Using the complete human NR set we made comparisons with the NR sets of C. elegans and Drosophila. Searches for the >200 NRs unique to C. elegans revealed no human homologs. The comparative analysis also revealed a Drosophila member of NR subfamily NR3, confirming an ancient metazoan origin for this subfamily. CONCLUSIONS: This work provides the basis for new insights into the evolution and functional relationships of NR superfamily members.

Amino Acid Sequence↗

PubMed2026

Genome-informed qPCR tracking revealed preferential persistence of Bacillus subtilis BS9 in the broiler chicken gastrointestinal tract.

This study aimed to develop a strain-specific quantitative PCR (qPCR) assay for Bacillus subtilis BS9 and characterize its persistence and spatial distribution in the broiler chicken gastrointestinal tract. Whole-genome sequencing and comparative genomic analysis identified a unique 110-bp sequence within a strain-specific genomic island, which was used to design a highly specific qPCR assay with excellent efficiency and sensitivity. In a 14-day in vivo trial, broiler chicks receiving daily oral doses of BS9 were analyzed using both culture-based methods and the newly developed qPCR. The assay was applied qualitatively, presence or absence, to detect BS9 in intestinal samples. BS9 was detected exclusively in the duodenum, jejunum, and cecum, with no presence in the gizzard or ileum. These findings demonstrate that BS9 exhibits region-specific persistence in the gut, likely reflecting adaptation to distinct physiological niches, which may contribute to its probiotic mechanisms.IMPORTANCEThis work provides the first detailed account of B. subtilis BS9's spatial persistence in poultry, revealing preferential adherence to specific intestinal regions. The strain-specific qPCR assay developed here offers a precise, culture-independent tool for tracking BS9 in complex gut environments. These insights into the genetic basis and tissue tropism of BS9 persistence advance our understanding of probiotic-host interactions and establish a framework for characterizing novel probiotic strains.

Bacillus subtilis↗

PubMed2006

Interphase chromosome positioning affects the spectrum of radiation-induced chromosomal aberrations.

In interphase, chromosomes occupy defined nuclear volumes known as chromosome territories. To probe the biological consequences of the described nonrandom spatial positioning of chromosome territories in human lymphocytes, we performed an extensive FISH-based analysis of ionizing radiation-induced interchanges involving chromosomes 1, 4, 18 and 19. Since the probability of exchange formation depends strongly on the spatial distance between the damage sites in the genome, a preferential formation of exchanges between proximally positioned chromosomes is expected. Here we show that the spectrum of interchanges deviates significantly from one expected based on random chromosome positioning. Moreover, the observed exchange interactions between specific chromosome pairs as well as the interactions between homologous chromosomes are consistent with the proposed gene density-related radial distribution of chromosome territories. The differences between expected and observed exchange frequencies are more pronounced after exposure to densely ionizing neutrons than after exposure to sparsely ionizing X rays. These experiments demonstrate that the spatial positioning of interphase chromosomes affects the spectrum of chromosome rearrangements.

Cells, Cultured↗

PubMed2026

Spatiotemporal patterns of Rift Valley fever virus in Africa: a retrospective genomic epidemiology and phylodynamic modelling study.

