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PubMed2024

Mannose receptor (MRC1) mediates uptake of dextran by bone marrow-derived macrophages.

Macrophages survey their environment using receptor-mediated endocytosis and pinocytosis. Receptor-mediated endocytosis allows internalization of specific ligands, whereas pinocytosis nonselectively internalizes extracellular fluids and solutes. CRISPR/Cas9 whole-genome screens were used to identify genes regulating constitutive and growth factor-stimulated dextran uptake in murine bone marrow-derived macrophages (BMDM). The mannose receptor c-type 1 (MRC1/CD206) was a top hit in the screen. Targeted gene disruptions of Mrc1 reduced dextran uptake but had little effect on fluid-phase uptake of Lucifer yellow. Other screen hits also differentially affected the uptake of dextran and Lucifer yellow, indicating internalization by separate mechanisms. Visualization of dextran and Lucifer yellow uptake by microscopy showed enrichment of dextran in small puncta, which was inhibitable by mannan, a ligand of MRC1. In contrast, Lucifer yellow predominantly was internalized in larger macropinosomes. In addition, IL4-treated BMDMs internalized more dextran than untreated BMDM correlating with increased MRC1 expression. Therefore, dextran is not an effective marker for pinocytosis in BMDMs since it is internalized by receptor-mediated process. Numerous genes that regulate dextran internalization in primary murine macrophages were identified in the whole-genome screens, which can inform understanding of the regulation of MRC1 expression and MRC1-mediated uptake in macrophages.

Animals↗
PubMedDate not supplied

Knowledge-assisted recognition of cluster boundaries in gene expression data.

BACKGROUND AND MOTIVATION: DNA microarray technology has made it possible to determine the expression levels of thousands of genes in parallel under multiple experimental conditions. Genome-wide analyses using DNA microarrays make a great contribution to the exploration of the dynamic state of genetic networks, and further lead to the development of new disease diagnosis technologies. An important step in the analysis of gene expression data is to classify genes with similar expression patterns into the same groups. To this end, hierarchical clustering algorithms have been widely used. Major advantages of hierarchical clustering algorithms are that investigators do not need to specify the number of clusters in advance and results are presented visually in the form of a dendrogram. However, since traditional hierarchical clustering methods simply provide results on the statistical characteristics of expression data, biological interpretations of the resulting clusters are not easy, and it requires laborious tasks to unveil hidden biological processes regulated by members in the clusters. Therefore, it has been a very difficult routine for experts. OBJECTIVE: Here, we propose a novel algorithm in which cluster boundaries are determined by referring to functional annotations stored in genome databases. MATERIALS AND METHODS: The algorithm first performs hierarchical clustering of gene expression profiles. Then, the cluster boundaries are determined by the Variance Inflation Factor among the Gene Function Vectors, which represents distributions of gene functions in each cluster. Our algorithm automatically specifies a cutoff that leads to functionally independent agglomerations of genes on the dendrogram derived from similarities among gene expression patterns. Finally, each cluster is annotated according to dominant gene functions within the respective cluster. RESULTS AND CONCLUSIONS: In this paper, we apply our algorithm to two gene expression datasets related to cell cycle and cold stress response in budding yeast Saccharomyces cerevisiae. As a result, we show that the algorithm enables us to recognize cluster boundaries characterizing fundamental biological processes such as the Early G1, Late G1, S, G2 and M phases in cell cycles, and also provides novel annotation information that has not been obtained by traditional hierarchical clustering methods. In addition, using formal cluster validity indices, high validity of our algorithm is verified by the comparison through other popular clustering algorithms, K-means, self-organizing map and AutoClass.

Algorithms↗
PubMed2006

Exploiting human anatomical variability as a link between genome and cognome.

Although talents and disabilities appear to run in families, direct links between genes and cognitive ability are difficult to establish. Investigators are currently searching for intermediate phenotypes with plausible links to both genome and cognome (the cognitive phenotype). Cortical anatomy could provide one such intermediate phenotype. Variation in cortical size, asymmetry and sulcal pattern is influenced by genetic variation in neurotrophic factors and can predict variation in verbal and mathematical talent. Anecdotal evidence suggests that individuals with a rare morphological variant of Sylvian fissure sometimes have superior visualization ability combined with verbal deficits. Documentation of such 'cognitive cortical syndromes' might prove as genetically informative as the identification of dysmorphic syndromes associated with mental retardation. A necessary prerequisite for the establishment of such syndromes is a reliable technique for the identification of cortical patterns. Recent technical advances in software for automatically labeling and measuring cortical sulci now provide the possibility of establishing standard measures for their shape, size and location. Such measures are a prerequisite for genetic studies of cortical patterns that could illuminate the neurodevelopmental pathways by which genes affect cognitive ability.

