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At least 19 recordsLinked to original sources
PubMed2025

Widespread induction of SINE-RNA expression in the mouse brain following transient focal ischemia.

Ischemic stroke triggers rapid transcriptional changes in the brain, including the induction of noncoding RNAs, which are well-established regulators of post-stroke pathophysiology. Among the numerous classes of noncoding RNAs, short interspersed nuclear element RNAs (SINE-RNAs) are transcribed by Pol III and reported to be upregulated in various paradigms of cellular stress. In the ischemic brain, Pol III-driven gene expression is not well-studied and the expression of SINE-RNAs is virtually unmapped. In the current study, we used a mouse model of transient focal ischemia to evaluate for the first time post-stroke SINE-RNA expression in the cerebral cortex on a genome-wide scale. We observed SINE-RNA induction as early as 0 to 3 h of reperfusion and peak expression at 6 h of reperfusion, with 335 SINE-RNAs induced at this timepoint as compared to sham controls. Many of these transcripts remained induced through later timepoints during the acute phase of reperfusion (24 h). Fluorescence in situ hybridization against the SINE-RNAs, combined with immunohistochemistry for cell-type markers, revealed that these RNAs are localized to the nuclei of post-ischemic neurons and microglia in the ipsilateral cortex and hippocampus in both males and females. Further, we found that SINE-RNA expression was recapitulated in vitro following oxygen-glucose deprivation in HT22 hippocampal neurons, showing that they are reproducibly expressed in neurons in both in vivo and in vitro models of ischemia. Together, this is the first study to map genome-wide SINE-RNA expression in the post-ischemic brain and reveals a new layer of the noncoding transcriptome that may play a role in the post-stroke pathophysiology.

Animals↗
PubMed2026

Cleavage region organizes the structural architecture of the SINE-derived B2 repressive ribozyme.

The SINE-encoded B2 retrotransposon is an RNA Polymerase III (POL-III)-derived transcript whose expression is substantially upregulated during various cellular stress responses. Beyond retrotransposition, the B2 non-coding RNA can directly bind and repress the activity of RNA Polymerase II (POL-II), leading to a significant downregulation of transcripts during stress. Notably, our recent findings have shown that B2 is a self-cleaving ribozyme whose activity can be induced by interactions with chromatin-modifying factors through non-canonical epigenetic mechanisms that co-regulate its function across distinct chromatin-binding target loci. Here, by integrating RNA chemical probing, small-angle X-ray scattering, and 3D motif modeling, we determine structural ensemble-to-function relations for the B2 SINE ribozyme RNA. Genetic perturbations of the RNA suggest that the B2 SINE ribozyme has a well-defined secondary and dynamic tertiary structure that depends on the integrity of the critical region, which confers ribozymatic activity and repressive extent by POL-II. Using an RNA engineering approach, we examine the effects of point mutations, deletions of the main cleavage site, and deletions of the cleavage domain on the structural ensemble of the RNA. Combining this approach with in vitro and in vivo functional perturbation methods highlights the relationships between structural ensembles and various biologically relevant functional outcomes.

RNA, Catalytic↗
PubMed1975

Harmonic composition and topographic distribution of responses to sine wave modulated light (SML), their reproducibility and their interhemispheric relationship.

1. Responses to sine wave modulated light (SML) were recorded bipolarly from the occipital, parietal and temporal scalp areas on the right and the left sides of 9 normal individuals. Their harmonic composition was determined by means of Fourier analysis. 2. The wave form of the responses was rather complex in relation to the stimulus and differed according to stimulation frequency and localization. 3. The components of the responses were principally the 1st and 2nd harmonics. 4. The amplitudes of the harmonics were usually largest over the occipital and smallest over the parietal scalp areas. 5. Considerable intra-individual amplitude variabilities of both harmonic component amplitudes existed in all areas of all individuals. 6. The interhemispheric amplitude correlations of 1st and 2nd harmonic components, simultaneously recorded in homologous occipital, parietal and temporal areas, were measured by means of Kendall's rank correlation test. 7. The interhemispheric synchrony of the harmonic components was measured by determining the phase differences between each of the response components in homologous right and left scalp areas. 2. In subjects with a high amplitude correlation a strong synchrony existed and vice versa. 9. It is suggested that the interhemispheric relationships between harmonic components of the responses to SML might be of importance for clinical application. This opinion is supported by the fact that through SML evoked responses a considerable data reduction is obtained in comparison with the responses to light flashes.

Adolescent↗
PubMed1978

Interhemispheric relationships of reponses to sine wave modulated light in normal subjects and patients.