BACKGROUND: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing outbreaks in humans and ruminants across Africa and the Arabian Peninsula. Originally restricted to the Great Rift Valley, RVFV has expanded geographically, prompting its classification by WHO as a pathogen of pandemic potential. We investigated the evolutionary and spatial dynamics of RVFV across Africa. METHODS: We used genomic data generated at the International Livestock Research Institute Nairobi genomic laboratory (BioProject PRJNA1106221) and combined with publicly available datasets retrieved from the National Center for Biotechnology (NCBI) GenBank nucleotide database. In retrieving RVFV genome sequences from the NCBI GenBank, we applied the search terms "Rift Valley fever virus segment L AND 6404[SLEN]", "Rift Valley fever virus segment M AND 3885[SLEN]", and "Rift Valley fever virus segment S AND 1520:1690[SLEN]" for L (Large), M (Medium), and S (Small) segments, respectively. For sequences without additional spatiotemporal information, we searched PubMed to extract the associated sequence metadata. We performed molecular clock analysis, phylogenetic inference, phylodynamic modelling (continuous phylogeographic reconstruction), and landscape phylogeography on the three RVFV genome segments (L, M, and S). We aimed to assess evolutionary rates, dispersal patterns, and environmental drivers. Focus was placed on lineage C, the most widely distributed variant. FINDINGS: The global dataset used in this study consisted of large (n=236), medium (n=237), and small (n=247), which were further filtered to exclude potential reassortants and vaccine strains. Genome sequences retrieved from NCBI GenBank database comprised large (n=180), medium (n=184), and small (n=202). The genome sequences from retrospective human and livestock isolates comprised large (n=56), medium (n=53), and small (n=45) collected in Burundi (2018), Kenya (2007, 2018, 2019, 2021, and 2022), and Rwanda (2018 and 2022). Our dataset revealed that RVFV exhibited low overall genetic diversity. Lineage C, however, showed evidence of active evolution, with substitution rates ranging from 3·58 × 10-4 to 9·76 × 10-4 substitutions per site per year. This lineage probably originated in Zimbabwe in the mid-1970s and has since expanded across eastern and southern Africa. Phylogeographic reconstructions revealed rapid spread, with diffusion coefficients exceeding 50 000 km2 per year. INTERPRETATION: Lineage C appears capable of establishing endemic transmission in new regions, with ongoing diversification observed during interepidemic periods. These observations reinforce the value of continuous genomic surveillance, particularly during cryptic transmission phases when adaptive mutations might emerge. Although further evidence is needed, observed trends in climate variability and land-use change point to the potential benefit of targeted surveillance in settings that could be at increased risk, including urban centres and wetlands. FUNDING: This work was supported by the German Federal Ministry for Economic Cooperation and Development, the Rockefeller Foundation, and the Africa Centres for Disease Control and Prevention.

Rift Valley fever virus↗

PubMed2003

Vertebrate evolution: doubling and shuffling with a full deck.

The number and role of whole-genome duplications in vertebrate evolution has intrigued evolutionary biologists since Ohno first proposed genome duplication as the force driving the 'big leap' in vertebrate morphological innovation. Attempts to resolve these issues have been thwarted by small and noisy datasets, and by lack of computational accuracy and statistical rigor. Recently, Ken Wolfe and colleagues presented a genome-scale, statistically rigorous analysis of evidence based on the spatial organization of duplicated genes, as well as estimates of duplication times. Their results provide the strongest evidence to date of large-scale duplication throughout the vertebrate genome, consistent with at least one whole-genome duplication.

Animals↗

PubMed2003

Phylogenetically and spatially conserved word pairs associated with gene-expression changes in yeasts.

BACKGROUND: Transcriptional regulation in eukaryotes often involves multiple transcription factors binding to the same transcription control region, and to understand the regulatory content of eukaryotic genomes it is necessary to consider the co-occurrence and spatial relationships of individual binding sites. The determination of conserved sequences (often known as phylogenetic footprinting) has identified individual transcription factor binding sites. We extend this concept of functional conservation to higher-order features of transcription control regions. RESULTS: We used the genome sequences of four yeast species of the genus Saccharomyces to identify sequences potentially involved in multifactorial control of gene expression. We found 989 potential regulatory 'templates': pairs of hexameric sequences that are jointly conserved in transcription regulatory regions and also exhibit non-random relative spacing. Many of the individual sequences in these templates correspond to known transcription factor binding sites, and the sets of genes containing a particular template in their transcription control regions tend to be differentially expressed in conditions where the corresponding transcription factors are known to be active. The incorporation of word pairs to define sequence features yields more specific predictions of average expression profiles and more informative regression models for genome-wide expression data than considering sequence conservation alone. CONCLUSIONS: The incorporation of both joint conservation and spacing constraints of sequence pairs predicts groups of target genes that are specific for common patterns of gene expression. Our work suggests that positional information, especially the relative spacing between transcription factor binding sites, may represent a common organizing principle of transcription control regions.

Base Sequence↗

PubMed1993

The avian embryo responding to microgravity of space flight.