Adult↗
PubMed1998

How many membrane proteins are there?

One of the basic issues that arises in functional genomics is the ability to predict the subcellular location of proteins that are deduced from gene and genome sequencing. In particular, one would like to be able to readily specify those proteins that are soluble and those that are inserted in a membrane. Traditional methods of distinguishing between these two locations have relied on extensive, time-consuming biochemical studies. The alternative approach has been to make inferences based on a visual search of the amino acid sequences of presumed gene products for stretches of hydrophobic amino acids. This numerical, sequence-based approach is usually seen as a first approximation pending more reliable biochemical data. The recent availability of large and complete sequence data sets for several organisms allows us to determine just how accurate such a numerical approach could be, and to attempt to minimize and quantify the error involved. We have optimized a statistical approach to protein location determination. Using our approach, we have determined that surprisingly few proteins are misallocated using the numerical method. We also examine the biological implications of the success of this technique.

Bacterial Proteins↗
PubMed2004

Towards a comprehensive understanding of Bacillus subtilis cell physiology by physiological proteomics.

Using Bacillus subtilis as a model system for functional genomics, this review will provide insights how proteomics can be used to bring the virtual life of genes to the real life of proteins. Physiological proteomics will generate a new and broad understanding of cellular physiology because the majority of proteins synthesized in the cell can be visualized. From a physiological point of view two major proteome fractions can be distinguished: proteomes of growing cells and proteomes of nongrowing cells. In the main analytical window almost 50% of the vegetative proteome expressed in growing cells of B. subtilis were identified. This proteomic view of growing cells can be employed for analyzing the regulation of entire metabolic pathways and thus opens the chance for a comprehensive understanding of metabolism and growth processes of bacteria. Proteomics, on the other hand, is also a useful tool for analyzing the adaptational network of nongrowing cells that consists of several partially overlapping regulation groups induced by stress/starvation stimuli. Furthermore, proteomic signatures for environmental stimuli can not only be applied to predict the physiological state of cells, but also offer various industrial applications from fermentation monitoring up to the analysis of the mode of action of drugs. Even if DNA array technologies currently provide a better overview of the gene expression profile than proteome approaches, the latter address biological problems in which they can not be replaced by mRNA profiling procedures. This proteomics of the second generation is a powerful tool for analyzing global control of protein stability, the protein interaction network, protein secretion or post-translational modifications of proteins on the way towards the elucidation of the mystery of life.

Bacillus subtilis↗
PubMed2004

Field evaluation of emmer wheat-derived synthetic hexaploid wheat for resistance to Russian wheat aphid (Homoptera: Aphididae).

Broadening the genetic base for resistance to Russian wheat aphid, Diuraphis noxia (Mordvilko) (Homoptera: Aphididae), in bread wheat, Triticum aestivum L., is desirable. To date, identified Russian wheat aphid resistance genes are either located to the D chromosomes or to rye translocation of wheat, and resistance derived from the A or B genomes of tetraploid Triticum spp. would therefore be highly beneficial. Fifty-eight synthetic hexaploid wheat, derived from interspecific crosses of Triticum dicoccum Schrank. and Aegilops tauschii (Coss.) Schmal. and their parents were evaluated for resistance to Russian wheat aphid under field conditions. Plots infested with aphids were compared with plots protected with insecticides. The T. dicoccum parents were highly resistant to Russian wheat aphids, whereas the Ae. tauschii parents were susceptible. Resistance levels observed in the synthetic hexaploids were slightly below the levels of their T. dicoccum parents when a visual damage scale was used. but no major resistance suppression was observed among the synthetics. Russian wheat aphid infestation on average reduced plant height and kernel weight at harvest in the synthetic hexaploids and the T. dicoccum parents by 3-4%, whereas the susceptible control 'Seri M82' suffered losses of above 20%. Because resistance in the synthetic hexaploid wheat is derived from their T. dicoccum parent, resistance gene(s) must be located on the A and/or B genomes. They must therefore be different from previously identified Russian wheat aphid resistance genes, which have all been located on the D genome of wheat or on translocated segments.

Animals↗
PubMed2000

Endothelial cell autoantibodies are a marker of disease susceptibility in inflammatory bowel disease but apparently not linked to persistent measles virus infection.

