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PubMed1995

Delivery of a foreign gene to sympathetic preganglionic neurons using recombinant herpes simplex virus.

Two recombinant herpes simplex type 1 viruses expressing beta-galactosidase (encoded by the Escherichia coli lacZ gene) inserted into the unique long 41 (encoding virus host shutoff) or unique short 5 (encoding glycoprotein J) open reading frames were generated. Purified recombinants or wild-type herpes simplex type 1 were injected into the left adrenal gland of hamsters. Three days later, virus-infected neurons were detected in spinal cord sections from all infected hamsters. Neurons were visualized with beta-galactosidase histochemistry in spinal cord sections from hamsters infected with either of the recombinants but not with the wild-type virus. Wild-type virus could only be detected with immunocytochemistry. Insertional mutagenesis into the unique long 41 or unique short 5 regions of the herpes simplex genome by lacZ did not disrupt the neurotropic properties of the virus. Both recombinant viruses labelled the central nervous system sympathoadrenal preganglionic neurons as well as brainstem neurons. Because the virus host shutoff recombinant more readily crossed synapses to reach the brainstem compared to the glycoprotein J recombinant, the presence of glycoprotein J may facilitate cell to cell transmission in vivo. Both recombinants may be useful for the study of synaptic organization of neural circuits. Our recombinant viruses were less lytic yet neurovirulent after mutation of either glycoprotein J or virus host shutoff of herpes simplex virus type 1 wild-type. These recombinant viruses express the bacterial beta-galactosidase which is readily detectable using simple histochemistry. Inoculation of the adrenal gland or kidney with these viruses led to clear labelling of spinal cord cells. These viruses may be useful markers of specific neural circuits.

Animals↗

PubMed2026

WWOX-related developmental and epileptic encephalopathy (WOREE): A case series of seven patients from Argentina.

PURPOSE: WWOX-related developmental and epileptic encephalopathy (WOREE) is a rare autosomal recessive disorder caused by biallelic pathogenic WWOX variants, characterized by very early-onset epilepsy, profound developmental delay, and progressive brain abnormalities. Detailed electroclinical descriptions remain limited. METHODS: We conducted a retrospective study of seven patients with pathogenic/likely pathogenic WWOX variants. Clinical features, seizure evolution, EEG findings, brain MRI, and genetic data were reviewed. Epilepsy syndromes were classified according to International League against Epilepsy (ILAE) criteria. Variants were identified through next-generation sequencing and interpreted following American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Median seizure onset was 3 months (range 2-6). Five patients presented with focal seizures evolving to infantile epileptic spasms syndrome (IESS), while two had IESS at onset. Epilepsy was drug-resistant in all. Developmental delay was evident from birth with generalized hypotonia, acquired microcephaly, and impaired visual attention. Four patients had dysmorphic features. During the IESS period, EEG showed hypsarrhythmia in six patients and a severely disorganized encephalopathic background that did not strictly fulfill the criteria for hypsarrhythmia in one. Brain MRI revealed abnormalities in all patients, including frontotemporal atrophy and corpus callosum hypoplasia; delayed myelination was observed in one case. Eight pathogenic/likely pathogenic WWOX variants were found; including one novel variant (NM_016373.4:c.571C>T, p.(Gln191*)). The recurrent splice-site variant NM_016373.4:c.107+1G>A was identified in five patients, suggesting a possible regional founder effect. CONCLUSION: WOREE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay. Recognition of this pattern may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.

Developmental and epileptic encephalopathy↗

PubMed2004

Activity-based probes for protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) are involved in the regulation of many aspects of cellular activity including proliferation, differentiation, metabolism, migration, and survival. Given the large number and complexity of PTPs in cell signaling, new strategies are needed for the integrated analysis of PTPs in the whole proteome. Unfortunately, the activities of many PTPs are tightly regulated by posttranslational mechanisms, limiting the utility of standard genomics and proteomics methods for functional characterization of these enzymes. To facilitate the global analysis of PTPs, we designed and synthesized two activity-based probes that consist of alpha-bromobenzylphosphonate as a PTP-specific trapping device and a linker that connects the trapping device with a biotin tag for visualization and purification. We showed that these probes are active site-directed irreversible inactivators of PTPs and form a covalent adduct with PTPs involving the active site Cys residue. Additionally, we demonstrated that the probes are extremely specific toward PTPs while remaining inert to other proteins, including the whole proteome from Escherichia coli. Consequently, these activity-based PTP probes can be used to profile PTP activity in complex proteomes. The ability to interrogate the entire PTP family on the basis of changes in their activity should greatly accelerate both the assignment of PTP function and the identification of potential therapeutic targets.