(1) The interhemispheric amplitude correlations of the fundamental (A1) and second harmonic (A2) components of responses to sine wave modulated light were determined in the occipital, parietal and temporal scalp areas of a group of normal subjects and a group of patients with unilateral irritative EEG phenomena. The interhemispheric amplitude correlation was computed at 10- and 16-c/sec stimulation frequencies and under 3 conditions: no modulation and no attention (M-, A-), modulation 30%, and no attention (M+, A-) and modulation 30% and attention (M+, A+). The correlations wre expressed in the rank correlation coefficient of Kendall (rK). (2) Analysis of variance revealed that the interhemispheric amplitude correlation of A1 in the normal group was significantly larger than that in the patient group at a stimulation frequency of 10 c/sec and under the conditions (M-, A-) and (M+, A-). (3) Both groups presented the largest correlation coefficients in the occipital scalp area. (4) In the normal group a significant increase of rK occurred under the influence of modulation. Attention caused a decrease of the correlation coefficient of A1. In the group of patients this influence was not clear. (5) The standard deviation of the mean interhemispheric phase differences was considered as a measure of synchrony of the response components between the two hemispheres. The smallest values of standard deviation were found in the occipital scalp area of the normal group at 10 c/sec stimulation frequency. Considerable variations between individuals were observed in both groups. (6) The correlation between the interhemispheric amplitude correlation (rK) and the interhemispheric synchrony was influenced by changing modulation depth from 0 to 30% and by introduction of attention, mostly in the group of normal subjects. This phenomenon was considered to support the theory that in patients with unilateral EEG disturbances the interhemispheric relations are different from those in normal subjects. (7) The findings as to amplitude correlation (rK) were the same under the condition (M-, A-) as under the condition (M+, A-).

Attention↗
PubMed1979

[Early auditory evoked potentials, triggered by a sine-wave stimulus (author's transl)].

Within the first 10 ms after a sine-shaped sound wave (tone pip) seven small-amplitude potentials can be recorded in persons with normal hearing and normal brainstem functions. These components, in the nanovolt range, correspond to the electrical activity of various pathways of the auditory tract. In accordance with this view the resulting potentials were assigned to the following structures in the region of the periphery and the brainstem: component I corresponds to the cochlea or acoustic nerve (receptor, II to the cochlear nucleus (medulla), III to the upper olive (caudal pons), IV to the lateral lemniscus (rostral pons), V to the inferior colliculus (midbrain), VI to the medial geniculate body (diencephalon), VII to the acoustic radiation (cortex). Clinically well defined lesions of the acoustic nerve and brainstem indicate that there is a close topographical relationship between the clinical localisation and absence or delay of the individual components.

Auditory Pathways↗
PubMed2026

A SINE-like insertion in intron 13 of the ATP7A gene is associated with a mild form of Menkes-like disease in a Cavalier King Charles Spaniel.

A 7-month-old intact male Cavalier King Charles Spaniel was presented for persistent glucosuria despite normoglycemia, failure to thrive, chronic diarrhea, and cerebellar ataxia. Fanconi syndrome was diagnosed, but the neurologic abnormalities were not fully explained. As a consequence of the early onset Fanconi syndrome, a hereditary process was suspected. Whole genome sequencing identified a private hemizygous SINE-like insertion into the ATP7A gene, at the end of intron 13, near the start of exon 14. In humans, variants in ATP7A are associated with Menkes disease, a disorder of copper metabolism associated with a spectrum of clinical signs including progressive neurodegeneration and connective tissue abnormalities. Clinically affected dogs with variants in ATP7A have not been reported previously. Although this case appears to represent a mild phenotypic presentation of Menkes-like disease, it raises the possibility that copper disorders aside from copper-associated hepatitis might exist in dogs. Further genetic screening and phenotypic characterization of rare genetic variants associated with copper metabolism would be beneficial to expand our knowledge of copper disorders in dogs and allow potential early intervention and modeling for metabolic diseases in humans.

Animals↗
PubMed2025

Recent Non-LTR Retrotransposon Activity Predicts Cancer Prevalence in Mammals.

Non-long terminal repeat retrotransposons (nLTRs), including long and short interspersed nuclear elements (L1 and SINEs), are the most abundant and active mobile elements in mammals. NLTRs play critical mutagenic and regulatory roles during oncogenesis in humans and model species. However, it is not known whether recent nLTR activity in the genome is related to the lifetime cancer risk of a species beyond humans and conventional model organisms. We examined whether recent nLTR activity predicts cancer prevalence across mammals using comparative analyses of de novo whole-genome repeat annotations from 55 species, each with over 20 published zoo pathology records. We quantified nLTR activity as the number of potentially active elements, their proximity to protein-coding genes and cancer gene orthologs (CGOs), and insertions within these genes. Across all three metrics, neoplasia prevalence was associated with both L1 and combined L1-SINE activity, while malignancy was linked exclusively to the L1-SINE predictors. This pattern suggests a complementary and escalating trajectory, where L1s contribute to early tumorigenic events, while SINE activity, driven by L1s, amplifies their impact and fuels the transition to malignancy. Moreover, genomes harboring more CGOs tended to exhibit higher neoplasia prevalence, and the number of fusion cancer genes was strongly correlated with the number of potentially active L1s across species. Our results further revealed a pattern wherein species with minimal cancer prevalence exhibit restricted activity of at least one major nLTR superfamily, suggesting that preserving genome stability through limited retrotransposition may serve as a protective mechanism against cancer.