Intestinal vasculitis caused by persistent measles virus infection of intestinal endothelial cells was described in Crohn's disease. Furthermore, endothelial cell autoantibodies have been demonstrated in inflammatory bowel disease (IBD). Autoantibodies against intestinal endothelial cells were visualized by indirect immunofluorescence in patients with IBD, in their healthy first-degree relatives, in patients with infectious enterocolitis, and in healthy, unrelated controls. In intestinal tissue specimens of 22 antibody-positive IBD patients a search for the measles virus genome was performed. Endothelial cell autoantibodies were significantly more frequent in patients with IBD, in both groups of first-degree relatives, and in patients with infectious enterocolitis than in the healthy controls (P = 0.0002 or less). The measles virus genome was found in none of the intestinal biopsies. Endothelial cell autoantibodies are not a genetic but rather an epigenetic (infectious) marker of disease susceptibility. The expression of these autoantibodies is unlikely to be triggered by a persistent measles virus infection.

Adolescent↗
PubMed1990

Molecular cytotaxonomy of primates by chromosomal in situ suppression hybridization.

A new strategy for analyzing chromosomal evolution in primates is presented using chromosomal in situ suppression (CISS) hybridization. Biotin-labeled DNA libraries from flow-sorted human chromosomes are hybridized to chromosome preparations of catarrhines, platyrrhines, and prosimians. By this approach rearrangements of chromosomes that occurred during hominoid evolution are visualized directly at the level of DNA sequences, even in primate species with pronounced chromosomal shuffles.

Animals↗
PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗
PubMed2005

DNA-loop formation on nucleosomes shown by in situ scanning force microscopy of supercoiled DNA.

The flexibility of the chromatin structure, necessary for the processing of the genomic DNA, is controlled by a number of factors where flexibility and mobility of the nucleosomes is essential. Here, the influence of DNA supercoiling on the structure of single nucleosomes is investigated. Circular supercoiled plasmid DNA sub-saturated with histones was visualized by scanning force microscopy (SFM) in aqueous solution. SFM-imaging compared with topological analysis indicates instability of nucleosomes when the salt concentration is raised from 10 mM to 100 mM NaCl. Nucleosomes were observed after the deposition to the used scanning surface, i.e. mica coated with polylysine. On the images, the nucleosomes appear with a high probability in end-loops near the apices of the superhelices. In 100 mM NaCl but not in 10 mM NaCl, a significant number of complexes present the nucleosomes on superhelical crossings mainly located adjacent to an end-loop. The morphology of these structures and statistical analysis suggest that DNA loops were formed on the histone octamers, where the loop size distribution shows a pronounced peak at 50 nm. Recently, the formation and diffusion of loops on octamers has been discussed as a mechanism of translocations of nucleosomes along DNA. The presented data likely confirm the occurrence of loops, which may be stabilized by supercoiling. Analysis of the structure of regular nucleosomes not located on crossings indicates that reducing the salt concentration leads to more conformations, where DNA is partially unwrapped from the distal ends of the octamer.

DNA, Superhelical↗
PubMed2026

Omics in optic neuropathies: From molecular landscapes to personalized therapeutics.

Optic neuropathies comprise a heterogeneous group of disorders involving transient or permanent injury to retinal ganglion cells (RGCs) and their axons. Clinically, these neurodegenerative conditions manifest as dyschromatopsia, decreased visual acuity, and visual field defects, and in severe cases may ultimately lead to blindness and disability. The marked heterogeneity across disease subtypes, incompletely understood etiologies, and complex pathogenic mechanisms pose substantial challenges to precise diagnosis and effective treatment. Recent advances in omics technologies - including genomics, transcriptomics, proteomics, metabolomics, lipidomics, single-cell and spatial sequencing, and integrative multi-omics approaches - have ushered optic nerve degenerative disease research into an era of high-resolution comprehensive investigation. In this review, we summarize representative applications of omics approaches to elucidate genetic alterations, signaling dysregulation, metabolic reprogramming, and immune responses in optic neuropathies. We further discuss the emerging potential of multi-omics in identifying early diagnostic biomarkers and informing individualized therapeutic strategies. Finally, we provide a forward-looking perspective on the future trajectory of omics technologies and their prospects in both fundamental research and clinical translation, with the overarching aim of accelerating the bench-to-bedside transition in this critical eye disease field.

biomarkers↗
PubMed2003

CGH and direct diagnosis of mosaic structural chromosomal abnormalities: description of a mosaic ring chromosome 17 and review of the literature.