Binding Sites↗

PubMed1984

Mutations affecting functions of the Drosophila gene glued.

Glued mutations in Drosophila comprise an essential complementation group with complex developmental effects. The original Glued mutation (Gl) has dominant nonlethal effects in heterozygous flies, principally on the morphogenesis of the visual system. Gl also has a recessive lethal effect early in development. Mutations that reverse the dominant visual effects of Gl (GlR mutations) were induced by gamma-radiation or by insertions of the transposable P element. The GlR(G) mutations induced by gamma-radiation do not reverse the lethal effect of Gl; these appear to be null mutations, some of which (and possibly all) delete segments of the Glued region. The GlR(P) mutations induced by insertion of the P element also reverse concomitantly a recessive lethal effect of Gl, suggesting that both the recessive and dominant effects are controlled by the same gene. The reversal of a lethal effect of Gl by the P element is remarkable, since it indicates that an essential gene function can be restored by insertion of unrelated DNA. Another class of lethal Glued mutations was induced in the normal Gl+ strain by ethyl methanesulfonate (EMS). The EMS mutations belong to the same essential complementation group as Gl, but do not have the strong dominant effects of Gl on the visual system. The GlR(P) mutations provide a molecular marker for the Glued gene, which was used to map the gene to the 70C2 band of chromosome 3L by in situ hybridization of a P element probe to polytene chromosomes from the GlR(P) strains and also to isolate clones of Glued genomic DNA for molecular studies of the normal gene and the various Glued mutations.

Animals↗

PubMed2024

PoweREST: Statistical Power Estimation for Spatial Transcriptomics Experiments to Detect Differentially Expressed Genes Between Two Conditions.

Recent advancements in Spatial Transcriptomics (ST) have significantly enhanced biological research in various domains. However, the high cost of current ST data generation techniques restricts its application in large-scale population studies. Consequently, there is a pressing need to maximize the use of available resources to achieve robust statistical power. One fundamental question in ST analysis is to detect differentially expressed genes (DEGs) among different conditions using ST data. Such DEG analysis is often performed but the associated power calculation is rarely discussed in the literature. To address this gap, we introduce, PoweREST (https://github.com/lanshui98/PoweREST), a power estimation tool designed to support power calculation of DEG detection with 10X Genomics Visium data. PoweREST enables power estimation both before any ST experiments or after preliminary data are collected, making it suitable for a wide variety of power analyses in ST studies. We also provide a user-friendly, program-free web application (https://lanshui.shinyapps.io/PoweREST/), allowing users to interactively calculate and visualize the study power along with relevant the parameters.

Differentially expressed genes↗

PubMedDate not supplied

Evaluation of the ELOVL4 gene in a Chinese family with autosomal dominant STGD3-like macular dystrophy.

Stargardt disease-3 (STGD3) is an autosomal dominant juvenile-onset macular dystrophy characterized by progressive decreasing visual acuity, bilateral atrophic changes in the macula and absence of characteristic dark choroids. We identified a STGD3-like macular dystrophy pedigree by clinical examination. To explore whether the STGD3-like phenotype in the kindred is linked to ELOVL4 gene or associated with any other identified STGD gene, we extracted genomic DNA from leukocytes of peripheral blood from the available family members and 50 normal controls for mutation analysis. Then the exons of ELOVL4, RDS and the three exons of ABCR were amplified by polymerase chain reaction (PCR). All PCR products were screened for mutations by combination of denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing. No mutation was found in the exons of three candidate genes, but we obtained three non-pathogenic polymorphisms, IVS5-2533T-->A in ELOVL4, 558C-->T (Val106Val) and 1150G-->C (Glu304Gln) in RDS. And IVS5-2533T-->A is never shown in the previous references. These data suggested that there exist other unknown genes responsible for the STGD3-like phenotype in the pedigree.

Angiography↗

PubMed2004

Cruciform DNA structure underlies the etiology for palindrome-mediated human chromosomal translocations.