Cancer Genes↗
PubMed2026

Nuclear export inhibition activates TP53 pathways and is a potent therapeutic strategy in atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. METHODS: We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. RESULTS: Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using 6 selective inhibitors of nuclear export (SINEs) in patient-derived atypical teratoid/rhabdoid tumor (ATRT) cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. CONCLUSIONS: Our data reveals XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.

atypical teratoid rhabdoid tumor↗
PubMed1977

Static and dynamic fusimotor action on the response of Ia fibres to low frequency sinusoidal stretching of widely ranging amplitude.

1. Single fusimotor fibres were stimulated repetitively to test their action on the responsiveness of muscle spindle primary endings in the cat soleus to sinusoidal stretching of both large and small amplitude. Frequencies of 0.06-4 Hz were used at amplitudes from 10 mum to 3 mm.2. The response was assessed by fitting a sinusoid to the cycle histogram of the afferent firing throughout the course of the cycle; this linear approximation measures the fundamental of the response and ignores any harmonics. The sine was allowed to project to negative values and any empty bins in the histogram were ignored when fitting.3. With small amplitudes of stretching the histograms were reasonably sinusoidal, but with large amplitudes they showed appreciable distortion of the wave form for the passive ending and during dynamic fusimotor stimulation. Non-linearity of response manifested itself also, with increasing amplitude of stretching, by an increase in the phase advance of the response, by increasing r.m.s. deviation of the histogram points from the fitted sine and (for dynamic stimulation) by an increase in the mean value of the fitted sine.4. With increasing amplitude the response modulation ceased to increase proportionately with the stimulus, so that the sensitivity of the ending to a large stretch (defined as afferent modulation/stretch amplitude) was appreciably less than for a small stretch. This effect was most pronounced for the passive ending.5. Whatever the amplitude of movement the modulation during static stimulation was less than that for the passive or during dynamic stimulation. For small amplitudes the response during dynamic stimulation was less than that of the passive, but for large amplitudes the response during dynamic stimulation was always the greater. At some intermediate cross-over amplitude the two responses were the same size, though still differing slightly in other respects. The value of the cross-over amplitude was usually about 200 mum at 1 Hz, and increased on lowering the frequency. Thus dynamic fusimotor action does not uniformly produce either an increase or a decrease in the sensitivity of the ending in relation to the passive.6. Bode plots, for each amplitude, of sensitivity and phase against frequency suggested that(a) under all conditions the ending is relatively insensitive to frequency in the range studied, for the slope of the log-log sensitivity lines was only 0.15-0.2 (3.5-6 db/decade);(b) the mechanism which makes for non-linearity is not particularly frequency sensitive;(c) static fusimotor stimulation does not change the frequency sensitivity of the ending;(d) dynamic fusimotor stimulation very slightly increases the frequency sensitivity of the ending for large amplitudes.In reaching these conclusions more attention was paid to the slope of the sensitivity lines than to the values of phase.7. It appears that the major effect of fusimotor action, whether static or dynamic, is to regulate the sensitivity of the primary ending to stretching for all amplitudes of movement (i.e. gain) rather than to control the relative values of its sensitivity to length and to velocity (i.e. crudely, the damping in a feed-back loop).

Action Potentials↗
PubMed2025

Endogenous Retroelement Activation is Implicated in Interferon-α Production and Anti-Cyclic Citrullinated Peptide Autoantibody Generation in Early Rheumatoid Arthritis.

OBJECTIVE: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in rheumatoid arthritis (RA). We investigated ERE expression in early RA (eRA), a period in which IFN-I levels are increased. METHODS: ERE expression (long terminal repeat [LTR] 5, long interspersed nuclear element 1 [LINE-1], and short interspersed nuclear element [SINE]) in disease-modifying treatment-na&#xef;ve eRA whole-blood and bulk synovial tissue samples was examined by reverse transcription-polymerase chain reaction and NanoString alongside IFN-&#x3b1; activity. Circulating lymphocyte subsets, including B cell subsets, from patients with eRA and early psoriatic arthritis (ePsA) were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data were reinterrogated to identify repeat elements, and associations were explored. RESULTS: There was significant coexpression of all ERE classes and IFNA in eRA synovial tissue samples (n = 22, P < 0.0001) and significant positive associations between whole-blood LINE-1 expression (n = 56) and circulating IFN-&#x3b1; protein (P = 0.018) and anti-cyclic citrullinated peptide (anti-CCP) titers (P < 0.0001). ERE expression was highest in circulating eRA B cells, particularly na&#xef;ve B cells compared with ePsA, with possible ERE regulation by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 transcription (SAMDH1) implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly human endogenous retroviral sequence K (HERVK), were most increased in RA compared with OA, in which, for all synovial subsets (monocytes, B cells, T cells, and fibroblasts), ERE expression associated with increased IFN-I signaling (P < 0.001). CONCLUSION: Peripheral blood and synovial ERE expression is examined for the first time in eRA, highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.

Humans↗