Central questions and paradigms of developmental biology have in recent decades evolved to stress gene regulation. (See Moore, 1987 for an excellent review). However, during fertilization and the pre-embryonic cleavage stages, cells of identical genome are responding to multiple microenvironmental factors, e.g., pH, spatial position, temperature, osmotic and barometric pressure, light, electrical field charge, and the extracellular concentration of substrates, cellular byproducts, gases, and electrolytes. These cells commonly retain their full potential until chance of spatial positioning alters their access to the internal or external environment. (The commercial exploitation of these techniques at the 8-cell stage is now well-developed in beef and dairy breeding.) Importantly, these factors are exerting their influence prior to the genome repression/activation, all of which leads to germ layer definition and basic tissue differentiation. Of all the many potential and real microenvironmental influences, only gravity would appear to have remained relatively constant and ubiquitous for developing organisms. Histo-and organogenesis as well as differential growth of the embryo and fetus may have evolved with a constant environmental factor of gravity (G=6.7 x 10(-8) c.g.s. units). Embryos of 2-d and 9-d stage of incubation were flown in an incubator on the Space Shuttle during a 5-d mission. Significant differences in embryo response to this microgravity environment were observed. This paper offers an analysis and suggests mechanisms which may contribute to these results.

Age Factors↗

PubMed2003

Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function.

DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1-/- mice. MBD1-/- mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1-/- neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1-/- mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.

Animals↗

PubMed2026

Integrating Radiogenomics and CSF-Based Liquid Biopsy Sequencing for Precision Neuro-Oncology.

Glioblastoma and diffuse gliomas pose major therapeutic challenges due to marked intratumoral heterogeneity, limited tissue accessibility, and the blood-brain barrier. Tissue-based next-generation sequencing (NGS) remains essential for WHO CNS5 molecular classification, yet it is invasive and poorly suited to serial monitoring. Two complementary non- or minimally invasive approaches have advanced rapidly: radiogenomics, which correlates multiparametric MRI features with genomic alterations, and cerebrospinal fluid (CSF) liquid biopsy sequencing, which detects circulating tumor DNA with high tissue concordance. This review examines the independent progress and synergistic integration of radiogenomics and CSF-NGS. Imaging signatures can non-invasively predict key drivers (IDH1/2, EGFR, TERT, PTEN, TP53) and molecular subtypes, while CSF-ctDNA sequencing enables real-time assessment of clonal evolution, therapy resistance (including post-temozolomide hypermutation), and residual disease. We discuss technical considerations, performance metrics, multimodal artificial-intelligence fusion, and emerging clinical applications for diagnosis, prognosis, treatment selection, and longitudinal surveillance. Critical challenges, standardization, prospective validation, and workflow integration are highlighted. By combining the spatial phenotypic information of radiogenomics with the temporal genomic resolution of CSF sequencing, this multimodal strategy offers a promising path toward precision neuro-oncology and reduced reliance on repeated invasive sampling.

Humans↗

PubMed2026

Moving Beyond Morphology to Multiplexed Molecular Imaging as the Next Frontier in Diagnostic Pathology.

Diagnostic pathology has long relied on the morphologic interpretation of hematoxylin and eosin-stained tissues to guide diagnosis and assess prognostic features. Although pathologists intuitively recognize spatial patterns and architectural organization, these assessments remain largely qualitative and difficult to quantify systematically. Immunohistochemistry and immunofluorescence have introduced molecular specificity but are limited in multiplexing capacity, whereas bulk genomic and transcriptomic assays provide high molecular depth but lose spatial context by averaging signals across heterogeneous cell populations. Recent advances in spatial proteomics-including mass spectrometry-based imaging and cyclic immunofluorescence-now enable multiplexed, single-cell protein analysis within intact tissue architecture. These technologies have revealed complex immune and stromal microenvironments, spatially organized biomarkers predictive of therapeutic response, and molecular gradients underlying disease progression. By integrating histologic and molecular information, spatial proteomics bridges traditional microscopy with high-dimensional omics, allowing quantitative, spatially resolved insights into tissue organization and disease mechanisms. This review summarizes recent developments in multiplexed spatial proteomics from both scientific and pathologic perspectives, highlighting how these technologies extend beyond morphology to quantify histologic patterns, refine biomarker discovery, and facilitate clinical translation. The review also examines translational challenges and barriers to clinical implementation, including costs, standardization requirements, and workflow integration.

Humans↗