There is accumulating evidence to suggest that palindromic AT-rich repeats (PATRRs) represent hot spots of double-strand breakage that lead to recurrent chromosomal translocations in humans. As a mechanism for such rearrangements, we proposed that the PATRR forms a cruciform structure that is the source of genomic instability. To test this hypothesis, we have investigated the tertiary structure of a cloned PATRR. We have observed that a plasmid containing this PATRR undergoes a conformational change, causing temperature-dependent mobility changes upon agarose gel electrophoresis. The mobility shift is observed in physiologic salt concentrations and is most prominent when the plasmid DNA is incubated at room temperature prior to electrophoresis. Analysis using two-dimensional gel electrophoresis indicates that the mobility shift results from the formation of a cruciform structure. S1 nuclease and T7 endonuclease both cut the plasmid into a linear form, also suggesting cruciform formation. Furthermore, anti-cruciform DNA antibody reduces the electrophoretic mobility of the PATRR-containing fragment. Finally, we have directly visualized cruciform extrusions from the plasmid DNA with the size expected of hairpin arms using atomic force microscopy. Our data imply that for human chromosomes, translocation susceptibility is mediated by PATRRs and likely results from their unstable conformation.

Animals↗

PubMed1990

Replicating single-stranded adenovirus type 5 DNA molecules accumulate within well-delimited intranuclear areas of lytically infected HeLa cells.

The intranuclear compartments which contain adenovirus type 5 (Ad5) genomes during productive infection of HeLa cells were determined by high resolution when the rate of viral DNA replication is at its maximum. In situ hybridization was performed with and without denaturation of Ad5 DNA to reveal those portions of both double-stranded and single-stranded viral DNA and of single-stranded viral DNA alone, respectively, which were present at the surface of Lowicryl thin sections. Autoradiography after short pulse incorporation of tritiated thymidine revealed sites of active DNA replication whereas a pulse-chase experiment visualized the migration of the synthesized DNA. Immunocytochemistry determined distribution of the Ad5 72 kDa protein. Viral DNA was contained within multiple, well-delimited, compact fibrillar structures and their immediately surrounding, less well-defined, fibrillo-granular areas of the cell nucleoplasm. The compact fibrillar masses were primarily storage sites of single-stranded viral DNA and its accompanying 72 kDa protein, so they were named ssDNA accumulation sites. They contained intermittent viral replicative activity. Conversely, viral ssDNA and 72 kDa protein were rare in the surrounding fibrillo-granular areas in which Ad5 replication DNA is continuous, so we referred to them as peripheral replicative zones. Well-delimited subnuclear structures induced by viruses, therefore, represent accumulations of specific components of their replicating genomes.

Adenoviruses, Human↗

PubMed2006

FiRe and microarrays: a fast answer to burning questions.

FiRe is a user-friendly Excel macro designed to survey microarray data rapidly. This software interactively assembles data from different experiments and produces lists of candidate genes according to patterns of gene expression. Furthermore, macros bundled with FiRe can compare lists of genes, merge information from different spreadsheets, link candidates to information available from web-based databases, and produce heat-maps for easy visualization of microarray data. FiRe is freely available at http://www.unifr.ch/plantbio/FiRe/main.html .

Database Management Systems↗

PubMed2005

Adenovirus protein IX: a new look at an old protein.

The success of gene therapy depends in part on our understanding of the biology of gene therapy vectors. This knowledge must be used to improve the function, safety, and versatility of the vector system. For decades, we have known which viral proteins are involved in formation of the adenovirus (Ad) capsid, but we are still learning how these proteins can be altered or manipulated to improve vector function. The Ad protein IX (pIX) was originally identified as a minor component of the Ad capsid, but was not essential for virion formation. However, more recent studies have suggested that pIX may have multiple roles in the Ad life cycle, including acting as a transcriptional activator and reorganizing nuclear proteins to provide an environment more conducive to virus replication. In gene therapy studies, removal of pIX from the Ad vector backbone was used to increase the cloning capacity of E1-deleted Ad vectors and to develop a new method for preparing helper-dependent Ad vectors. pIX has also been at the center of numerous attempts to eliminate the problem of replication-competent Ad in Ad vector preparations. Finally, pIX represents a versatile platform for the presentation of polypeptides on the surface of the viral capsid, including ligands for virus retargeting and fluorescent proteins for visualizing the virus in vitro and in vivo. Thus, the importance and uses of this "minor" capsid protein have changed significantly over the past few years.

