[Electric states of muscle layers by single sine current (author's transl)].
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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.
Adaptation to a 9 cycles deg-1 sine wave makes the apparent brightness profile of a 3 cycles deg-1 square wave look less "square" even when it does not look like that of a sine wave. Adaptation to a 3 cycles deg-1 sine wave has no noticeable effect. Hypotheses based on "excitation patterns" across spatial-frequency-selective channels can account for these results; it is not clear whether variations in local light adaptation can also account for them.
1. Extracellular recordings were obtained from units in the dorsal lateral geniculate nucleus of anaesthetized cats. 2. Of sixty-nine units, sixty-three could be unambiguously identified as either X (n = 33) or Y (n = 30) by testing the presence of a null response to stationary sine wave gratings presented in different spatial phases. 3. In response to stationary gratings flashed on and off, Y cells exhibited bigger, more transient responses than X cells. 4. All Y cells but few X cells exhibited a shift effect (modulated periphery effect). 5. In response to drifting sine wave gratings of different spatial frequencies, X cells preferred higher spatial frequencies and showed smaller peak contrast sensitivities and somewhat narrower tuning curves than Y cells. 6. In response to a sine wave grafting of optimal spatial frequency drifting at different velocities, X and Y cells had similar temporal tuning curves. However, Y cells, largely because they preferred lower spatial frequencies, preferred higher drift velocities than X cells. 7. Our data suggest that X and Y cells can be differentiated objectively on the basis of a number of discharge parameters. These parameters are compared with similar data collected by others from neurones in the visual cortex.
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.
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).
There are indications in the literature on speech perception that differences in rise and decay times of the amplitude envelope are relevant physical correlates in phonemic contrasts. Yet, little is known about the perception of rise and decay times as such. In the present study we have attempted to establish JND's for both rise and decay times of 1000-Hz sine waves as well as white noise bursts by means of an adjustment method. The rise and decay of stimulus amplitude were synthesized to be linear functions of time. Results show that the JND for a change in rise/decay time is generally about 25% of the duration of the rise/decay time. This Weber fraction is a minimum at rise/decay times of about 80 ms and increases significantly for rise/decay times below 20 ms. Of the four signal condition noise bursts were performed with the greatest accuracy (at moderate rise/decay times), while changes in onset time of sine waves were discriminated best at very short rise times (where energy splatter may have contributed an additional cue).
Histology and clonal analysis are used to look at the time of action of the mutant Drosophila genes eyeless, eyeless dominant and sine oculis. The findings suggest that eyeless dominant has its effect during the first two larval instars, whilst eyeless and sine oculis act during the third larval instar.
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-naïve eRA whole-blood and bulk synovial tissue samples was examined by reverse transcription-polymerase chain reaction and NanoString alongside IFN-α 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-α 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 naïve 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.
Recently, alterations in contrast (modulation) sensitivity functions of patients with high refractive errors have been noted. For example, this seems to be a common finding in aphakia. In some measure the observed alterations are due to the effect of the corrective lens and the optics of the eyes. These optical effects (in addition to blur) must be factored out in order to determine whether residual effects on the visual system remain. The argument is applicable to photographs of sine wave fringes as well as devices designed to produce interference patterns directly on the retina. A simple means for largely correcting these lens effects is discussed.
Macaque monkeys were trained to fall asleep while sitting in a primate chair with their heads restrained. A gentle vibratory stimulus was delivered to the glabrous skin of the hand; it did not provoke awakening or change the sleep cycle of the macaque. Postcentral neuronal response to the amplitude of a sine wave mechanical stimulus and neuronal spontaneous activity were observed repetitively during all the phases of normal night sleep cycles. One hundred six neurons which could be entrained by a cutaneous mechanical stimulus were studied during both waking and sleep. At threshold, cyclic entrainment of the discharges of postcentral neurons decreased to 81 +/- 0.25% during light sleep (S1 + S2), to 64 +/- 0.26% during deep sleep (S3 + S4), and to 9 +/- 0.98% during desynchronized sleep with rapid eye movements (REMs).