We report the characterisation of a de novo supernumerary chromosome marker in a mosaic state (50%) by comparative genomic hybridisation (CGH) in an 8-year-old child with hypotonia, dysmorphia and mild-to-moderate mental retardation. We describe the combined use of CGH and fluorescence in situ hybridisation (FISH) to identify the origin of the additional chromosomal material. Visual analysis of 10 CGH-metaphase spreads revealed a gain of green fluorescent signal on pericentromeric region of chromosome 17. The CGH finding was confirmed by FISH analysis using a whole chromosome 17 paint, a chromosome 17 centromeric probe and the probe coding for the Smith-Magenis locus in 17p11.2. These results show that performing both CGH and FISH in combination with classical karyotyping will certainly allow the identification of imbalanced chromosome rearrangements and, by the way, allow the identification of genes involved in mental retardation and/or malformative pathology.

Child↗
PubMed1994

m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC.

Five muscarinic receptor genes (m1-m5) that encode distinct muscarinic receptor subtypes have been cloned. Because of their structural homology and pharmacological similarity, ligand binding probes currently available do not clearly distinguish among the subtypes. To obtain a clear distribution within the CNS of molecularly defined muscarinic receptor subtypes, seven brain regions were examined for the expression of the respective mRNAs. The most sensitive method for detecting mRNA is through amplification of the respective cDNAs. Brain regions were obtained from male Wistar rats, and total RNA was isolated. The isolates were extensively treated with RNase-free DNase to remove any residual genomic DNA. Total RNA (1 microgram) was reverse-transcribed using random primers and reverse transcriptase. The resulting cDNA was amplified using a thermal cycler, and the polymerase chain reaction (PCR)-amplified products were analyzed by gel electrophoresis containing ethidium bromide and visualized with fluorescent illumination. PCR-amplified samples were also injected directly onto an HPLC anion exchange column and quantified by UV detection. Each of the five muscarinic subtypes was found in every brain region examined. The m1 subtype was most abundant in cortex and gradually declined in content caudally to the spinal cord. The m2 subtype was most abundant in thalamus-hypothalamus and ponsmedulla. The m4 subtype was found in greatest amount in the striatum, whereas m3 and m5 were expressed consistently throughout the CNS. The combination of RT-PCR and HPLC provides a rapid and sensitive method for quantifying the expression of mRNA coding for all five muscarinic receptor subtypes derived from the CNS.

Animals↗
PubMed1997

[High-risk HPV types in oral and laryngeal papilloma and leukoplakia].

BACKGROUND: Juvenile and adult laryngeal papillomas (JLP and ALP) and oral papillomas (OP) are important benign tumors of the head and neck. Laryngeal leukoplakia (LL) may be a precancerous lesion. The etiology of the papillomas is associated with human papillomavirus infection (HPV). The important noxes for the development of laryngeal leukoplakias are nicotine, alcohol, and HPV. Adult laryngeal papillomas and OP can also undergo malignant conversion. Today, there is no marker known to distinguish in progressive lesions and in those which show a regression. Different types of HPV were detected in head and neck cancer too. There is a important similarity to the genesis of cervical cancer. The 77 known HPV types were divided into benign types, e.g., 6 and 11, and those with oncogene potential, e.g., 16, 18, 31, 33, and 35. The detection of oncogene HPV may be a sensitive marker for prognosis of primary benign lesions. PATIENTS AND METHODS: In this study, the presence of HPV genomes 6, 11, 16, 18, 31, 33, and 35 in 17 JLP, 27 ALP, 15 OP, and 11 LL was examined. DNA extracted from archived samples embedded in paraffin was amplified using the E6 specific polymerase chain reaction (PCR). The products were visualized by electrophoresis, and positive identification was achieved by Southern blot analysis and hybridization to specific biotinylated oligonucleotide. RESULTS: Our data show the presence of HPV 6/11 in all JLP (17 of 17), in all ALP (27 of 27), in 13 of 15 (87%) OP, and in seven of 11 (63%) LL. The "malignant" types HPV 16, 18, and 33 were found in six of 27 (22%) of the ALP, in three of 15 (20%) of the OP, and in four of 11 (36%) of the LL. the dominant type was HPV 16, HPV 31 and 35 were not detectable. Three ALP, one OP, and the four LL of the cases with oncogene HPV showed histologic features of moderate dysplasia. CONCLUSIONS: The role of HPV in malignant transformation of infected cells remains unclear. It is well known that the carcinogenesis must depend on promoters such as alcohol, tobacco, and metabolites of chronic inflammations. All patients with positive biopsies confirming HPV 16, 18, or 33 must receive special care to prevent the development of a carcinoma.

Adolescent↗
PubMed2002

Enhanced green fluorescent protein expression may be used to monitor murine coronavirus spread in vitro and in the mouse central nervous system.