Adenoviridae↗

PubMed2000

The EcoCyc and MetaCyc databases.

EcoCyc is an organism-specific Pathway/Genome Database that describes the metabolic and signal-transduction pathways of Escherichia coli, its enzymes, and-a new addition-its transport proteins. MetaCyc is a new metabolic-pathway database that describes pathways and enzymes of many different organisms, with a microbial focus. Both databases are queried using the Pathway Tools graphical user interface, which provides a wide variety of query operations and visualization tools. EcoCyc and MetaCyc are available at http://ecocyc.PangeaSystems.com/ecocyc/

Database Management Systems↗

PubMed1980

The rolling circle . capsid complex as an intermediate in phi X DNA replication and viral assembly.

Late in the life cycle of the single-stranded DNA phage phi X, the synthesis of positive strand DNA is coupled to the maturation of progeny virions. DNA synthesis and packaging take place in a replication-assembly complex, which we have purified to homogeneity and characterized. The following conclusions can be drawn: 1. The DNA component of the replication-assembly complex is a rolling circle with a single-stranded DNA tail which is less than or equal to genome length. 2. The major protein component of the replication-assembly complex is an intact viral capsid, as shown by gel analysis of 35S-labeled complexes. As replication proceeds at the DNA growing point, the positive strand tail of the rolling circle is displaced directly into the capsid. In addition to the capsid, the complex contains at least 1 molecule of the phi X gene A nicking protein, which appears to be covalently linked to the DNA. 3. The rolling circle . capsid complex can be purified to homogeneity by taking advantage of its uniform sedimentation velocity (35 S) and its uniform density upon equilibrium centrifugation in CsCl (1.50 g/cc). 4. The replication-assembly complex can be visualized in the electron microscope. An electron-dense particle, which has the dimensions of a viral capsid, is observed attached to a rolling circle at the DNA growing point. 5. Hybridization of specific phi X restriction fragments to the deproteinized, single-stranded tails of intact rolling circles has allowed the use of these replicating intermediates to determine both the origin/terminus and the direction of phi X positive strand DNA synthesis. The ends of the rolling circle tails map in the Hae III restriction Fragment Z6b, at the position on the phi X genome at which the gene A endonuclease is known to cut. This result indicates that this endonuclease participates in the "termination" of each round of synthesis by cutting off unit-length viral genomes. 6. Rolling circle . capsid complexes were also isolated from two other icosahedral, single-stranded DNA phages: G4 and St-1. The rolling circle . capsid complex seen in the case of the single-stranded DNA phages represents the first example of a structure in which DNA synthesis and viral assembly occur in a coupled manner. This tight coordination explains why double-stranded DNA circles are the net product of synthesis early in the viral life cycle while only single-stranded DNA circles are produced later. The single-stranded tails of the rolling circle intermediates are available for conversion to the duplex state at early times, whereas the concentration of preformed capsids later is high enough to bind to all of the replicating molecules and package the emerging positive strand DNA.

Bacteriophage phi X 174↗

PubMed2026

XXYLT1 and Mendelian Retinal Dystrophy.

IMPORTANCE: Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases. OBJECTIVE: To leverage a GWAS for the discovery of IRD-associated genes. DESIGN, SETTING, AND PARTICIPANTS: This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort. MAIN OUTCOMES AND MEASURES: The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant. RESULTS: This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant. CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.

Humans↗

PubMed2006

Developmental instability and the neural dynamics of the speed-intelligence relationship.

Two of the most securely established findings in the biology of intelligence are the relationship between reaction time (RT) and intelligence, and the heritability of intelligence. To investigate why RT may related to intelligence, researchers have used a variety of techniques to subdivide RT into cognitive and motor components. In the current study, magnetoencephalographic (MEG) dipole latencies were used to examine the speed and timing of specific brain processing stages engaged during visually cued simple and choice reaction time tasks. Simple and choice reaction time and timing of MEG sources were considered in relation to fluid intelligence (as measured by the Raven's Advanced Progressive Matrices, RAPM). To address heritability of intelligence, developmental instability (DI) was assessed, measured here as fluctuating asymmetry. DI represents the degree to which an organism is susceptible to developmental stress arising from both environmental and genomic sources. Analyses showed that choice, but not simple reaction time was negatively correlated with RAPM score. MEG revealed a set of complex relationships between the timing of regional brain activations and psychometric intelligence. The neural component associated with integration of sensory and motor information was most associated with RAPM compared to other components. Higher values of fluctuating asymmetry predicted reduced psychometric intelligence, a result suggesting that some part of the variance of the heritability of intelligence reflects DI. Fluctuating asymmetry was significantly and negatively correlated with timing during all components of task completion. These observations suggest that fluid intelligence is primarily related to speed during processing associated with decision time, while fluctuating asymmetry predicted slower processing across all stages of information processing.