Sequential input adaptive system theory is applied to human eye tracking of targets with one-dimensional motion defined by since functions, sums of sine functions and triangle functions. The sequential theory describes the mean eye tracking movements of two subjects for these inputs. The theory is predictive for irregular inputs in that when its parameters for a subject are identified and adjusted for a reference input, it then predicts mean eye tracking behavior for that subject for inputs of comparable complexity.
Attention is drawn to the fact that under normal visual conditions the sensitivity of the receptor units of the visual system are subject to spatial and temporal variations, and that consequently in performing pattern recognition the visual cortex has to discriminate between external luminance structure and internal sensitivity structure. It is suggested that eye movements are the method by which this discrimination is performed. In a simplified model analysis it is shown that eye movements are a suitable mechanism for this discrimination. Implications of this model for detection threshold and stabilized retinal images are discussed. A new interpretation of the adaptation to sine wave grids is given.
The effect of external electric fields on photo-accumulations of Phormidium uncinatum in light traps has been studied. 1. In direct current fields the phobic reaction of trichoms leaving the light field is not impaired if a voltage of 2.5 V is not exceeded. With voltages between 3 and 7 V the trichoms are motile, but phobic reactions are cancelled, provided the organisms are oriented more or less parallel to the electric field lines. Higher voltages cause the algae to die within minutes. 2. Only alternating current fields of very low frequencies (less than or equal 10(-3) Hz) have similar effects. Sine waves are more effective than triangular ones, but less than square waves. A hypothesis is proposed according to which sensory transduction of photophobic reactions in blue-green algae is mediated by changes in the endogenous membrane potential. This potential might be interfered with by the application of an external electric field, thus inhibiting photophobic reactions.
In normal human volunteers, when urinary pH was plotted versus time, the circadian sine-wave type curve was not altered by chronic administration of a commercially available suspension containing a mixture of magnesium and aluminum hydroxides, although the antacid perturbed the entire curve in a more alkaline direction. A single dose of the antacid had little effect on urinary pH. There was a highly significant linear relationship between the change in hydrogen ion concentration during chronic antacid treatment and the initial control urinary hydrogen ion concentration, but there was no significant correlation between change in urinary pH and initial control urinary pH as has been previously reported. The above results were based on the evaluation of the hydrogen ion concentrations of 1562 separate urine samples collected from 24 normal subjects in a three treatment crossover study. It is recommended that: (1) research studies involving drug-drug interactions with antacids be designed to consider the effect of the antacid on the circadian rhythm of urinary pH, and (2) pH values not be averaged as commonly reported in the literature, but rather the pH values be converted to hydrogen ion concentrations before statistical analysis.
The impedance of Necturus gallbladder epithelium was determined using sine wave currents of 1 Hz to 30 kHz. In control Ringer's solution the impedance locus exhibited a simple semicircle with minute shift of the high frequency end along the real axis and a minute depression of the center below the real axis (average 0.9 +/- 0.7 degrees). Neglecting the slight suppression, the impedance of 1 cm2 of epithelium can be represented by an electrical analogue consisting of a parallel RC element of 115 +/- 26 omega and 5.16 +/- 0.9 muF in series with a small resistor of 5.3 +/- 1.3 omega. In agreement with experimental results obtained under ionic or osmotic substitutions, the applicability of this simple RC analogue to gallbladder epithelium under control conditions can be explained by the influence of the paracellular shunt and by assuming the time constants of the apical and basal cell membranes to be comparable. Based on these data and on voltage divider measurements obtained with microelectrodes the capacitances of the apical and basal cell membrane can be estimated to be approximately 7 and approximately 18 muF/cm2. The latter value agrees well with estimates of the surface folding obtained from electromicrographs, if the specific cell membrane capacitance is assumed to be approximately 1 muF/cm2 as in other cell membranes.