Targeted recombination was used to select mouse hepatitis virus isolates with stable and efficient expression of the gene encoding the enhanced green fluorescent protein (EGFP). The EGFP gene was inserted into the murine coronavirus genome in place of the nonessential gene 4. These viruses expressed the EGFP gene from an mRNA of slightly slower electrophoretic mobility than mRNA 4. EGFP protein was detected on a Western blot of infected cell lysates and EGFP activity (fluorescence) was visualized by microscopy in infected cells and in viral plaques. Expression of EGFP remained stable through at least six passages in tissue culture and during acute infection in the mouse central nervous system. These viruses replicated with similar kinetics and to similar final extents as wild-type virus both in tissue culture and in the mouse central nervous system (CNS). They caused encephalitis and demyelination in animals as wild-type virus; however, they were somewhat attenuated in virulence. Isogenic EGFP-expressing viruses that differ only in the spike gene and express either the spike gene of the highly neurovirulent MHV-4 strain or the more weakly neurovirulent MHV-A59 strain were compared; the difference in virulence and patterns of spread of viral antigen reflected the differences between parental viruses expressing each of these spike genes. Thus, EGFP-expressing viruses will be useful in the studies of murine coronavirus pathogenesis in mice.

Animals↗
PubMed2004

HPID: the Human Protein Interaction Database.

UNLABELLED: The Human Protein Interaction Database (http://www.hpid.org) was designed (1) to provide human protein interaction information pre-computed from existing structural and experimental data, (2) to predict potential interactions between proteins submitted by users and (3) to provide a depository for new human protein interaction data from users. Two types of interaction are available from the pre-computed data: (1) interactions at the protein superfamily level and (2) those transferred from the interactions of yeast proteins. Interactions at the superfamily level were obtained by locating known structural interactions of the PDB in the SCOP domains and identifying homologs of the domains in the human proteins. Interactions transferred from yeast proteins were obtained by identifying homologs of the yeast proteins in the human proteins. For each human protein in the database and each query submitted by users, the protein superfamilies and yeast proteins assigned to the protein are shown, along with their interacting partners. We have also developed a set of web-based programs so that users can visualize and analyze protein interaction networks in order to explore the networks further. AVAILABILITY: http://www.hpid.org.

Algorithms↗
PubMed2026

Analyzing Meiosis in Maize.

Meiosis is central to sexual reproduction and the main source of genetic diversity in plants. Understanding how meiotic processes are regulated has direct relevance to agriculture. As meiotic recombination is the vehicle of plant breeding, gaining the ability to influence recombination patterns can accelerate crop improvement. Maize is a powerful model for studying plant meiosis, thanks to its large chromosomes, well-developed genetics, and the availability of diverse cytogenetic and molecular tools. Insights gained from maize studies can extend to other species. In this review, we describe a variety of approaches for examining meiosis and meiotic recombination in maize. Cytological techniques, including protein immunolocalization and fluorescence in situ hybridization (FISH), enable visualization of chromosome structure and behavior, as well as crossover (CO) formation. Chromatin immunoprecipitation (ChIP) is used in meiosis research to determine locations of recombination proteins, identify recombination sites, and elucidate chromatin features, such as histone modifications. Quantification of COs at specific genomic sites through pollen typing by droplet digital PCR allows precise high-resolution measurement of recombination rates. Combining cytology, protein localization, and molecular assays provides a multiscale picture of meiosis, linking molecular mechanisms to chromosome behavior and, ultimately, to genetic variation.

Journal Article↗
PubMed2001

First evidence for a restriction-modification system in Leptospira sp.

The LE1 leptophage exhibited a host range restricted to the saprophytic Leptospira biflexa [Saint Girons et al., Res. Microbiol. 141 (1990) 1131-1133] and mainly to the Patoc 1 strain (hereafter called PFRA) kept in the Paris, France collection. Results of titration of LE1 lysates indicated the presence of a host-controlled modification and restriction system within PUSA (Patoc 1 strain maintained in the Morgantown, WV, USA collection) that was absent in PFRA. Because genomic DNA of PITAL (Patoc 1 strain maintained in Trieste, Italy) appeared smeared in pulsed field gel electrophoresis (PFGE), this strain is likely to contain nucleases that are activated upon DNA isolation. Moreover, comparative NotI digestions of PUSA and PFRA DNAs, as visualized by PFGE, indicated that PUSA belonged to a different serovar than PFRA. Finally, 16S ribosomal sequence analysis indicated that PUSA belonged to the saprophytic Leptospira meyeri species, while PITAL and PFRA appertained to L. biflexa. The evolutionary significance and the importance of the restriction and modification enzymes or non-specific nucleases within strains for genetic experiments are discussed.

Amino Acid Sequence↗