Adolescent↗

PubMed1998

An automatic image analysis system for RLGS films.

The RLGS (Restriction Landmark Genome Scanning) method was originally developed as a powerful method for enabling viewing of thousands of restriction landmarks. It offers a tool for obtaining information about genetic loci, with a single RLGS profile displaying approximately 2000 restriction landmarks as spots. One of the most useful applications is RLGS spot mapping, which allows the efficient, low-cost construction of the genetic map of any organism. However, analyses of the profiles depend mainly on human visual observation and are tedious and laborious. Although several commercially available image analyzing systems for profile comparison have been examined, they cannot be used for the RLGS spot mapping system owing to the background characteristics of the RLGS profiles, unsatisfactory rates of correspondence, and inefficient correction of informative genetic data. We therefore developed a novel automatic image analysis system for RLGS spot mapping, using an original algorithm based on the binary image transferred from the original RLGS profile. This system was employed for identifying non-polymorphic and parental strain-specific polymorphic spots of the F1 mouse profile and yielded efficient initial screening of RLGS profiles.

Animals↗

PubMed2026

From Static to Dynamic: Fluorescence Imaging Technology Advances Precise Embryo Evaluation.

Live-cell imaging technology has revolutionized our understanding of preimplantation embryonic development, shifting the field from static morphological descriptions to dynamic functional analyses. This has tremendously advanced the fields of in vitro fertilization (IVF) and embryonic development. At the heart of this transition lies the strategic application of fluorescent probes, which provide the requisite sensitivity and specificity to resolve complex biological events. This review provides a comprehensive overview of fluorescent probe-based strategies designed to address four cardinal questions in peri-implantation embryology: genomic stability, cell fate determination, tissue morphogenesis, and embryo-maternal interactions. We systematically evaluate the chemical design principles and imaging modalities of various probes, which range from small-molecule organic fluorophores to genetically encoded reporters and nanoparticle-based sensors. Furthermore, we discuss how these tools facilitate the real-time visualization of chromosomal aberrations, lineage segregation, biomechanical forces, and enzymatic activities within the delicate embryonic microenvironment. This review summarizes methodological strategies for selecting and developing optimal probes across diverse application contexts. By identifying current technical bottlenecks and proposing future directions, such as NIR-II imaging and noninvasive labeling, it aims to drive the translation of basic embryonic research into advanced reproductive medicine.

Humans↗

PubMed2000

Cloning and characterization of the human retinoid X receptor alpha gene: conservation of structure with the mouse homolog.

Retinoid X receptors (RXRs) are members of the steroid/thyroid hormone receptor superfamily which, along with retinoic acid receptors (RARs), mediate the biological effects of retinoids. These effects include the regulation of many aspects of embryonic development, reproductive and visual function, and the maintenance of epithelial homeostasis throughout life. The genes for three distinct retinoid X receptors, RXRalpha, beta, and gamma, have been localized to separate chromosomes. In order to determine the organization of the human RXRalpha gene, we have isolated a clone containing the majority of the gene from a human genomic bacterial artificial chromosome (BAC) library and generated a physical map. The gene spans over 40 kilobases in size and contains at least 10 exons. Comparison with mapped portions of the mouse RXRalpha gene indicates highly conserved intron-exon positioning. These results provide information necessary to generate constructs for targeting the RXRalpha gene in human cell lines, which may eventually lead to an understanding of the function of RXRalpha in human cancer.

Animals↗

PubMed1996

A gene for autosomal dominant congenital nystagmus localizes to 6p12.

Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at theta = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor nystagmus to an 18-cM region between D6S271 and D6S455.

Chromosome Mapping↗